Vglut1 and Vglut2 synapses on cholinergic neurons in the sublenticular gray of the rat basal forebrain: a double-label electron microscopic study

PubMed Central

Hur, Elizabeth E.; Edwards, Robert H.; Rommer, Erzsebet; Zaborszky, Laszlo

2009-01-01

The basal forebrain (BF) comprises morphologically and functionally heterogeneous cell populations, including cholinergic and non-cholinergic corticopetal neurons that are implicated in sleep-wake modulation, learning, memory and attention. Several studies suggest that glutamate may be among inputs affecting cholinergic corticopetal neurons but such inputs have not been demonstrated unequivocally. We examined glutamatergic axon terminals in the sublenticular substantia innominata in rats using double-immunolabeling for vesicular glutamate transporters (Vglut1 and Vglut2) and choline acetyltransferase (ChAT) at the electron microscopic level. In a total surface area of 30,000 μm2, we classified the pre- and postsynaptic elements of 813 synaptic boutons. Vglut1 and Vglut2 boutons synapsed with cholinergic dendrites, and occasionally Vglut2 axon terminals also synapsed with cholinergic cell bodies. Vglut1 terminals formed synapses with unlabeled dendrites and spines with equal frequency, while Vglut2 boutons were mainly in synaptic contact with unlabeled dendritic shafts and occasionally with unlabeled spines. In general, Vglut1 boutons contacted more distal dendritic compartments than Vglut2 boutons. About 21% of all synaptic boutons (n=347) detected in tissue that was stained for Vglut1 and ChAT were positive for Vglut1, and 14% of the Vglut1 synapses were made on cholinergic profiles. From separate cases stained for Vglut2 and ChAT, 35% of all synaptic boutons (n=466) were positive for Vglut2, and 23% of the Vglut2 synapses were made on cholinergic profiles. On average, Vglut1 boutons were significantly smaller than Vglut2 synaptic boutons. The Vglut2 boutons that synapsed cholinergic profiles tended to be larger than the Vglut2 boutons that contacted unlabeled, non-cholinergic postsynaptic profiles. The presence of two different subtypes of Vgluts, the size differences of the Vglut synaptic boutons, and their preference for different postsynaptic targets suggest that the action of glutamate on BF neurons is complex and may arise from multiple afferent sources. PMID:19778580

Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation

PubMed Central

Grace, Kevin P.; Horner, Richard L.

2015-01-01

Rapid eye movement (REM) sleep – characterized by vivid dreaming, motor paralysis, and heightened neural activity – is one of the fundamental states of the mammalian central nervous system. Initial theories of REM sleep generation posited that induction of the state required activation of the “pontine REM sleep generator” by cholinergic inputs. Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail. PMID:26388832

Neuropharmacology of cognition and memory: a unifying theory of neuromodulator imbalance in psychiatry and amnesia.

PubMed

Vakalopoulos, Costa

2006-01-01

The case of HM, a man with intractable epilepsy who became amnesic following bilateral medial temporal lobe surgery nearly half a century ago has instigated ongoing research and theoretical speculation on the nature of memory and the role of the hippocampus. Neuropsychological testing showed that although HM had extensive anterograde memory loss he could still acquire motor and cognitive skills implicitly, but could not remember the context of this learning. This has lead to declarative and procedural descriptions of the memory process. Cholinergic and monoaminergic neurotransmitter systems have also been implicated in the memory process and anticholinergic drugs traditionally have been associated with impairment of declarative memory. The cholinergic hypothesis of Alzheimer's disease is a classic example of an application of these neuropharmacological findings. In schizophrenia, preattentive deficits have been amply demonstrated by unconscious priming studies. Memory processes are also impaired in these patients. Dopamine, glutamate and even cholinergic dysfunction has been implicated in the clinical picture of schizophrenia. The present paper will attempt to bring together both the anatomical and pharmacological data from these disparate fields of research under a cohesive theory of cognition and memory. A hypothesis is presented for an inverse relationship between monoaminergic and cholinergic systems in the modulation of implicit (unconscious) and explicit (conscious) cognitive processes. It is postulated that muscarinic cholinergic receptors and monoaminergic systems facilitate unconscious and conscious processes, respectively, and they disfacilitate conscious and unconscious processes, respectively (the purported inverse relationship). In fact, the muscarinic and monoaminergic modulations of a neural network are proposed to be finely balanced such that, if, the activity of one receptor system is modified then this by necessity has effects on the other system. It takes into account receptor subtypes and their effects mediated through excitatory and inhibitory G-protein complexes. For example, m1/D2 and D1/m4 paired receptor subtypes, colocalized on separate neurons would have opposing functional effects. A theory is then presented that the critical underlying pathophysiology of schizophrenia involves a hypofunctional muscarinic cholinergic system, which induces abnormal facilitation of monoaminergic subsystems such as dopamine (e.g., a decrease in m1R function would potentiate D2R function). This extends the idea of an inverted U function for optimal monoaminergic concentrations. Not only would this impair unconscious preattentive processes, but according to the hypothesis, explicit cognition as well including memory deficits and would underlie the mechanism of psychosis. Contrary to current thinking a different view is also presented for the role of the hippocampus in the memory process. It is postulated that long-term explicit memory traces in the neocortex are laid down by phasic coactivation of forebrain projecting monoaminergic systems above some basal firing rate, such as the rostral serotonergic raphe, which projects diffusely to the cortex and according to a modified Hebbian principle. This is the proposed principal function of the hippocampal theta rhythm. The phasic activation of the cholinergic basal forebrain is mediated by projections from a separate cortical structure, possibly the lateral prefrontal cortex. Phasic muscarinic receptor activation is proposed to strengthen implicit memory traces (at a synaptic level) in the neocortex. Thus, the latter are spared by medial temporal surgery explaining the dissociation of explicit from implicit memory.

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity.

PubMed

Klawonn, Anna M; Wilhelms, Daniel B; Lindström, Sarah H; Singh, Anand Kumar; Jaarola, Maarit; Wess, Jürgen; Fritz, Michael; Engblom, David

2018-01-01

The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression ( cFos and FosB ) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

A specific role for septohippocampal acetylcholine in memory?

PubMed Central

Easton, Alexander; Douchamps, Vincent; Eacott, Madeline; Lever, Colin

2012-01-01

Acetylcholine has long been implicated in memory, including hippocampal-dependent memory, but the specific role for this neurotransmitter is difficult to identify in human neuropsychology. Here, we review the evidence for a mechanistic model of acetylcholine function within the hippocampus and consider its explanatory power for interpreting effects resulting from both pharmacological anticholinergic manipulations and lesions of the cholinergic input to the hippocampus in animals. We argue that these effects indicate that acetylcholine is necessary for some, but not all, hippocampal-dependent processes. We review recent evidence from lesion, pharmacological and electrophysiological studies to support the view that a primary function of septohippocampal acetylcholine is to reduce interference in the learning process by adaptively timing and separating encoding and retrieval processes. We reinterpret cholinergic-lesion based deficits according to this view and propose that acetylcholine reduces the interference elicited by the movement of salient locations between events. PMID:22884957

New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

PubMed

Greig, Nigel H; Reale, Marcella; Tata, Ada M

2013-08-01

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer's disease drugs.

New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors

PubMed Central

Greig, Nigel H.; Reale, Marcella; Tata, Ada Maria

2016-01-01

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer’s disease drugs. PMID:23597304

Optimizing cholinergic tone through lynx modulators of nicotinic receptors: implications for plasticity and nicotine addiction.

PubMed

Miwa, Julie M; Lester, Henry A; Walz, Andreas

2012-08-01

The cholinergic system underlies both adaptive (learning and memory) and nonadaptive (addiction and dependency) behavioral changes through its ability to shape and regulate plasticity. Protein modulators such as lynx family members can fine tune the activity of the cholinergic system and contribute to the graded response of the cholinergic system, stabilizing neural circuitry through direct interaction with nicotinic receptors. Release of this molecular brake can unmask cholinergic-dependent mechanisms in the brain. Lynx proteins have the potential to provide top-down control over plasticity mechanisms, including addictive propensity. If this is indeed the case, then, what regulates the regulator? Transcriptional changes of lynx genes in response to pharmacological, physiological, and pathological alterations are explored in this review.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex.

PubMed

Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

2016-01-01

Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by ¹⁸F-2-fluoro-2-deoxyglucose positron emission tomography. During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

The effects of abnormalities of glucose homeostasis on the expression and binding of muscarinic receptors in cerebral cortex of rats.

PubMed

Sherin, Antony; Peeyush, Kumar T; Naijil, George; Nandhu, Mohan Sobhana; Jayanarayanan, Sadanandan; Jes, Paul; Paulose, Cheramadathikudiyil Skaria

2011-01-25

Glucose homeostasis in humans is an important factor for the functioning of nervous system. Both hypo and hyperglycemia contributes to neuronal functional deficit. In the present study, effect of insulin induced hypoglycemia and streptozotocin induced diabetes on muscarinic receptor binding, cholinergic enzymes; AChE, ChAT expression and GLUT3 in the cerebral cortex of experimental rats were analysed. Total muscarinic, muscarinic M(1) receptor showed a significant decrease and muscarinic M(3) receptor subtype showed a significant increased binding in the cerebral cortex of hypoglycemic rats compared to diabetic and control. Real-Time PCR analysis of muscarinic M(1), M(3) receptor subtypes confirmed the receptor binding studies. Immunohistochemistry of muscarinic M(1), M(3) receptors using specific antibodies were also carried out. AChE and GLUT3 expression up regulated and ChAT expression down regulated in hypoglycemic rats compared to diabetic and control rats. Our results showed that hypo/hyperglycemia caused impaired glucose transport in neuronal cells as shown by altered expression of GLUT3. Increased AChE and decreased ChAT expression is suggested to alter cortical acetylcholine metabolism in experimental rats along with altered muscarinic receptor binding in hypo/hyperglycemic rats, impair cholinergic transmission, which subsequently lead to cholinergic dysfunction thereby causing learning and memory deficits. We observed a prominent cholinergic functional disturbance in hypoglycemic condition than in hyperglycemia. Hypoglycemia exacerbated the neurochemical changes in cerebral cortex induced by hyperglycemia. These findings have implications for both therapy and identification of causes contributing to neuronal dysfunction in diabetes. Copyright © 2010 Elsevier B.V. All rights reserved.

Frontal Decortication and Adaptive Changes in Striatal Cholinergic Neurons: Neuropharmacological and Behavioral Implications

DTIC Science & Technology

1990-09-28

the muscarinic cholinergic agonist oxotremorine (OT’O) in the striatulm. Frontal decortication did not affect the activation of phosphoinositjde...Congress abstracts 3 List of abbreviations: ACh, acetylcholine; C h A T cholitie-o-acetyl/transferase; OTMVN, oxotremorine ; OXI, oxirucetam:, SDHACU

Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice.

PubMed

Mabe, Abigail M; Hoover, Donald B

2009-04-01

Previous work provided indirect evidence that the neurotrophic factor neurturin (NRTN) is required for normal cholinergic innervation of the heart. This study used nrtn knockout (KO) and wild-type (WT) mice to determine the effect of nrtn deletion on cardiac cholinergic innervation and function in the adult heart. Immunohistochemistry, confocal microscopy, and quantitative image analysis were used to directly evaluate intrinsic cardiac neuronal development. Atrial acetylcholine (ACh) levels were determined as an indirect index of cholinergic innervation. Cholinergic function was evaluated by measuring negative chronotropic responses to right vagal nerve stimulation in anaesthetized mice and responses of isolated atria to muscarinic agonists. KO hearts contained only 35% the normal number of cholinergic neurons, and the residual cholinergic neurons were 15% smaller than in WT. Cholinergic nerve density at the sinoatrial node was reduced by 87% in KOs, but noradrenergic nerve density was unaffected. Atrial ACh levels were substantially lower in KO mice (0.013 +/- 0.004 vs. 0.050 +/- 0.011 pmol/microg protein; P < 0.02) as expected from cholinergic neuron and nerve fibre deficits. Maximum bradycardia evoked by vagal stimulation was reduced in KO mice (38 +/- 6% vs. 69 +/- 3% decrease at 20 Hz; P < 0.001), and chronotropic responses took longer to develop and fade. In contrast to these deficits, isolated atria from KO mice had normal post-junctional sensitivity to carbachol and bethanechol. These findings demonstrate that NRTN is essential for normal cardiac cholinergic innervation and cholinergic control of heart rate. The presence of residual cardiac cholinergic neurons and vagal bradycardia in KO mice suggests that additional neurotrophic factors may influence this system.

Differentiation of muscarinic cholinergic receptor subtypes in human cortex and pons - Implications for anti-motion sickness therapy

NASA Technical Reports Server (NTRS)

Mccarthy, Bruce G.; Peroutka, Stephen J.

1988-01-01

Radioligand binding studies were used to analyze muscarinic cholinergic receptor subtypes in human cortex and pons. Muscarinic cholinergic receptors were labeled by H-3-quinuclidinyl benzilate (H-3-QNB). Scopolamine was equipotent in both brain regions and did not discriminate subtypes of H-3-QNB binding. By contrast, the M1 selective antagonist pirenzepine was approximately 33-fold more potent in human cortex than pons. Carbachol, a putative M2 selective agonist, was more than 100-fold more potent in human pons than cortex. These results demonstrate that the human pons contains a relatively large proportion of carbachol-sensitive muscarinic cholinergic receptors. Drugs targeted to this subpopulation of muscarinic cholinergic receptors may prove to be effective anti-motion sickness agents with less side effects than scopolamine.

Cholinergic modulation of hippocampal network function

PubMed Central

Teles-Grilo Ruivo, Leonor M.; Mellor, Jack R.

2013-01-01

Cholinergic septohippocampal projections from the medial septal area to the hippocampus are proposed to have important roles in cognition by modulating properties of the hippocampal network. However, the precise spatial and temporal profile of acetylcholine release in the hippocampus remains unclear making it difficult to define specific roles for cholinergic transmission in hippocampal dependent behaviors. This is partly due to a lack of tools enabling specific intervention in, and recording of, cholinergic transmission. Here, we review the organization of septohippocampal cholinergic projections and hippocampal acetylcholine receptors as well as the role of cholinergic transmission in modulating cellular excitability, synaptic plasticity, and rhythmic network oscillations. We point to a number of open questions that remain unanswered and discuss the potential for recently developed techniques to provide a radical reappraisal of the function of cholinergic inputs to the hippocampus. PMID:23908628

Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status.

PubMed

Wang, Naitao; Dong, Bai-Jun; Quan, Yizhou; Chen, Qianqian; Chu, Mingliang; Xu, Jin; Xue, Wei; Huang, Yi-Ran; Yang, Ru; Gao, Wei-Qiang

2016-05-10

Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS) in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3) was upregulated in a large subset of benign prostatic hyperplasia (BPH) tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Cholinergic control of male mating behavior in hamsters: effects of central oxotremorine treatment.

PubMed

Floody, Owen R; Katin, Michael J; Harrington, Lia X; Schassburger, Rachel L

2011-12-01

The responses of rats to intracranial injections of cholinergic drugs implicate acetylcholine in the control of male mating behavior and suggest specific brain areas as mediators of these effects. In particular, past work has linked the medial preoptic area (MPOA) to the control of intromission frequency but implicated areas near the lateral ventricles in effects on the initiation and spacing of intromissions. Studies of responses to systemic cholinergic treatments suggest that acetylcholine is even more important for the control of mating behavior in male hamsters but provide no information on the relevant brain areas. To fill this gap, we observed the effects of central injections of the cholinergic agonist oxotremorine that approached the MPOA along contrasting paths. Both studies suggest that increased cholinergic activity in or near the MPOA can facilitate behavior by reducing the postejaculatory interval and possibly affecting other parts of the mechanisms controlling the initiation of copulation and the efficiency of performance early in an encounter. In addition, oxotremorine caused other changes in behavior that could not be tied to the MPOA and may reflect actions at more dorsal sites, possibly including the bed nucleus of the stria terminalis and medial septum. These effects were notably heterogeneous, including facilitatory and disruptive effects on male behavior along with a facilitation of lordosis responses to manual stimulation. These results emphasize the number and diversity of elements of sexual behavior in hamsters that are under the partial control of forebrain cholinergic mechanisms. Copyright © 2011 Elsevier Inc. All rights reserved.

Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

PubMed

Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan

2016-08-01

Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

The role of muscarinic cholinergic signaling in cost-benefit decision making

NASA Astrophysics Data System (ADS)

Fobbs, Wambura

Animals regularly face decisions that affect both their immediate success and long term survival. Such decisions typically involve some form of cost-benefit analysis and engage a number of high level cognitive processes, including learning, memory and motivational influences. While decision making has been a focus of study for over a century, it's only in the last 20 years that researchers have begun to identify functional neural circuits that subserve different forms of cost-benefit decision making. Even though the cholinergic system is both functionally and anatomically positioned to modulate cost-benefit decision circuits, the contribution of the cholinergic system to decision making has been little studied. In this thesis, I investigated the cognitive and neural contribution of muscarinic cholinergic signaling to cost-benefit decision making. I, first, re-examined the effects of systemic administration of 0.3 mg/kg atropine on delay and probability discounting tasks and found that blockade of muscarinic acetylcholine receptors by atropine induced suboptimal choices (impulsive and risky) in both tasks. Since the effect on delay discounting was restricted to the No Cue version of the delay discounting task, I concluded that muscarinic cholinergic signaling mediates both forms of cost-benefit decision making and is selectively engaged when decisions require valuation of reward options whose costs are not externally signified. Second, I assessed the impact of inactivating the nucleus basalis (NBM) on both forms decision making and the effect of injecting atropine locally into the orbitofrontal cortex (OFC), basolateral amygdala (BLA), or nucleus accumbens (NAc) core during the No Cue version of the delay discounting task. I discovered that although NBM inactivation failed to affect delay discounting, it induced risk aversion in the probability discounting task; and blockade of intra- NAc core, but not intra-OFC or intra-BLA, muscarinic cholinergic signaling lead to increased choice of the delayed reward. While those findings implicate the NBM in supporting risky choices and intra-NAc core muscarinic signaling in discouraging delayed choice, more work is needed to fully elucidate the underlying mechanisms.

Cholinergic mechanisms in spinal locomotion—potential target for rehabilitation approaches

PubMed Central

Jordan, Larry M.; McVagh, J. R.; Noga, B. R.; Cabaj, A. M.; Majczyński, H.; Sławińska, Urszula; Provencher, J.; Leblond, H.; Rossignol, Serge

2014-01-01

Previous experiments implicate cholinergic brainstem and spinal systems in the control of locomotion. Our results demonstrate that the endogenous cholinergic propriospinal system, acting via M2 and M3 muscarinic receptors, is capable of consistently producing well-coordinated locomotor activity in the in vitro neonatal preparation, placing it in a position to contribute to normal locomotion and to provide a basis for recovery of locomotor capability in the absence of descending pathways. Tests of these suggestions, however, reveal that the spinal cholinergic system plays little if any role in the induction of locomotion, because MLR-evoked locomotion in decerebrate cats is not prevented by cholinergic antagonists. Furthermore, it is not required for the development of stepping movements after spinal cord injury, because cholinergic agonists do not facilitate the appearance of locomotion after spinal cord injury, unlike the dramatic locomotion-promoting effects of clonidine, a noradrenergic α-2 agonist. Furthermore, cholinergic antagonists actually improve locomotor activity after spinal cord injury, suggesting that plastic changes in the spinal cholinergic system interfere with locomotion rather than facilitating it. Changes that have been observed in the cholinergic innervation of motoneurons after spinal cord injury do not decrease motoneuron excitability, as expected. Instead, the development of a “hyper-cholinergic” state after spinal cord injury appears to enhance motoneuron output and suppress locomotion. A cholinergic suppression of afferent input from the limb after spinal cord injury is also evident from our data, and this may contribute to the ability of cholinergic antagonists to improve locomotion. Not only is a role for the spinal cholinergic system in suppressing locomotion after SCI suggested by our results, but an obligatory contribution of a brainstem cholinergic relay to reticulospinal locomotor command systems is not confirmed by our experiments. PMID:25414645

Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.

PubMed

Mattsson, Anna; Lindqvist, Eva; Ogren, Sven Ove; Olson, Lars

2005-11-07

Altered cholinergic function is considered as a potential contributing factor in the pathogenesis of schizophrenia. We hypothesize that cortical cholinergic denervation may result in changes in glutamatergic activity. Therefore, we lesioned the cholinergic corticopetal projections by local infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of rats. Possible effects of this lesion on glutamatergic systems were examined by phencyclidine-induced locomotor activity, and also by N-methyl-D-aspartate receptor binding. We find that cholinergic lesioning of neocortex leads to enhanced sensitivity to phencyclidine in the form of a dramatic increase in horizontal activity. Further, N-methyl-D-aspartate receptor binding is unaffected in denervated rats. These results suggest that aberrations in cholinergic function might lead to glutamatergic dysfunctions, which might be of relevance for the pathophysiology for schizophrenia.

Antidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review

PubMed Central

Drevets, Wayne C.; Zarate, Carlos A.; Furey, Maura L.

2014-01-01

The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine's pharmacokinetic properties and an emerging literature that characterizes scopolamine's effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism. PMID:23200525

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum.

PubMed

Mattsson, Anna; Olson, Lars; Svensson, Torgny H; Schilström, Björn

2007-11-01

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults

PubMed Central

2012-01-01

Background The deterioration of the central cholinergic system in aging is hypothesized to underlie declines in several cognitive domains, including memory and executive functions. However, there is surprisingly little direct evidence regarding acetylcholine’s specific role(s) in normal human cognitive aging. Methods We used short-latency afferent inhibition (SAI) with transcranial magnetic stimulation (TMS) as a putative marker of cholinergic activity in vivo in young (n = 24) and older adults (n = 31). Results We found a significant age difference in SAI, concordant with other evidence of cholinergic decline in normal aging. We also found clear age differences on several of the memory and one of the executive function measures. Individual differences in SAI levels predicted memory but not executive functions. Conclusion Individual differences in SAI levels were better predictors of memory than executive functions. We discuss cases in which the relations between SAI and cognition might be even stronger, and refer to other age-related biological changes that may interact with cholinergic activity in cognitive aging. PMID:22537877

Diagnostics and therapy of Alzheimer's disease.

PubMed

Mikiciuk-Olasik, Elzbieta; Szymański, Paweł; Zurek, Elzbieta

2007-04-01

Alzheimer's Disease (AD) is described as a degenerative disease of the central nervous system characterized by a noticeable cognitive decline defined by a loss of memory and learning ability, together with a reduced ability to perform basic activities of daily living. In the brain of an AD patients is the dramatic decrease in cholinergic innervation in the cortex and hippocampus due to the loss of neurons in the basal forebrain. The above findings led to the development of the cholinergic hypothesis, which proposes that the cognitive loss associated with AD is related to decreased cortical cholinergic neurotransmission. In brain of Alzheimer's patient's one ascertained presence of neuritic plaques containing the beta-amyloid peptide and protein tau. Biochemical and genetics studies implicated a central role for beta-amyloid in the pathological cascade of events in AD. The most therapeutic strategies in AD have been directed to two main targets: the beta-amyloid peptide and the cholinergic neurotransmission. The first approach is to act on the amyloid precursor protein (APP) processing. The second main approach is to slow of decline of neuronal degeneration or increasing cholinergic transmission. Diagnosis of AD is very difficult and to date no specific diagnostic tests of the disease are available. Intellectual function testing to determine the degree of cognitive status during routine medical examination is a useful supplementary method of diagnosing dementia. The permissible result, come down from radiopharmacy, which is an integral part of a nuclear medicine. A radiopharmaceutical may be defined as a pharmaceutical substance containing radioactive atoms. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are capable of mapping the distribution of radionuclides in three dimensions, producing maps of brain biochemical and physiological processes. The techniques are reasonably sensitive and specific in differentiating AD from other dementias.

Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction

PubMed Central

Gavioli, Mariana; Lara, Aline; Almeida, Pedro W. M.; Lima, Augusto Martins; Damasceno, Denis D.; Rocha-Resende, Cibele; Ladeira, Marina; Resende, Rodrigo R.; Martinelli, Patricia M.; Melo, Marcos Barrouin; Brum, Patricia C.; Fontes, Marco Antonio Peliky; Souza Santos, Robson A.; Prado, Marco A. M.; Guatimosim, Silvia

2014-01-01

Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease. PMID:24992197

A Cell Line Producing Recombinant Nerve Growth Factor Evokes Growth Responses in Intrinsic and Grafted Central Cholinergic Neurons

NASA Astrophysics Data System (ADS)

Ernfors, Patrik; Ebendal, Ted; Olson, Lars; Mouton, Peter; Stromberg, Ingrid; Persson, Hakan

1989-06-01

The rat β nerve growth factor (NGF) gene was inserted into a mammalian expression vector and cotransfected with a plasmid conferring resistance to neomycin into mouse 3T3 fibroblasts. From this transfection a stable cell line was selected that contains several hundred copies of the rat NGF gene and produces excess levels of recombinant NGF. Such genetically modified cells were implanted into the rat brain as a probe for in vivo effects of NGF on central nervous system neurons. In a model of the cortical cholinergic deficits in Alzheimer disease, we demonstrate a marked increase in the survival of, and fiber outgrowth from, grafts of fetal basal forebrain cholinergic neurons, as well as stimulation of fiber formation by intact adult intrinsic cholinergic circuits in the cerebral cortex. Adult cholinergic interneurons in intact striatum also sprout vigorously toward implanted fibroblasts. Our results suggest that this model has implications for future treatment of neurodegenerative diseases.

Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.

PubMed

Pang, Min-Hee; Kim, Nam-Soo; Kim, Il-Hwan; Kim, Hyun; Kim, Hyun-Taek; Choi, June-Seek

2010-09-01

Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected. Copyright 2010 Elsevier Inc. All rights reserved.

Cholinergic manipulations bidirectionally regulate object memory destabilization

PubMed Central

Stiver, Mikaela L.; Jacklin, Derek L.; Mitchnick, Krista A.; Vicic, Nevena; Carlin, Justine; O'Hara, Matthew

2015-01-01

Consolidated memories can become destabilized and open to modification upon retrieval. Destabilization is most reliably prompted when novel information is present during memory reactivation. We hypothesized that the neurotransmitter acetylcholine (ACh) plays an important role in novelty-induced memory destabilization because of its established involvement in new learning. Accordingly, we investigated the effects of cholinergic manipulations in rats using an object recognition paradigm that requires reactivation novelty to destabilize object memories. The muscarinic receptor antagonist scopolamine, systemically or infused directly into the perirhinal cortex, blocked this novelty-induced memory destabilization. Conversely, systemic oxotremorine or carbachol, muscarinic receptor agonists, administered systemically or intraperirhinally, respectively, mimicked the destabilizing effect of novel information during reactivation. These bidirectional effects suggest a crucial influence of ACh on memory destabilization and the updating functions of reconsolidation. This is a hitherto unappreciated mnemonic role for ACh with implications for its potential involvement in cognitive flexibility and the dynamic process of long-term memory storage. PMID:25776038

Cholinergic Hypofunction in Presbycusis-Related Tinnitus With Cognitive Function Impairment: Emerging Hypotheses

PubMed Central

Ruan, Qingwei; Yu, Zhuowei; Zhang, Weibin; Ruan, Jian; Liu, Chunhui; Zhang, Ruxin

2018-01-01

Presbycusis (age-related hearing loss) is a potential risk factor for tinnitus and cognitive deterioration, which result in poor life quality. Presbycusis-related tinnitus with cognitive impairment is a common phenotype in the elderly population. In these individuals, the central auditory system shows similar pathophysiological alterations as those observed in Alzheimer’s disease (AD), including cholinergic hypofunction, epileptiform-like network synchronization, chronic inflammation, and reduced GABAergic inhibition and neural plasticity. Observations from experimental rodent models indicate that recovery of cholinergic function can improve memory and other cognitive functions via acetylcholine-mediated GABAergic inhibition enhancement, nicotinic acetylcholine receptor (nAChR)-mediated anti-inflammation, glial activation inhibition and neurovascular protection. The loss of cholinergic innervation of various brain structures may provide a common link between tinnitus seen in presbycusis-related tinnitus and age-related cognitive impairment. We hypothesize a key component of the condition is the withdrawal of cholinergic input to a subtype of GABAergic inhibitory interneuron, neuropeptide Y (NPY) neurogliaform cells. Cholinergic denervation might not only cause the degeneration of NPY neurogliaform cells, but may also result in decreased AChR activation in GABAergic inhibitory interneurons. This, in turn, would lead to reduced GABA release and inhibitory regulation of neural networks. Reduced nAChR-mediated anti-inflammation due to the loss of nicotinic innervation might lead to the transformation of glial cells and release of inflammatory mediators, lowering the buffering of extracellular potassium and glutamate metabolism. Further research will provide evidence for the recovery of cholinergic function with the use of cholinergic input enhancement alone or in combination with other rehabilitative interventions to reestablish inhibitory regulation mechanisms of involved neural networks for presbycusis-related tinnitus with cognitive impairment. PMID:29681847

Role of acetylcholine in control of sexual behavior of male and female mammals.

PubMed

Floody, Owen R

2014-05-01

The results of studies using systemic or central applications of cholinergic drugs suggest that acetylcholine makes important contributions to the neurochemical control of male- and female-typical reproductive behaviors. In males, cholinergic control seems largely specific to some elements or aspects of copulatory behavior that can vary significantly across species. Synapses in or near the medial preoptic area represent part of this mechanism, but the entire system appears to extend more widely, perhaps especially to one or more structures flanking some part of the lateral ventricle. In females, the lordosis response that essentially defines sexual receptivity is clearly responsive to cholinergic drugs. The same seems likely to be true of other elements of female sexual behavior, but additional studies will be needed to confirm this. Changes in cholinergic activity may help to mediate estrogenic effects on female sexual behavior. However, estrogen exposure can increase or decrease cholinergic effects, suggesting a relationship that is complex and requires further analysis. Also presently unclear is the localization of the cholinergic effects on female sexual responses. Though periventricular sites again have been implicated, their identity is presently unknown. This review discusses these and other aspects of the central cholinergic systems affecting male and female sexual behaviors. Copyright © 2014 Elsevier Inc. All rights reserved.

Involvement of decreased muscarinic receptor function in prepulse inhibition deficits in mice reared in social isolation

PubMed Central

Koda, K; Ago, Y; Yano, K; Nishimura, M; Kobayashi, H; Fukada, A; Takuma, K; Matsuda, T

2011-01-01

BACKGROUND AND PURPOSE We have previously reported that galantamine, a weak acetylcholinesterase inhibitor, improves prepulse inhibition (PPI) deficits in mice reared in social isolation. ACh receptors are involved in the underlying mechanism of PPI, but whether rearing in social isolation causes dysfunction of the cholinergic system is unknown. In this study, we examined the involvement of muscarinic receptors in the improvement of PPI deficits induced by galantamine, and whether the cholinergic system is altered in mice reared in isolation. EXPERIMENTAL APPROACH Three-week-old male ddY mice were housed in isolated cages for 6 weeks before the initiation of experiments to create PPI deficits. Cholinergic functions were determined by measuring the behavioural and neurochemical responses to nicotinic and muscarinic receptor agonists. KEY RESULTS The improvement by galantamine of social isolation-induced PPI deficits was blocked by scopolamine, a non-selective muscarinic antagonist, and telenzepine, a preferential M1 receptor antagonist. Activation of M1 receptors improved social isolation-induced PPI deficits. Social isolation did not affect choline acetyltransferase and acetylcholinesterase activities in the prefrontal cortex and hippocampus, but it reduced the locomotor-suppressive response to muscarinic agonist oxotremorine, but not to nicotine. The isolation also attenuated the M1 receptor agonist N-desmethylclozapine-induced increase in prefrontal dopamine release. CONCLUSIONS AND IMPLICATIONS Galantamine improves PPI deficits of mice reared in social isolation via activation of M1 receptors. Social isolation reduces the muscarinic, especially M1, receptor function and this is involved in PPI deficits. PMID:20958289

Treatment of phenothiazine induced bulbar persistent dyskinesia with deanol acetamidobenzoate.

PubMed

Curran, D J; Nagaswami, S; Mohan, K J

1975-02-01

The late manifestation of neuroleptic-induced dyskinesia (persistent dyskinesia) is an irreversible complication of long-term treatment that is poorly understood and difficult to treat. Recently, a theory of dopamine receptor hypersensitivity in the dopaminergic-cholinergic system has suggested an explanation of choreiform movements and, thus, an implication for the management of persistent dyskinesia. The case presented is that of bulbar persistent dyskinesia in a patient who had been prescribed a phenothiazine derivative for eleven years; his symptoms improved with the use of deanol, which probably converts to acetylcholine after crossing the blood brain barrier. This improvement suggests that deanol may shift the neuroleptic-induced dopaminergic-cholinergic system unbalance toward equilibrium by matching predominant dopaminergic effect or by enhancing deficient cholinergic action in the dopaminergic-cholinergic system. This isolated finding needs to be confirmed by more research in neuropharmacology.

Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention

PubMed Central

Ricciardi, Emiliano; Handjaras, Giacomo; Bernardi, Giulio; Pietrini, Pietro; Furey, Maura L.

2012-01-01

Enhancing cholinergic function improves performance on various cognitive tasks and alters neural responses in task specific brain regions. Previous findings by our group strongly suggested that the changes in neural activity observed during increased cholinergic function may reflect an increase in neural efficiency that leads to improved task performance. The current study was designed to assess the effects of cholinergic enhancement on regional brain connectivity and BOLD signal variability. Nine subjects participated in a double-blind, placebo-controlled crossover functional magnetic resonance imaging (fMRI) study. Following an infusion of physostigmine (1mg/hr) or placebo, echo-planar imaging (EPI) was conducted as participants performed a selective attention task. During the task, two images comprised of superimposed pictures of faces and houses were presented. Subjects were instructed periodically to shift their attention from one stimulus component to the other and to perform a matching task using hand held response buttons. A control condition included phase-scrambled images of superimposed faces and houses that were presented in the same temporal and spatial manner as the attention task; participants were instructed to perform a matching task. Cholinergic enhancement improved performance during the selective attention task, with no change during the control task. Functional connectivity analyses showed that the strength of connectivity between ventral visual processing areas and task-related occipital, parietal and prefrontal regions was reduced significantly during cholinergic enhancement, exclusively during the selective attention task. Cholinergic enhancement also reduced BOLD signal temporal variability relative to placebo throughout temporal and occipital visual processing areas, again during the selective attention task only. Together with the observed behavioral improvement, the decreases in connectivity strength throughout task-relevant regions and BOLD variability within stimulus processing regions provide further support to the hypothesis that cholinergic augmentation results in enhanced neural efficiency. PMID:22906685

Carbachol-Induced Reduction in the Activity of Adult Male Zebra Finch RA Projection Neurons.

PubMed

Meng, Wei; Wang, Song-Hua; Li, Dong-Feng

2016-01-01

Cholinergic mechanism is involved in motor behavior. In songbirds, the robust nucleus of the arcopallium (RA) is a song premotor nucleus in the pallium and receives cholinergic inputs from the basal forebrain. The activity of projection neurons in RA determines song motor behavior. Although many evidences suggest that cholinergic system is implicated in song production, the cholinergic modulation of RA is not clear until now. In the present study, the electrophysiological effects of carbachol, a nonselective cholinergic receptor agonist, were investigated on the RA projection neurons of adult male zebra finches through whole-cell patch-clamp techniques in vitro. Our results show that carbachol produced a significant decrease in the spontaneous and evoked action potential (AP) firing frequency of RA projection neurons, accompanying a hyperpolarization of the membrane potential, an increase in the evoked AP latency, afterhyperpolarization (AHP) peak amplitude, and AHP time to peak, and a decrease in the membrane input resistance, membrane time constant, and membrane capacitance. These results indicate that carbachol reduces the activity of RA projection neurons by hyperpolarizing the resting membrane potential and increasing the AHP and the membrane conductance, suggesting that the cholinergic modulation of RA may play an important role in song production.

Remodeling of cardiac cholinergic innervation and control of heart rate in mice with streptozotocin-induced diabetes.

PubMed

Mabe, Abigail M; Hoover, Donald B

2011-07-05

Cardiac autonomic neuropathy is a frequent complication of diabetes and often presents as impaired cholinergic regulation of heart rate. Some have assumed that diabetics have degeneration of cardiac cholinergic nerves, but basic knowledge on this topic is lacking. Accordingly, our goal was to evaluate the structure and function of cardiac cholinergic neurons and nerves in C57BL/6 mice with streptozotocin-induced diabetes. Electrocardiograms were obtained weekly from conscious control and diabetic mice for 16 weeks. Resting heart rate decreased in diabetic mice, but intrinsic heart rate was unchanged. Power spectral analysis of electrocardiograms revealed decreased high frequency and increased low frequency power in diabetic mice, suggesting a relative reduction of parasympathetic tone. Negative chronotropic responses to right vagal nerve stimulation were blunted in 16-week diabetic mice, but postjunctional sensitivity of isolated atria to muscarinic agonists was unchanged. Immunohistochemical analysis of hearts from diabetic and control mice showed no difference in abundance of cholinergic neurons, but cholinergic nerve density was increased at the sinoatrial node of diabetic mice (16 weeks: 14.9±1.2% area for diabetics versus 8.9±0.8% area for control, P<0.01). We conclude that disruption of cholinergic function in diabetic mice cannot be attributed to a loss of cardiac cholinergic neurons and nerve fibers or altered cholinergic sensitivity of the atria. Instead, decreased responses to vagal stimulation might be caused by a defect of preganglionic cholinergic neurons and/or ganglionic neurotransmission. The increased density of cholinergic nerves observed at the sinoatrial node of diabetic mice might be a compensatory response. Copyright © 2011 Elsevier B.V. All rights reserved.

Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats.

PubMed

Laplante, François; Zhang, Zi-Wei; Huppé-Gourgues, Frédéric; Dufresne, Marc M; Vaucher, Elvire; Sullivan, Ron M

2012-11-01

In rats, selective depletion of the cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) results in heightened behavioural sensitivity to amphetamine and impaired sensorimotor gating processes, suggesting a hyper-responsiveness to dopamine (DA) activity in the N.Acc. We hypothesized that local cholinergic depletion may also trigger distal functional alterations, particularly in prefrontal cortex (PFC). Adult male Sprague-Dawley rats were injected bilaterally in the N.Acc. with an immunotoxin targeting choline acetyltransferase. Two weeks later, cognitive function was assessed using the delayed alternation paradigm in the T-maze. The rats were then implanted with voltammetric recording electrodes in the ventromedial PFC to measure in vivo extracellular DA release in response to mild tail pinch stress. The PFC was also examined for density of tyrosine hydroxylase (TH)-labelled varicosities. In another cohort of control and lesioned rats, we measured post mortem tissue content of DA. Depletion of cholinergic neurons (restricted to N.Acc.) significantly impaired delayed alternation performance across delay intervals. While (basal) post mortem indices of PFC DA function were unaffected by N.Acc. lesions, in vivo mesocortical DA activation was markedly reduced; this deficit correlated significantly with cognitive impairments. TH-labelled varicosities however, were unaffected in cortical layer V relative to controls. These data suggest that selective depletion of cholinergic interneurons in N.Acc. triggers widespread functional impairments in mesocorticolimbic DA function and cognition. The possible relevance of these findings is also discussed in relation to schizophrenia, where reduced density of cholinergic neurons in ventral striatum has been reported. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cholinergic left-right asymmetry in the habenulo-interpeduncular pathway.

PubMed

Hong, Elim; Santhakumar, Kirankumar; Akitake, Courtney A; Ahn, Sang Jung; Thisse, Christine; Thisse, Bernard; Wyart, Claire; Mangin, Jean-Marie; Halpern, Marnie E

2013-12-24

The habenulo-interpeduncular pathway, a highly conserved cholinergic system, has emerged as a valuable model to study left-right asymmetry in the brain. In larval zebrafish, the bilaterally paired dorsal habenular nuclei (dHb) exhibit prominent left-right differences in their organization, gene expression, and connectivity, but their cholinergic nature was unclear. Through the discovery of a duplicated cholinergic gene locus, we now show that choline acetyltransferase and vesicular acetylcholine transporter homologs are preferentially expressed in the right dHb of larval zebrafish. Genes encoding the nicotinic acetylcholine receptor subunits α2 and β4 are transcribed in the target interpeduncular nucleus (IPN), suggesting that the asymmetrical cholinergic pathway is functional. To confirm this, we activated channelrhodopsin-2 specifically in the larval dHb and performed whole-cell patch-clamp recording of IPN neurons. The response to optogenetic or electrical stimulation of the right dHb consisted of an initial fast glutamatergic excitatory postsynaptic current followed by a slow-rising cholinergic current. In adult zebrafish, the dHb are divided into discrete cholinergic and peptidergic subnuclei that differ in size between the left and right sides of the brain. After exposing adults to nicotine, fos expression was activated in subregions of the IPN enriched for specific nicotinic acetylcholine receptor subunits. Our studies of the newly identified cholinergic gene locus resolve the neurotransmitter identity of the zebrafish habenular nuclei and reveal functional asymmetry in a major cholinergic neuromodulatory pathway of the vertebrate brain.

The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited

PubMed Central

van Enkhuizen, Jordy; Janowsky, David S; Olivier, Berend; Minassian, Arpi; Perry, William; Young, Jared W; Geyer, Mark A

2014-01-01

Bipolar disorder is a unique illness characterized by fluctuations between mood states of depression and mania. Originally, an adrenergic-cholinergic balance hypothesis was postulated to underlie these different affective states. In this review, we update this hypothesis with recent findings from human and animal studies, suggesting that a catecholaminergic-cholinergic hypothesis may be more relevant. Evidence from neuroimaging studies, neuropharmacological interventions, and genetic associations support the notion that increased cholinergic functioning underlies depression, whereas increased activations of the catecholamines (dopamine and norepinephrine) underlie mania. Elevated functional acetylcholine during depression may affect both muscarinic and nicotinic acetylcholine receptors in a compensatory fashion. Increased functional dopamine and norepinephrine during mania on the other hand may affect receptor expression and functioning of dopamine reuptake transporters. Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems that could explain cycling between states of depression and mania is missing. Future studies should focus on the influence of environmental stimuli and genetic susceptibilities that may affect the catecholaminergic-cholinergic balance underlying cycling between the affective states. Overall, observations from recent studies add important data to this revised balance theory of bipolar disorder, renewing interest in this field of research. PMID:25107282

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum.

PubMed

Frick, Luciana R; Rapanelli, Maximiliano; Jindachomthong, Kantiya; Grant, Paul; Leckman, James F; Swedo, Susan; Williams, Kyle; Pittenger, Christopher

2018-03-01

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Distribution and co-localization of choline acetyltransferase and p75 neurotrophin receptors in the sheep basal forebrain: implications for the use of a specific cholinergic immunotoxin.

PubMed

Ferreira, G; Meurisse, M; Tillet, Y; Lévy, F

2001-01-01

The basal forebrain cholinergic system is involved in different forms of memory. To study its role in social memory in sheep, an immunotoxin, ME20.4 immunoglobulin G (IgG)-saporin, was developed that is specific to basal forebrain cholinergic neurons bearing the p75 neurotrophin receptor. The distribution of sheep cholinergic neurons was mapped with an antibody against choline acetyltransferase. To assess the localization of the p75 receptor on basal forebrain cholinergic neurons, the distribution of p75 receptor-immunoreactive neurons with ME20.4 IgG was examined, and a double-labeling study with antibodies against choline acetyltransferase and p75 receptor was undertaken. The loss of basal forebrain cholinergic neurons and acetylcholinesterase fibers in basal forebrain projection areas was assessed in ewes that had received intracerebroventricular injections of the immunotoxin (50, 100 or 150 microg) alone, as well as, in some of the ewes treated with the highest dose, with bilateral immunotoxin injections in the nucleus basalis (11 microg/side). Results indicated that choline acetyltransferase- and p75 receptor-immunoreactive cells had similar distributions in the medial septum, the vertical and horizontal limbs of the band of Broca, and the nucleus basalis. The double-labeling procedure revealed that 100% of the cholinergic neurons are also p75 receptor positive in the medial septum and in the vertical and horizontal limbs of the band of Broca, and 82% in the nucleus basalis. Moreover, 100% of the p75 receptor-immunoreactive cells of these four nuclei were cholinergic. Combined immunotoxin injections into ventricles and the nucleus basalis produced a near complete loss (80-95%) of basal forebrain cholinergic neurons and acetylcholinesterase-positive fibers in the hippocampus, olfactory bulb and entorhinal cortex. This study provides the first anatomical data concerning the basal forebrain cholinergic system in ungulates. The availability of a selective cholinergic immunotoxin effective in sheep provides a new tool to probe the involvement of basal forebrain cholinergic neurons in cognitive processes in this species.

Carbachol-Induced Reduction in the Activity of Adult Male Zebra Finch RA Projection Neurons

PubMed Central

Meng, Wei; Wang, Song-Hua; Li, Dong-Feng

2016-01-01

Cholinergic mechanism is involved in motor behavior. In songbirds, the robust nucleus of the arcopallium (RA) is a song premotor nucleus in the pallium and receives cholinergic inputs from the basal forebrain. The activity of projection neurons in RA determines song motor behavior. Although many evidences suggest that cholinergic system is implicated in song production, the cholinergic modulation of RA is not clear until now. In the present study, the electrophysiological effects of carbachol, a nonselective cholinergic receptor agonist, were investigated on the RA projection neurons of adult male zebra finches through whole-cell patch-clamp techniques in vitro. Our results show that carbachol produced a significant decrease in the spontaneous and evoked action potential (AP) firing frequency of RA projection neurons, accompanying a hyperpolarization of the membrane potential, an increase in the evoked AP latency, afterhyperpolarization (AHP) peak amplitude, and AHP time to peak, and a decrease in the membrane input resistance, membrane time constant, and membrane capacitance. These results indicate that carbachol reduces the activity of RA projection neurons by hyperpolarizing the resting membrane potential and increasing the AHP and the membrane conductance, suggesting that the cholinergic modulation of RA may play an important role in song production. PMID:26904300

Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation.

PubMed

Yanai, Joseph; Huleihel, Rabab; Izrael, Michal; Metsuyanim, Sally; Shahak, Halit; Vatury, Ori; Yaniv, Shiri P

2003-09-01

Opioid drugs act primarily on the opiate receptors; they also exert their effect on other innervations resulting in non-opioidergic behavioural deficits. Similarly, opioid neurobehavioural teratogenicity is attested in numerous behaviours and neural processes which hinder the research on the mechanisms involved. Therefore, in order to be able to ascertain the mechanism we have established an animal (mouse) model for the teratogenicity induced by opioid abuse, which focused on behaviours related to specific brain area and innervation. Diacetylmorphine (heroin) and not morphine was applied because heroin exerts a unique action, distinguished from that of morphine. Pregnant mice were exposed to heroin (10 mg/kg per day) and the offspring were tested for behavioural deficits and biochemical alterations related to the septohippocampal cholinergic innervation. Some studies employing the chick embryo were concomitantly added as a control for the confounding indirect variables. Prenatal exposure to heroin in mice induced global hyperactivation both pre- and post-synaptic along the septohippocampal cholinergic innervation, including basal protein kinase C (PKC) activity accompanied by a desensitization of PKC activity in response to cholinergic agonist. Functionally, the heroin-exposed offspring displayed deficits in hippocampus-related behaviours, suggesting deficits in the net output of the septohippocampal cholinergic innervation. Grafting of cholinergic cells to the impaired hippocampus reversed both pre- and post-synaptic hyperactivity, resensitized PKC activity, and restored the associated behaviours to normality. Consistently, correlation studies point to the relative importance of PKC to the behavioural deficits. The chick model, which dealt with imprinting related to a different brain region, confirmed that the effect of heroin is direct. Taken together with studies by others on the effect of prenatal exposure to opioids on the opioidergic innervation and with what is known on the opioid regulation of the cholinergic innervation, it appears that heroin exerts its neuroteratogenicity by inducing alterations in the opioidergic innervation, which by means of its regulatory action, attenuates the functional output of the cholinergic innervation. In our model, there was hyperactivity mostly of the post-synaptic components of the cholinergic innervation. However, the net cholinergic output is decreased because PKC is desensitized to the effect of the cholinergic agonist, and this is further evidenced by the extensive deficits in the related behaviours.

Selective preservation of cholinergic MeCP2 rescues specific Rett-syndrome-like phenotypes in MeCP2stop mice.

PubMed

Zhou, Huanhuan; Wu, Wei; Zhang, Ying; He, Haiyang; Yuan, Zhefeng; Zhu, Zhiwei; Zhao, Zhengyan

2017-03-30

RTT is a neurodevelopmental disorder characterized by growth regression, motor dysfunction, stereotypic hand movements, and autism features. Typical Rett syndrome (RTT) is predominantly caused by mutations in X-linked MeCP2 gene which encodes methyl-CpG-binding protein 2 (MeCP2). The brain-abundant MeCP2 protein mainly functions as a transcriptional regulator for neurodevelopment-associated genes. Specific functions of MeCP2 in certain neuron types remain to be known. Although cholinergic system is an important modulating system in brain, how MeCP2 in cholinergic neurons contribute to RTT has not been clearly understood. Here we use a mouse model with selectively activated endogenous MeCP2 in cholinergic neurons in otherwise MeCP2 stop mice to determine the cholinergic MeCP2 effects on rescuing the RTT-like phenotypes. We found cholinergic MeCP2 preservation could reverse some aspects of the RTT-like phenotypes in mice including hypolocomotion and increased anxiety level, and delay the onset of underweight, instead of improving the hypersocial abnormality and the poor general conditions such as short lifespan, low brain weight, and increasing severity score. Our findings suggest that selective activation of cholinergic MeCP2 is sufficient to reverse the locomotor impairment and increased anxiety-like behaviors at least in early symptomatic stage, supporting future development of RTT therapies associated with cholinergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

Sympathetic sprouting in visual cortex stimulated by cholinergic denervation rescues expression of two forms of long-term depression at layer 2/3 synapses.

PubMed

McCoy, P A; McMahon, L L

2010-07-14

Cholinergic innervation of hippocampus and cortex is required for some forms of learning and memory. Several reports have shown that activation of muscarinic m1 receptors induces a long-term depression (mLTD) at glutamate synapses in hippocampus and in several areas of cortex, including perirhinal and visual cortices. This plasticity likely contributes to cognitive function dependent upon the cholinergic system. In rodent models, degeneration of hippocampal cholinergic innervation following lesion of the medial septum stimulates sprouting of adrenergic sympathetic axons, originating from the superior cervical ganglia (SCG), into denervated hippocampal subfields. We previously reported that this adrenergic sympathetic sprouting occurs simultaneously with a reappearance of cholinergic fibers in hippocampus and rescue of mLTD at CA3-CA1 synapses. Because cholinergic neurons throughout basal forebrain degenerate in aging and Alzheimer's disease, it is critical to determine if this compensatory sprouting occurs in other regions impacted by cholinergic cell loss. To this end, we investigated whether lesion of the nucleus basalis magnocellularis (NbM) to cholinergically denervate cortex stimulates adrenergic sympathetic sprouting and the accompanying increase in cholinergic innervation. Further, we assessed whether the presence of sprouting positively correlates with the ability of glutamate synapses in acute visual cortex slices to express mLTD and low frequency stimulation induced LTD (LFS LTD), another cholinergic dependent form of plasticity in visual cortex. We found that both mLTD and LFS LTD are absent in animals when NbM lesion is combined with bilateral removal of the SCG to prevent possible compensatory sprouting. In contrast, when the SCG remain intact to permit sprouting in animals with NbM lesion, cholinergic fiber density is increased concurrently with adrenergic sympathetic sprouting, and mLTD and LFS LTD are preserved. Our findings suggest that autonomic compensation for central cholinergic degeneration is not specific to hippocampus, but is a general repair mechanism occurring in other brain regions important for normal cognitive function. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Cholinergic regulation of fear learning and extinction.

PubMed

Wilson, Marlene A; Fadel, Jim R

2017-03-01

Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Regional acetylcholinesterase activity and its correlation with behavioral performances in 15-month old transgenic mice expressing the human C99 fragment of APP.

PubMed

Dumont, M; Lalonde, R; Ghersi-Egea, J-F; Fukuchi, K; Strazielle, C

2006-09-01

In addition to Abeta plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by increased brain levels of APP C-terminal fragments. In the present investigation, the cholinergic innervation in forebrain regions of transgenic mice (Tg13592) expressing the human betaAPP C99 fragment was compared to that of non-transgenic controls by measuring the activity of the non-specific catabolic enzyme, acetylcholinesterase (AChE). The AchE activity of Tg13592 mice was altered in several regions implicated in the functional loop of regulation between septum and hippocampus, vulnerable in Alzheimer pathology and critically involved in cognitive functions. In particular, AChE activity was upregulated in three basal forebrain regions containing cholinergic cell bodies, prelimbic cortex, anterior subiculum, and paraventricular thalamus, but downregulated in lateral septum and reticular thalamus. The increased activity in medial septum and anterior subiculum was linearly correlated with poor performances in a spatial learning task, possibly due to cell stress mechanisms. Because of some similarities in terms of neurochemistry and behavior, this mouse model may be of use for studying prodromal AD.

The lymphocytic cholinergic system and its contribution to the regulation of immune activity.

PubMed

Kawashima, Koichiro; Fujii, Takeshi

2003-12-26

Lymphocytes express most of the cholinergic components found in the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase. Stimulation of T and B cells with ACh or another mAChR agonist elicits intracellular Ca2+ signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and IL-2-induced signal transduction, probably via M3 and M5 mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca2+ signaling in T and B cells, probably via alpha7 nAChR subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Activation of T cells with phytohemagglutinin or antibodies against cell surface molecules enhances lymphocytic cholinergic transmission by activating expression of ChAT and M5 mAChR, which is suggestive of local cholinergic regulation of immune system activity. This idea is supported by the facts that lymphocytic cholinergic activity reflects well the changes in immune system function seen in animal models of immune deficiency and immune acceleration. Collectively, these data provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.

Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior.

PubMed

Kamii, Hironori; Kurosawa, Ryo; Taoka, Naofumi; Shinohara, Fumiya; Minami, Masabumi; Kaneda, Katsuyuki

2015-05-01

The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Novel channel-mediated choline transport in cholinergic neurons of the mouse retina.

PubMed

Ishii, Toshiyuki; Homma, Kohei; Mano, Asuka; Akagi, Takumi; Shigematsu, Yasuhide; Shimoda, Yukio; Inoue, Hiroyoshi; Kakinuma, Yoshihiko; Kaneda, Makoto

2017-10-01

Choline uptake into the presynaptic terminal of cholinergic neurons is mediated by the high-affinity choline transporter and is essential for acetylcholine synthesis. In a previous study, we reported that P2X 2 purinoceptors are selectively expressed in OFF-cholinergic amacrine cells of the mouse retina. Under specific conditions, P2X 2 purinoceptors acquire permeability to large cations, such as N -methyl-d-glucamine, and therefore potentially could act as a noncanonical pathway for choline entry into neurons. We tested this hypothesis in OFF-cholinergic amacrine cells of the mouse retina. ATP-induced choline currents were observed in OFF-cholinergic amacrine cells, but not in ON-cholinergic amacrine cells, in mouse retinal slice preparations. High-affinity choline transporters are expressed at higher levels in ON-cholinergic amacrine cells than in OFF-cholinergic amacrine cells. In dissociated preparations of cholinergic amacrine cells, ATP-activated cation currents arose from permeation of extracellular choline. We also examined the pharmacological properties of choline currents. Pharmacologically, α,β-methylene ATP did not produce a cation current, whereas ATPγS and benzoyl-benzoyl-ATP (BzATP) activated choline currents. However, the amplitude of the choline current activated by BzATP was very small. The choline current activated by ATP was strongly inhibited by pyridoxalphosphate-6-azophenyl-2',4'-sulfonic acid. Accordingly, P2X 2 purinoceptors expressed in HEK-293T cells were permeable to choline and similarly functioned as a choline uptake pathway. Our physiological and pharmacological findings support the hypothesis that P2 purinoceptors, including P2X 2 purinoceptors, function as a novel choline transport pathway and may provide a new regulatory mechanism for cholinergic signaling transmission at synapses in OFF-cholinergic amacrine cells of the mouse retina. NEW & NOTEWORTHY Choline transport across the membrane is exerted by both the high-affinity and low-affinity choline transporters. We found that choline can permeate P2 purinergic receptors, including P2X 2 purinoceptors, in cholinergic neurons of the retina. Our findings show the presence of a novel choline transport pathway in cholinergic neurons. Our findings also indicate that the permeability of P2X 2 purinergic receptors to choline observed in the heterologous expression system may have a physiological relevance in vivo. Copyright © 2017 the American Physiological Society.

A Threshold Model for Opposing Actions of Acetylcholine on Reward Behavior: Molecular Mechanisms and Implications for Treatment of Substance Abuse Disorders

PubMed Central

Grasing, Kenneth

2016-01-01

The cholinergic system plays important roles in both learning and addiction. Medications that modify cholinergic tone can have pronounced effects on behaviors reinforced by natural and drug reinforcers. Importantly, enhancing the action of acetylcholine (ACh) in the nucleus accumbens and ventral tegmental area (VTA) dopamine system can either augment or diminish these behaviors. A threshold model is presented that can explain these seemingly contradictory results. Relatively low levels of ACh rise above a lower threshold, facilitating behaviors supported by drugs or natural reinforcers. Further increases in cholinergic tone that rise above a second upper threshold oppose the same behaviors. Accordingly, cholinesterase inhibitors, or agonists for nicotinic or muscarinic receptors, each have the potential to produce biphasic effects on reward behaviors. Pretreatment with either nicotinic or muscarinic antagonists can block drug- or food- reinforced behavior by maintaining cholinergic tone below its lower threshold. Potential threshold mediators include desensitization of nicotinic receptors and biphasic effects of ACh on the firing of medium spiny neurons. Nicotinic receptors with high- and low-affinity appear to play greater roles in reward enhancement and inhibition, respectively. Cholinergic inhibition of natural and drug rewards may serve as mediators of previously described opponent processes. Future studies should evaluate cholinergic agents across a broader range of doses, and include a variety of reinforced behaviors. PMID:27316344

Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca2+-dependent Cl− and K+ channels

PubMed Central

Hollenhorst, Monika I; Lips, Katrin S; Wolff, Miriam; Wess, Jürgen; Gerbig, Stefanie; Takats, Zoltan; Kummer, Wolfgang; Fronius, Martin

2012-01-01

BACKGROUND AND PURPOSE Recent studies detected the expression of proteins involved in cholinergic metabolism in airway epithelial cells, although the function of this non-neuronal cholinergic system is not known in detail. Thus, this study focused on the effect of luminal ACh as a regulator of transepithelial ion transport in epithelial cells. EXPERIMENTAL APPROACH RT-PCR experiments were performed using mouse tracheal epithelial cells for ChAT and organic cation transporter (OCT) transcripts. Components of tracheal airway lining fluid were analysed with desorption electrospray ionization (DESI) MS. Effects of nicotine on mouse tracheal epithelial ion transport were examined with Ussing-chamber experiments. KEY RESULTS Transcripts encoding ChAT and OCT1–3 were detected in mouse tracheal epithelial cells. The DESI experiments identified ACh in the airway lining fluid. Luminal ACh induced an immediate, dose-dependent increase in the transepithelial ion current (EC50: 23.3 µM), characterized by a transient peak and sustained plateau current. This response was not affected by the Na+-channel inhibitor amiloride. The Cl−-channel inhibitor niflumic acid or the K+-channel blocker Ba2+ attenuated the ACh effect. The calcium ionophore A23187 mimicked the ACh effect. Luminal nicotine or muscarine increased the ion current. Experiments with receptor gene-deficient animals revealed the participation of muscarinic receptor subtypes M1 and M3. CONCLUSIONS AND IMPLICATIONS The presence of luminal ACh and activation of transepithelial ion currents by luminal ACh receptors identifies a novel non-neuronal cholinergic pathway in the airway lining fluid. This pathway could represent a novel drug target in the airways. PMID:22300281

Cholinergic and serotonergic modulation of visual information processing in monkey V1.

PubMed

Shimegi, Satoshi; Kimura, Akihiro; Sato, Akinori; Aoyama, Chisa; Mizuyama, Ryo; Tsunoda, Keisuke; Ueda, Fuyuki; Araki, Sera; Goya, Ryoma; Sato, Hiromichi

2016-09-01

The brain dynamically changes its input-output relationship depending on the behavioral state and context in order to optimize information processing. At the molecular level, cholinergic/monoaminergic transmitters have been extensively studied as key players for the state/context-dependent modulation of brain function. In this paper, we review how cortical visual information processing in the primary visual cortex (V1) of macaque monkey, which has a highly differentiated laminar structure, is optimized by serotonergic and cholinergic systems by examining anatomical and in vivo electrophysiological aspects to highlight their similarities and distinctions. We show that these two systems have a similar layer bias for axonal fiber innervation and receptor distribution. The common target sites are the geniculorecipient layers and geniculocortical fibers, where the appropriate gain control is established through a geniculocortical signal transformation. Both systems exert activity-dependent response gain control across layers, but in a manner consistent with the receptor subtype. The serotonergic receptors 5-HT1B and 5HT2A modulate the contrast-response curve in a manner consistent with bi-directional response gain control, where the sign (facilitation/suppression) is switched according to the firing rate and is complementary to the other. On the other hand, cholinergic nicotinic/muscarinic receptors exert mono-directional response gain control without a sign reversal. Nicotinic receptors increase the response magnitude in a multiplicative manner, while muscarinic receptors exert both suppressive and facilitative effects. We discuss the implications of the two neuromodulator systems in hierarchical visual signal processing in V1 on the basis of the developed laminar structure. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention.

PubMed

Ricciardi, Emiliano; Handjaras, Giacomo; Bernardi, Giulio; Pietrini, Pietro; Furey, Maura L

2013-01-01

Enhancing cholinergic function improves performance on various cognitive tasks and alters neural responses in task specific brain regions. We have hypothesized that the changes in neural activity observed during increased cholinergic function reflect an increase in neural efficiency that leads to improved task performance. The current study tested this hypothesis by assessing neural efficiency based on cholinergically-mediated effects on regional brain connectivity and BOLD signal variability. Nine subjects participated in a double-blind, placebo-controlled crossover fMRI study. Following an infusion of physostigmine (1 mg/h) or placebo, echo-planar imaging (EPI) was conducted as participants performed a selective attention task. During the task, two images comprised of superimposed pictures of faces and houses were presented. Subjects were instructed periodically to shift their attention from one stimulus component to the other and to perform a matching task using hand held response buttons. A control condition included phase-scrambled images of superimposed faces and houses that were presented in the same temporal and spatial manner as the attention task; participants were instructed to perform a matching task. Cholinergic enhancement improved performance during the selective attention task, with no change during the control task. Functional connectivity analyses showed that the strength of connectivity between ventral visual processing areas and task-related occipital, parietal and prefrontal regions reduced significantly during cholinergic enhancement, exclusively during the selective attention task. Physostigmine administration also reduced BOLD signal temporal variability relative to placebo throughout temporal and occipital visual processing areas, again during the selective attention task only. Together with the observed behavioral improvement, the decreases in connectivity strength throughout task-relevant regions and BOLD variability within stimulus processing regions support the hypothesis that cholinergic augmentation results in enhanced neural efficiency. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Modulation of skeletal muscle contraction by the non-toxic fraction of Buthus occitanus tunetanus venom via the cholinergic receptors].

PubMed

Cheikh, A; Cognard, C; Potreau, D; Bescond, J; Raymond, G; El Ayeb, M; Benkhalifa, R

2007-01-01

Cholinergic receptors have an essential physiological role in the central nervous system because of their implication in higher functions in the neuromuscular junction within the brain and also in the peripheral nervous system by activating nicotinic (nAChRs) or muscarinic (mAChRs) receptors. Moreover, cholinergic receptors could be recognized by animal toxins isolated from snake venoms or alkaloids having animal or vegetal origin. In this context, we aim to find such molecules in a non toxic venom fraction of Buthus occitanus tunetanus scorpion, M1, which could therefore constitute promising medical tool. We present here a physiological study in skeletal muscle cells that regroups data that have been recently published and some new results reinforcing the last ones. The global effect of M1, was firstly studied on isolated nerve-muscle preparation. In cultured myotubes, we have found that the intracellular calcium increase, induced by M1 was blocked when ryanodine or inositol 1,4,5-triphosphate receptors are inhibited. Moreover, we have shown that M1 application on myotubes, induced a membrane depolarization as seen with acetylcholine. The treatment of myotubes with alpha-bungarotoxin blocked in most parts the depolarization amplitude. Thus, these results confirm the presence of at least one component in M1 active in nAChRs.

Enhancement of learning capacity and cholinergic synaptic function by carnitine in aging rats.

PubMed

Ando, S; Tadenuma, T; Tanaka, Y; Fukui, F; Kobayashi, S; Ohashi, Y; Kawabata, T

2001-10-15

The effects of a carnitine derivative, acetyl-L-carnitine (ALCAR), on the cognitive and cholinergic activities of aging rats were examined. Rats were given ALCAR (100 mg/kg) per os for 3 months and were subjected to the Hebb-Williams tasks and a new maze task, AKON-1, to assess their learning capacity. The learning capacity of the ALCAR-treated group was superior to that of the control. Cholinergic activities were determined with synaptosomes isolated from the cortices. The high-affinity choline uptake by synaptosomes, acetylcholine synthesis in synaptosomes, and acetylcholine release from synaptosomes on membrane depolarization were all enhanced in the ALCAR group. This study indicates that chronic administration of ALCAR increases cholinergic synaptic transmission and consequently enhances learning capacity as a cognitive function in aging rats. Copyright 2001 Wiley-Liss, Inc.

A cellular and regulatory map of the cholinergic nervous system of C. elegans

PubMed Central

Pereira, Laura; Kratsios, Paschalis; Serrano-Saiz, Esther; Sheftel, Hila; Mayo, Avi E; Hall, David H; White, John G; LeBoeuf, Brigitte; Garcia, L Rene; Alon, Uri; Hobert, Oliver

2015-01-01

Nervous system maps are of critical importance for understanding how nervous systems develop and function. We systematically map here all cholinergic neuron types in the male and hermaphrodite C. elegans nervous system. We find that acetylcholine (ACh) is the most broadly used neurotransmitter and we analyze its usage relative to other neurotransmitters within the context of the entire connectome and within specific network motifs embedded in the connectome. We reveal several dynamic aspects of cholinergic neurotransmitter identity, including a sexually dimorphic glutamatergic to cholinergic neurotransmitter switch in a sex-shared interneuron. An expression pattern analysis of ACh-gated anion channels furthermore suggests that ACh may also operate very broadly as an inhibitory neurotransmitter. As a first application of this comprehensive neurotransmitter map, we identify transcriptional regulatory mechanisms that control cholinergic neurotransmitter identity and cholinergic circuit assembly. DOI: http://dx.doi.org/10.7554/eLife.12432.001 PMID:26705699

Localization of cholinergic innervation and neurturin receptors in adult mouse heart and expression of the neurturin gene.

PubMed

Mabe, Abigail M; Hoard, Jennifer L; Duffourc, Michelle M; Hoover, Donald B

2006-10-01

Neurturin (NRTN) is a neurotrophic factor required during development for normal cholinergic innervation of the heart, but whether NRTN continues to function in the adult heart is unknown. We have therefore evaluated NRTN expression in adult mouse heart and the association of NRTN receptors with intracardiac cholinergic neurons and nerve fibers. Mapping the regional distribution and density of cholinergic nerves in mouse heart was an integral part of this goal. Analysis of RNA from adult C57BL/6 mouse hearts demonstrated NRTN expression in atrial and ventricular tissue. Virtually all neurons in the cardiac parasympathetic ganglia exhibited the cholinergic phenotype, and over 90% of these cells contained both components of the NRTN receptor, Ret tyrosine kinase and GDNF family receptor alpha2 (GFRalpha2). Cholinergic nerve fibers, identified by labeling for the high affinity choline transporter, were abundant in the sinus and atrioventricular nodes, ventricular conducting system, interatrial septum, and much of the right atrium, but less abundant in the left atrium. The right ventricular myocardium contained a low density of cholinergic nerves, which were sparse in other regions of the working ventricular myocardium. Some cholinergic nerves were also associated with coronary vessels. GFRalpha2 was present in most cholinergic nerve fibers and in Schwann cells and their processes throughout the heart. Some cholinergic nerve fibers, such as those in the sinus node, also exhibited Ret immunoreactivity. These findings provide the first detailed mapping of cholinergic nerves in mouse heart and suggest that the neurotrophic influence of NRTN on cardiac cholinergic innervation continues in mature animals.

Sympathetic sprouting drives hippocampal cholinergic reinnervation that prevents loss of a muscarinic receptor-dependent long-term depression at CA3-CA1 synapses.

PubMed

Scheiderer, Cary L; McCutchen, Eve; Thacker, Erin E; Kolasa, Krystyna; Ward, Matthew K; Parsons, Dee; Harrell, Lindy E; Dobrunz, Lynn E; McMahon, Lori L

2006-04-05

Degeneration of septohippocampal cholinergic neurons results in memory deficits attributable to loss of cholinergic modulation of hippocampal synaptic circuits. A remarkable consequence of cholinergic degeneration is the sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. The functional impact of sympathetic ingrowth on synaptic physiology has never been investigated. Here, we report that, at CA3-CA1 synapses, a Hebbian form of long-term depression (LTD) induced by muscarinic M1 receptor activation (mLTD) is lost after medial septal lesion. Unexpectedly, expression of mLTD is rescued by sympathetic sprouting. These effects are specific because LTP and other forms of LTD are unaffected. The rescue of mLTD expression is coupled temporally with the reappearance of cholinergic fibers in hippocampus, as assessed by the immunostaining of fibers for VAChT (vesicular acetylcholine transporter). Both the cholinergic reinnervation and mLTD rescue are prevented by bilateral superior cervical ganglionectomy, which also prevents the noradrenergic sympathetic sprouting. The new cholinergic fibers likely originate from the superior cervical ganglia because unilateral ganglionectomy, performed when cholinergic reinnervation is well established, removes the reinnervation on the ipsilateral side. Thus, the temporal coupling of the cholinergic reinnervation with mLTD rescue, together with the absence of reinnervation and mLTD expression after ganglionectomy, demonstrate that the autonomic-driven cholinergic reinnervation is essential for maintaining mLTD after central cholinergic cell death. We have discovered a novel phenomenon whereby the autonomic and central nervous systems experience structural rearrangement to replace lost cholinergic innervation in hippocampus, with the consequence of preserving a form of LTD that would otherwise be lost as a result of cholinergic degeneration.

B6eGFPChAT mice overexpressing the vesicular acetylcholine transporter exhibit spontaneous hypoactivity and enhanced exploration in novel environments

PubMed Central

Nagy, Paul M; Aubert, Isabelle

2013-01-01

Cholinergic innervation is extensive throughout the central and peripheral nervous systems. Among its many roles, the neurotransmitter acetylcholine (ACh) contributes to the regulation of motor function, locomotion, and exploration. Cholinergic deficits and replacement strategies have been investigated in neurodegenerative disorders, particularly in cases of Alzheimer's disease (AD). Focus has been on blocking acetylcholinesterase (AChE) and enhancing ACh synthesis to improve cholinergic neurotransmission. As a first step in evaluating the physiological effects of enhanced cholinergic function through the upregulation of the vesicular acetylcholine transporter (VAChT), we used the hypercholinergic B6eGFPChAT congenic mouse model that has been shown to contain multiple VAChT gene copies. Analysis of biochemical and behavioral paradigms suggest that modest increases in VAChT expression can have a significant effect on spontaneous locomotion, reaction to novel stimuli, and the adaptation to novel environments. These observations support the potential of VAChT as a therapeutic target to enhance cholinergic tone, thereby decreasing spontaneous hyperactivity and increasing exploration in novel environments. PMID:24381809

The cholinergic anti-inflammatory pathway: An innovative treatment strategy for neurological diseases.

PubMed

Han, Bin; Li, Xiuping; Hao, Junwei

2017-06-01

Acetylcholine (ACh), as a classical neurotransmitter, regulates the neuronal network in response to internal and external stimuli. In recent decades, the biology of ACh has been endowed with unparalleled new insights, especially with respect to cholinergic anti-inflammatory properties in non-neuronal cells. In fact, a mechanism frequently referred to as the "cholinergic anti-inflammatory pathway" has been termed to describe interactions between the central nervous system (CNS) and the immune system via vagus nerve. As well documented, immune cells express choline acetyltransferase, a direct synthetase for ACh, and other corresponding cholinergic components. Alternatively, the ACh released from immune cells or cholinergic neurons modulates immune function in an autocrine/paracrine manner by acting on its receptors. Moreover, muscarinic or nicotinic ACh receptors on various immune cells and CNS glial cells administer the work of their respective agonists, causing functional and biochemical changes. In this review, we focus on the anti-inflammatory benefits of non-neuronal and neuronal ACh as a means of providing new insights into treating inflammation-related neurological diseases, as exemplified by those described herein. Copyright © 2017 Elsevier Ltd. All rights reserved.

The role of 5-HT(1A) receptors in learning and memory.

PubMed

Ogren, Sven Ove; Eriksson, Therese M; Elvander-Tottie, Elin; D'Addario, Claudio; Ekström, Joanna C; Svenningsson, Per; Meister, Björn; Kehr, Jan; Stiedl, Oliver

2008-12-16

The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.

Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming human beta cell function

PubMed Central

Rodriguez-Diaz, Rayner; Dando, Robin; Jacques-Silva, M. Caroline; Fachado, Alberto; Molina, Judith; Abdulreda, Midhat; Ricordi, Camillo; Roper, Stephen D.; Berggren, Per-Olof; Caicedo, Alejandro

2011-01-01

Acetylcholine is a neurotransmitter that plays a major role in the function of the insulin secreting pancreatic beta cell1,2. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species1,3,4, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of the human islet provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. We anticipate these results to revise models about neural input and cholinergic signaling in the endocrine pancreas. Cholinergic signaling within the islet represents a potential therapeutic target in diabetes5, highlighting the relevance of this advance to future drug development. PMID:21685896

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

PubMed Central

Bartolini, Alessandro; Cesare Mannelli, Lorenzo Di; Ghelardini, Carla

2011-01-01

The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed. PMID:21585331

Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammatory Pathway.

PubMed

Zhai, Qian; Lai, Dengming; Cui, Ping; Zhou, Rui; Chen, Qixing; Hou, Jinchao; Su, Yunting; Pan, Libiao; Ye, Hui; Zhao, Jing-Wei; Fang, Xiangming

2017-10-01

Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored. Animal research. University research laboratory. Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice. The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used. Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation. These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis.

Glycinergic Input to the Mouse Basal Forebrain Cholinergic Neurons

PubMed Central

Bardóczi, Zsuzsanna; Pál, Balázs; Kőszeghy, Áron; Wilheim, Tamás; Záborszky, László; Liposits, Zsolt

2017-01-01

The basal forebrain (BF) receives afferents from brainstem ascending pathways, which has been implicated first by Moruzzi and Magoun (1949) to induce forebrain activation and cortical arousal/waking behavior; however, it is very little known about how brainstem inhibitory inputs affect cholinergic functions. In the current study, glycine, a major inhibitory neurotransmitter of brainstem neurons, and gliotransmitter of local glial cells, was tested for potential interaction with BF cholinergic (BFC) neurons in male mice. In the BF, glycine receptor α subunit-immunoreactive (IR) sites were localized in choline acetyltransferase (ChAT)-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs (sIPSCs; 0.81 ± 0.25 × 10−1 Hz) recorded in whole-cell conditions. Potential neuronal as well as glial sources of glycine were indicated in the extracellular space of cholinergic neurons by glycine transporter type 1 (GLYT1)- and GLYT2-IR processes found in apposition to ChAT-IR cells. Ultrastructural analyses identified synapses of GLYT2-positive axon terminals on ChAT-IR neurons, as well as GLYT1-positive astroglial processes, which were localized in the vicinity of synapses of ChAT-IR neurons. The brainstem raphe magnus was determined to be a major source of glycinergic axons traced retrogradely from the BF. Our results indicate a direct effect of glycine on BFC neurons. Furthermore, the presence of high levels of plasma membrane glycine transporters in the vicinity of cholinergic neurons suggests a tight control of extracellular glycine in the BF. SIGNIFICANCE STATEMENT Basal forebrain cholinergic (BFC) neurons receive various activating inputs from specific brainstem areas and channel this information to the cortex via multiple projections. So far, very little is known about inhibitory brainstem afferents to the BF. The current study established glycine as a major regulator of BFC neurons by (1) identifying glycinergic neurons in the brainstem projecting to the BF, (2) showing glycine receptor α subunit-immunoreactive (IR) sites in choline acetyltransferase (ChAT)-IR neurons, (3) demonstrating glycine transporter type 2 (GLYT2)-positive axon terminals synapsing on ChAT-IR neurons, and (4) localizing GLYT1-positive astroglial processes in the vicinity of synapses of ChAT-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs recorded in whole-cell conditions. PMID:28874448

Cholinergic and perfusion brain networks in Parkinson disease dementia.

PubMed

Colloby, Sean J; McKeith, Ian G; Burn, David J; Wyper, David J; O'Brien, John T; Taylor, John-Paul

2016-07-12

To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil. Forty-nine participants (25 PDD and 24 elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs). We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor-naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks. Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition. © 2016 American Academy of Neurology.

Cholinergic and perfusion brain networks in Parkinson disease dementia

PubMed Central

McKeith, Ian G.; Burn, David J.; Wyper, David J.; O'Brien, John T.; Taylor, John-Paul

2016-01-01

Objective: To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil. Methods: Forty-nine participants (25 PDD and 24 elderly controls) underwent 123I-QNB and 99mTc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs). Results: We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor–naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks. Conclusion: Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition. PMID:27306636

Chronic Lithium Treatment in a Rat Model of Basal Forebrain Cholinergic Depletion: Effects on Memory Impairment and Neurodegeneration.

PubMed

Gelfo, Francesca; Cutuli, Debora; Nobili, Annalisa; De Bartolo, Paola; D'Amelio, Marcello; Petrosini, Laura; Caltagirone, Carlo

2017-01-01

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with multifactorial etiopathogenesis, characterized by progressive loss of memory and other cognitive functions. A fundamental neuropathological feature of AD is the early and severe brain cholinergic neurodegeneration. Lithium is a monovalent cation classically utilized in the treatment of mood disorders, but recent evidence also advances a beneficial potentiality of this compound in neurodegeneration. Interestingly, lithium acts on several processes whose alterations characterize the brain cholinergic impairment at short and long term. On this basis, the aim of the present research was to evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes, by investigating memory functions and neurodegeneration correlates. Adult male rats were lesioned by bilateral injections of the immunotoxin 192 IgG-Saporin into the basal forebrain. Starting 7 days before the surgery, the animals were exposed to a 30-day lithium treatment, consisting of a 0.24% Li2CO3 diet. Memory functions were investigated by the open field test with objects, the sociability and preference for social novelty test, and the Morris water maze. Hippocampal and neocortical choline acetyltransferase (ChAT) levels and caspase-3 activity were determined. Cholinergic depletion significantly impaired spatial and social recognition memory, decreased hippocampal and neocortical ChAT levels and increased caspase-3 activity. The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory.

PubMed

Okada, Kana; Nishizawa, Kayo; Kobayashi, Tomoko; Sakata, Shogo; Kobayashi, Kazuto

2015-08-06

Recognition memory requires processing of various types of information such as objects and locations. Impairment in recognition memory is a prominent feature of amnesia and a symptom of Alzheimer's disease (AD). Basal forebrain cholinergic neurons contain two major groups, one localized in the medial septum (MS)/vertical diagonal band of Broca (vDB), and the other in the nucleus basalis magnocellularis (NBM). The roles of these cell groups in recognition memory have been debated, and it remains unclear how they contribute to it. We use a genetic cell targeting technique to selectively eliminate cholinergic cell groups and then test spatial and object recognition memory through different behavioural tasks. Eliminating MS/vDB neurons impairs spatial but not object recognition memory in the reference and working memory tasks, whereas NBM elimination undermines only object recognition memory in the working memory task. These impairments are restored by treatment with acetylcholinesterase inhibitors, anti-dementia drugs for AD. Our results highlight that MS/vDB and NBM cholinergic neurons are not only implicated in recognition memory but also have essential roles in different types of recognition memory.

Transplantation of Human Chorion-Derived Cholinergic Progenitor Cells: a Novel Treatment for Neurological Disorders.

PubMed

Mohammadi, Alireza; Maleki-Jamshid, Ali; Sanooghi, Davood; Milan, Peiman Brouki; Rahmani, Arash; Sefat, Farshid; Shahpasand, Koorosh; Soleimani, Mansoureh; Bakhtiari, Mehrdad; Belali, Rafie; Faghihi, Faezeh; Joghataei, Mohammad Taghi; Perry, George; Mozafari, Masoud

2018-03-16

A neurological disorder is any disorder or abnormality in the nervous system. Among different neurological disorders, Alzheimer's disease (AD) is recognized as the sixth leading cause of death globally. Considerable research has been conducted to find pioneer treatments for this devastating disorder among which cell therapy has attracted remarkable attentions over the last decade. Up to now, targeted differentiation into specific desirable cell types has remained a major obstacle to clinical application of cell therapy. Also, potential risks including uncontrolled growth of stem cells could be disastrous. In our novel protocol, we used basal forebrain cholinergic progenitor cells (BFCN) derived from human chorion-derived mesenchymal stem cells (hC-MSCs) which made it possible to obtain high-quality population of cholinergic neurons and in vivo in much shorter time period than previous established methods. Remarkably, the transplanted progenitors fully differentiated to cholinergic neurons which in turn integrated in higher cortical networks of host brains, resulting in significant improvement in cognitive assessments. This method may have profound implications in cell therapies for any other neurodegenerative disorders. Graphical Abstract ᅟ.

Cholinergic dysfunction and amnesia in patients with Wernicke-Korsakoff syndrome: a transcranial magnetic stimulation study.

PubMed

Nardone, Raffaele; Bergmann, Jürgen; De Blasi, Pierpaolo; Kronbichler, Martin; Kraus, Jörg; Caleri, Francesca; Tezzon, Frediano; Ladurner, Gunther; Golaszewski, Stefan

2010-03-01

The specific neurochemical substrate underlying the amnesia in patients with Wernicke-Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Corsi's Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents.

PubMed

Dickson, S L; Hrabovszky, E; Hansson, C; Jerlhag, E; Alvarez-Crespo, M; Skibicka, K P; Molnar, C S; Liposits, Z; Engel, J A; Egecioglu, E

2010-12-29

Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

PubMed Central

Cook, Daniel P.; Rector, Michael V.; Bouzek, Drake C.; Michalski, Andrew S.; Gansemer, Nicholas D.; Reznikov, Leah R.; Li, Xiaopeng; Stroik, Mallory R.; Ostedgaard, Lynda S.; Abou Alaiwa, Mahmoud H.; Thompson, Michael A.; Prakash, Y. S.; Krishnan, Ramaswamy; Meyerholz, David K.; Seow, Chun Y.

2016-01-01

Rationale: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Objectives: Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Methods: Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision-cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. Measurements and Main Results: We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. Conclusions: Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing. PMID:26488271

Possibility of Acetylcholinesterase Overexpression in Alzheimer Disease Patients after Therapy with Acetylcholinesterase Inhibitors.

PubMed

Kračmarová, Alžběta; Drtinová, Lucie; Pohanka, Miroslav

2015-01-01

Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing cholinergic function using inhibitors of acetylcholinesterase like rivastigmine, donepezil or galantamine. These drugs can influence not only the acetylcholinesterase activity but also other processes in treated organism. The paper is aimed mainly on possibility of increased expression and protein level of acetylcholinesterase caused by the therapy with acetylcholinesterase inhibitors.

Nervous control of fish swimbladders.

PubMed

Nilsson, Stefan

2009-01-01

The swimbladder of teleost fish receives a rich and complex innervation by nerve fibres of the autonomic nervous system. While an understanding of the form and function of a non-adrenergic, non-cholinergic innervation is slowly emerging, the pattern of control by the "classical" cholinergic and adrenergic innervation is becoming relatively well understood. This short review describes the autonomic innervation patterns, and attempts to summarise the role of cholinergic and adrenergic pathways in the control of gas secretion and resorption in the teleost swimbladder.

Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction.

PubMed

Miki, Takanori; Kusaka, Takashi; Yokoyama, Toshifumi; Ohta, Ken-ichi; Suzuki, Shingo; Warita, Katsuhiko; Jamal, Mostofa; Wang, Zhi-Yu; Ueki, Masaaki; Liu, Jun-Qian; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

2014-02-01

Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor α1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription-polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction.

Central cholinergic dysfunction could be associated with oropharyngeal dysphagia in early Parkinson's disease.

PubMed

Lee, Kyung Duck; Koo, Jung Hoi; Song, Sun Hong; Jo, Kwang Deog; Lee, Moon Kyu; Jang, Wooyoung

2015-11-01

Dysphagia is an important issue in the prognosis of Parkinson's disease (PD). Although several studies have reported that oropharyngeal dysphagia may be associated with cognitive dysfunction, the exact relationship between cortical function and swallowing function in PD patients is unclear. Therefore, we investigated the association between an electrophysiological marker of central cholinergic function, which reflected cognitive function, and swallowing function, as measured by videofluoroscopic studies (VFSS). We enrolled 29 early PD patients. Using the Swallowing Disturbance Questionnaire (SDQ), we divided the enrolled patients into two groups: PD with dysphagia and PD without dysphagia. The videofluoroscopic dysphagia scale (VDS) was applied to explore the nature of the dysphagia. To assess central cholinergic dysfunction, short latency afferent inhibition (SAI) was evaluated. We analyzed the relationship between central cholinergic dysfunction and oropharyngeal dysphagia and investigated the characteristics of the dysphagia. The SAI values were significantly different between the two groups. The comparison of each VFSS component between the PD with dysphagia group and the PD without dysphagia group showed statistical significance for most of the oral phase components and for a single pharyngeal phase component. The total score on the VDS was higher in the PD with dysphagia group than in the PD without dysphagia group. The Mini-Mental State Examination and SAI values showed significant correlations with the total score of the oral phase components. According to binary logistic regression analysis, SAI value independently contributed to the presence of dysphagia in PD patients. Our findings suggest that cholinergic dysfunction is associated with dysphagia in early PD and that an abnormal SAI value is a good biomarker for predicting the risk of dysphagia in PD patients.

Roles of p75NTR, long-term depression and cholinergic transmission in anxiety and acute stress coping

PubMed Central

Martinowich, Keri; Schloesser, Robert J.; Lu, Yuan; Jimenez, Dennisse V.; Paredes, Daniel; Greene, Joshua S.; Greig, Nigel H.; Manji, Husseini K.; Lu, Bai

2011-01-01

Background Stress is causally associated with anxiety. While the underlying cellular mechanisms are not well understood, the basal forebrain cholinergic neurons (BFCNs) have been implicated in stress response. p75NTR is a pan-neurotrophin receptor expressed almost exclusively in BFCNs in adult brain. The present study investigates whether and how p75NTR, via regulation of the cholinergic system and hippocampal synaptic plasticity, influences stress-related behaviors. Methods We used a combination of slice electrophysiology, behavioral analyses, pharmacology, in vivo microdialysis and neuronal activity mapping to assess the role of p75NTR in mood and stress-related behaviors and its underlying cellular and molecular mechanisms. Results We show that acute stress enables hippocampal long-term depression (LTD) in adult wild-type mice, but not in mice lacking p75NTR. The p75NTR mutant mice also exhibit two distinct behavioral impairments: baseline anxiety-like behavior and a deficit in coping with and recovering from stressful situations. Blockade of stress-enabled LTD with a GluA2-derived peptide impaired stress recovery without affecting baseline anxiety. Pharmacological manipulations of cholinergic transmission mimicked the p75NTR perturbation in both baseline anxiety and responses to acute stress. Finally, we show evidence of misregulated cholinergic signaling in animals with p75NTR deletion. Conclusions Our results suggest that loss of p75NTR leads to changes in hippocampal cholinergic signaling, which may be involved in regulation of stress-enabled hippocampal LTD and in modulating behaviors related to stress and anxiety. PMID:21978521

Cholinergic regulation of the vasopressin neuroendocrine system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michels, K.M.

1987-01-01

To clarify the physical and functional relationship between the cholinergic system, and the neurodocrine cells of the supraoptic nucleus, a combination of experiments on receptor binding, localization and function were carried out. The putative nicotinic receptor probe (/sup 125/I)alpha bungarotoxin ((/sup 125/I)alpha BTX) bound with high affinity and specificity to the vasopressin and oxytocin magnocellular neurons of the supraoptic nucleus, nucleus circularis, and paraventricular nucleus. Binding of (/sup 125/I)alpha BTX within the neural lobe was very low. In contrast, the muscarinic cholinergic receptor probe (/sup 3/H)quinuclidinylbenzilate ((/sup 3/H)QNB) did not bind to magnocellular vasopressin and oxytocin cell groups. The medianmore » eminence, which contains the neurosecretory axons, and the neural lobe of the pituitary contain low levels of (/sup 3/H)QNB binding. The physiological significance of these cholinergic receptors in regulation of vasopressin release was tested using an in vitro preparation of the supraoptic - neural lobe system.« less

Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging-associated olfactory circuit degeneration in Drosophila

PubMed Central

Loschek, Laura F; La Fortezza, Marco; Friedrich, Anja B; Blais, Catherine-Marie; Üçpunar, Habibe K; Yépez, Vicente A; Lehmann, Martin; Gompel, Nicolas; Gagneur, Julien; Sigrist, Stephan J

2018-01-01

Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies. Together, our data suggest that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls. Given the important role of the cholinergic system in neurodegeneration, the fly olfactory system could be a useful model for the identification of drug targets. PMID:29345616

The production of nitric oxide in the coeliac ganglion modulates the effect of cholinergic neurotransmission on the rat ovary during the preovulatory period.

PubMed

Delsouc, María B; Della Vedova, María C; Ramírez, Darío; Delgado, Silvia M; Casais, Marilina

2018-05-01

The aim of the present work was to investigate whether the nitric oxide produced by the nitric oxide/nitric oxide synthase (NO/NOS) system present in the coeliac ganglion modulates the effects of cholinergic innervation on oxidative status, steroidogenesis and apoptotic mechanisms that take place in the rat ovary during the first proestrous. An ex vivo Coeliac Ganglion- Superior Ovarian Nerve- Ovary (CG-SON-O) system was used. Cholinergic stimulation of the CG was achieved by 10 -6  M Acetylcholine (Ach). Furthermore, 400 μM Aminoguanidine (AG) - an inhibitor of inducible-NOS was added in the CG compartment in absence and presence of Ach. It was found that Ach in the CG compartment promotes apoptosis in ovarian tissue, probably due to the oxidative stress generated. AG in the CG compartment decreases the release of NO and progesterone, and increases the release of estradiol from the ovary. The CG co-treatment with Ach and AG counteracts the effects of the ganglionic cholinergic agonist on ovarian oxidative stress, increases hormone production and decreases Fas mRNA expression. These results suggest that NO is an endogenous modulator of cholinergic neurotransmission in CG, with implication in ovarian steroidogenesis and the apoptotic mechanisms that take place in the ovary during the preovulatory period in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

Vagal-immune interactions involved in cholinergic anti-inflammatory pathway.

PubMed

Zila, I; Mokra, D; Kopincova, J; Kolomaznik, M; Javorka, M; Calkovska, A

2017-09-22

Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.

Cholinergic innervation of human mesenteric lymphatic vessels.

PubMed

D'Andrea, V; Bianchi, E; Taurone, S; Mignini, F; Cavallotti, C; Artico, M

2013-11-01

The cholinergic neurotransmission within the human mesenteric lymphatic vessels has been poorly studied. Therefore, our aim is to analyse the cholinergic nerve fibres of lymphatic vessels using the traditional enzymatic techniques of staining, plus the biochemical modifications of acetylcholinesterase (AChE) activity. Specimens obtained from human mesenteric lymphatic vessels were subjected to the following experimental procedures: 1) drawing, cutting and staining of tissues; 2) staining of total nerve fibres; 3) enzymatic staining of cholinergic nerve fibres; 4) homogenisation of tissues; 5) biochemical amount of proteins; 6) biochemical amount of AChE activity; 6) quantitative analysis of images; 7) statistical analysis of data. The mesenteric lymphatic vessels show many AChE positive nerve fibres around their wall with an almost plexiform distribution. The incubation time was performed at 1 h (partial activity) and 6 h (total activity). Moreover, biochemical dosage of the same enzymatic activity confirms the results obtained with morphological methods. The homogenates of the studied tissues contain strong AChE activity. In our study, the lymphatic vessels appeared to contain few cholinergic nerve fibres. Therefore, it is expected that perivascular nerve stimulation stimulates cholinergic nerves innervating the mesenteric arteries to release the neurotransmitter AChE, which activates muscarinic or nicotinic receptors to modulate adrenergic neurotransmission. These results strongly suggest, that perivascular cholinergic nerves have little or no effect on the adrenergic nerve function in mesenteric arteries. The cholinergic nerves innervating mesenteric arteries do not mediate direct vascular responses.

Cholinergic enhancement of visual attention and neural oscillations in the human brain.

PubMed

Bauer, Markus; Kluge, Christian; Bach, Dominik; Bradbury, David; Heinze, Hans Jochen; Dolan, Raymond J; Driver, Jon

2012-03-06

Cognitive processes such as visual perception and selective attention induce specific patterns of brain oscillations. The neurochemical bases of these spectral changes in neural activity are largely unknown, but neuromodulators are thought to regulate processing. The cholinergic system is linked to attentional function in vivo, whereas separate in vitro studies show that cholinergic agonists induce high-frequency oscillations in slice preparations. This has led to theoretical proposals that cholinergic enhancement of visual attention might operate via gamma oscillations in visual cortex, although low-frequency alpha/beta modulation may also play a key role. Here we used MEG to record cortical oscillations in the context of administration of a cholinergic agonist (physostigmine) during a spatial visual attention task in humans. This cholinergic agonist enhanced spatial attention effects on low-frequency alpha/beta oscillations in visual cortex, an effect correlating with a drug-induced speeding of performance. By contrast, the cholinergic agonist did not alter high-frequency gamma oscillations in visual cortex. Thus, our findings show that cholinergic neuromodulation enhances attentional selection via an impact on oscillatory synchrony in visual cortex, for low rather than high frequencies. We discuss this dissociation between high- and low-frequency oscillations in relation to proposals that lower-frequency oscillations are generated by feedback pathways within visual cortex. Copyright © 2012 Elsevier Ltd. All rights reserved.

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

PubMed

Ray, Nicola J; Bradburn, Steven; Murgatroyd, Christopher; Toseeb, Umar; Mir, Pablo; Kountouriotis, George K; Teipel, Stefan J; Grothe, Michel J

2018-01-01

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism.

PubMed

Tubert, Cecilia; Taravini, Irene R E; Flores-Barrera, Eden; Sánchez, Gonzalo M; Prost, María Alejandra; Avale, María Elena; Tseng, Kuei Y; Rela, Lorena; Murer, Mario Gustavo

2016-09-06

The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Acetylcholine and the alpha 7 nicotinic receptor: a potential therapeutic target for the treatment of periodontal disease?

PubMed Central

2013-01-01

Objectives The aim of this review is to examine the evidence for a functional cholinergic system operating within the periodontium and determine the evidence for its role in periodontal immunity. Introduction Acetylcholine can influence the immune system via the ‘cholinergic anti-inflammatory pathway’. This pathway is mediated by the vagus nerve which releases acetylcholine to interact with the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) on proximate immuno-regulatory cells. Activation of the α7nAChR on these cells leads to down-regulated expression of pro-inflammatory mediators and thus regulates localised inflammatory responses. The role of the vagus nerve in periodontal pathophysiology is currently unknown. However, non-neuronal cells can also release acetylcholine and express the α7nAChR; these include keratinocytes, fibroblasts, T cells, B cells and macrophages. Therefore, by both autocrine and paracrine methods non-neuronal acetylcholine can also be hypothesised to modulate the localised immune response. Methods A Pubmed database search was performed for studies providing evidence for a functional cholinergic system operating in the periodontium. In addition, literature on the role of the ‘cholinergic anti-inflammatory pathway’ in modulating the immune response was extrapolated to hypothesise that similar mechanisms of immune regulation occur within the periodontium. Conclusion The evidence suggests a functional nonneuronal ‘cholinergic anti-inflammatory pathway’ may operate in the periodontium and that this may be targeted therapeutically to treat periodontal disease. PMID:22777144

TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine

PubMed Central

Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.

2015-01-01

Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitro inhibited the acid-sensitive K+ current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activity in vivo using freely behaving wild-type (n = 12) and ChAT-Cre:TASKf/f mice (n = 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/f mice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activation in vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrain in vivo. SIGNIFICANCE STATEMENT Attentive states and cognitive function are associated with the generation of γ EEG activity. Basal forebrain cholinergic neurons are important modulators of cortical arousal and γ activity, and in this study we investigated the mechanism by which these neurons are activated by the wake-active neurotransmitter histamine. We found that histamine inhibited a class of K+ leak channels called TASK channels and that deletion of TASK channels selectively on cholinergic neurons modulated baseline EEG activity as well as histamine-induced changes in γ activity. By identifying a discrete brain circuit where TASK channels can influence γ activity, these results represent new knowledge that enhances our understanding of how subcortical arousal systems may contribute to the generation of attentive states. PMID:26446210

Behavior and the cholinergic parameters in olfactory bulbectomized female rodents: Difference between rats and mice.

PubMed

Stepanichev, Mikhail; Markov, Daniil; Pasikova, Natalia; Gulyaeva, Natalia

2016-01-15

Olfactory bulbectomy (OBX) in rodents induces a wide spectrum of functional disturbances, including behavioral, neurochemical, and neuromorphological alterations. We have examined the effects of OBX on behavior and the parameters of the cholinergic system in female rats and mice. In rats, OBX resulted in the appearance of some depressive-like behavioral marks, such as the decreased sucrose consumption, hyperactivity, impaired short-term memory and anxiety-like behavioral features, such as shortened presence in the center of the open field arena or open arms of the elevated plus-maze and an enhancement of avoidance behavior. These behavioral abnormalities could be associated with disturbances in hippocampal function, this suggestion being supported by the presence of cellular changes in this brain structure. No effect of OBX on the number of cholinergic neurons in the medial septum-diagonal band as well as on the acetylcholine content and acetylcholinesterase activity in the septum, hippocampus, and neocortex could be detected. In contrast, in mice, OBX impaired spontaneous alternation behavior and decreased the number of cholinergic neurons in the medial septum-diagonal band. These data demonstrate that rats and mice differently respond to OBX, in particular, OBX does not significantly affect the cholinergic system in rats. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel strains of mice deficient for the vesicular acetylcholine transporter: insights on transcriptional regulation and control of locomotor behavior.

PubMed

Martins-Silva, Cristina; De Jaeger, Xavier; Guzman, Monica S; Lima, Ricardo D F; Santos, Magda S; Kushmerick, Christopher; Gomez, Marcus V; Caron, Marc G; Prado, Marco A M; Prado, Vania F

2011-03-10

Defining the contribution of acetylcholine to specific behaviors has been challenging, mainly because of the difficulty in generating suitable animal models of cholinergic dysfunction. We have recently shown that, by targeting the vesicular acetylcholine transporter (VAChT) gene, it is possible to generate genetically modified mice with cholinergic deficiency. Here we describe novel VAChT mutant lines. VAChT gene is embedded within the first intron of the choline acetyltransferase (ChAT) gene, which provides a unique arrangement and regulation for these two genes. We generated a VAChT allele that is flanked by loxP sequences and carries the resistance cassette placed in a ChAT intronic region (FloxNeo allele). We show that mice with the FloxNeo allele exhibit differential VAChT expression in distinct neuronal populations. These mice show relatively intact VAChT expression in somatomotor cholinergic neurons, but pronounced decrease in other cholinergic neurons in the brain. VAChT mutant mice present preserved neuromuscular function, but altered brain cholinergic function and are hyperactive. Genetic removal of the resistance cassette rescues VAChT expression and the hyperactivity phenotype. These results suggest that release of ACh in the brain is normally required to "turn down" neuronal circuits controlling locomotion.

High-Throughput All-Optical Analysis of Synaptic Transmission and Synaptic Vesicle Recycling in Caenorhabditis elegans

PubMed Central

Wabnig, Sebastian; Liewald, Jana Fiona; Yu, Szi-chieh; Gottschalk, Alexander

2015-01-01

Synaptic vesicles (SVs) undergo a cycle of biogenesis and membrane fusion to release transmitter, followed by recycling. How exocytosis and endocytosis are coupled is intensively investigated. We describe an all-optical method for identification of neurotransmission genes that can directly distinguish SV recycling factors in C. elegans, by motoneuron photostimulation and muscular RCaMP Ca2+ imaging. We verified our approach on mutants affecting synaptic transmission. Mutation of genes affecting SV recycling (unc-26 synaptojanin, unc-41 stonin, unc-57 endophilin, itsn-1 intersectin, snt-1 synaptotagmin) showed a distinct ‘signature’ of muscle Ca2+ dynamics, induced by cholinergic motoneuron photostimulation, i.e. faster rise, and earlier decrease of the signal, reflecting increased synaptic fatigue during ongoing photostimulation. To facilitate high throughput, we measured (3–5 times) ~1000 nematodes for each gene. We explored if this method enables RNAi screening for SV recycling genes. Previous screens for synaptic function genes, based on behavioral or pharmacological assays, allowed no distinction of the stage of the SV cycle in which a protein might act. We generated a strain enabling RNAi specifically only in cholinergic neurons, thus resulting in healthier animals and avoiding lethal phenotypes resulting from knockdown elsewhere. RNAi of control genes resulted in Ca2+ measurements that were consistent with results obtained in the respective genomic mutants, albeit to a weaker extent in most cases, and could further be confirmed by opto-electrophysiological measurements for mutants of some of the genes, including synaptojanin. We screened 95 genes that were previously implicated in cholinergic transmission, and several controls. We identified genes that clustered together with known SV recycling genes, exhibiting a similar signature of their Ca2+ dynamics. Five of these genes (C27B7.7, erp-1, inx-8, inx-10, spp-10) were further assessed in respective genomic mutants; however, while all showed electrophysiological phenotypes indicative of reduced cholinergic transmission, no obvious SV recycling phenotypes could be uncovered for these genes. PMID:26312752

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness.

PubMed

Hubbard, Nicholas A; Hutchison, Joanna L; Motes, Michael A; Shokri-Kojori, Ehsan; Bennett, Ilana J; Brigante, Ryan M; Haley, Robert W; Rypma, Bart

2014-05-01

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM.

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness

PubMed Central

Hubbard, Nicholas A.; Hutchison, Joanna L.; Motes, Michael A.; Shokri-Kojori, Ehsan; Bennett, Ilana J.; Brigante, Ryan M.; Haley, Robert W.; Rypma, Bart

2015-01-01

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM. PMID:25767746

Generalised smooth-muscle disease with defective muscarinic-receptor function.

PubMed

Bannister, R; Hoyes, A D

1981-03-28

A patient with widespread smooth-muscle disease presented with chronic intestinal pseudo-obstruction but had in addition defects of the bladder, pupils, sweating, and cardiovascular function. There was no evidence of a primary neural lesion, and minor changes in the muscle did not resemble those of a myopathy. In each organ affected muscarinic cholinergic function was at fault, but instead of supersensitivity to cholinergic drugs, which occurs in postganglionic autonomic neuropathies, there was a lack of response to cholinergic drugs and anticholinesterases. It was therefore concluded that the patient had a new type of defect of muscarinic-receptor function. The cause was unknown, but it may have been an autoimmune disease resembling myasthenia, in which there is a postjunctional defect of muscarinic receptors. In similar cases binding of muscarinic agonists and antagonists should be tested. When antibodies to purified human muscarinic receptors become available different patterns of smooth-muscle defect may be identifiable, enabling the lesion to be defined more precisely.

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice

PubMed Central

Kroeger, Daniel; Ferrari, Loris L.; Mahoney, Carrie E.; Arrigoni, Elda

2017-01-01

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. SIGNIFICANCE STATEMENT More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep–wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states. PMID:28039375

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

PubMed

Kroeger, Daniel; Ferrari, Loris L; Petit, Gaetan; Mahoney, Carrie E; Fuller, Patrick M; Arrigoni, Elda; Scammell, Thomas E

2017-02-01

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states. Copyright © 2017 the authors 0270-6474/17/371352-15$15.00/0.

Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

PubMed Central

Yu, Kuai; Lujan, Rafael; Marmorstein, Alan; Gabriel, Sherif; Hartzell, H. Criss

2010-01-01

Anion transport by the colonic mucosa maintains the hydration and pH of the colonic lumen, and its disruption causes a variety of diarrheal diseases. Cholinergic agonists raise cytosolic Ca2+ levels and stimulate anion secretion, but the mechanisms underlying this effect remain unclear. Cholinergic stimulation of anion secretion may occur via activation of Ca2+-activated Cl– channels (CaCCs) or an increase in the Cl– driving force through CFTR after activation of Ca2+-dependent K+ channels. Here we investigated the role of a candidate CaCC protein, bestrophin-2 (Best2), using Best2–/– mice. Cholinergic stimulation of anion current was greatly reduced in Best2–/– mice, consistent with our proposed role for Best2 as a CaCC. However, immunostaining revealed Best2 localized to the basolateral membrane of mucin-secreting colonic goblet cells, not the apical membrane of Cl–-secreting enterocytes. In addition, in the absence of HCO3–, cholinergic-activated current was identical in control and Best2–/– tissue preparations, which suggests that most of the Best2 current was carried by HCO3–. These data delineate an alternative model of cholinergic regulation of colonic anion secretion in which goblet cells play a critical role in HCO3– homeostasis. We therefore propose that Best2 is a HCO3– channel that works in concert with a Cl:HCO3– exchanger in the apical membrane to affect transcellular HCO3– transport. Furthermore, previous models implicating CFTR in cholinergic Cl– secretion may be explained by substantial downregulation of Best2 in Cftr–/– mice. PMID:20407206

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

PubMed Central

Mishra, Nibha; Milikovsky, Dan Z.; Hanin, Geula; Zelig, Daniel; Sheintuch, Liron; Berson, Amit; Greenberg, David S.; Friedman, Alon

2017-01-01

Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy. PMID:28584127

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity.

PubMed

Bekenstein, Uriya; Mishra, Nibha; Milikovsky, Dan Z; Hanin, Geula; Zelig, Daniel; Sheintuch, Liron; Berson, Amit; Greenberg, David S; Friedman, Alon; Soreq, Hermona

2017-06-20

Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca 2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.

Responses to central oxotremorine and scopolamine support the cholinergic control of male mating behavior in hamsters.

PubMed

Floody, Owen R; Lusk, Laina G

2013-04-01

The responses of hamsters to intracranial injections of the cholinergic agonist oxotremorine (OXO) implicate cholinergic mechanisms in the medial preoptic area (MPOA) in the control of male mating behavior. To extend these observations, we ran three studies of responses to cholinergic drugs delivered singly or in combination to the vicinity of the MPOA. The first tested responses to OXO, confirming its ability to reduce the postejaculatory interval. The second complemented the first by examining responses to MPOA microinjections of the cholinergic antagonist scopolamine (SCO). These caused several changes revolving around intromission. These included increases in intromission frequency and ejaculation latency. They also included a change in the patterning of intromissions, marked by continuous strings without the usual separation by dismounts. The final study resembled the others in examining the effects of MPOA injections of OXO and SCO but focused on the ability of each drug to antagonize responses to the other. Most of the responses to OXO and SCO individually replicated earlier findings, though the measures examined here also permitted the description of effects on some noncopulatory sexual behaviors, specifically the male's inspection of the female. However, the most interesting results may be those suggesting asymmetry in the responses to the addition of the second drug: Whereas responses to OXO tended to be antagonized by SCO, OXO was less effective at counteracting responses to SCO. Though the explanation of this asymmetry is not completely clear, it is consistent with previous suggestions of differences in the affinities of these drugs for subtypes of muscarinic receptors. Therefore, it suggests that the cholinergic synapses and circuits controlling distinct elements of male behavior could differ in their dependence on these receptors. Copyright © 2013 Elsevier Inc. All rights reserved.

Acute effects of donepezil in healthy young adults underline the fractionation of executive functioning.

PubMed

Ginani, G E; Tufik, S; Bueno, O F A; Pradella-Hallinan, M; Rusted, J; Pompéia, S

2011-11-01

The cholinergic system is involved in the modulation of both bottom-up and top-down attentional control. Top-down attention engages multiple executive control processes, but few studies have investigated whether all or selective elements of executive functions are modulated by the cholinergic system. To investigate the acute effects of the pro-cholinergic donepezil in young, healthy volunteers on distinct components of executive functions we conducted a double-blind, placebo-controlled, independent-groups design study including 42 young healthy male participants who were randomly assigned to one of three oral treatments: glucose (placebo), donepezil 5 mg or donepezil 7.5 mg. The test battery included measures of different executive components (shifting, updating, inhibition, dual-task performance, planning, access to long-term memory), tasks that evaluated arousal/vigilance/visuomotor performance, as well as functioning of working memory subsidiary systems. Donepezil improved sustained attention, reaction times, dual-task performance and the executive component of digit span. The positive effects in these executive tasks did not correlate with arousal/visuomotor/vigilance measures. Among the various executive domains investigated donepezil selectively increased dual-task performance in a manner that could not be ascribed to improvement in arousal/vigilance/visuomotor performance nor working memory slave systems. Other executive tasks that rely heavily on visuospatial processing may also be modulated by the cholinergic system.

Nicotine increases brain functional network efficiency.

PubMed

Wylie, Korey P; Rojas, Donald C; Tanabe, Jody; Martin, Laura F; Tregellas, Jason R

2012-10-15

Despite the use of cholinergic therapies in Alzheimer's disease and the development of cholinergic strategies for schizophrenia, relatively little is known about how the system modulates the connectivity and structure of large-scale brain networks. To better understand how nicotinic cholinergic systems alter these networks, this study examined the effects of nicotine on measures of whole-brain network communication efficiency. Resting state fMRI was acquired from fifteen healthy subjects before and after the application of nicotine or placebo transdermal patches in a single blind, crossover design. Data, which were previously examined for default network activity, were analyzed with network topology techniques to measure changes in the communication efficiency of whole-brain networks. Nicotine significantly increased local efficiency, a parameter that estimates the network's tolerance to local errors in communication. Nicotine also significantly enhanced the regional efficiency of limbic and paralimbic areas of the brain, areas which are especially altered in diseases such as Alzheimer's disease and schizophrenia. These changes in network topology may be one mechanism by which cholinergic therapies improve brain function. Published by Elsevier Inc.

Nicotine Increases Brain Functional Network Efficiency

PubMed Central

Wylie, Korey P.; Rojas, Donald C.; Tanabe, Jody; Martin, Laura F.; Tregellas, Jason R.

2012-01-01

Despite the use of cholinergic therapies in Alzheimer’s disease and the development of cholinergic strategies for schizophrenia, relatively little is known about how the system modulates the connectivity and structure of large-scale brain networks. To better understand how nicotinic cholinergic systems alter these networks, this study examined the effects of nicotine on measures of whole-brain network communication efficiency. Resting-state fMRI was acquired from fifteen healthy subjects before and after the application of nicotine or placebo transdermal patches in a single blind, crossover design. Data, which were previously examined for default network activity, were analyzed with network topology techniques to measure changes in the communication efficiency of whole-brain networks. Nicotine significantly increased local efficiency, a parameter that estimates the network’s tolerance to local errors in communication. Nicotine also significantly enhanced the regional efficiency of limbic and paralimbic areas of the brain, areas which are especially altered in diseases such as Alzheimer’s disease and schizophrenia. These changes in network topology may be one mechanism by which cholinergic therapies improve brain function. PMID:22796985

Role of Nicotinic and Muscarinic Receptors on Synaptic Plasticity and Neurological Diseases.

PubMed

Fuenzalida, Marco; Pérez, Miguel Ángel; Arias, Hugo R

2016-01-01

The cholinergic activity in the brain is fundamental for cognitive functions. The modulatory activity of the neurotransmitter acetylcholine (ACh) is mediated by activating a variety of nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Accumulating evidence indicates that both nAChR and mAChRs can modulate the release of several other neurotransmitters, modify the threshold of long-term plasticity, finally improving learning and memory processes. Importantly, the expression, distribution, and/or function of these systems are altered in several neurological diseases. The aim of this review is to discuss our current knowledge on cholinergic receptors and their regulating synaptic functions and neuronal network activities as well as their use as targets for the development of new and clinically useful cholinergic ligands. These new therapies involve the development of novel and more selective cholinergic agonists and allosteric modulators as well as selective cholinesterase inhibitors, which may improve cognitive and behavioral symptoms, and also provide neuroprotection in several brain diseases. The review will focus on two nAChR receptor subtypes found in the mammalian brain and the most commonly targeted in drug discovery programs for neuropsychiatric disorder, the ligands of α4β2 nAChR and α7 nAChRs.

Deletion of neurturin impairs development of cholinergic nerves and heart rate control in postnatal mouse hearts.

PubMed

Downs, Anthony M; Jalloh, Hawa B; Prater, Kayla J; Fregoso, Santiago P; Bond, Cherie E; Hampton, Thomas G; Hoover, Donald B

2016-05-01

The neurotrophic factor neurturin is required for normal cholinergic innervation of adult mouse heart and bradycardic responses to vagal stimulation. Our goals were to determine effects of neurturin deletion on development of cardiac chronotropic and dromotropic functions, vagal baroreflex response, and cholinergic nerve density in nodal regions of postnatal mice. Experiments were performed on postnatal C57BL/6 wild-type (WT) and neurturin knockout (KO) mice. Serial electrocardiograms were recorded noninvasively from conscious pups using an ECGenie apparatus. Mice were treated with atenolol to evaluate and block sympathetic effects on heart rate (HR) and phenylephrine (PE) to stimulate the baroreflex. Immunohistochemistry was used to label cholinergic nerves in paraffin sections. WT and KO mice showed similar age-dependent increases in HR and decreases in PR interval between postnatal days (P) 2.5 and 21. Treatment with atenolol reduced HR significantly in WT and KO pups at P7.5. PE caused a reflex bradycardia that was significantly smaller in KO pups. Cholinergic nerve density was significantly less in nodal regions of P7.5 KO mice. We conclude that cholinergic nerves have minimal influence on developmental changes in HR and PR, QRS, and QTc intervals in mouse pups. However, cholinergic nerves mediate reflex bradycardia by 1 week postnatally. Deletion of neurturin impairs cholinergic innervation of the heart and the vagal efferent component of the baroreflex early during postnatal development. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis

PubMed Central

Casas, Caty; Herrando-Grabulosa, Mireia; Manzano, Raquel; Mancuso, Renzo; Osta, Rosario; Navarro, Xavier

2013-01-01

Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1G93A ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1G93A mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis. PMID:23531559

Coordinate High-Frequency Pattern of Stimulation and Calcium Levels Control the Induction of LTP in Striatal Cholinergic Interneurons

ERIC Educational Resources Information Center

Bonsi, Paola; De Persis, Cristiano; Calabresi, Paolo; Bernardi, Giorgio; Pisani, Antonio

2004-01-01

Current evidence appoints a central role to cholinergic interneurons in modulating striatal function. Recently, a long-term potentiation (LTP) of synaptic transmission has been reported to occur in these neurons. The relationship between the pattern of cortico/thalamostriatal fibers stimulation, the consequent changes in the intracellular calcium…

Central administration of a 5-HT2 receptor agonist and antagonist: lack of effect on rapid eye movement sleep and pgo waves.

PubMed

Sanford, L D; Hunt, W K; Ross, R J; Pack, A I; Morrison, A R

1998-01-01

Serotonin (5-HT) has a role in regulating behavioral state and controlling the production of ponto-geniculo-occipital (PGO) waves, though the exact mechanism of action is not known. The most prevailing explanation is that 5-HT exerts its influence on behavioral state and PGO waves by inhibiting and disinhibiting cholinergic cells in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT), which have been implicated in their generation. Recent work in rats has demonstrated 5-HT2 receptors on most cholinergic cells in PPT/LDT. We microinfused the relatively specific 5-HT2 agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), the relatively specific 5-HT2 antagonist, ketanserin, and the nonspecific 5-HT antagonist, methysergide, locally into the peribrachial region of PPT in cats and monitored behavioral state and PGO waves. Neither drug significantly affected behavioral state or PGO wave activity. These results suggest that 5-HT2 receptors associated with cholinergic cells are minimally involved in the control of behavioral state and, together with the recent findings of others, suggest that 5-HT may not modulate PGO wave generation via direct action on cholinergic neurons in PPT/LDT, a departure from the long-held but minimally-tested view.

Cholinergic, But Not Dopaminergic or Noradrenergic, Enhancement Sharpens Visual Spatial Perception in Humans

PubMed Central

Wallace, Deanna L.

2017-01-01

The neuromodulator acetylcholine modulates spatial integration in visual cortex by altering the balance of inputs that generate neuronal receptive fields. These cholinergic effects may provide a neurobiological mechanism underlying the modulation of visual representations by visual spatial attention. However, the consequences of cholinergic enhancement on visuospatial perception in humans are unknown. We conducted two experiments to test whether enhancing cholinergic signaling selectively alters perceptual measures of visuospatial interactions in human subjects. In Experiment 1, a double-blind placebo-controlled pharmacology study, we measured how flanking distractors influenced detection of a small contrast decrement of a peripheral target, as a function of target-flanker distance. We found that cholinergic enhancement with the cholinesterase inhibitor donepezil improved target detection, and modeling suggested that this was mainly due to a narrowing of the extent of facilitatory perceptual spatial interactions. In Experiment 2, we tested whether these effects were selective to the cholinergic system or would also be observed following enhancements of related neuromodulators dopamine or norepinephrine. Unlike cholinergic enhancement, dopamine (bromocriptine) and norepinephrine (guanfacine) manipulations did not improve performance or systematically alter the spatial profile of perceptual interactions between targets and distractors. These findings reveal mechanisms by which cholinergic signaling influences visual spatial interactions in perception and improves processing of a visual target among distractors, effects that are notably similar to those of spatial selective attention. SIGNIFICANCE STATEMENT Acetylcholine influences how visual cortical neurons integrate signals across space, perhaps providing a neurobiological mechanism for the effects of visual selective attention. However, the influence of cholinergic enhancement on visuospatial perception remains unknown. Here we demonstrate that cholinergic enhancement improves detection of a target flanked by distractors, consistent with sharpened visuospatial perceptual representations. Furthermore, whereas most pharmacological studies focus on a single neurotransmitter, many neuromodulators can have related effects on cognition and perception. Thus, we also demonstrate that enhancing noradrenergic and dopaminergic systems does not systematically improve visuospatial perception or alter its tuning. Our results link visuospatial tuning effects of acetylcholine at the neuronal and perceptual levels and provide insights into the connection between cholinergic signaling and visual attention. PMID:28336568

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions.

PubMed

Muir, Ryan T; Lam, Benjamin; Honjo, Kie; Harry, Robin D; McNeely, Alicia A; Gao, Fu-Qiang; Ramirez, Joel; Scott, Christopher J M; Ganda, Anoop; Zhao, Jiali; Zhou, X Joe; Graham, Simon J; Rangwala, Novena; Gibson, Erin; Lobaugh, Nancy J; Kiss, Alex; Stuss, Donald T; Nyenhuis, David L; Lee, Byung-Chul; Kang, Yeonwook; Black, Sandra E

2015-10-01

Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute-subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. Multiple linear regression analyses were completed. Although larger infarcts (β=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (β=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (β=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting. © 2015 American Heart Association, Inc.

Monosynaptic rabies virus reveals premotor network organization and synaptic specificity of cholinergic partition cells.

PubMed

Stepien, Anna E; Tripodi, Marco; Arber, Silvia

2010-11-04

Movement is the behavioral output of neuronal activity in the spinal cord. Motor neurons are grouped into motor neuron pools, the functional units innervating individual muscles. Here we establish an anatomical rabies virus-based connectivity assay in early postnatal mice. We employ it to study the connectivity scheme of premotor neurons, the neuronal cohorts monosynaptically connected to motor neurons, unveiling three aspects of organization. First, motor neuron pools are connected to segmentally widely distributed yet stereotypic interneuron populations, differing for pools innervating functionally distinct muscles. Second, depending on subpopulation identity, interneurons take on local or segmentally distributed positions. Third, cholinergic partition cells involved in the regulation of motor neuron excitability segregate into ipsilaterally and bilaterally projecting populations, the latter exhibiting preferential connections to functionally equivalent motor neuron pools bilaterally. Our study visualizes the widespread yet precise nature of the connectivity matrix for premotor interneurons and reveals exquisite synaptic specificity for bilaterally projecting cholinergic partition cells. Copyright © 2010 Elsevier Inc. All rights reserved.

Plasticity of cardiovascular function in snapping turtle embryos (Chelydra serpentina): chronic hypoxia alters autonomic regulation and gene expression.

PubMed

Eme, John; Rhen, Turk; Tate, Kevin B; Gruchalla, Kathryn; Kohl, Zachary F; Slay, Christopher E; Crossley, Dane A

2013-06-01

Reptile embryos tolerate large decreases in the concentration of ambient oxygen. However, we do not fully understand the mechanisms that underlie embryonic cardiovascular short- or long-term responses to hypoxia in most species. We therefore measured cardiac growth and function in snapping turtle embryos incubated under normoxic (N21; 21% O₂) or chronic hypoxic conditions (H10; 10% O₂). We determined heart rate (fH) and mean arterial pressure (Pm) in acute normoxic (21% O₂) and acute hypoxic (10% O₂) conditions, as well as embryonic responses to cholinergic, adrenergic, and ganglionic pharmacological blockade. Compared with N21 embryos, chronic H10 embryos had smaller bodies and relatively larger hearts and were hypotensive, tachycardic, and following autonomic neural blockade showed reduced intrinsic fH at 90% of incubation. Unlike other reptile embryos, cholinergic and ganglionic receptor blockade both increased fH. β-Adrenergic receptor blockade with propranolol decreased fH, and α-adrenergic blockade with phentolamine decreased Pm. We also measured cardiac mRNA expression. Cholinergic tone was reduced in H10 embryos, but cholinergic receptor (Chrm2) mRNA levels were unchanged. However, expression of adrenergic receptor mRNA (Adrb1, Adra1a, Adra2c) and growth factor mRNA (Igf1, Igf2, Igf2r, Pdgfb) was lowered in H10 embryos. Hypoxia altered the balance between cholinergic receptors, α-adrenoreceptor and β-adrenoreceptor function, which was reflected in altered intrinsic fH and adrenergic receptor mRNA levels. This is the first study to link gene expression with morphological and cardioregulatory plasticity in a developing reptile embryo.

Are there any functional differences of the enteric nervous system between the right-sided diverticular colon and the left-sided diverticular colon? An in vitro study.

PubMed

Tomita, Ryouichi

2014-05-01

To evaluate functional differences of the enteric nervous system (ENS) in patients between right-side colonic diverticula (RCD) and left-sided colonic diverticula (LCD), the author compared the ENS responses between RCD and LCD. Ten specimens were obtained from 10 patients with RCD, and 16 specimens were taken from 16 LCD. As a control, twenty-two specimens of right-sided normal colon (RNC) were obtained from 22 colonic cancers. Twenty-four specimens of left sided normal colon (LNC) were obtained from 24 colonic cancers. A mechanography was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) before and after treatment with various autonomic nerve blockers. Before blockade of the adrenergic and cholinergic nerves, the incidences of contraction via cholinergic nerve in the colons with diverticula were significantly greater than those in the normal colons (right-sided colon; p = 0.0022, left-sided colon; p < 0.0001). There were no significant differences between RNC and LNC (p = 0.3606), and between RCD and LCD (p = 0.7684). After the blockade of adrenergic and cholinergic nerves, the incidence of relaxation via non-adrenergic non-cholinergic inhibitory (NANC) nerve in the normal colons was significantly greater than that in the diverticular colons (right-sided colon; p = 0.0435, left-sided colon; p = 0.0034). There were no significant differences between RNC and LNC (p = 0.2909) and between RCD and LCD (p = 0.9464). Cholinergic nerves were dominant in bilateral diverticular colon compared with bilateral normal colon. NANC inhibitory nerves were dominant in bilateral normal colon compared with bilateral diverticular colon. There were also no functional differences of the ENS between RCD and LCD.

Midbrain interaction with the hypothalamus in expression of aggressive behavior in cats.

PubMed

Romaniuk, A; Golebiewski, H

1977-01-01

The effects of injections of M- and N-cholinergic blocking agents into the antero-medial hypothalamus (HM) and the midbrain central gray (GC) on the aggressive behavior of cats, evoked by microinjections of carbachol into those areas, were investigated in chronic experiments. The influence of pharmacological suppression of the M-cholinergic system in HM on the carbachol-induced aggression response from GC and vice versa was also studied. In the experiments a quantitative method was applied for measuring the specific vocalization - growling, which is a characteristic of aggressive behavior. In the HM and GC areas of the cat the N- and the M-cholinergic systems participated in the control of aggressive behavior, but the M-component dominated in the process. The suppression of M-cholinergic system in GC prevented the appearance of aggressive behavior evoked by injections of carbachol into HM, and the M-cholinergic blockade in HM reduced (by 90 percent) the aggression response evoked by the injections of carbachol into GC. It is concluded that a concurrent action of the hypothalamic and the midbrain cholinergic systems is necessary for the appearance of a fully expressed aggressive behavior. The hypothalamus and the midbrain are probably links of the same functional circuit, and that the control of aggressive behavior is based on a circulatory action between these structures.

Selective immunotoxic lesions of basal forebrain cholinergic neurons: twenty years of research and new directions.

PubMed

Baxter, Mark G; Bucci, David J

2013-10-01

The advent of the selective cholinergic toxin, 192 IgG-saporin, dramatically shaped subsequent research on the role of the basal forebrain in learning and memory. In particular, several articles (including the authors' 1995 Behavioral Neuroscience paper; M. G. Baxter, D. J. Bucci, L. K., Gorman, R. G. Wiley, & M. Gallagher, 1995) revealed that selective removal of basal forebrain cholinergic neurons had surprisingly little effect on spatial learning and memory. Here, as part of the series commemorating the 30th anniversary of Behavioral Neuroscience, we describe how our earlier findings prompted a reconsideration of the cholinergic contribution to cognitive function and also led to several new research directions, including renewed interest in basal forebrain GABA-ergic neurons and cholinergic contributions to neurocognitive development. The authors also describe how the successful use of 192 IgG-saporin led to the development and popularity of a wide range of selective new neurotoxic agents. Finally, they consider the utility of the permanent lesion approach in the wake of new transgenic and optogenetic methods. 2013 APA, all rights reserved

Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus

PubMed Central

Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

2016-01-01

Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2−/y) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2−/y mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2−/y mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes. PMID:27103432

Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus.

PubMed

Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

2016-06-01

Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.

Mice deficient for striatal Vesicular Acetylcholine Transporter (VAChT) display impaired short-term but normal long-term object recognition memory.

PubMed

Palmer, Daniel; Creighton, Samantha; Prado, Vania F; Prado, Marco A M; Choleris, Elena; Winters, Boyer D

2016-09-15

Substantial evidence implicates Acetylcholine (ACh) in the acquisition of object memories. While most research has focused on the role of the cholinergic basal forebrain and its cortical targets, there are additional cholinergic networks that may contribute to object recognition. The striatum contains an independent cholinergic network comprised of interneurons. In the current study, we investigated the role of this cholinergic signalling in object recognition using mice deficient for Vesicular Acetylcholine Transporter (VAChT) within interneurons of the striatum. We tested whether these striatal VAChT(D2-Cre-flox/flox) mice would display normal short-term (5 or 15min retention delay) and long-term (3h retention delay) object recognition memory. In a home cage object recognition task, male and female VAChT(D2-Cre-flox/flox) mice were impaired selectively with a 15min retention delay. When tested on an object location task, VAChT(D2-Cre-flox/flox) mice displayed intact spatial memory. Finally, when object recognition was tested in a Y-shaped apparatus, designed to minimize the influence of spatial and contextual cues, only females displayed impaired recognition with a 5min retention delay, but when males were challenged with a 15min retention delay, they were also impaired; neither males nor females were impaired with the 3h delay. The pattern of results suggests that striatal cholinergic transmission plays a role in the short-term memory for object features, but not spatial location. Copyright © 2016 Elsevier B.V. All rights reserved.

Dysfunctional penile cholinergic nerves in diabetic impotent men

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanco, R.; Saenz de Tejada, I.; Goldstein, I.

1990-08-01

Impotence in the diabetic man may be secondary to a neuropathic condition of the autonomic penile nerves. The relationship between autonomic neuropathy and impotence in diabetes was studied in human corporeal tissue obtained during implantation of a penile prosthesis in 19 impotent diabetic and 15 nondiabetic patients. The functional status of penile cholinergic nerves was assessed by determining their ability to accumulate tritiated choline (34), and synthesize (34) and release (19) tritiated-acetylcholine after incubation of corporeal tissue with tritiated-choline (34). Tritiated-choline accumulation, and tritiated-acetylcholine synthesis and release were significantly reduced in the corporeal tissue from diabetic patients compared to thatmore » from nondiabetic patients (p less than 0.05). The impairment in acetylcholine synthesis worsened with the duration of diabetes (p less than 0.025). No differences in the parameters measured were found between insulin-dependent (11) and noninsulin-dependent (8) diabetic patients. The ability of the cholinergic nerves to synthesize acetylcholine could not be predicted clinically with sensory vibration perception threshold testing. It is concluded that there is a functional penile neuropathic condition of the cholinergic nerves in the corpus cavernosum of diabetic impotent patients that may be responsible for the erectile dysfunction.« less

Physiology and immunology of the cholinergic antiinflammatory pathway

PubMed Central

Tracey, Kevin J.

2007-01-01

Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus. PMID:17273548

Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive α4 nicotinic receptors via a cholinergic-dependent mechanism

PubMed Central

Zhao-Shea, Rubing; Cohen, Bruce N.; Just, Herwig; McClure-Begley, Tristan; Whiteaker, Paul; Grady, Sharon R.; Salminen, Outi; Gardner, Paul D.; Lester, Henry A.; Tapper, Andrew R.

2010-01-01

Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits (α4β2*) functionally interact with G-protein-coupled dopamine (DA) D2 receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9′Ala) rendering α4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D2-receptor agonist. When challenged with the D2R agonist, quinpirole (0.5–10 mg/kg), Leu9′Ala mice, but not wild-type (WT) littermates, developed severe, reversible motor impairment characterized by rigidity, catalepsy, akinesia, and tremor. While striatal DA tissue content, baseline release, and quinpirole-induced DA depletion did not differ between Leu9′Ala and WT mice, quinpirole dramatically increased activity of cholinergic striatal interneurons only in mutant animals, as measured by increased c-Fos expression in choline acetyltransferase (ChAT)-positive interneurons. Highlighting the importance of the cholinergic system in this mouse model, inhibiting the effects of ACh by blocking muscarinic receptors, or by selectively activating hypersensitive nAChRs with nicotine, rescued motor symptoms. This novel mouse model mimics the imbalance between striatal DA/ACh function associated with severe motor impairment in disorders such as Parkinson’s disease, and the data suggest that a D2R–α4*-nAChR functional interaction regulates cholinergic interneuron activity.—Zhao-Shea, R., Cohen, B. N., Just, H., McClure-Begley, T., Whiteaker, P., Grady, S. R., Salminen, O., Gardner, P. D., Lester, H. A., Tapper, A. R. Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive α4 nicotinic receptors via a cholinergic-dependent mechanism. PMID:19720621

Cholinergic control of attention to cues guiding established performance versus learning: theoretical comment on Maddux, Kerfoot, Chatterjee, and Holland (2007).

PubMed

Sarter, Martin

2007-02-01

Previous views on the cognitive functions of the basal forebrain cholinergic system often suggested that this neuromodulator system influences fundamental attentional processes but not learning. The results from an elegant series of studies by J. M. Maddux, E. C. Kerfoot, S. Chatterjee, and P. Holland reveal the intricate relationships between the levels of attentional processing of stimuli and the rate of learning about such stimuli. Moreover, their results indicate a double dissociation between the role of prefrontal and posterior parietal cholinergic inputs, respectively, in attentional performance and the learning rate of stimuli that command different levels of attentional processing. Separate yet interacting components of the cortical cholinergic input system modulate the attentional processing of cues that guide well-practiced performance or that serve as conditioned stimuli during learning. Copyright (c) 2007 APA, all rights reserved.

Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [¹⁸F]fluoroethoxybenzovesamicol.

PubMed

Cyr, Marilyn; Parent, Maxime J; Mechawar, Naguib; Rosa-Neto, Pedro; Soucy, Jean-Paul; Clark, Stewart D; Aghourian, Meghmik; Bedard, Marc-Andre

2015-02-01

Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals. Copyright © 2014 Elsevier B.V. All rights reserved.

BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer's disease.

PubMed

Burke, Rebecca M; Norman, Timothy A; Haydar, Tarik F; Slack, Barbara E; Leeman, Susan E; Blusztajn, Jan Krzysztof; Mellott, Tiffany J

2013-11-26

Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5- and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.

Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo

PubMed Central

Zucca, Stefano; Zucca, Aya; Nakano, Takashi; Aoki, Sho

2018-01-01

The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output. PMID:29578407

Decreased subcortical cholinergic arousal in focal seizures

PubMed Central

Motelow, Joshua E.; Li, Wei; Zhan, Qiong; Mishra, Asht M.; Sachdev, Robert N. S.; Liu, Geoffrey; Gummadavelli, Abhijeet; Zayyad, Zaina; Lee, Hyun Seung; Chu, Victoria; Andrews, John P.; Englot, Dario J.; Herman, Peter; Sanganahalli, Basavaraju G.; Hyder, Fahmeed; Blumenfeld, Hal

2015-01-01

SUMMARY Impaired consciousness in temporal lobe seizures has a major negative impact on quality of life. The prevailing view holds that this disorder impairs consciousness by seizure spread to the bilateral temporal lobes. We propose instead that seizures invade subcortical regions and depress arousal, causing impairment through decreases rather than through increases in activity. Using functional magnetic resonance imaging in a rodent model, we found increased activity in regions known to depress cortical function including lateral septum and anterior hypothalamus. Importantly, we found suppression of intralaminar thalamic and brainstem arousal systems and suppression of the cortex. At a cellular level, we found reduced firing of identified cholinergic neurons in the brainstem pedunculopontine tegmental nucleus and basal forebrain. Finally, we used enzyme-based amperometry to demonstrate reduced cholinergic neurotransmission in both cortex and thalamus. Decreased subcortical arousal is a novel mechanism for loss of consciousness in focal temporal lobe seizures. PMID:25654258

COMPARISON OF WEEKLY EXPOSURES TO ANATOXIN-A AND NICOTINE ON THE MOTOR ACTIVITY OF RATS.

EPA Science Inventory

Anatoxin-a is a nicotinic cholinergic agonist that is produced by several genera of cyanobacteria, and has been implicated in several poisoning episodes of wildlife, livestock, domestic animals and people. Previous research on nicotine has obtained tolerance and sensitization ...

Crystal structure of a catalytically active, non-toxic endopeptidase derivative of Clostridium botulinum toxin A.

PubMed

Masuyer, Geoffrey; Thiyagarajan, Nethaji; James, Peter L; Marks, Philip M H; Chaddock, John A; Acharya, K Ravi

2009-03-27

Botulinum neurotoxins (BoNTs) modulate cholinergic nerve terminals to result in neurotransmitter blockade. BoNTs consists of catalytic (LC), translocation (Hn) and cell-binding domains (Hc). The binding function of the Hc domain is essential for BoNTs to bind the neuronal cell membrane, therefore, removal of the Hc domain results in a product that retains the endopeptidase activity of the LC but is non-toxic. Thus, a molecule consisting of LC and Hn domains of BoNTs, termed LHn, is a suitable molecule for engineering novel therapeutics. The structure of LHA at 2.6 A reported here provides an understanding of the structural implications and challenges of engineering therapeutic molecules that combine functional properties of LHn of BoNTs with specific ligand partners to target different cell types.

Peripheral type of choline acetyltransferase: biological and evolutionary implications for novel mechanisms in cholinergic system.

PubMed

Bellier, J-P; Kimura, H

2011-12-01

The peripheral type of choline acetyltransferase (pChAT) is an isoform of the well-studied common type of choline acetyltransferase (cChAT), the synthesizing enzyme of acetylcholine. Since pChAT arises by exons skipping, its amino acid sequence is similar to that of cChAT, except the lack of a continuous peptide sequence encoded by all the four exons from 6 to 9. While cChAT expression has been observed in both the central and peripheral nervous systems, pChAT is preferentially expressed in the peripheral nervous system. pChAT appears to be a reliable marker for the visualization of peripheral cholinergic neurons and their processes, whereas other conventional markers including cChAT have not been used successfully for it. In mammals like rodents, pChAT immunoreactivity has been observed in most, if not all, physiologically identified peripheral cholinergic structures such as all parasympathetic postganglionic neurons and most neurons of the enteric nervous system. In addition, pChAT has been found in many peripheral neurons that are derived from the neural crest. These include sensory neurons of the trigeminal ganglion and the dorsal root ganglion, and sympathetic postganglionic neurons. Recent studies moreover indicate that pChAT, as well as cChAT, appears ubiquitously expressed among various species not only of vertebrate mammals but also of invertebrate mollusks. This finding implies that the alternative splicing mechanism to generate pChAT and cChAT has been preserved during evolution, probably for some functional benefits. Copyright © 2011 Elsevier B.V. All rights reserved.

Impairment of skin barrier function via cholinergic signal transduction in a dextran sulphate sodium-induced colitis mouse model.

PubMed

Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

2015-10-01

Dry skin has been clinically associated with visceral diseases, including liver disease, as well as for our previously reported small intestinal injury mouse model, which have abnormalities in skin barrier function. To clarify this disease-induced skin disruption, we used a dextran sulphate sodium (DSS)-induced colitis mouse model. Following treatment with DSS, damage to the colon and skin was monitored using histological and protein analysis methods as well as the detection of inflammatory mediators in the plasma. Notably, transepidermal water loss was higher, and skin hydration was lower in DSS-treated mice compared to controls. Tumor necrosis factor-alpha (TNF-α), interleukin 6 and NO2-/NO3- levels were also upregulated in the plasma, and a decrease in body weight and colon length was observed in DSS-treated mice. However, when administered TNF-α antibody or an iNOS inhibitor, no change in skin condition was observed, indicating that another signalling mechanism is utilized. Interestingly, the number of tryptase-expressing mast cells, known for their role in immune function via cholinergic signal transduction, was elevated. To evaluate the function of cholinergic signalling in this context, atropine (a muscarinic cholinoceptor antagonist) or hexamethonium (a nicotinic cholinergic ganglion-blocking agent) was administered to DSS-treated mice. Our data indicate that muscarinic acetylcholine receptors (mAChRs) are the primary receptors functioning in colon-to-skin signal transduction, as DSS-induced skin disruption was suppressed by atropine. Thus, skin disruption is likely associated with DSS-induced colitis, and the activation of mast cells via mAChRs is critical to this association. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives.

PubMed

Scherma, Maria; Muntoni, Anna Lisa; Melis, Miriam; Fattore, Liana; Fadda, Paola; Fratta, Walter; Pistis, Marco

2016-05-01

Several lines of evidence suggest that endocannabinoid and nicotinic cholinergic systems are implicated in the regulation of different physiological processes, including reward, and in the neuropathological mechanisms of psychiatric diseases, such as addiction. A crosstalk between these two systems is substantiated by the overlapping distribution of cannabinoid and nicotinic acetylcholine receptors in many brain structures. We will review recent preclinical data showing how the endocannabinoid and nicotinic cholinergic systems interact bidirectionally at the level of the brain reward pathways, and how this interaction plays a key role in modulating nicotine and cannabinoid intake and dependence. Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids. Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence. Research by Steven R. Goldberg has significantly contributed to the progress in this research field.

Localization of multiple neurotransmitters in surgically derived specimens of human atrial ganglia.

PubMed

Hoover, D B; Isaacs, E R; Jacques, F; Hoard, J L; Pagé, P; Armour, J A

2009-12-15

Dysfunction of the intrinsic cardiac nervous system is implicated in the genesis of atrial and ventricular arrhythmias. While this system has been studied extensively in animal models, far less is known about the intrinsic cardiac nervous system of humans. This study was initiated to anatomically identify neurotransmitters associated with the right atrial ganglionated plexus (RAGP) of the human heart. Biopsies of epicardial fat containing a portion of the RAGP were collected from eight patients during cardiothoracic surgery and processed for immunofluorescent detection of specific neuronal markers. Colocalization of markers was evaluated by confocal microscopy. Most intrinsic cardiac neuronal somata displayed immunoreactivity for the cholinergic marker choline acetyltransferase and the nitrergic marker neuronal nitric oxide synthase. A subpopulation of intrinsic cardiac neurons also stained for noradrenergic markers. While most intrinsic cardiac neurons received cholinergic innervation evident as punctate immunostaining for the high affinity choline transporter, some lacked cholinergic inputs. Moreover, peptidergic, nitrergic, and noradrenergic nerves provided substantial innervation of intrinsic cardiac ganglia. These findings demonstrate that the human RAGP has a complex neurochemical anatomy, which includes the presence of a dual cholinergic/nitrergic phenotype for most of its neurons, the presence of noradrenergic markers in a subpopulation of neurons, and innervation by a host of neurochemically distinct nerves. The putative role of multiple neurotransmitters in controlling intrinsic cardiac neurons and mediating efferent signaling to the heart indicates the possibility of novel therapeutic targets for arrhythmia prevention.

Lentiviral Infection of Rhesus Macaques Causes Long-Term Injury to Cortical and Hippocampal Projections of Prostaglandin-Expressing Cholinergic Basal Forebrain Neurons

PubMed Central

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E.

2011-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human HIV-AIDS and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenases 1 and 2 (COX1 and 2) in brains of SIV-infected macaques with and without encephalitis and antiretroviral therapy, and uninfected controls. COX1 but not COX2 was co-expressed with markers of cholinergic phenotype, i.e. choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human samples. COX1 was decreased in basal forebrain neurons in macaques with AIDS vs. uninfected and asymptomatic SIV-infected macaques. VAChT-positive fiber density was reduced in frontal, parietal and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2′,3′-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent, irreversible brain damage. PMID:22157616

Cholinergic suppression of visual responses in primate V1 is mediated by GABAergic inhibition

PubMed Central

Aoki, Chiye; Hawken, Michael J.

2012-01-01

Acetylcholine (ACh) has been implicated in selective attention. To understand the local circuit action of ACh, we iontophoresed cholinergic agonists into the primate primary visual cortex (V1) while presenting optimal visual stimuli. Consistent with our previous anatomical studies showing that GABAergic neurons in V1 express ACh receptors to a greater extent than do excitatory neurons, we observed suppressed visual responses in 36% of recorded neurons outside V1's primary thalamorecipient layer (4c). This suppression is blocked by the GABAA receptor antagonist gabazine. Within layer 4c, ACh release produces a response gain enhancement (Disney AA, Aoki C, Hawken MJ. Neuron 56: 701–713, 2007); elsewhere, ACh suppresses response gain by strengthening inhibition. Our finding contrasts with the observation that the dominant mechanism of suppression in the neocortex of rats is reduced glutamate release. We propose that in primates, distinct cholinergic receptor subtypes are recruited on specific cell types and in specific lamina to yield opposing modulatory effects that together increase neurons' responsiveness to optimal stimuli without changing tuning width. PMID:22786955

Cholinergic suppression of visual responses in primate V1 is mediated by GABAergic inhibition.

PubMed

Disney, Anita A; Aoki, Chiye; Hawken, Michael J

2012-10-01

Acetylcholine (ACh) has been implicated in selective attention. To understand the local circuit action of ACh, we iontophoresed cholinergic agonists into the primate primary visual cortex (V1) while presenting optimal visual stimuli. Consistent with our previous anatomical studies showing that GABAergic neurons in V1 express ACh receptors to a greater extent than do excitatory neurons, we observed suppressed visual responses in 36% of recorded neurons outside V1's primary thalamorecipient layer (4c). This suppression is blocked by the GABA(A) receptor antagonist gabazine. Within layer 4c, ACh release produces a response gain enhancement (Disney AA, Aoki C, Hawken MJ. Neuron 56: 701-713, 2007); elsewhere, ACh suppresses response gain by strengthening inhibition. Our finding contrasts with the observation that the dominant mechanism of suppression in the neocortex of rats is reduced glutamate release. We propose that in primates, distinct cholinergic receptor subtypes are recruited on specific cell types and in specific lamina to yield opposing modulatory effects that together increase neurons' responsiveness to optimal stimuli without changing tuning width.

The hybrid modulatory/pattern generating N1L interneuron in the buccal feeding system of Lymnaea is cholinergic.

PubMed

Vehovszky, A; Elliott, C J

1995-01-01

This study examines neurotransmission between identified buccal interneurons in the feeding system of the snail Lymnaea stagnalis. We compare the pharmacology of the individual synaptic connections from a hybrid modulatory/pattern generating interneuron (N1L) to a pattern generating interneuron (N1M) with that from a modulatory interneuron (SO) to the same follower cell (N1M). The pharmacological properties of the N1L to N1M and the SO to N1M connections closely resemble each other. Both interneurons produce fast cholinergic EPSPs as judged by the blocking effects of cholinergic antagonists hexamethonium, d-tubocurarine and the cholinergic neurotoxin AF-64A. A slower, more complex but non-cholinergic component of the synaptic response is also present after stimulating either the presynaptic N1L or SO interneurons. This second component of the postsynaptic response is not dopaminergic, on the basis of its persistence in the presence of dopaminergic antagonists ergometrine and fluphenazine and the dopaminergic neurotoxin MPP+. We conclude that, although there has been an evolutionary divergence in function, the modulatory SO and the hybrid modulatory/pattern generating N1L are pharmacologically similar. Neither of them contributes directly to dopaminergic modulation of the feeding activity. These neurons also resemble the N1M protraction phase pattern generating neurons which are cholinergic (Elliott and Kemenes, 1992).

Ameliorative effect of Noni fruit extract on streptozotocin-induced memory impairment in mice.

PubMed

Pachauri, Shakti D; Verma, Priya Ranjan P; Dwivedi, Anil K; Tota, Santoshkumar; Khandelwal, Kiran; Saxena, Jitendra K; Nath, Chandishwar

2013-08-01

This study evaluated the effects of a standardized ethyl acetate extract of Morinda citrifolia L. (Noni) fruit on impairment of memory, brain energy metabolism, and cholinergic function in intracerebral streptozotocin (STZ)-treated mice. STZ (0.5 mg/kg) was administered twice at an interval of 48 h. Noni (50 and 100 mg/kg, postoperatively) was administered for 21 days following STZ administration. Memory function was evaluated using Morris Water Maze and passive avoidance tests, and brain levels of cholinergic function, oxidative stress, energy metabolism, and brain-derived neurotrophic factor (BDNF) were estimated. STZ caused memory impairment in Morris Water Maze and passive avoidance tests along with reduced brain levels of ATP, BDNF, and acetylcholine and increased acetylcholinesterase activity and oxidative stress. Treatment with Noni extract (100 mg/kg) prevented the STZ-induced memory impairment in both behavioral tests along with reduced oxidative stress and acetylcholinesterase activity, and increased brain levels of BDNF, acetylcholine, and ATP level. The study shows the beneficial effects of Noni fruit against STZ-induced memory impairment, which may be attributed to improved brain energy metabolism, cholinergic neurotransmission, BDNF, and antioxidative action.

Cholinergic and cytoprotective signaling cascades mediate the mitigative effect of erythropoietin on acute radiation syndrome.

PubMed

Galal, Shereen Mohamed; Abdel-Rafei, Mohamed Khairy; Hasan, Hesham Farouk

2018-05-01

The present investigation aimed to evaluate the radiomitigative efficacy of the recombinant human erythropoietin (EPO) against acute radiation syndrome (ARS) in a rat model. Rats were irradiated with a single sublethal dose of γ-radiation (7 Gy; total body irradiation; TBI) on the 1st day of experimental course, then received EPO (5000 IU/kg; i.p.) 24 h after irradiation, and rats were observed for 30 days of survival analysis. Administration of EPO improved 30-day survival, alleviated TBI-induced myelosuppression and pancytopenia, by augmenting lymphocytes and other white blood cells in the peripheral blood of rats, while bone marrow and spleen cellularity were restored. EPO post-exposure treatment alleviated hepatotoxicity biomarkers and restored splenic function. EPO abrogated radiation-induced oxidative stress through the upregulation of the cholinergic anti-inflammatory nicotinic acetylcholine receptor (α-7-nAChR) and the pro-survival Janus kinase-2 and signal transducers and activators of transcription JAK-2/STAT-3 signaling mediated via enhancing nuclear factor erythroid-2 related factor-2 (Nrf-2) cytoprotective machinery in liver and spleen of irradiated rats. Moreover, EPO treatment prevented hepatic and splenic apoptosis. The present study establishes the implication of α-7-nAChR-JAK-2/STAT-3-Nrf-2 signaling cascade in the radiomitigative potential of EPO against ARS.

Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction

PubMed Central

Christensen, Mark H.; Ishibashi, Masaru; Nielsen, Michael L.; Leonard, Christopher S.; Kohlmeier, Kristi A.

2015-01-01

The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on several parameters affecting LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7-P15), nicotine was found to induce larger intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15-P34). Nicotine increased neuronal firing of cholinergic cells to a greater degree in younger animals, possibly linked to development associated differences found in nicotinic effects on action potential shape and afterhyperpolarization. We conclude that in addition to age-associated alterations of several properties expected to affect resting cell excitability, parameters affecting cell excitability are altered by nicotine differentially across ontogeny. Taken together, our data suggest that nicotine induces a larger excitatory response in cholinergic LDT neurons from the youngest animals, which could result in a greater excitatory output from these cells to target regions involved in development of addiction. Such output would be expected to be promotive of addiction; therefore, ontogenetic differences in nicotine-mediated increases in the excitability of the LDT could contribute to the differential susceptibility to nicotine addiction seen across age. PMID:24863041

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

PubMed Central

Broad, J; Kung, V W S; Boundouki, G; Aziz, Q; De Maeyer, J H; Knowles, C H; Sanger, G J

2013-01-01

BACKGROUND AND PURPOSE Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. EXPERIMENTAL APPROACH Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in ‘area under the curve’. KEY RESULTS Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30–100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3–7, each concentration). CONCLUSIONS AND IMPLICATIONS Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction. PMID:24032987

Role of cyclooxygenase isoforms in the altered excitatory motor pathways of human colon with diverticular disease

PubMed Central

Fornai, M; Colucci, R; Antonioli, L; Ippolito, C; Segnani, C; Buccianti, P; Marioni, A; Chiarugi, M; Villanacci, V; Bassotti, G; Blandizzi, C; Bernardini, N

2014-01-01

BACKGROUND AND PURPOSE The COX isoforms (COX-1, COX-2) regulate human gut motility, although their role under pathological conditions remains unclear. This study examines the effects of COX inhibitors on excitatory motility in colonic tissue from patients with diverticular disease (DD). EXPERIMENTAL APPROACH Longitudinal muscle preparations, from patients with DD or uncomplicated cancer (controls), were set up in organ baths and connected to isotonic transducers. Indomethacin (COX-1/COX-2 inhibitor), SC-560 (COX-1 inhibitor) or DFU (COX-2 inhibitor) were assayed on electrically evoked, neurogenic, cholinergic and tachykininergic contractions, or carbachol- and substance P (SP)-induced myogenic contractions. Distribution and expression of COX isoforms in the neuromuscular compartment were assessed by RT-PCR, Western blot and immunohistochemical analysis. KEY RESULTS In control preparations, neurogenic cholinergic contractions were enhanced by COX inhibitors, whereas tachykininergic responses were blunted. Carbachol-evoked contractions were increased by indomethacin or SC-560, but not DFU, whereas all inhibitors reduced SP-induced motor responses. In preparations from DD patients, COX inhibitors did not affect electrically evoked cholinergic contractions. Both indomethacin and DFU, but not SC-560, decreased tachykininergic responses. COX inhibitors did not modify carbachol-evoked motor responses, whereas they counteracted SP-induced contractions. COX-1 expression was decreased in myenteric neurons, whereas COX-2 was enhanced in glial cells and smooth muscle. CONCLUSIONS AND IMPLICATIONS In control colon, COX-1 and COX-2 down-regulate cholinergic motility, whereas both isoforms enhance tachykininergic motor activity. In the presence of DD, there is a loss of modulation by both COX isoforms on the cholinergic system, whereas COX-2 displays an enhanced facilitatory control on tachykininergic contractile activity. PMID:24758697

Axons giving rise to the palisade endings of feline extraocular muscles display motor features.

PubMed

Zimmermann, Lars; Morado-Díaz, Camilo J; Davis-López de Carrizosa, María A; de la Cruz, Rosa R; May, Paul J; Streicher, Johannes; Pastor, Ángel M; Blumer, Roland

2013-02-13

Palisade endings are nerve specializations found in the extraocular muscles (EOMs) of mammals, including primates. They have long been postulated to be proprioceptors. It was recently demonstrated that palisade endings are cholinergic and that in monkeys they originate from the EOM motor nuclei. Nevertheless, there is considerable difference of opinion concerning the nature of palisade ending function. Palisade endings in EOMs were examined in cats to test whether they display motor or sensory characteristics. We injected an anterograde tracer into the oculomotor or abducens nuclei and combined tracer visualization with immunohistochemistry and α-bungarotoxin staining. Employing immunohistochemistry, we performed molecular analyses of palisade endings and trigeminal ganglia to determine whether cat palisade endings are a cholinergic trigeminal projection. We confirmed that palisade endings are cholinergic and showed, for the first time, that they, like extraocular motoneurons, are also immunoreactive for calcitonin gene-related peptide. Following tracer injection into the EOM nuclei, we observed tracer-positive palisade endings that exhibited choline acetyl transferase immunoreactivity. The tracer-positive nerve fibers supplying palisade endings also established motor terminals along the muscle fibers, as demonstrated by α-bungarotoxin. Neither the trigeminal ganglion nor the ophthalmic branch of the trigeminal nerve contained cholinergic elements. This study confirms that palisade endings originate in the EOM motor nuclei and further indicates that they are extensions of the axons supplying the muscle fiber related to the palisade. The present work excludes the possibility that they receive cholinergic trigeminal projections. These findings call into doubt the proposed proprioceptive function of palisade endings.

Axons Giving Rise to the Palisade Endings of Feline Extraocular Muscles Display Motor Features

PubMed Central

Zimmermann, Lars; Morado-Díaz, Camilo J.; de Carrizosa, María A. Davis-López; de la Cruz, Rosa R.; May, Paul J.; Streicher, Johannes; Pastor, Ángel M.; Blumer, Roland

2016-01-01

Palisade endings are nerve specializations found in the extraocular muscles (EOMs) of mammals, including primates. They have long been postulated to be proprioceptors. It was recently demonstrated that palisade endings are cholinergic and that in monkeys they originate from the EOM motor nuclei. Nevertheless, there is considerable difference of opinion concerning the nature of palisade ending function. Palisade endings in EOMs were examined in cats to test whether they display motor or sensory characteristics. We injected an anterograde tracer into the oculomotor or abducens nuclei and combined tracer visualization with immunohistochemistry and α-bungarotoxin staining. Employing immunohistochemistry, we performed molecular analyses of palisade endings and trigeminal ganglia to determine whether cat palisade endings are a cholinergic trigeminal projection. We confirmed that palisade endings are cholinergic and showed, for the first time, that they, like extraocular motoneurons, are also immunoreactive for calcitonin gene-related peptide. Following tracer injection into the EOM nuclei, we observed tracer-positive palisade endings that exhibited choline acetyl transferase immunoreactivity. The tracer-positive nerve fibers supplying palisade endings also established motor terminals along the muscle fibers, as demonstrated by α-bungarotoxin. Neither the trigeminal ganglion nor the ophthalmic branch of the trigeminal nerve contained cholinergic elements. This study confirms that palisade endings originate in the EOM motor nuclei and further indicates that they are extensions of the axons supplying the muscle fiber related to the palisade. The present work excludes the possibility that they receive cholinergic trigeminal projections. These findings call into doubt the proposed proprioceptive function of palisade endings. PMID:23407938

Burn Injury Alters Epidermal Cholinergic Mediators and Increases HMGB1 and Caspase 3 in Autologous Donor Skin and Burn Margin

PubMed Central

Holmes, Casey J.; Plichta, Jennifer K.; Gamelli, Richard L.; Radek, Katherine A.

2016-01-01

Burn wound healing complications, such as graft failure or infection, are a major source of morbidity and mortality in burn patients. The mechanisms by which local burn injury alters epidermal barrier function in autologous donor skin and surrounding burn margin are largely undefined. We hypothesized that defects in the epidermal cholinergic system may impair epidermal barrier function and innate immune responses. The objective was to identify alterations in the epidermal cholinergic pathway, and their downstream targets, associated with inflammation and cell death. We established that protein levels, but not gene expression, of the α7 nicotinic acetylcholine receptor (CHRNA7) were significantly reduced in both donor and burn margin skin. Furthermore, the gene and protein levels of an endogenous allosteric modulator of CHRNA7, secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP1) and acetylcholine were significantly elevated in donor and burn margin skin. As downstream proteins of inflammatory and cell death targets of nAChR activation, we found significant elevations in epidermal High Mobility Group Box Protein 1 (HMGB1) and caspase 3 in donor and burn margin skin. Lastly, we employed a novel in vitro keratinocyte burn model to establish that burn injury influences the gene expression of these cholinergic mediators and their downstream targets. These results indicate that defects in cholinergic mediators and inflammatory/apoptotic molecules in donor and burn margin skin may directly contribute to graft failure or infection in burn patients. PMID:27648692

Cholinergic Modulation of Visual Attention and Working Memory: Dissociable Effects of Basal Forebrain 192-IgG-Saporin Lesions and Intraprefrontal Infusions of Scopolamine

ERIC Educational Resources Information Center

Chudasama, Yogita; Dalley, Jeffrey W.; Nathwani, Falgyni; Bouger, Pascale; Robbins, Trevor W.

2004-01-01

Two experiments examined the effects of reductions in cortical cholinergic function on performance of a novel task that allowed for the simultaneous assessment of attention to a visual stimulus and memory for that stimulus over a variable delay within the same test session. In the first experiment, infusions of the muscarinic receptor antagonist…

Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine -- a PDE1 inhibitor.

PubMed

Deshmukh, Rahul; Sharma, Vivek; Mehan, Sidharth; Sharma, Nidhi; Bedi, K L

2009-10-12

Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative-nitritive stress and induced cholinergic hypofunction in rats. Chronic treatment with vinpocetine (5, 10 and 20 mg/kg i.p.) for 21 days following first i.c.v. streptozotocin infusion significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Further, vinpocetine significantly reduced the oxidative-nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Chronic treatment with vinpocetine also reduced significantly the increase in acetylcholinesterase activity and lactate dehydrogenase levels indicating restorative capacity of vinpocetine with respect to cholinergic functions and preventing the neuronal damage. The observed beneficial effects of vinpocetine on spatial memory may be due to its ability to favorably modulate cholinergic functions, prevent neuronal cell damage and possibly through its antioxidant mechanism also.

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects.

PubMed

Voss, Bianca; Thienel, Renate; Reske, Martina; Kellermann, Thilo; Sheldrick, Abigail J; Halfter, Sarah; Radenbach, Katrin; Shah, Nadim J; Habel, Ute; Kircher, Tilo T J

2012-06-01

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.

Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior.

PubMed

Hall, Joseph M; Savage, Lisa M

2016-04-01

Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time points: 24-h or 2-weeks post-exercise. It was found that only after the 2-week adaption period did exercise lead to an interrelated sequence of events in PTD rats that included: (1) restored spatial working memory; (2) rescued behaviorally-stimulated hippocampal acetylcholine efflux; and (3) within the medial septum/diagonal band, the re-emergence of the cholinergic (choline acetyltransferase [ChAT+]) phenotype, with the greatest change occurring in the ChAT+/nestin+ neurons. Furthermore, in control rats, exercise followed by a 2-week adaption period improved hippocampal acetylcholine efflux and increased the number of neurons co-expressing the ChAT and nestin phenotype. These findings demonstrate a novel mechanism by which exercise can modulate the mature cholinergic/nestin neuronal phenotype leading to improved neurotransmitter function as well as enhanced learning and memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

PubMed Central

Pappas, Samuel S; Darr, Katherine; Holley, Sandra M; Cepeda, Carlos; Mabrouk, Omar S; Wong, Jenny-Marie T; LeWitt, Tessa M; Paudel, Reema; Houlden, Henry; Kennedy, Robert T; Levine, Michael S; Dauer, William T

2015-01-01

Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model. DOI: http://dx.doi.org/10.7554/eLife.08352.001 PMID:26052670

Rapid changes in synaptic vesicle cytochemistry after depolarization of cultured cholinergic sympathetic neurons

PubMed Central

1985-01-01

Sympathetic neurons taken from rat superior cervical ganglia and grown in culture acquire cholinergic function under certain conditions. These cholinergic sympathetic neurons, however, retain a number of adrenergic properties, including the enzymes involved in the synthesis of norepinephrine (NE) and the storage of measurable amounts of NE. These neurons also retain a high affinity uptake system for NE; despite this, the majority of the synaptic vesicles remain clear even after incubation in catecholamines. The present study shows, however, that if these neurons are depolarized before incubation in catecholamine, the synaptic vesicles acquire dense cores indicative of amine storage. These manipulations are successful when cholinergic function is induced with either a medium that contains human placental serum and embryo extract or with heart-conditioned medium, and when the catecholamine is either NE or 5-hydroxydopamine. In some experiments, neurons are grown at low densities and shown to have cholinergic function by electrophysiological criteria. After incubation in NE, only 6% of the synaptic vesicles have dense cores. In contrast, similar neurons depolarized (80 mM K+) before incubation in catecholamine contain 82% dense-cored vesicles. These results are confirmed in network cultures where the percentage of dense-cored vesicles is increased 2.5 to 6.5 times by depolarizing the neurons before incubation with catecholamine. In both single neurons and in network cultures, the vesicle reloading is inhibited by reducing vesicle release during depolarization with an increased Mg++/Ca++ ratio or by blocking NE uptake either at the plasma membrane (desipramine) or at the vesicle membrane (reserpine). In addition, choline appears to play a competitive role because its presence during incubation in NE or after reloading results in decreased numbers of dense-cored vesicles. We conclude that the depolarization step preceding catecholamine incubation acts to empty the vesicles of acetylcholine, thus allowing them to reload with catecholamine. These data also suggest that the same vesicles may contain both neurotransmitters simultaneously. PMID:4008529

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

PubMed

Uchida, Sae; Kagitani, Fusako

2017-05-12

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Cholinergic modulation of mesolimbic dopamine function and reward.

PubMed

Mark, Gregory P; Shabani, Shkelzen; Dobbs, Lauren K; Hansen, Stephen T

2011-07-25

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems. Copyright © 2011 Elsevier Inc. All rights reserved.

Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic basal forebrain neurons.

PubMed

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E

2012-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiency syndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenase isotypes 1 and 2 (COX1 and COX2) in the brains of SIV-infected macaques with or without encephalitis and antiretroviral therapy and uninfected controls.Cyclooxygenase isotype 1, but not COX2, was coexpressed with markers of cholinergic phenotype, that is, choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human, brain. Cyclooxygenase isotype 1 was decreased in basal forebrain neurons in macaques with AIDS versus uninfected and asymptomatic SIV-infected macaques. The VAChT-positive fiber density was reduced in frontal, parietal, and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2',3'-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results further imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent irreversible brain damage.

[The extraneuronal cholinergic system of the skin. Basic facts and clinical relevance].

PubMed

Kurzen, H

2004-05-01

Acetylcholine (ACh) is a prototypical neurotransmitter that has recently been recognized to occur extraneuronally in a large variety of cells. ACh and its nicotinic and muscarinic receptors are produced in the epidermis and in the adnexal structures of the skin in a highly complicated pattern. They are also produced in melanocytes, fibroblasts, endothelial cells and immune cells. Through autocrine, paracrine and endocrine mechanisms, the cholinergic system is involved in the basic functions of the skin, such as keratinocyte differentiation, epidermal barrier formation, sweating, sebum production, blood circulation, angiogenesis and a variety of immune reactions. Hence diseases like acne vulgaris, vitiligo, psoriasis, pemphigus vulgaris and atopic dermatitis may be influenced. The exploration of the extraneuronal cholinergic system of the skin has only just begun.

Carbachol inhibits basal and forskolin-evoked adult rat striatal acetylcholine release.

PubMed

Login, I S

1997-05-27

Acutely dissociated adult rat striatal cholinergic neurons labeled with [3H]choline were used in a perifusion system to study muscarinic regulation of basal and forskolin-stimulated fractional [3H]acetylcholine ([3H]-ACh) efflux in the absence of synaptic modulation. Carbachol inhibited basal (40% maximal inhibition; IC50 approximately 0.7 microM) and forskolin-evoked release (75% inhibition; IC50 approximately 0.05 microM) in a concentration-dependent manner, and both carbachol actions were abolished with atropine. Thus, activation of striatal muscarinic cholinergic autoreceptors potently inhibits basal and adenylate cyclase-stimulated ACh release. Tonic inhibitory control of cholinergic activity by functional striatal circuitry apparently prevents detection of these important physiological interactions in slices or in situ.

The nestin-expressing and non-expressing neurons in rat basal forebrain display different electrophysiological properties and project to hippocampus

PubMed Central

2011-01-01

Background Nestin-immunoreactive (nestin-ir) neurons have been identified in the medial septal/diagonal band complex (MS/DBB) of adult rat and human, but the significance of nestin expression in functional neurons is not clear. This study investigated electrophysiological properties and neurochemical phenotypes of nestin-expressing (nestin+) neurons using whole-cell recording combined with single-cell RT-PCR to explore the significance of nestin expression in functional MS/DBB neurons. The retrograde labelling and immunofluorescence were used to investigate the nestin+ neuron related circuit in the septo-hippocampal pathway. Results The results of single-cell RT-PCR showed that 87.5% (35/40) of nestin+ cells expressed choline acetyltransferase mRNA (ChAT+), only 44.3% (35/79) of ChAT+ cells expressed nestin mRNA. Furthermore, none of the nestin+ cells expressed glutamic acid decarboxylases 67 (GAD67) or vesicular glutamate transporters (VGLUT) mRNA. All of the recorded nestin+ cells were excitable and demonstrated slow-firing properties, which were distinctive from those of GAD67 or VGLUT mRNA-positive neurons. These results show that the MS/DBB cholinergic neurons could be divided into nestin-expressing cholinergic neurons (NEChs) and nestin non-expressing cholinergic neurons (NNChs). Interestingly, NEChs had higher excitability and received stronger spontaneous excitatory synaptic inputs than NNChs. Retrograde labelling combined with choline acetyltransferase and nestin immunofluorescence showed that both of the NEChs and NNChs projected to hippocampus. Conclusions These results suggest that there are two parallel cholinergic septo-hippocampal pathways that may have different functions. The significance of nestin expressing in functional neurons has been discussed. PMID:22185478

In two minds? Is schizophrenia a state 'trapped' between waking and dreaming?

PubMed

Llewellyn, Sue

2009-10-01

This paper proposes that schizophrenia is a state of mind/brain 'trapped' in-between waking and dreaming. Furthermore, it suggests that both waking and dreaming are functional. An in-between state would be disordered; neither waking nor dreaming would function properly, as the mind/brain would be attempting two, ultimately incompatible, sets of tasks simultaneously. In support of this hypothesis, evidence is synthesised across four different domains: the chemistry of the dreaming state; work on dreaming as functional for memory; the membrane theory of schizophrenia; and chaos theory. The brain produces itself; self-organizing through its modulatory systems. Differentiation between dreaming and waking is achieved through aminergic/cholinergic/dopaminergic reciprocity. Chaos theory indicates that self-organizing systems function most creatively on the 'edge of chaos'; a state which lies between order and disorder. In the mind/brain 'order' represents rigid differentiation between waking and dreaming, whereas 'disorder' results from their interpenetration. How could the latter occur? In sum, the causal sequence would be as follows. Genetic susceptibility to schizophrenia is expressed through fatty acid deficiencies which precipitate neuronal cell membrane abnormalities. In consequence, all neurotransmitter systems become disrupted. Ultimately, the reciprocal interaction between aminergic/cholinergic neuromodulation breaks down. Disrupted cholinergic input interferes with the reciprocal relationship between mesolimbic and mesocortical dopaminergic systems. Loss of reciprocity between aminergic, cholinergic and dopaminergic neuromodulation results in chronic interpenetration; a 'trapped' state, in-between waking and dreaming results. This would be 'schizophrenia'. Currently, imaging techniques do not capture dynamic neuromodulation, so this hypothesis cannot yet be tested inductively. However, the paper suggests that further evidence would be gained through a closer attention to the phenomenology of schizophrenia in the waking and dreaming states.

Cholinergic innervation of the zebrafish olfactory bulb.

PubMed

Edwards, Jeffrey G; Greig, Ann; Sakata, Yoko; Elkin, Dimitry; Michel, William C

2007-10-20

A number of fish species receive forebrain cholinergic input but two recent reports failed to find evidence of cholinergic cell bodies or fibers in the olfactory bulbs (OBs) of zebrafish. In the current study we sought to confirm these findings by examining the OBs of adult zebrafish for choline acetyltransferase (ChAT) immunoreactivity. We observed a diffuse network of varicose ChAT-positive fibers associated with the nervus terminalis ganglion innervating the mitral cell/glomerular layer (MC/GL). The highest density of these fibers occurred in the anterior region of the bulb. The cellular targets of this cholinergic input were identified by exposing isolated OBs to acetylcholine receptor (AChR) agonists in the presence of agmatine (AGB), a cationic probe that permeates some active ion channels. Nicotine (50 microM) significantly increased the activity-dependent labeling of mitral cells and juxtaglomerular cells but not of tyrosine hydroxlase-positive dopaminergic neurons (TH(+) cells) compared to control preparations. The nAChR antagonist mecamylamine, an alpha7-nAChR subunit-specific antagonist, calcium-free artificial cerebrospinal fluid, or a cocktail of ionotropic glutamate receptor (iGluR) antagonists each blocked nicotine-stimulated labeling, suggesting that AGB does not enter the labeled neurons through activated nAChRs but rather through activated iGluRs following ACh-stimulated glutamate release. Deafferentation of OBs did not eliminate nicotine-stimulated labeling, suggesting that cholinergic input is primarily acting on bulbar neurons. These findings confirm the presence of a functioning cholinergic system in the zebrafish OB.

Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.

PubMed

Patel, Kruti R; Bai, Yan; Trieu, Kenneth G; Barrios, Juliana; Ai, Xingbin

2017-10-01

Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas β2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.-Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. © FASEB.

SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans

PubMed Central

Liu, Ping; Chen, Bojun; Wang, Zhao-Wen

2014-01-01

Slo2 channels are prominent K+ channels in mammalian neurons but their physiological functions are not well understood. Here we investigate physiological functions and regulation of the C. elegans homologue SLO-2 in motor neurons through electrophysiological analyses of wild-type and mutant worms. We find that SLO-2 is the primary K+ channel conducting delayed outward current in cholinergic motor neurons, and one of two K+ channels with this function in GABAergic motor neurons. Loss-of-function mutation of slo-2 increases the duration and charge transfer rate of spontaneous postsynaptic current bursts at the neuromuscular junction, which are physiological signals used by motor neurons to control muscle cells, without altering postsynaptic receptor sensitivity. SLO-2 activity in motor neurons depends on Ca2+ entry through EGL-19, an L-type voltage-gated Ca2+ channel (CaV1), but not on other proteins implicated in either Ca2+ entry or intracellular Ca2+ release. Thus, SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release. PMID:25300429

Cerebellar theta burst stimulation modulates short latency afferent inhibition in Alzheimer's disease patients

PubMed Central

Di Lorenzo, Francesco; Martorana, Alessandro; Ponzo, Viviana; Bonnì, Sonia; D'Angelo, Egidio; Caltagirone, Carlo; Koch, Giacomo

2013-01-01

The dysfunction of cholinergic neurons is a typical hallmark in Alzheimer's disease (AD). Previous findings demonstrated that high density of cholinergic receptors is found in the thalamus and the cerebellum compared with the cerebral cortex and the hippocampus. We aimed at investigating whether activation of the cerebello-thalamo-cortical pathway by means of cerebellar theta burst stimulation (TBS) could modulate central cholinergic functions evaluated in vivo by using the neurophysiological determination of Short-Latency Afferent Inhibition (SLAI). We tested the SLAI circuit before and after administration of cerebellar continuous TBS (cTBS) in 12 AD patients and in 12 healthy age-matched control subjects (HS). We also investigated potential changes of intracortical circuits of the contralateral primary motor cortex (M1) by assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF). SLAI was decreased in AD patients compared to HS. Cerebellar cTBS partially restored SLAI in AD patients at later inter-stimulus intervals (ISIs), but did not modify SLAI in HS. SICI and ICF did not differ in the two groups and were not modulated by cerebellar cTBS. These results demonstrate that cerebellar magnetic stimulation is likely to affect mechanisms of cortical cholinergic activity, suggesting that the cerebellum may have a direct influence on the cholinergic dysfunction in AD. PMID:23423358

Muscimol increases acetylcholine release by directly stimulating adult striatal cholinergic interneurons.

PubMed

Login, I S; Pal, S N; Adams, D T; Gold, P E

1998-01-01

Because GabaA ligands increase acetylcholine (ACh) release from adult striatal slices, we hypothesized that activation of GabaA receptors on striatal cholinergic interneurons directly stimulates ACh secretion. Fractional [3H]ACh release was recorded during perifusion of acutely dissociated, [3H]choline-labeled, adult male rat striata. The GabaA agonist, muscimol, immediately stimulated release maximally approximately 300% with EC50 = approximately 1 microM. This action was enhanced by the allosteric GabaA receptor modulators, diazepam and secobarbital, and inhibited by the GabaA antagonist, bicuculline, by ligands for D2 or muscarinic cholinergic receptors or by low calcium buffer, tetrodotoxin or vesamicol. Membrane depolarization inversely regulated muscimol-stimulated secretion. Release of endogenous and newly synthesized ACh was stimulated in parallel by muscimol without changing choline release. Muscimol pretreatment inhibited release evoked by K+ depolarization or by receptor-mediated stimulation with glutamate. Thus, GabaA receptors on adult striatal cholinergic interneurons directly stimulate voltage- and calcium-dependent exocytosis of ACh stored in vesamicol-sensitive synaptic vesicles. The action depends on the state of membrane polarization and apparently depolarizes the membrane in turn. This functional assay demonstrates that excitatory GabaA actions are not limited to neonatal tissues. GabaA-stimulated ACh release may be prevented in situ by normal tonic dopaminergic and muscarinic input to cholinergic neurons.

Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function.

PubMed

Batool, Zehra; Agha, Faiza; Ahmad, Saara; Liaquat, Laraib; Tabassum, Saiqa; Khaliq, Saima; Anis, Lubna; Sajid, Irfan; Emad, Shaista; Perveen, Tahira; Haider, Saida

2017-01-01

Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium-induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats.

Purinergic and cholinergic components of bladder contractility and flow.

PubMed

Theobald, R J

1995-01-01

The role of ATP as a neurotransmitter/neuromodulator in the urinary tract has been the subject of much study, particularly whether ATP has a functional role in producing urine flow. Recent studies suggested significant species variation, specifically a variation between cat and other species. This study was performed to determine the in vivo response of cat urinary bladder to pelvic nerve stimulation (PNS) and to the exogenous administration of cholinergic and purinergic agents. In anesthetized cats, bladder contractions and fluid expulsion was measured in response to PNS and to the exogenous administration of cholinergic and purinergic agents. Fluid was instilled into the bladder and any fluid expelled by bladder contractions induced by PNS or exogenous agents was collected in a beaker. The volume was measured in a graduated cylinder and recorded. PNS, carbachol and APPCP produced sustained contractions with significant expulsion of fluid. ATP, ACh and hypogastric nerve stimulation did not produce any significant expulsion of fluid. Atropine, a cholinergic antagonist, inhibited PNS contractions and fluid expulsion with no effect on purinergic actions. There was a significant relationship between the magnitude of the contraction, duration of the contractions and volume of fluid expelled. The data and information from other studies, strongly suggests a functional role for ATP as a cotransmitter in the lower urinary tract different from ACh's role. ATP stimulation of a specific purinergic receptor plays a role in initiation of bladder contractions and perhaps in the initiation of urine flow from the bladder. ACh's role is functionally different and appears to be more involved in maintenance of contractile activity and flow.

Targeting the Cholinergic System to Develop a Novel Therapy for Huntington's Disease.

PubMed

D'Souza, Gary X; Waldvogel, Henry J

2016-12-15

In this review, we outline the role of the cholinergic system in Huntington's disease, and briefly describe the dysfunction of cholinergic transmission, cholinergic neurons, cholinergic receptors and cholinergic survival factors observed in post-mortem human brains and animal models of Huntington's disease. We postulate how the dysfunctional cholinergic system can be targeted to develop novel therapies for Huntington's disease, and discuss the beneficial effects of cholinergic therapies in pre-clinical and clinical studies.

Substance P is a functional neurotransmitter in the rat parotid gland.

PubMed

Gallacher, D V

1983-09-01

The technique of electrical field stimulation was employed to stimulate the intrinsic nerves of isolated rat parotid gland fragments. Responses to field stimulation were recorded as changes in enzyme secretion (amylase release), radiolabelled ion fluxes (86Rb efflux) and electrophysiological effects (changes in acinar cell membrane potential and input resistance). All effects of field stimulation were abolished by the neurotoxin, tetrodotoxin (TTX). Selective use of pharmacological antagonists revealed that both the sympathetic and parasympathetic nerves to this tissue were being excited by field stimulation. Importantly a significant component of the response to field stimulation persisted in the presence of combined autonomic receptor blockade by atropine, phentolamine and propranolol, i.e. due to release of a non-cholinergic, non-adrenergic neurotransmitter. The non-cholinergic, non-adrenergic neurotransmitter evoked amylase release, 86Rb efflux and electrophysiological effects seen as changes in acinar cell membrane potential and conductance, i.e. stimulus-permeability coupled. Two biologically active peptides, substance P (SP) and vasoactive intestinal polypeptide (VIP) were shown to evoke amylase release in the presence of combined autonomic blockade. VIP however did not evoke any increase in 86Rb efflux, i.e. not stimulus-permeability coupled. All the effects of the non-cholinergic, non-adrenergic transmitter were mimicked by substance P which evokes 86Rb efflux and electrophysiological effects in addition to amylase release. The non-cholinergic, non-adrenergic field stimulus effects on amylase release and 86Rb efflux were abolished or markedly attenuated in tissues which had been desensitized by prior exposure to exogenous substance P. In the presence of VIP, however, the non-cholinergic, non-adrenergic effects persisted and were apparently potentiated. Acute application of the neurotoxin capsaicin first stimulated a transient release of amylase and subsequently abolished the non-cholinergic, non-adrenergic field stimulus-evoked enzyme release. The putative substance P antagonist, D-Pro2, D-Trp7,9 substance P, reversibly blocked the response to both non-cholinergic, non-adrenergic nerve stimulation and exogenous substance P. It was demonstrated however that prolonged exposure to this antagonist is associated with non-reversible and, importantly, non-specific neurotoxic effects. It is concluded that substance P or a closely related peptide is a functional neurotransmitter in the rat parotid gland.

Functional Consequences of Repeated Organophosphate Exposure: Potential Non-Cholinergic Mechanisms

PubMed Central

Terry, A.V.

2012-01-01

The class of chemicals known as the “organophosphates” (OPs) comprises many of the most common agricultural and commercial pesticides that are used worldwide as well as the highly toxic chemical warfare agents. The mechanism of the acute toxicity of OPs in both target and non-target organisms is primarily attributed to inhibitory actions on various forms of cholinesterase leading to excessive peripheral and central cholinergic activity. However, there is now substantial evidence that this canonical (cholinesterase-based) mechanism cannot alone account for the wide-variety of adverse consequences of OP exposure that have been described, especially those associated with repeated exposures to levels that produce no overt signs of acute toxicity. This type of exposure has been associated with prolonged impairments in attention, memory, and other domains of cognition, as well as chronic illnesses where these symptoms are manifested (e.g., Gulf War Illness, Alzheimer’s disease). Due to their highly reactive nature, it is not surprising that OPs might alter the function of a number of enzymes and proteins (in addition to cholinesterase). However, the wide variety of long-term neuropsychiatric symptoms that have been associated with OPs suggests that some basic or fundamental neuronal process was adversely affected during the exposure period. The purpose of this review is to discuss several non-cholinesterase targets of OPs that might affect such fundamental processes and includes cytoskeletal and motor proteins involved in axonal transport, neurotrophins and their receptors, and mitochondria (especially their morphology and movement in axons). Potential therapeutic implications of these OP interactions are also discussed. PMID:22465060

REM sleep latency and neurocognitive dysfunction in schizophrenia

PubMed Central

Das, Mrinmay; Das, Ruchika; Khastgir, Udayan; Goswami, Utpal

2005-01-01

Background: Cognitive deficits—the hallmark of schizophrenic deterioration—still remain elusive as far as their pathophysiology is concerned. Various neurotransmitter systems have been implicated to explain these deficits. Abnormalities in cholinergic neurotransmission in the brain are one of the postulations; acetylcholine has also been postulated to regulate rapid eye movement (REM) sleep, especially REM latency. Thus, REM latency in patients with schizophrenia might provide a non-invasive window to look into the cholinergic functions of the brain. Aim: To study REM sleep measures and neurocognitive function in schizophrenia, and the changes occurring in these parameters following pharmacological treatment. Methods: Thirty subjects (15 with schizophrenia and 15 normal non-relative controls) were evaluated in this study. Most patients with schizophrenia had prominent negative symptoms and deficits in the performance in neurocognitive tests battery. They were treated with antipsychotics for a variable period of time and post-treatment evaluation was done using the same battery of neurocognitive tests and polysomnography. Patients were either drug-naïve or kept drug-free for at least two weeks both at baseline as well as at the post-treatment stage. Results: A positive correlation between the severity of negative symptoms and neurocognitive deficits (especially on the Wisconsin Card Sorting), and a negative correlation between these two parameters and REM latency was observed. Conclusion: It can be hypothesized that the acetylcholine deficit model of dementia cannot be applied to schizophrenic dementia, rather a hypercholinergic state results. This state warrants anticholinergic medication as a treatment option for negative symptoms of schizophrenia. PMID:20814454

Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo.

PubMed

Kleiman, Robin J; Chapin, Douglas S; Christoffersen, Curt; Freeman, Jody; Fonseca, Kari R; Geoghegan, Kieran F; Grimwood, Sarah; Guanowsky, Victor; Hajós, Mihály; Harms, John F; Helal, Christopher J; Hoffmann, William E; Kocan, Geralyn P; Majchrzak, Mark J; McGinnis, Dina; McLean, Stafford; Menniti, Frank S; Nelson, Fredrick; Roof, Robin; Schmidt, Anne W; Seymour, Patricia A; Stephenson, Diane T; Tingley, Francis David; Vanase-Frawley, Michelle; Verhoest, Patrick R; Schmidt, Christopher J

2012-05-01

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep.

PubMed

Shouse, M N; Siegel, J M

1992-01-31

Transection, lesion and unit recording studies have localized rapid eye movement (REM) sleep mechanisms to the pons. Recent work has emphasized the role of pontine cholinergic cells, especially those of the pedunculopontine tegmentum (PPT). The present study differentiated REM sleep deficits associated with lesions of the PPT from other pontine regions implicated in REM sleep generation, including those with predominantly cholinergic vs non-cholinergic cells. Twelve hour polygraphic recordings were obtained in 18 cats before and 1-2 weeks after bilateral electrolytic or radio frequency lesions of either: (1) PPT, which contains the dorsolateral pontine cholinergic cell column; (2) laterodorsal tegmental nucleus (LDT), which contains the dorsomedial pontine cholinergic cell column; (3) locus ceruleus (LC), which contains mostly noradrenergic cells; or (4) subceruleus (LC alpha, peri-LC alpha and the lateral tegmental field), which also contains predominantly noncholinergic cells. There were three main findings: (i) Only lesions of PPT and subceruleus significantly affected REM sleep time. These lesions produced comparable reductions in REM sleep time but influenced REM sleep components quite differently: (ii) PPT lesions, estimated to damage 90 +/- 4% of cholinergic cells, reduced the number of REM sleep entrances and phasic events, including ponto-geniculooccipital (PGO) spikes and rapid eye movements (REMs), but did not prevent complete atonia during REM sleep: (iii) Subceruleus lesions eliminated atonia during REM sleep. Mobility appeared to arouse the cat prematurely from REM sleep and may explain the brief duration of REM sleep epochs seen exclusively in this group. Despite the reduced amount of REM sleep, the total number of PGO spikes and REM sleep entrances increased over baseline values. Collectively, the results distinguish pontine loci regulating phasic events vs atonia. PPT lesions reduced phasic events, whereas subceruleus lesions created REM sleep without atonia. Severe REM sleep deficits after large pontine lesions, including PPT and subceruleus, might be explained by simultaneous production of both REM sleep syndromes. However, extensive loss of ACh neurons in the PPT does not disrupt REM sleep atonia.

Effects of neonatal handling on the basal forebrain cholinergic system of adult male and female rats.

PubMed

Pondiki, S; Stamatakis, A; Fragkouli, A; Philippidis, H; Stylianopoulou, F

2006-10-13

Neonatal handling is an early experience which results in improved function of the hypothalamic-pituitary-adrenal axis, increased adaptability and coping as a response to stress, as well as better cognitive abilities. In the present study, we investigated the effect of neonatal handling on the basal forebrain cholinergic system, since this system is known to play an important role in cognitive processes. We report that neonatal handling results in increased number of choline-acetyl transferase immunopositive cells in the septum/diagonal band, in both sexes, while no such effect was observed in the other cholinergic nuclei, such as the magnocellular preoptic nucleus and the nucleus basalis of Meynert. In addition, neonatal handling resulted in increased M1 and M2 muscarinic receptor binding sites in the cingulate and piriform cortex of both male and female rats. A handling-induced increase in M1 muscarinic receptor binding sites was also observed in the CA3 and CA4 (fields 3 and 4 of Ammon's horn) areas of the hippocampus. Furthermore, a handling-induced increase in acetylcholinesterase staining was found only in the hippocampus of females. Our results thus show that neonatal handling acts in a sexually dimorphic manner on one of the cholinergic parameters, and has a beneficial effect on BFCS function, which could be related to the more efficient and adaptive stress response and the superior cognitive abilities of handled animals.

β-Amyloid-acetylcholine molecular interaction: new role of cholinergic mediators in anti-Alzheimer therapy?

PubMed

Grimaldi, Manuela; Marino, Sara Di; Florenzano, Fulvio; Ciotta, Maria Teresa; Nori, Stefania Lucia; Rodriquez, Manuela; Sorrentino, Giuseppe; D'Ursi, Anna Maria; Scrima, Mario

2016-07-01

For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation.

Cholinergic Interneurons Are Differentially Distributed in the Human Striatum

PubMed Central

Bernácer, Javier; Prensa, Lucía; Giménez-Amaya, José Manuel

2007-01-01

Background The striatum (caudate nucleus, CN, and putamen, Put) is a group of subcortical nuclei involved in planning and executing voluntary movements as well as in cognitive processes. Its neuronal composition includes projection neurons, which connect the striatum with other structures, and interneurons, whose main roles are maintaining the striatal organization and the regulation of the projection neurons. The unique electrophysiological and functional properties of the cholinergic interneurons give them a crucial modulating function on the overall striatal response. Methodology/Principle Findings This study was carried out using stereological methods to examine the volume and density (cells/mm3) of these interneurons, as visualized by choline acetyltransferase (ChAT) immunoreactivity, in the following territories of the CN and Put of nine normal human brains: 1) precommissural head; 2) postcommissural head; 3) body; 4) gyrus and 5) tail of the CN; 6) precommissural and 7) postcommissural Put. The distribution of ChAT interneurons was analyzed with respect to the topographical, functional and chemical territories of the dorsal striatum. The CN was more densely populated by cholinergic neurons than the Put, and their density increased along the anteroposterior axis of the striatum with the CN body having the highest neuronal density. The associative territory of the dorsal striatum was by far the most densely populated. The striosomes of the CN precommissural head and the postcommissural Put contained the greatest number of ChAT-ir interneurons. The intrastriosomal ChAT-ir neurons were abundant on the periphery of the striosomes throughout the striatum. Conclusions/Significance All these data reveal that cholinergic interneurons are differentially distributed in the distinct topographical and functional territories of the human dorsal striatum, as well as in its chemical compartments. This heterogeneity may indicate that the posterior aspects of the CN require a special integration of information by interneurons. Interestingly, these striatal regions have been very much left out in functional studies. PMID:18080007

White matter lesions and the cholinergic deficit in aging and mild cognitive impairment.

PubMed

Richter, Nils; Michel, Anne; Onur, Oezguer A; Kracht, Lutz; Dietlein, Markus; Tittgemeyer, Marc; Neumaier, Bernd; Fink, Gereon R; Kukolja, Juraj

2017-05-01

In Alzheimer's disease (AD), white matter lesions (WMLs) are associated with an increased risk of progression from mild cognitive impairment (MCI) to dementia, while memory deficits have, at least in part, been linked to a cholinergic deficit. We investigated the relationship between WML load assessed with the Scheltens scale, cerebral acetylcholinesterase (AChE) activity measured with [ 11 C]N-methyl-4-piperidyl acetate PET, and neuropsychological performance in 17 patients with MCI due to AD and 18 cognitively normal older participants. Only periventricular, not nonperiventricular, WML load negatively correlated with AChE activity in both groups. Memory performance depended on periventricular and total WML load across groups. Crucially, AChE activity predicted memory function better than WML load, gray matter atrophy, or age. The effects of WML load on memory were fully mediated by AChE activity. Data suggest that the contribution of WML to the dysfunction of the cholinergic system in MCI due to AD depends on WML distribution. Pharmacologic studies are warranted to explore whether this influences the response to cholinergic treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness

PubMed Central

Papouin, Thomas; Dunphy, Jaclyn; Tolman, Michaela; Dineley, Kelly T.; Haydon, Philip G.

2017-01-01

Summary The activation of the N-methyl D-aspartate receptor (NMDAR) is controlled by a glutamate-binding site and a distinct, independently regulated, co-agonist-binding site. In most brain regions, the NMDAR co-agonist is the astrocyte-derived gliotransmitter D-serine. We found that D-serine levels oscillate in mouse hippocampus as a function of wakefulness, in vitro and in vivo. This causes a full saturation of the NMDAR co-agonist site in the dark (active)-phase that dissipates to sub-saturating levels during the light (sleep)-phase, and influences learning performance throughout the day. We demonstrate that hippocampal astrocytes sense the wakefulness-dependent activity of septal cholinergic fibers through the α7-nicotinic acetylcholine receptor (α7nAChR), whose activation drives D-serine release. We conclude that astrocytes tune the gating of synaptic NMDARs to the vigilance state and demonstrate that this is directly relevant to schizophrenia, a disorder characterized by NMDAR and cholinergic hypofunctions. Indeed, bypassing cholinergic activity with a clinically-tested α7nAChR agonist successfully enhances NMDARs activation. PMID:28479102

Cholinergic Neurotransmission: Function and Dysfunction, International Cholinergic Symposium (8th) Held at Montreal (Quebec) on 26-30 July 1992

DTIC Science & Technology

1992-12-31

receptor were decreased. In the presence of nicotine 1.0pM, the Kd values of rat cerebral muscarinic receptor bound with its agonist P3H] oxotremorine -M...inhibitory effects of GTPrS on [1 3H] oxotremorine -M binding were potentiated.It is suggsted that the binding properties of brain muscarinic receptor...interval) the dose-response curves of M-agonists arecoline and oxotremorine for producing salivation shifted leftward. Above demonstrated phenomena

Future perspectives of a cardiac non-neuronal acetylcholine system targeting cardiovascular diseases as an adjunctive tool for metabolic intervention.

PubMed

Kakinuma, Yoshihiko

2015-11-01

It has been several years since the function of the non-neuronal cholinergic system was independently reported in cardiomyocytes by several research groups. Although these findings initially seemed to be negligible and insignificant, extraordinary findings about cardiomyocytes were subsequently reported in studies involving the knockdown of the non-neuronal cholinergic system. These studies provide the evidence that this system may be indispensable for maintaining principal cardiac functions. Despite the absence of an appropriate and reliable technology to detect cellular ACh in real time in cardiomyocytes, studies of this system have progressed, albeit very slowly, to gradually consolidate the significance of this system. Based on the many significant findings regarding this system, these will be critical to develop adjunctive intervention therapy against cardiovascular diseases, including peripheral artery disease and heart failure. In this study, previous studies focusing on the non-neuronal cholinergic system are reviewed along with our studies, both indicating the biologically significant roles of the cardiac non-neuronal acetylcholine system from a clinical perspective. Copyright © 2015 Elsevier B.V. All rights reserved.

Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta–Gamma Coupling during Cue Detection

PubMed Central

Hetrick, Vaughn L.; Berke, Joshua D.

2017-01-01

The capacity for using external cues to guide behavior (“cue detection”) constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta–gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection. SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding (“cue detection”) is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection. PMID:28213446

A Non-Neuronal Cardiac Cholinergic System Plays a Protective Role in Myocardium Salvage during Ischemic Insults

PubMed Central

Kakinuma, Yoshihiko; Akiyama, Tsuyoshi; Okazaki, Kayo; Arikawa, Mikihiko; Noguchi, Tatsuya; Sato, Takayuki

2012-01-01

Background In our previous study, we established the novel concept of a non-neuronal cardiac cholinergic system–cardiomyocytes produce ACh in an autocrine and/or paracrine manner. Subsequently, we determined the biological significance of this system–it played a critical role in modulating mitochondrial oxygen consumption. However, its detailed mechanisms and clinical implications have not been fully investigated. Aim We investigated if this non-neuronal cardiac cholinergic system was upregulated by a modality other than drugs and if the activation of the system contributes to favorable outcomes. Results Choline acetyltransferase knockout (ChAT KO) cells with the lowest cellular ACh levels consumed more oxygen and had increased MTT activity and lower cellular ATP levels compared with the control cells. Cardiac ChAT KO cells with diminished connexin 43 expression formed poor cell–cell communication, evidenced by the blunted dye transfer. Similarly, the ChAT inhibitor hemicholinium-3 decreased ATP levels and increased MTT activity in cardiomyocytes. In the presence of a hypoxia mimetic, ChAT KO viability was reduced. Norepinephrine dose-dependently caused cardiac ChAT KO cell death associated with increased ROS production. In in vivo studies, protein expression of ChAT and the choline transporter CHT1 in the hindlimb were enhanced after ischemia-reperfusion compared with the contralateral non-treated limb. This local effect also remotely influenced the heart to upregulate ChAT and CHT1 expression as well as ACh and ATP levels in the heart compared with the baseline levels, and more intact cardiomyocytes were spared by this remote effect as evidenced by reduced infarction size. In contrast, the upregulated parameters were abrogated by hemicholinium-3. Conclusion The non-neuronal cholinergic system plays a protective role in both myocardial cells and the entire heart by conserving ATP levels and inhibiting oxygen consumption. Activation of this non-neuronal cardiac cholinergic system by a physiotherapeutic modality may underlie cardioprotection through the remote effect of hindlimb ischemia-reperfusion. PMID:23209825

A non-neuronal cardiac cholinergic system plays a protective role in myocardium salvage during ischemic insults.

PubMed

Kakinuma, Yoshihiko; Akiyama, Tsuyoshi; Okazaki, Kayo; Arikawa, Mikihiko; Noguchi, Tatsuya; Sato, Takayuki

2012-01-01

In our previous study, we established the novel concept of a non-neuronal cardiac cholinergic system--cardiomyocytes produce ACh in an autocrine and/or paracrine manner. Subsequently, we determined the biological significance of this system--it played a critical role in modulating mitochondrial oxygen consumption. However, its detailed mechanisms and clinical implications have not been fully investigated. We investigated if this non-neuronal cardiac cholinergic system was upregulated by a modality other than drugs and if the activation of the system contributes to favorable outcomes. Choline acetyltransferase knockout (ChAT KO) cells with the lowest cellular ACh levels consumed more oxygen and had increased MTT activity and lower cellular ATP levels compared with the control cells. Cardiac ChAT KO cells with diminished connexin 43 expression formed poor cell-cell communication, evidenced by the blunted dye transfer. Similarly, the ChAT inhibitor hemicholinium-3 decreased ATP levels and increased MTT activity in cardiomyocytes. In the presence of a hypoxia mimetic, ChAT KO viability was reduced. Norepinephrine dose-dependently caused cardiac ChAT KO cell death associated with increased ROS production. In in vivo studies, protein expression of ChAT and the choline transporter CHT1 in the hindlimb were enhanced after ischemia-reperfusion compared with the contralateral non-treated limb. This local effect also remotely influenced the heart to upregulate ChAT and CHT1 expression as well as ACh and ATP levels in the heart compared with the baseline levels, and more intact cardiomyocytes were spared by this remote effect as evidenced by reduced infarction size. In contrast, the upregulated parameters were abrogated by hemicholinium-3. The non-neuronal cholinergic system plays a protective role in both myocardial cells and the entire heart by conserving ATP levels and inhibiting oxygen consumption. Activation of this non-neuronal cardiac cholinergic system by a physiotherapeutic modality may underlie cardioprotection through the remote effect of hindlimb ischemia-reperfusion.

Glycogen synthase kinase-3 reduces acetylcholine level in striatum via disturbing cellular distribution of choline acetyltransferase in cholinergic interneurons in rats.

PubMed

Zhao, L; Chu, C-B; Li, J-F; Yang, Y-T; Niu, S-Q; Qin, W; Hao, Y-G; Dong, Q; Guan, R; Hu, W-L; Wang, Y

2013-01-01

Cholinergic interneurons, which provide the main source of acetylcholine (ACh) in the striatum, control the striatal local circuits and deeply involve in the pathogenesis of neurodegenerative diseases. Glycogen synthase kinase-3 (GSK-3) is a crucial kinase with diverse fundamental functions and accepted that deregulation of GSK-3 activity also plays important roles in diverse neurodegenerative diseases. However, up to now, there is no direct proof indicating whether GSK-3 activation is responsible for cholinergic dysfunction. In the present study, with combined intracerebroventricular injection of Wortmannin and GF-109203X, we activated GSK-3 and demonstrated the increased phosphorylation level of microtubule-associated protein tau and neurofilaments (NFs) in the rat striatum. The activated GSK-3 consequently decreased ACh level in the striatum as a result of the reduction of choline acetyltransferase (ChAT) activity. The alteration of ChAT activity was due to impaired ChAT distribution rather than its expression. Furthermore, we proved that cellular ChAT distribution was dependent on low phosphorylation level of NFs. Nevertheless, the cholinergic dysfunction in the striatum failed to induce significant neuronal number reduction. In summary, our data demonstrates the link between GSK-3 activation and cholinergic dysfunction in the striatum and provided beneficial evidence for the pathogenesis study of relevant neurodegenerative diseases. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Mangifera indica Fruit Extract Improves Memory Impairment, Cholinergic Dysfunction, and Oxidative Stress Damage in Animal Model of Mild Cognitive Impairment

PubMed Central

Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-Mee, Wipawee; Ingkaninan, Kornkanok; Wittaya-Areekul, Sakchai

2014-01-01

To date, the effective preventive paradigm against mild cognitive impairment (MCI) is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180–200 g, were orally given the extract at doses of 12.5, 50, and 200 mg·kg−1 BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv). At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg·kg−1 BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism. PMID:24672632

Mangifera indica fruit extract improves memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment.

PubMed

Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-Mee, Wipawee; Ingkaninan, Kornkanok; Wittaya-Areekul, Sakchai

2014-01-01

To date, the effective preventive paradigm against mild cognitive impairment (MCI) is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180-200 g, were orally given the extract at doses of 12.5, 50, and 200 mg · kg(-1) BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv). At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg · kg(-1) BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism.

Septohippocampal Acetylcholine: Involved in but not Necessary for Learning and Memory?

PubMed Central

Parent, Marise B.; Baxter, Mark G.

2006-01-01

The neurotransmitter acetylcholine (ACh) has been accorded an important role in supporting learning and memory processes in the hippocampus. Cholinergic activity in the hippocampus is correlated with memory, and restoration of ACh in the hippocampus after disruption of the septohippocampal pathway is sufficient to rescue memory. However, selective ablation of cholinergic septohippocampal projections is largely without effect on hippocampal-dependent learning and memory processes. We consider the evidence underlying each of these statements, and the contradictions they pose for understanding the functional role of hippocampal ACh in memory. We suggest that although hippocampal ACh is involved in memory in the intact brain, it is not necessary for many aspects of hippocampal memory function. PMID:14747512

Deanol in the treatment of tardive dyskinesia.

PubMed

Casey, D E; Denny, D

1975-08-01

A patient who developed severe tardive dyskinesia after the termination of long-term phenothiazine therapy was successfully treated with deanol, a possible precursor of acetylcholine. Physiological measurements were obtained to quantify the clinical course. The authors discuss the practical and heuristic implications of these observations and suggest further consideration of therapy directed toward enhancement of cholinergic activity in the central nervous system.

Reciprocal cholinergic and GABAergic modulation of the small ventrolateral pacemaker neurons of Drosophila's circadian clock neuron network.

PubMed

Lelito, Katherine R; Shafer, Orie T

2012-04-01

The relatively simple clock neuron network of Drosophila is a valuable model system for the neuronal basis of circadian timekeeping. Unfortunately, many key neuronal classes of this network are inaccessible to electrophysiological analysis. We have therefore adopted the use of genetically encoded sensors to address the physiology of the fly's circadian clock network. Using genetically encoded Ca(2+) and cAMP sensors, we have investigated the physiological responses of two specific classes of clock neuron, the large and small ventrolateral neurons (l- and s-LN(v)s), to two neurotransmitters implicated in their modulation: acetylcholine (ACh) and γ-aminobutyric acid (GABA). Live imaging of l-LN(v) cAMP and Ca(2+) dynamics in response to cholinergic agonist and GABA application were well aligned with published electrophysiological data, indicating that our sensors were capable of faithfully reporting acute physiological responses to these transmitters within single adult clock neuron soma. We extended these live imaging methods to s-LN(v)s, critical neuronal pacemakers whose physiological properties in the adult brain are largely unknown. Our s-LN(v) experiments revealed the predicted excitatory responses to bath-applied cholinergic agonists and the predicted inhibitory effects of GABA and established that the antagonism of ACh and GABA extends to their effects on cAMP signaling. These data support recently published but physiologically untested models of s-LN(v) modulation and lead to the prediction that cholinergic and GABAergic inputs to s-LN(v)s will have opposing effects on the phase and/or period of the molecular clock within these critical pacemaker neurons.

Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species

PubMed Central

Blanchard, Alexandra; Charvet, Claude L.; Sauvé, Christine; Duguet, Thomas; O’Connor, Vincent; Castagnone-Sereno, Philippe; Wolstenholme, Adrian J.; Beech, Robin N.; Holden-Dye, Lindy

2018-01-01

Cholinergic agonists such as levamisole and pyrantel are widely used as anthelmintics to treat parasitic nematode infestations. These drugs elicit spastic paralysis by activating acetylcholine receptors (AChRs) expressed in nematode body wall muscles. In the model nematode Caenorhabditis elegans, genetic screens led to the identification of five genes encoding levamisole-sensitive-AChR (L-AChR) subunits: unc-38, unc-63, unc-29, lev-1 and lev-8. These subunits form a functional L-AChR when heterologously expressed in Xenopus laevis oocytes. Here we show that the majority of parasitic species that are sensitive to levamisole lack a gene orthologous to C. elegans lev-8. This raises important questions concerning the properties of the native receptor that constitutes the target for cholinergic anthelmintics. We demonstrate that the closely related ACR-8 subunit from phylogenetically distant animal and plant parasitic nematode species functionally substitutes for LEV-8 in the C. elegans L-AChR when expressed in Xenopus oocytes. The importance of ACR-8 in parasitic nematode sensitivity to cholinergic anthelmintics is reinforced by a ‘model hopping’ approach in which we demonstrate the ability of ACR-8 from the hematophagous parasitic nematode Haemonchus contortus to fully restore levamisole sensitivity, and to confer high sensitivity to pyrantel, when expressed in the body wall muscle of C. elegans lev-8 null mutants. The critical role of acr-8 to in vivo drug sensitivity is substantiated by the successful demonstration of RNAi gene silencing for Hco-acr-8 which reduced the sensitivity of H. contortus larvae to levamisole. Intriguingly, the pyrantel sensitivity remained unchanged thus providing new evidence for distinct modes of action of these important anthelmintics in parasitic species versus C. elegans. More broadly, this highlights the limits of C. elegans as a predictive model to decipher cholinergic agonist targets from parasitic nematode species and provides key molecular insight to inform the discovery of next generation anthelmintic compounds. PMID:29719008

Nuclear 82-kDa choline acetyltransferase decreases amyloidogenic APP metabolism in neurons from APP/PS1 transgenic mice.

PubMed

Albers, Shawn; Inthathirath, Fatima; Gill, Sandeep K; Winick-Ng, Warren; Jaworski, Ewa; Wong, Daisy Y L; Gros, Robert; Rylett, R Jane

2014-09-01

Alzheimer disease (AD) is associated with increased amyloidogenic processing of amyloid precursor protein (APP) to β-amyloid peptides (Aβ), cholinergic neuron loss with decreased choline acetyltransferase (ChAT) activity, and cognitive dysfunction. Both 69-kDa ChAT and 82-kDa ChAT are expressed in cholinergic neurons in human brain and spinal cord with 82-kDa ChAT localized predominantly to neuronal nuclei, suggesting potential alternative functional roles for the enzyme. By gene microarray analysis, we found that 82-kDa ChAT-expressing IMR32 neural cells have altered expression of genes involved in diverse cellular functions. Importantly, genes for several proteins that regulate APP processing along amyloidogenic and non-amyloidogenic pathways are differentially expressed in 82-kDa ChAT-containing cells. The predicted net effect based on observed changes in expression patterns of these genes would be decreased amyloidogenic APP processing with decreased Aβ production. This functional outcome was verified experimentally as a significant decrease in BACE1 protein levels and activity and a concomitant reduction in the release of endogenous Aβ1-42 from neurons cultured from brains of AD-model APP/PS1 transgenic mice. The expression of 82-kDa ChAT in neurons increased levels of GGA3, which is involved in trafficking BACE1 to lysosomes for degradation. shRNA-induced decreases in GGA3 protein levels attenuated the 82-kDa ChAT-mediated decreases in BACE1 protein and activity and Aβ1-42 release. Evidence that 82-kDa ChAT can enhance GGA3 gene expression is shown by enhanced GGA3 gene promoter activity in SN56 neural cells expressing this ChAT protein. These studies indicate a novel relationship between cholinergic neurons and APP processing, with 82-kDa ChAT acting as a negative regulator of Aβ production. This decreased formation of Aβ could result in protection for cholinergic neurons, as well as protection of other cells in the vicinity that are sensitive to increased levels of Aβ. Decreasing levels of 82-kDa ChAT due to increasing age or neurodegeneration could alter the balance towards increasing Aβ production, with this potentiating the decline in function of cholinergic neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice

PubMed Central

Hemmati, Ali Asghar; Ahangarpour, Akram

2018-01-01

The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30–35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice. PMID:29719448

Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice.

PubMed

Hemmati, Ali Asghar; Alboghobeish, Soheila; Ahangarpour, Akram

2018-05-01

The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30-35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice.

Potential Mechanisms Underlying Intercortical Signal Regulation via Cholinergic Neuromodulators

PubMed Central

Whittington, Miles A.; Kopell, Nancy J.

2015-01-01

The dynamical behavior of the cortex is extremely complex, with different areas and even different layers of a cortical column displaying different temporal patterns. A major open question is how the signals from different layers and different brain regions are coordinated in a flexible manner to support function. Here, we considered interactions between primary auditory cortex and adjacent association cortex. Using a biophysically based model, we show how top-down signals in the beta and gamma regimes can interact with a bottom-up gamma rhythm to provide regulation of signals between the cortical areas and among layers. The flow of signals depends on cholinergic modulation: with only glutamatergic drive, we show that top-down gamma rhythms may block sensory signals. In the presence of cholinergic drive, top-down beta rhythms can lift this blockade and allow signals to flow reciprocally between primary sensory and parietal cortex. SIGNIFICANCE STATEMENT Flexible coordination of multiple cortical areas is critical for complex cognitive functions, but how this is accomplished is not understood. Using computational models, we studied the interactions between primary auditory cortex (A1) and association cortex (Par2). Our model is capable of replicating interaction patterns observed in vitro and the simulations predict that the coordination between top-down gamma and beta rhythms is central to the gating process regulating bottom-up sensory signaling projected from A1 to Par2 and that cholinergic modulation allows this coordination to occur. PMID:26558772

Pharmacological identification of cholinergic receptor subtypes on Drosophila melanogaster larval heart.

PubMed

Malloy, Cole A; Ritter, Kyle; Robinson, Jonathan; English, Connor; Cooper, Robin L

2016-01-01

The Drosophila melanogaster heart is a popular model in which to study cardiac physiology and development. Progress has been made in understanding the role of endogenous compounds in regulating cardiac function in this model. It is well characterized that common neurotransmitters act on many peripheral and non-neuronal tissues as they flow through the hemolymph of insects. Many of these neuromodulators, including acetylcholine (ACh), have been shown to act directly on the D. melanogaster larval heart. ACh is a primary neurotransmitter in the central nervous system (CNS) of vertebrates and at the neuromuscular junctions on skeletal and cardiac tissue. In insects, ACh is the primary excitatory neurotransmitter of sensory neurons and is also prominent in the CNS. A full understanding regarding the regulation of the Drosophila cardiac physiology by the cholinergic system remains poorly understood. Here we use semi-intact D. melanogaster larvae to study the pharmacological profile of cholinergic receptor subtypes, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), in modulating heart rate (HR). Cholinergic receptor agonists, nicotine and muscarine both increase HR, while nAChR agonist clothianidin exhibits no significant effect when exposed to an open preparation at concentrations as low as 100 nM. In addition, both nAChR and mAChR antagonists increase HR as well but also display capabilities of blocking agonist actions. These results provide evidence that both of these receptor subtypes display functional significance in regulating the larval heart's pacemaker activity.

Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter.

PubMed

English, Brett A; Appalsamy, Martin; Diedrich, Andre; Ruggiero, Alicia M; Lund, David; Wright, Jane; Keller, Nancy R; Louderback, Katherine M; Robertson, David; Blakely, Randy D

2010-09-01

Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT(-/-)) mice exhibit early postnatal lethality, CHT heterozygous (CHT(+/-)) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT(+/-) mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT(+/-) mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT(+/-) mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.

Treatment effects in multiple cognitive domains in Alzheimer’s disease: a two-year cohort study

PubMed Central

2014-01-01

Introduction Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort. Methods A cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE). Results At one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function. Conclusions The present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system. PMID:25484926

Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer's disease.

PubMed

Soodi, Maliheh; Saeidnia, Soodabeh; Sharifzadeh, Mohammad; Hajimehdipoor, Homa; Dashti, Abolfazl; Sepand, Mohammad Reza; Moradi, Shahla

2016-04-01

Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Aβ was injected into the hippocampus of each rat bilaterally (10 μg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Aβ injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Aβ impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Aβ-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Aβ- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Aβ- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Aβ-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Aβ-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD.

Effects of lateral fluid percussion injury on cholinergic markers in the newborn piglet brain.

PubMed

Donat, Cornelius K; Walter, Bernd; Kayser, Tanja; Deuther-Conrad, Winnie; Schliebs, Reinhard; Nieber, Karen; Bauer, Reinhard; Härtig, Wolfgang; Brust, Peter

2010-02-01

Traumatic brain injury is a leading cause of death and disability in children. Studies using adult animal models showed alterations of the central cholinergic neurotransmission as a result of trauma. However, there is a lack of knowledge about consequences of brain trauma on cholinergic function in the immature brain. It is hypothesized that trauma affects the relative acetylcholine esterase activity and causes a loss of cholinergic neurons in the immature brain. Severe fluid percussion trauma (FP-TBI, 3.8+/-0.3atm) was induced in 15 female newborn piglets, monitored for 6h and compared with 12 control animals. The hemispheres ipsilateral to FP-TBI obtained from seven piglets were used for acetylcholine esterase histochemistry on frozen sagittal slices, while regional cerebral blood flow and oxygen availability was determined in the remaining eight FP-TBI animals. Post-fixed slices were immunohistochemically labelled for choline acetyltransferase as well as for low-affinity neurotrophin receptor in order to characterize cholinergic neurons in the basal forebrain. Regional cerebral blood flow and brain oxygen availability were reduced during the first 2h after FP-TBI (P<0.05). In addition, acetylcholine esterase activity was significantly increased in the neocortex, basal forebrain, hypothalamus and medulla after trauma (P<0.05), whereas the number of choline acetyltransferase and low-affinity neurotrophin receptor positive cells in the basal forebrain were unaffected by the injury. Thus, traumatic brain injury evoked an increased relative activity of the acetylcholine esterase in the immature brain early after injury, without loss of cholinergic neurons in the basal forebrain. These changes may contribute to developmental impairments after immature traumatic brain injury. Copyright 2009 ISDN. Published by Elsevier Ltd. All rights reserved.

Immunotoxic cholinergic lesions in the basal forebrain reverse the effects of entorhinal cortex lesions on conditioned odor aversion in the rat.

PubMed

Ferry, Barbara; Herbeaux, Karin; Cosquer, Brigitte; Traissard, Natalia; Galani, Rodrigue; Cassel, Jean-Christophe

2007-07-01

Conditioned odor aversion (COA) corresponds to the avoidance of an odorized-tasteless solution (conditioned stimulus, CS) previously paired with toxicosis. COA occurs only when the interstimulus interval (ISI) is kept short, suggesting that the memory trace of the odor is subject to rapid decay. Previous experiments have shown that the entorhinal cortex (EC) is involved in the acquisition of COA, since lesion of the EC rendered COA tolerant to long ISI. Because EC lesions induce a septo-hippocampal cholinergic sprouting, the present experiment investigated whether COA tolerance to long ISI may be linked to this sprouting reaction. In a first experiment, male Long-Evans rats subjected to bilateral excitotoxic EC lesions combined to intracerebroventricular infusions of the selective cholinergic immunotoxin 192 IgG-saporin were exposed to odor-toxicosis pairing using a long ISI (120 min). Results showed that EC-lesioned rats displayed COA with the long ISI but not the control groups. In rats with EC combined to 192 IgG-saporin lesions, histological analysis demonstrated no evidence for cholinergic septo-hippocampal sprouting. In a second experiment, animals with 192-IgG saporin lesion showed a marked COA with a short ISI (5 min). These results suggest that the COA with the long ISI found in rats with EC lesions might involve a functional activity related to the EC lesion-induced hippocampal cholinergic sprouting. As the injection of 192 IgG-saporin alone did not affect COA with a short ISI, our data also point to a possible role of hippocampal cholinergic neurons in the modulation of memory processes underlying COA.

Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease.

PubMed

Pienaar, Ilse S; Gartside, Sarah E; Sharma, Puneet; De Paola, Vincenzo; Gretenkord, Sabine; Withers, Dominic; Elson, Joanna L; Dexter, David T

2015-09-23

Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.

Increased acetylcholine esterase activity produced by the administration of an aqueous extract of the seed kernel of Thevetia peruviana and its role on acute and subchronic intoxication in mice

PubMed Central

Marroquín-Segura, Rubén; Calvillo-Esparza, Ricardo; Mora-Guevara, José Luis Alfredo; Tovalín-Ahumada, José Horacio; Aguilar-Contreras, Abigail; Hernández-Abad, Vicente Jesús

2014-01-01

Background: The real mechanism for Thevetia peruviana poisoning remains unclear. Cholinergic activity is important for cardiac function regulation, however, the effect of T. peruviana on cholinergic activity is not well-known. Objective: To study the effect of the acute administration of an aqueous extract of the seed kernel of T. peruviana on the acetylcholine esterase (AChE) activity in CD1 mice as well its implications in the sub-chronic toxicity of the extract. Materials and Methods: A dose of 100 mg/kg of the extract was administered to CD1 mice and after 7 days, serum was obtained for ceruloplasmin (CP) quantitation and liver function tests. Another group of mice received a 50 mg/kg dose of the extract 3 times within 1 h time interval and AChE activity was determined for those animals. Heart tissue histological preparation was obtained from a group of mice that received a daily 50 mg/kg dose of the extract by a 30-days period. Results: CP levels for the treated group were higher than those for the control group (Student's t-test, P ≤ 0.001). AChE activity in the treated group was significantly higher than the control group (Tukey test, control vs. T. peruviana, P ≤ 0.001). Heart tissue histological preparations showed leukocyte infiltrates and necrotic areas, consistent with infarcts. Conclusion: The increased levels of AChE and the hearth tissue infiltrative lesions induced by the aqueous seed kernel extract of T. peruviana explains in part the poisoning caused by this plant, which can be related to an inflammatory process. PMID:24914300

Increased acetylcholine esterase activity produced by the administration of an aqueous extract of the seed kernel of Thevetia peruviana and its role on acute and subchronic intoxication in mice.

PubMed

Marroquín-Segura, Rubén; Calvillo-Esparza, Ricardo; Mora-Guevara, José Luis Alfredo; Tovalín-Ahumada, José Horacio; Aguilar-Contreras, Abigail; Hernández-Abad, Vicente Jesús

2014-01-01

The real mechanism for Thevetia peruviana poisoning remains unclear. Cholinergic activity is important for cardiac function regulation, however, the effect of T. peruviana on cholinergic activity is not well-known. To study the effect of the acute administration of an aqueous extract of the seed kernel of T. peruviana on the acetylcholine esterase (AChE) activity in CD1 mice as well its implications in the sub-chronic toxicity of the extract. A dose of 100 mg/kg of the extract was administered to CD1 mice and after 7 days, serum was obtained for ceruloplasmin (CP) quantitation and liver function tests. Another group of mice received a 50 mg/kg dose of the extract 3 times within 1 h time interval and AChE activity was determined for those animals. Heart tissue histological preparation was obtained from a group of mice that received a daily 50 mg/kg dose of the extract by a 30-days period. CP levels for the treated group were higher than those for the control group (Student's t-test, P ≤ 0.001). AChE activity in the treated group was significantly higher than the control group (Tukey test, control vs. T. peruviana, P ≤ 0.001). Heart tissue histological preparations showed leukocyte infiltrates and necrotic areas, consistent with infarcts. The increased levels of AChE and the hearth tissue infiltrative lesions induced by the aqueous seed kernel extract of T. peruviana explains in part the poisoning caused by this plant, which can be related to an inflammatory process.

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, Pranay; Yadav, Rajesh S.; Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenicmore » exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected by curcumin • Functional and structural changes in mitochondria by arsenic protected by curcumin.« less

Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays.

PubMed

Hammond, Mark W; Xydas, Dimitris; Downes, Julia H; Bucci, Giovanna; Becerra, Victor; Warwick, Kevin; Constanti, Andrew; Nasuto, Slawomir J; Whalley, Benjamin J

2013-03-26

Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat ('artificial animal') applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown. Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion. We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.

Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems.

PubMed

Coppola, Jennifer J; Disney, Anita A

2018-01-01

Acetylcholine (ACh) is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies. The results of these studies have been combined into singular models of function-a practice based on an implicit assumption that the various model systems are equivalent and interchangeable. However, comparative anatomy both within and across species reveals important differences in the structure of the cholinergic system. Here, we will review anatomical data including innervation patterns, receptor expression, synthesis and release compared across species and cortical area with a focus on rodents and primates. We argue that these data suggest no canonical cortical model system exists for the cholinergic system. Further, we will argue that as a result, care must be taken both in combining data from studies across cortical areas and species, and in choosing the best model systems to improve our understanding and support of human health.

Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet

PubMed Central

Molina, Judith; Rodriguez-Diaz, Rayner; Fachado, Alberto; Jacques-Silva, M. Caroline

2014-01-01

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeostasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is primarily a paracrine signal released from α-cells rather than primarily a neural signal as in rodent islets. In this study, we demonstrate that the effects acetylcholine produces in the human islet are different and more complex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcholine not only stimulates the insulin-secreting β-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting δ-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin secretion, we hypothesized that cholinergic input to the δ-cell indirectly regulates β-cell function. Indeed, when all muscarinic signaling was blocked, somatostatin secretion decreased and insulin secretion unexpectedly increased, suggesting a reduced inhibitory input to β-cells. Endogenous cholinergic signaling therefore provides direct stimulatory and indirect inhibitory input to β-cells to regulate insulin secretion from the human islet. PMID:24658304

Catecholaminergic and cholinergic systems of mouse brain are modulated by LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids.

PubMed

Fernández-Fernández, Laura; Esteban, Gerard; Giralt, Mercedes; Valente, Tony; Bolea, Irene; Solé, Montse; Sun, Ping; Benítez, Susana; Morelló, José Ramón; Reguant, Jordi; Ramírez, Bartolomé; Hidalgo, Juan; Unzeta, Mercedes

2015-04-01

The possible modulatory effect of the functional LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids, on the catecholaminergic and cholinergic neurotransmission, affecting cognition decline during aging has been studied. 129S1/SvlmJ mice were fed for 10, 20, 30 and 40 days with either LMN or control diets. The enzymes involved in catecholaminergic and cholinergic metabolism were determined by both immunohistological and western blot analyses. Noradrenalin, dopamine and other metabolites were quantified by HPLC analysis. Theobromine, present in cocoa, the main LMN diet component, was analysed in parallel using SH-SY5Y and PC12 cell lines. An enhanced modulatory effect on both cholinergic and catecholaminergic transmissions was observed on 20 day fed mice. Similar effect was observed with theobromine, besides its antioxidant capacity inducing SOD-1 and GPx expression. The enhancing effect of the LMN diet and theobromine on the levels of acetylcholine-related enzymes, dopamine and specially noradrenalin confirms the beneficial role of this diet on the "cognitive reserve" and hence a possible reducing effect on cognitive decline underlying aging and Alzheimer's disease.

Effects of scopolamine on morphine-induced conditioned place preference in mice.

PubMed

Tan, Hua; Liu, Ning; Wilson, Fraser A W; Ma, Yuanye

2007-09-01

It is well known that the cholinergic system plays a crucial role in learning and memory. Psychopharmacological studies in humans and animals have shown that a systemic cholinergic blockade may induce deficits in learning and memory. Accumulated studies have indicated that learning and memory play an important role in drug addition. In the present study, in order to get a further understanding about the functions of the cholinergic system in drug-related learning and memory, we examined the effects of scopolamine (0.5, 1.0 and 2.0 mg/kg) on morphine-induced conditioned place preference (CPP). Two kinds of morphine exposure durations (4 days and 12 days) were used. The main finding was that all doses of scopolamine enhanced the extinction of morphine-induced CPP in mice treated with morphine for 12 days. However, in mice treated with morphine for 4 days, all doses of scopolamine did not inhibit morphine-induced CPP. The highest dose (2.0 mg/kg) of scopolamine even significantly delayed the extinction of morphine-induced CPP. Our results suggest that the effects of a systemic cholinergic blockade on morphine-induced CPP depend on the morphine exposure time.

Elimination of GRK2 from cholinergic neurons reduces behavioral sensitivity to muscarinic receptor activation.

PubMed

Daigle, Tanya L; Caron, Marc G

2012-08-15

Although G-protein-coupled receptor kinase 2 (GRK2) is the most widely studied member of a family of kinases that has been shown to exert powerful influences on a variety of G-protein-coupled receptors, its role in the brain remains largely unknown. Here we report the localization of GRK2 in the mouse brain and generate novel conditional knock-out (KO) mice to assess the physiological importance of this kinase in cholinergic neurons. Mice with the selective deletion of GRK2 in this cell population (ChAT(IRES-cre)Grk2(f/f) KO mice) exhibit reduced behavioral responsiveness to challenge with oxotremorine-M (Oxo-M), a nonselective muscarinic acetylcholine receptor agonist. Specifically, Oxo-M-induced hypothermia, hypolocomotion, and salivation were markedly reduced in these animals, while analgesic responses were unaltered. In contrast, we found that GRK2 deficiency in cholinergic neurons does not alter cocaine-induced psychomotor activation, behavioral sensitization, or conditioned place preference. These results demonstrate that the elimination of GRK2 in cholinergic neurons reduces sensitivity to select muscarinic-mediated behaviors, while dopaminergic effects remain intact and further suggests that GRK2 may selectively impair muscarinic acetylcholine receptor-mediated function in vivo.

Cerebellar nicotinic cholinergic receptors are intrinsic to the cerebellum: implications for diverse functional roles.

PubMed

Turner, Jill R; Ortinski, Pavel I; Sherrard, Rachel M; Kellar, Kenneth J

2011-12-01

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum.

Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

PubMed Central

Turner, Jill R.; Ortinski, Pavel I.; Sherrard, Rachel M.

2016-01-01

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum. PMID:21562921

Calcium Imaging of Basal Forebrain Activity during Innate and Learned Behaviors

PubMed Central

Harrison, Thomas C.; Pinto, Lucas; Brock, Julien R.; Dan, Yang

2016-01-01

The basal forebrain (BF) plays crucial roles in arousal, attention, and memory, and its impairment is associated with a variety of cognitive deficits. The BF consists of cholinergic, GABAergic, and glutamatergic neurons. Electrical or optogenetic stimulation of BF cholinergic neurons enhances cortical processing and behavioral performance, but the natural activity of these cells during behavior is only beginning to be characterized. Even less is known about GABAergic and glutamatergic neurons. Here, we performed microendoscopic calcium imaging of BF neurons as mice engaged in spontaneous behaviors in their home cages (innate) or performed a go/no-go auditory discrimination task (learned). Cholinergic neurons were consistently excited during movement, including running and licking, but GABAergic and glutamatergic neurons exhibited diverse responses. All cell types were activated by overt punishment, either inside or outside of the discrimination task. These findings reveal functional similarities and distinctions between BF cell types during both spontaneous and task-related behaviors. PMID:27242444

"Old drugs" for the treatment of rheumatoid arthritis: will the cholinergic anti-inflammatory pathway and anti-nociceptive pathway work?

PubMed

Pan, Xiaohua; Yu, Xiaowei; Qin, Ling; Zhang, Peng

2010-12-01

Based on the newly discovered cholinergic anti-inflammatory pathway, on the anti-nociceptive pathway and on our preliminary research, we raise a new strategy for the treatment of rheumatoid arthritis (RA) which mainly focuses on the application of old drugs that can activate both of the above mentioned pathways. It has been reported that nicotinic receptor agonists used for the treatment of neurological diseases were expected to be applied to the therapy of inflammatory diseases (RA). Therefore, it is promising that old drugs available in clinics may exert new functions for the treatment of RA, which may greatly reduce the expense of such treatment, once applied. These currently-used old drugs should be considered as another new resource in exploring anti-rheumatic agents under the guidance of the newly discovered cholinergic anti-inflammatory pathway and the anti-nociceptive pathway.

Thyroid hormone modulates the development of cholinergic terminal fields in the rat forebrain: relation to nerve growth factor receptor.

PubMed

Oh, J D; Butcher, L L; Woolf, N J

1991-04-24

Hyperthyroidism, induced in rat pups by the daily intraperitoneal administration of 1 microgram/g body weight triiodothyronine, facilitated the development of ChAT fiber plexuses in brain regions innervated by basal forebrain cholinergic neurons, leading to an earlier and increased expression of cholinergic markers in those fibers in the cortex, hippocampus and amygdala. A similar enhancement was seen in the caudate-putamen complex. This histochemical profile was correlated with an accelerated appearance of ChAT-positive telencephalic puncta, as well as with a larger total number of cholinergic terminals expressed, which persisted throughout the eight postnatal week, the longest time examined in the present study. Hypothyroidism was produced in rat pups by adding 0.5% propylthiouracil to the dams' diet beginning the day after birth. This dietary manipulation resulted in the diminished expression of ChAT in forebrain fibers and terminals. Hypothyroid treatment also reduced the quantity of ChAT puncta present during postnatal weeks 2 and 3, and, from week 4 and continuing through week 6, the number of ChAT-positive terminals in the telencephalic regions examined was actually less than the amount extant during the former developmental epoch. Immunostaining for nerve growth factor receptor (NGF-R), which is associated almost exclusively with ChAT-positive somata and fibers in the basal forebrain, demonstrated a different time course of postnatal development. Forebrain fibers and terminals demonstrating NGF-R were maximally visualized 1 week postnatally, a time at which these same neuronal elements evinced minimal ChAT-like immunopositivity. Thereafter and correlated with increased immunoreactivity for ChAT, fine details of NGF-R stained fibers were observed less frequently. Although propylthiouracil administration decreased NGF-R immunodensity, no alteration in the development of that receptor was observed as a function of triiodothyronine treatment. Cholinergic terminals in the ventrobasal thalamus, which derive from ChAT-positive neurons in the pedunculopontine and laterodorsal tegmental nucleus, were unaffected by either hyperthyroid or hypothyroid conditions. These cells also do not demonstrate NGF-R. We conclude from these experiments (1) that cholinergic fiber plexuses eventually exhibiting ChAT positivity in the telencephalon demonstrate NGF-R prior to the cholinergic synthetic enzyme, (2) that susceptibility to thyroid hormone manipulations may involve sensitivity to NGF, at least in some forebrain cholinergic systems and (3) that the effects of thyroid hormone imbalances on brain cholinergic neurons are regionally selective.

Cholinergic and nitrergic neuronal networks in the goldfish telencephalon.

PubMed

Giraldez-Perez, Rosa M; Gaytan, Susana P; Pasaro, Rosario

2013-01-01

The general organization of cholinergic and nitrergic elements in the central nervous system seems to be highly conserved among vertebrates, with the involvement of these neurotransmitter systems now well established in sensory, motor and cognitive processing. The goldfish is a widely used animal model in neuroanatomical, neurophysiological, and behavioral research. The purpose of this study was to examine pallial and subpallial cholinoceptive, cholinergic and nitrergic populations in the goldfish telencephalon by means of histochemical and immunohistochemical techniques in order to identify neurons containing acetylcholinesterase (AChE), choline acetyltransferase (ChAT), NADPH-diaphorase (NADPHd), and neuronal nitric oxide synthase (nNOS), and to relate their distribution to their putative functional significance. Regions containing AChE-labeled neurons represented terminal fields of cholinergic inputs as well as a widespread distribution of AChE-related enzymes; these regions also usually contained NADPHd-labeled neurons and often contained small numbers of nNOS-positive cells. However, the ventral subdivisions of the medial and lateral parts of the dorsal telencephalic area, and the ventral and lateral parts of the ventral telencephalic area, were devoid of nNOS-labeled cells. ChAT-positive neurons were found only in the lateral part of the ventral telencephalic area. ChAT- and nNOS-positive fibers exhibited a radial orientation, and were seen as thin axons with en-passant boutons. The distribution of these elements could help to elucidate the role of cholinergic and nitrergic neuronal networks in the goldfish telencephalon.

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function.

PubMed

Sarter, Martin; Albin, Roger L; Kucinski, Aaron; Lustig, Cindy

2014-07-01

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson's disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive-behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional-motor integration by striatal circuitry. Copyright © 2014 Elsevier Inc. All rights reserved.

Changes in Ca(2+) channel expression upon differentiation of SN56 cholinergic cells.

PubMed

Kushmerick, C; Romano-Silva, M A; Gomez, M V; Prado, M A

2001-10-19

The SN56 cell line, a fusion of septal neurons and neuroblastoma cells, has been used as a model for central cholinergic neurons. These cells show increased expression of cholinergic neurochemical features upon differentiation, but little is known about how differentiation affects their electrophysiological properties. We examined the changes in Ca(2+) channel expression that occur as these cells undergo morphological differentiation in response to serum withdrawal and exposure to dibutyryl-cAMP. Undifferentiated cells expressed a T-type current with biophysical and pharmacological properties similar, although not identical, to those reported for the current generated by the alpha(1H) (CaV3.2) Ca(2+) channel subunit. Differentiated cells expressed, in addition to this T-type current, high voltage activated currents which were inhibited 38% by the L-type channel antagonist nifedipine (5 microM), 37% by the N-type channel antagonist omega-conotoxin-GVIA (1 microM), and 15% by the P/Q-type channel antagonist omega-agatoxin-IVA (200 nM). Current resistant to these inhibitors accounted for 15% of the high voltage activated current in differentiated SN56 cells. Our data demonstrate that differentiation increases the expression of neuronal type voltage gated Ca(2+) channels in this cell line, and that the channels expressed are comparable to those reported for native basal forebrain cholinergic neurons. This cell line should thus provide a useful model system to study the relationship between calcium currents and cholinergic function and dysfunction.

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease.

PubMed

Kwakowsky, Andrea; Milne, Michael R; Waldvogel, Henry J; Faull, Richard L

2016-12-17

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

PubMed Central

Kwakowsky, Andrea; Milne, Michael R.; Waldvogel, Henry J.; Faull, Richard L.

2016-01-01

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease. PMID:27999310

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function

PubMed Central

Sarter, Martin; Albin, Roger L.; Kucinski, Aaron; Lustig, Cindy

2015-01-01

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson’s disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive–behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional–motor integration by striatal circuitry. PMID:24805070

Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

PubMed Central

Rothermel, Markus; Carey, Ryan M.; Puche, Adam; Shipley, Michael T.

2014-01-01

Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment. PMID:24672011

The role of cholinergic and peptidergic pathways in the regulation of pancreatic exocrine function during postnatal development in pigs.

PubMed

Lesniewska, V; Gregard, A; Weström, B; Hedemann, M S; Laerke, H N; Kruszewska, D; Pierzynowski, S G

2001-05-01

The aim of this study was to investigate the role of the parasympathetic (cholinergic and peptidergic) nervous system in the regulation of exocrine pancreas function in piglets during their early postnatal development. The cholinergic and peptidergic regulatory pathways of exocrine pancreatic function were tested by the specific muscarinic receptor blocker 4-diphenylacetoxy-N-methylpiperidine-methiodide (4-DAMP) and bombesin, respectively. At the age of 2 weeks, piglets were surgically fitted with a chronic pancreatic duct catheter, a duodenal re-entrant cannula and a jugular vein catheter. The experiments comprised a pre-weaning period, and a post-weaning period that commenced at the beginning of the 5th week of age. Intravenous infusion of 4-DAMP (100 pmol x kg(-1) x h(-1)) reduced the outflow of pancreatic juice, the output of total protein and the activity of trypsin, chymotrypsin, carboxyl ester hydrolase and amylase during preprandial and postprandial pancreatic secretion, in both the pre- and post-weaning periods. However, the inhibitory effect of 4-DAMP during postprandial secretion was significantly greater (P < 0.05) in suckling piglets. The infusion of bombesin (10, 100 and 1000 pmol x kg(-1) x h(-1)) stimulated exocrine pancreatic secretion in a dose-dependent manner during both the pre- and post-weaning periods. However, the stimulatory effect of 1000 pmol x kg(-1) x h(-1) bombesin on total protein output and the activities of trypsin, chymotrypsin and amylase were significantly higher (P < 0.05) in suckling piglets. In summary, our study showed that cholinergic and peptidergic mechanisms are involved in the regulation of exocrine pancreas function in piglets in both the pre- and post-weaning stages. 4-DAMP had a greater inhibitory effect on exocrine pancreatic secretion in piglets during the pre-weaning period. Thus, these observations suggest that the parasympathetic nervous system plays a dominant role in the functioning of the exocrine pancreas at this time. The action of bombesin suggests that it is a potent secretagogue for the exocrine pancreas in pigs during their postnatal development.

Review. Neurobiology of nicotine dependence.

PubMed

Markou, Athina

2008-10-12

Nicotine is a psychoactive ingredient in tobacco that significantly contributes to the harmful tobacco smoking habit. Nicotine dependence is more prevalent than dependence on any other substance. Preclinical research in animal models of the various aspects of nicotine dependence suggests a critical role of glutamate, gamma-aminobutyric acid (GABA), cholinergic and dopamine neurotransmitter interactions in the ventral tegmental area and possibly other brain sites, such as the central nucleus of the amygdala and the prefrontal cortex, in the effects of nicotine. Specifically, decreasing glutamate transmission or increasing GABA transmission with pharmacological manipulations decreased the rewarding effects of nicotine and cue-induced reinstatement of nicotine seeking. Furthermore, early nicotine withdrawal is characterized by decreased function of presynaptic inhibitory metabotropic glutamate 2/3 receptors and increased expression of postsynaptic glutamate receptor subunits in limbic and frontal brain sites, while protracted abstinence may be associated with increased glutamate response to stimuli associated with nicotine administration. Finally, adaptations in nicotinic acetylcholine receptor function are also involved in nicotine dependence. These neuroadaptations probably develop to counteract the decreased glutamate and cholinergic transmission that is hypothesized to characterize early nicotine withdrawal. In conclusion, glutamate, GABA and cholinergic transmission in limbic and frontal brain sites are critically involved in nicotine dependence.

Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection.

PubMed

Howe, William M; Gritton, Howard J; Lusk, Nicholas A; Roberts, Erik A; Hetrick, Vaughn L; Berke, Joshua D; Sarter, Martin

2017-03-22

The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection. SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection. Copyright © 2017 the authors 0270-6474/17/373215-16$15.00/0.

Modulation of social deficits and repetitive behaviors in a mouse model of autism: the role of the nicotinic cholinergic system.

PubMed

Wang, Li; Almeida, Luis E F; Spornick, Nicholas A; Kenyon, Nicholas; Kamimura, Sayuri; Khaibullina, Alfia; Nouraie, Mehdi; Quezado, Zenaide M N

2015-12-01

Accumulating evidence implicates the nicotinic cholinergic system in autism spectrum disorder (ASD) pathobiology. Neuropathologic studies suggest that nicotinic acetylcholine (ACh) receptor (nAChR) subtypes are altered in brain of autistic individuals. In addition, strategies that increase ACh, the neurotransmitter for nicotinic and muscarinic receptors, appear to improve cognitive deficits in neuropsychiatric disorders and ASD. The aim of this study is to examine the role of the nicotinic cholinergic system on social and repetitive behavior abnormalities and exploratory physical activity in a well-studied model of autism, the BTBR T(+) Itpr3 (tf) /J (BTBR) mouse. Using a protocol known to up-regulate expression of brain nAChR subtypes, we measured behavior outcomes before and after BTBR and C57BL/6J (B6) mice were treated (4 weeks) with vehicle or nicotine (50, 100, 200, or 400 μg/ml). Increasing nicotine doses were associated with decreases in water intake, increases in plasma cotinine levels, and at the higher dose (400 μg/ml) with weight loss in BTBR mice. At lower (50, 100 μg/ml) but not higher (200, 400 μg/ml) doses, nicotine increased social interactions in BTBR and B6 mice and at higher, but not lower doses, it decreased repetitive behavior in BTBR. In the open-field test, nicotine at 200 and 400 μg/ml, but not 100 μg/ml compared with vehicle, decreased overall physical activity in BTBR mice. These findings support the hypotheses that the nicotinic cholinergic system modulates social and repetitive behaviors and may be a therapeutic target to treat behavior deficits in ASD. Further, the BTBR mouse may be valuable for investigations of the role of nAChRs in social deficits and repetitive behavior.

Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition

PubMed Central

Brown, Ritchie E.; Hussain Shuler, Marshall G.; Petersen, Carl C.H.; Kepecs, Adam

2015-01-01

The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders. SIGNIFICANCE STATEMENT Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity. PMID:26468190

Suppression of noise-induced hyperactivity in the dorsal cochlear nucleus following application of the cholinergic agonist, carbachol

PubMed Central

Manzoor, N.F.; Chen, G.; Kaltenbach, J.A.

2013-01-01

Increased spontaneous firing (hyperactivity) is induced in fusiform cells of the dorsal cochlear nucleus (DCN) following intense sound exposure and is implicated as a possible neural correlate of noise-induced tinnitus. Previous studies have shown that in normal hearing animals, fusiform cell activity can be modulated by activation of parallel fibers, which represent the axons of granule cells. The modulation consists of a transient excitation followed by a more prolonged period of inhibition, presumably reflecting direct excitatory inputs to fusiform cells and an indirect inhibitory input to fusiform cells from the granule cell-cartwheel cell system. We hypothesized that since granule cells can be activated by cholinergic inputs, it might be possible to suppress tinnitus-related hyperactivity of fusiform cells using the cholinergic agonist, carbachol. To test this hypothesis, we recorded multiunit spontaneous activity in the fusiform soma layer (FSL) of the DCN in control and tone-exposed hamsters (10 kHz, 115 dB SPL, 4 h) before and after application of carbachol to the DCN surface. In both exposed and control animals, 100 µM carbachol had a transient excitatory effect on spontaneous activity followed by a rapid weakening of activity to near or below normal levels. In exposed animals, the weakening of activity was powerful enough to completely abolish the hyperactivity induced by intense sound exposure. This suppressive effect was partially reversed by application of atropine and was not associated with significant changes in neural best frequencies (BF) or BF thresholds. These findings demonstrate that noise-induced hyperactivity can be pharmacologically controlled and raise the possibility that attenuation of tinnitus may be achievable by using an agonist of the cholinergic system. PMID:23721928

Suppression of noise-induced hyperactivity in the dorsal cochlear nucleus following application of the cholinergic agonist, carbachol.

PubMed

Manzoor, N F; Chen, G; Kaltenbach, J A

2013-07-26

Increased spontaneous firing (hyperactivity) is induced in fusiform cells of the dorsal cochlear nucleus (DCN) following intense sound exposure and is implicated as a possible neural correlate of noise-induced tinnitus. Previous studies have shown that in normal hearing animals, fusiform cell activity can be modulated by activation of parallel fibers, which represent the axons of granule cells. The modulation consists of a transient excitation followed by a more prolonged period of inhibition, presumably reflecting direct excitatory inputs to fusiform cells and an indirect inhibitory input to fusiform cells from the granule cell-cartwheel cell system. We hypothesized that since granule cells can be activated by cholinergic inputs, it might be possible to suppress tinnitus-related hyperactivity of fusiform cells using the cholinergic agonist, carbachol. To test this hypothesis, we recorded multiunit spontaneous activity in the fusiform soma layer (FSL) of the DCN in control and tone-exposed hamsters (10 kHz, 115 dB SPL, 4h) before and after application of carbachol to the DCN surface. In both exposed and control animals, 100 μM carbachol had a transient excitatory effect on spontaneous activity followed by a rapid weakening of activity to near or below normal levels. In exposed animals, the weakening of activity was powerful enough to completely abolish the hyperactivity induced by intense sound exposure. This suppressive effect was partially reversed by application of atropine and was usually not associated with significant changes in neural best frequencies (BF) or BF thresholds. These findings demonstrate that noise-induced hyperactivity can be pharmacologically controlled and raise the possibility that attenuation of tinnitus may be achievable by using an agonist of the cholinergic system. Copyright © 2013 Elsevier B.V. All rights reserved.

The Caenorhabditis elegans choline transporter CHO-1 sustains acetylcholine synthesis and motor function in an activity-dependent manner.

PubMed

Matthies, Dawn Signor; Fleming, Paul A; Wilkes, Don M; Blakely, Randy D

2006-06-07

Cholinergic neurotransmission supports motor, autonomic, and cognitive function and is compromised in myasthenias, cardiovascular diseases, and neurodegenerative disorders. Presynaptic uptake of choline via the sodium-dependent, hemicholinium-3-sensitive choline transporter (CHT) is believed to sustain acetylcholine (ACh) synthesis and release. Analysis of this hypothesis in vivo is limited in mammals because of the toxicity of CHT antagonists and the early postnatal lethality of CHT-/- mice (Ferguson et al., 2004). In Caenorhabditis elegans, in which cholinergic signaling supports motor activity and mutant alleles impacting ACh secretion and response can be propagated, we investigated the contribution of CHT (CHO-1) to facets of cholinergic neurobiology. Using the cho-1 promoter to drive expression of a translational, green fluorescent protein-CHO-1 fusion (CHO-1:GFP) in wild-type and kinesin (unc-104) mutant backgrounds, we establish in the living nematode that the transporter localizes to cholinergic synapses, and likely traffics on synaptic vesicles. Using embryonic primary cultures, we demonstrate that CHO-1 mediates hemicholinium-3-sensitive, high-affinity choline uptake that can be enhanced with depolarization in a Ca(2+)-dependent manner supporting ACh synthesis. Although homozygous cho-1 null mutants are viable, they possess 40% less ACh than wild-type animals and display stress-dependent defects in motor activity. In a choline-free liquid environment, cho-1 mutants demonstrate premature paralysis relative to wild-type animals. Our findings establish a requirement for presynaptic choline transport activity in vivo in a model amenable to a genetic dissection of CHO-1 regulation.

Hippocampal theta, gamma, and theta-gamma coupling: effects of aging, environmental change, and cholinergic activation

PubMed Central

Jacobson, Tara K.; Howe, Matthew D.; Schmidt, Brandy; Hinman, James R.; Escabí, Monty A.

2013-01-01

Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics of encoding and retrieval. One major influence on hippocampal rhythmicity is from cholinergic afferents. In both humans and rodents, aging is linked to impairments in hippocampus-dependent function along with degradation of cholinergic function. Cholinomimetics can reverse some age-related memory impairments and modulate oscillations in the hippocampus. Therefore, one would expect corresponding changes in these oscillations and possible rescue with the cholinomimetic physostigmine. Hippocampal activity was recorded while animals explored a familiar or a novel maze configuration. Reexposure to a familiar situation resulted in minimal aging effects or changes in theta or gamma oscillations. In contrast, exploration of a novel maze configuration increased theta power; this was greater in adult than old animals, although the deficit was reversed with physostigmine. In contrast to the theta results, the effects of novelty, age, and/or physostigmine on gamma were relatively weak. Unrelated to the behavioral situation were an age-related decrease in the degree of theta-gamma coupling and the fact that physostigmine lowered the frequency of theta in both adult and old animals. The results indicate that age-related changes in gamma and theta modulation of gamma, while reflecting aging changes in hippocampal circuitry, seem less related to aging changes in information processing. In contrast, the data support a role for theta and the cholinergic system in encoding and that hippocampal aging is related to impaired encoding of new information. PMID:23303862

Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice.

PubMed

Palotai, Miklós; Telegdy, Gyula; Jászberényi, Miklós

2014-07-01

Orexins are hypothalamic neuropeptides, which are involved in several physiological functions of the central nervous system, including anxiety and stress. Several studies provide biochemical and behavioral evidence about the anxiogenic action of orexin A. However, we have little evidence about the underlying neuromodulation. Therefore, the aim of the present study was to investigate the involvement of neurotransmitters in the orexin A-induced anxiety-like behavior in elevated plus maze (EPM) test in mice. Accordingly, mice were pretreated with a non-selective muscarinic cholinergic antagonist, atropine; a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; a non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol 30min prior to the intracerebroventricular administration of orexin A. The EPM test started 30min after the i.c.v. injection of the neuropeptide. Our results show that orexin A decreases significantly the time spent in the arms (open/open+closed) and this action is reversed by bicuculline, phenoxybenzamine and propranolol, but not by atropine, haloperidol or nitro-l-arginine. Our results provide evidence for the first time that the orexin A-induced anxiety-like behavior is mediated through GABA-A-ergic, α- and β-adrenergic neurotransmissions, whereas muscarinic cholinergic, dopaminergic and nitrergic neurotransmissions may not be implicated. Copyright © 2014 Elsevier Inc. All rights reserved.

Variable expression of GFP in different populations of peripheral cholinergic neurons of ChATBAC-eGFP transgenic mice.

PubMed

Brown, T Christopher; Bond, Cherie E; Hoover, Donald B

2018-03-01

Immunohistochemistry is used widely to identify cholinergic neurons, but this approach has some limitations. To address these problems, investigators developed transgenic mice that express enhanced green fluorescent protein (GFP) directed by the promoter for choline acetyltransferase (ChAT), the acetylcholine synthetic enzyme. Although, it was reported that these mice express GFP in all cholinergic neurons and non-neuronal cholinergic cells, we could not detect GFP in cardiac cholinergic nerves in preliminary experiments. Our goals for this study were to confirm our initial observation and perform a qualitative screen of other representative autonomic structures for the presences of GFP in cholinergic innervation of effector tissues. We evaluated GFP fluorescence of intact, unfixed tissues and the cellular localization of GFP and vesicular acetylcholine transporter (VAChT), a specific cholinergic marker, in tissue sections and intestinal whole mounts. Our experiments identified two major tissues where cholinergic neurons and/or nerve fibers lacked GFP: 1) most cholinergic neurons of the intrinsic cardiac ganglia and all cholinergic nerve fibers in the heart and 2) most cholinergic nerve fibers innervating airway smooth muscle. Most cholinergic neurons in airway ganglia stained for GFP. Cholinergic systems in the bladder and intestines were fully delineated by GFP staining. GFP labeling of input to ganglia with long preganglionic projections (vagal) was sparse or weak, while that to ganglia with short preganglionic projections (spinal) was strong. Total absence of GFP might be due to splicing out of the GFP gene. Lack of GFP in nerve projections from GFP-positive cell bodies might reflect a transport deficiency. Copyright © 2017 Elsevier B.V. All rights reserved.

The character of sleep disturbances produced by multiple administrations of atropine the antagonist of brain muscarinic cholinergic system.

PubMed

Maglakelidze, N T; Chkhartishvili, E V; Mchedlidze, O M; Dzadzamiia, Sh Sh; Nachkebiia, N G

2012-03-01

Modification of brain muscarinic cholinergic system normal functioning can be considered as an appropriate strategy for the study of its role in sleep-wakefulness cycle basic mechanisms in general and in the course/maintenance of PS in particular. For this aim systemic application of muscarinic cholinoreceptors antagonists is significant because it gives possibility to modify functioning all of known five sub-types of muscarinic cholinoreceptors and to study the character of sleep disturbances in these conditions. Problem is very topical because the question about the intimate aspects of BMChS involvement in PS maintaining mechanisms still remains unsolved. In cats Atropine systemic administration was made once daily at 10:00 a.m. and continuous EEG registration of sleep-wakefulness cycle ultradian structure, lasting for 10 hour daily, was started immediately. In sum each animal received anti-muscarinic drugs for 12 times. Thereafter drug administrations were ceased and EEG registration of sleep-wakefulness cycle ultradian structure was continued during 10 consecutive days. On the basis of results obtained in these conditions we can conclude that brain muscarinic cholinergic system normal functioning is significant for basic mechanisms of sleep-wakefulness cycle. During wakefulness, at the level of neocortex and hippocampus, MChS supports only EEG activation, while it is one of the main factors in PS triggering and maintaining mechanisms.

Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter

PubMed Central

English, Brett A.; Appalsamy, Martin; Diedrich, Andre; Ruggiero, Alicia M.; Lund, David; Wright, Jane; Keller, Nancy R.; Louderback, Katherine M.; Robertson, David

2010-01-01

Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT−/−) mice exhibit early postnatal lethality, CHT heterozygous (CHT+/−) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT+/− mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT+/− mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT+/− mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease. PMID:20601463

The role of nicotinic receptors in shaping and functioning of the glutamatergic system: a window into cognitive pathology.

PubMed

Molas, Susanna; Dierssen, Mara

2014-10-01

The involvement of the cholinergic system in learning, memory and attention has long been recognized, although its neurobiological mechanisms are not fully understood. Recent evidence identifies the endogenous cholinergic signaling via nicotinic acetylcholine receptors (nAChRs) as key players in determining the morphological and functional maturation of the glutamatergic system. Here, we review the available experimental and clinical evidence of nAChRs contribution to the establishment of the glutamatergic system, and therefore to cognitive function. We provide some clues of the putative underlying molecular mechanisms and discuss recent human studies that associate genetic variability of the genes encoding nAChR subunits with cognitive disorders. Finally, we discuss the new avenues to therapeutically targeting nAChRs in persons with cognitive dysfunction for which the α7-nAChR subunit is an important etiological mechanism. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cholinergic Mesopontine Signals Govern Locomotion and Reward Through Dissociable Midbrain Pathways

PubMed Central

Xiao, Cheng; Cho, Jounhong Ryan; Zhou, Chunyi; Treweek, Jennifer B.; Chan, Ken; McKinney, Sheri L.; Yang, Bin; Gradinaru, Viviana

2016-01-01

The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons, however although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders. PMID:27100197

Frontal Decortication and Adaptive Changes in Striatal Cholinergic Neurons: Neuropharmacological and Behavioral Implications

DTIC Science & Technology

1989-11-24

ACh); choline (Oh); apomnorphine (APO); oxotremorine (OTMN); OXI, oxiracetam; SDHACU, sodium-dependent high affinity choline uptake: PC...control group, Dunnett’s test. TABLE 3- Restoration of the ACh increasing effect of oxotremorine by piracetam in DC rats. Striatal ACh content (nmoles/g...ACh content induced by oxotremorine and apomorphine useful model for studying means to restore the deficit in stria- acting at muscarine and dopamine

Novel Food Supplement "CP1" Improves Motor Deficit, Cognitive Function, and Neurodegeneration in Animal Model of Parkinson's Disease.

PubMed

Wattanathorn, Jintanaporn; Sutalangka, Chatchada

2016-08-01

Based on pivotal roles of oxidative stress, dopaminergic and cholinergic systems on the pathophysiology of Parkinson's disease (PD), the searching for functional food for patients attacked with PD from Cyperus rotundus and Zingiber officinale, the substances possessing antioxidant activity, and the suppression effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) have been considered. In this study, we aimed to determine the effect of the combined extract of C. rotundus and Z. officinale (CP1) to improve motor and memory deficits, neurodegeneration, oxidative stress, and functions of both cholinergic and dopaminergic systems in the animal model of PD induced by 6-hydroxydopamine hydrochloride (6-OHDA). Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantia nigra by 6-OHDA and were orally given CP1 at doses of 100, 200, and 300 mg/kg body weight for 14 days after 6-OHDA injection. The results showed that the 6-OHDA rats treated with CP1 increased spatial memory, but decreased neurodegeneration, malondialdehyde level, and AChE activity in hippocampus. The decreased motor disorder and neurodegeneration in substantia nigra together with the enhanced catalase activity, but decreased MAO-B activity in striatum, were also observed. The memory enhancing effect of CP1 might occur through the improved oxidative stress and the enhanced cholinergic function, whereas the effect to improve motor disorder of CP1 might occur through the enhanced dopaminergic function in striatum by decreasing the degeneration of dopaminergic neurons and the suppression of MAO-B. Therefore, CP1 is the potential functional food against PD. However, further researches in clinical trial and drug interactions are essential.

α5 nAChR modulation of the prefrontal cortex makes attention resilient.

PubMed

Howe, William M; Brooks, Julie L; Tierney, Patrick L; Pang, Jincheng; Rossi, Amie; Young, Damon; Dlugolenski, Keith; Guillmette, Ed; Roy, Marc; Hales, Katherine; Kozak, Rouba

2018-03-01

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated. In the present studies, we used RNA interference to knockdown the α5 nAChR subunit in the PFC of adult rats. We provide evidence that through its contribution to cholinergic modulation of cholinergic modulation of neurons in the PFC, the α5 nAChR plays a specific role in the recovery of attention task performance following distraction. Our combined data reveal the potent ability of this subunit to modulate the PFC and cognitive functions controlled by this brain region that are impaired in disease.

In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention

PubMed Central

Lindner, Michael; Bell, Tiffany; Iqbal, Somya; Mullins, Paul Gerald

2017-01-01

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans. PMID:28192451

Heterogeneous targeting of centrifugal inputs to the glomerular layer of the main olfactory bulb.

PubMed

Gómez, C; Briñón, J G; Barbado, M V; Weruaga, E; Valero, J; Alonso, J R

2005-06-01

The centrifugal systems innervating the olfactory bulb are important elements in the functional regulation of the olfactory pathway. In this study, the selective innervation of specific glomeruli by serotonergic, noradrenergic and cholinergic centrifugal axons was analyzed. Thus, the morphology, distribution and density of positive axons were studied in the glomerular layer of the main olfactory bulb of the rat, using serotonin-, serotonin transporter- and dopamine-beta-hydroxylase-immunohistochemistry and acetylcholinesterase histochemistry in serial sections. Serotonin-, serotonin transporter-immunostaining and acetylcholinesterase-staining revealed a higher heterogeneity in the glomerular layer of the main olfactory bulb than previously reported. In this sense, four types of glomeruli could be identified according to their serotonergic innervation. The main distinctive feature of these four types of glomeruli was their serotonergic fibre density, although they also differed in their size, morphology and relative position throughout the rostro-caudal main olfactory bulb. In this sense, some specific regions of the glomerular layer were occupied by glomeruli with a particular morphology and a characteristic serotonergic innervation pattern that was consistent from animal to animal. Regarding the cholinergic system, we offer a new subclassification of glomeruli based on the distribution of cholinergic fibres in the glomerular structure. Finally, the serotonergic and cholinergic innervation patterns were compared in the glomerular layer. Sexual differences concerning the density of serotonergic fibres were observed in the atypical glomeruli (characterized by their strong cholinergic innervation). The present report provides new data on the heterogeneity of the centrifugal innervation of the glomerular layer that constitutes the morphological substrate supporting the existence of differential modulatory levels among the entire glomerular population.

Effect of Placenta-Derived Mesenchymal Stem Cells in a Dementia Rat Model via Microglial Mediation: a Comparison between Stem Cell Transplant Methods.

PubMed

Cho, Jae Sung; Lee, Jihyeon; Jeong, Da Un; Kim, Han Wool; Chang, Won Seok; Moon, Jisook; Chang, Jin Woo

2018-05-01

Loss of cholinergic neurons in the hippocampus is a hallmark of many dementias. Administration of stem cells as a therapeutic intervention for patients is under active investigation, but the optimal stem cell type and transplantation modality has not yet been established. In this study, we studied the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyzed their mechanisms of therapeutic action. Dementia modeling was established by intraventricular injection of 192 IgG-saporin, which causes lesion of cholinergic neurons. Sixty-five male Sprague-Dawley rats were divided into five groups: control, lesion, lesion+ICV injection of pMSCs, lesion+IV injection of pMSCs, and lesion+donepezil. Rats were subjected to the Morris water maze and subsequent immunostaining analyses. Both ICV and IV pMSC administrations allowed significant cognitive recovery compared to the lesioned rats. Acetylcholinesterase activity was significantly rescued in the hippocampus of rats injected with pMSCs post-lesion. Choline acetyltransferase did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Number of microglial cells increased in lesioned rats and significantly decreased back to normal levels with pMSC injection. Our results suggest that ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons. © Copyright: Yonsei University College of Medicine 2018.

Transplantation of NSC-derived cholinergic neuron-like cells improves cognitive function in APP/PS1 transgenic mice.

PubMed

Gu, G; Zhang, W; Li, M; Ni, J; Wang, P

2015-04-16

The ability to selectively control the differentiation of neural stem cells (NSCs) into cholinergic neurons in vivo would be an important step toward cell replacement therapy. First, green fluorescent protein (GFP)-NSCs were induced to differentiate into cholinergic neuron-like cells (CNLs) with retinoic acid (RA) pre-induction followed by nerve growth factor (NGF) induction. Then, these CNLs were transplanted into bilateral hippocampus of APP/PS1 transgenic mice. Behavioral parameters showed by Morris water maze (MWM) tests and the percentages of GFP-labeled cholinergic neurons of CNL transplanted mice were compared with those of controls. Brain levels of choline acetyltransferase (ChAT) mRNA and proteins were analyzed by quantitative real-time PCR and Western blotting, ChAT activity and acetylcholine (ACh) concentration were also evaluated by ChAT activity and ACh concentration assay kits. Immunofluorescence analysis showed that 80.3±1.5% NSCs differentiated into CNLs after RA pre-induction followed by NGF induction in vitro. Three months after transplantation, 82.4±6.3% CNLs differentiated into cholinergic neurons in vivo. APP/PS1 mice transplanted with CNLs showed a significant improvement in learning and memory ability compared with control groups at different time points. Furthermore, CNLs transplantation dramatically increased in the expressions of ChAT mRNA and protein, as well ChAT activity and ACh concentration in APP/PS1 mice. Our findings support the prospect of using NSC-derived CNLs in developing therapies for Alzheimer's disease (AD). Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Urtica dioica leaves modulates muscarinic cholinergic system in the hippocampus of streptozotocin-induced diabetic mice.

PubMed

Patel, Sita Sharan; Parashar, Arun; Udayabanu, Malairaman

2015-06-01

Diabetes mellitus is a chronic metabolic disorder and has been associated with cognitive dysfunction. In our earlier study, chronic Urtica dioica (UD) treatment significantly ameliorated diabetes induced associative and spatial memory deficit in mice. The present study was designed to explore the effect of UD leaves extract on muscarinic cholinergic system, which has long been known to be involved in cognition. Streptozotocin (STZ) (50 mg/kg, i.p., consecutively for 5 days) was used to induce diabetes followed by treatment with UD extract (50 mg/kg, oral) or rosiglitazone (5 mg/kg, oral) for 8 weeks. STZ-induced diabetic mice showed significant reduction in hippocampal muscarinic acetylcholine receptor-1 and choline acetyltransferase expressions. Chronic diabetes significantly up-regulated the protein expression of acetylcholinesterase associated with oxidative stress in hippocampus. Besides, STZ-induced diabetic mice showed hypolocomotion with up-regulation of muscarinic acetylcholine receptor-4 expression in striatum. Chronic UD treatment significantly attenuated the cholinergic dysfunction and oxidative stress in the hippocampus of diabetic mice. UD had no effect on locomotor activity and muscarinic acetylcholine receptor-4 expression in striatum. In conclusion, UD leaves extract has potential to reverse diabetes mediated alteration in muscarinic cholinergic system in hippocampus and thereby improve memory functions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krall, J.F.; Morin, A.

Cells growing in culture with previously described properties of rat uterine smooth muscle accumulated /sup 45/Ca/sup 2 +/ from the medium. Ca/sup 2 +/ uptake by these cells was stimulated by the addition to the medium of 8-bromo-cGMP but not by 8-bromo-cAMP. Ca/sup 2 +/ uptake was also stimulated by carbachol and by the nitro-vasodilator nitroprusside. Although cholinergic agonists have been shown previously to stimulate contraction but not cGMP synthesis in the rat myometrium, both carbachol and nitroprusside stimulated cGMP production by the cultured cells. These results suggested the cells had cholinergic receptor-medicated functions that reflected some neurotransmitter-sensitive properties ofmore » uterine smooth muscle in situ. When determined by a specific radioligand binding assay, subcellular fractions of the cultured cells bound muscarinic cholinergic agonists and antagonists with affinities expected of the muscarinic receptor. The cells were also sensitive to the ..beta..-adrenergic catecholamine agonist isoproterenol, which stimulated cAMP production but not Ca/sup 2 +/ uptake. Carbachol failed to inhibit isoproterenol-dependent cAMP production, which is an important property of the cholinergic receptor in uterine smooth muscle in situ. These results suggest some but not all acetylcholine-sensitive properties of uterine smooth muscle may be retained in cell culture.« less

Nuclear organization and morphology of cholinergic, putative catecholaminergic and serotonergic neurons in the brain of the rock hyrax, Procavia capensis.

PubMed

Gravett, Nadine; Bhagwandin, Adhil; Fuxe, Kjell; Manger, Paul R

2009-09-01

The nuclear subdivisions of the cholinergic, putative catecholaminergic and serotonergic systems within the brain of the rock hyrax (Procavia capensis) were identified following immunohistochemistry for acetylcholinesterase, tyrosine hydroxylase and serotonin. The aim of the present study was to investigate possible differences in the complement of nuclear subdivisions of these systems by comparing those of the rock hyrax to published studies of other mammals. The rock hyrax belongs to the order Hyracoidea and forms part of the Afroplacentalia mammalian cohort. For the most part, the nuclear organization of these three systems closely resembled that described for many other mammalian species. The nuclear organization of the serotonergic system was identical to that seen in all eutherian mammals. The nuclear organization of the putative catecholaminergic system was very similar to that seen in rodents except for the lack of a C3 nucleus and the compact division of the locus coeruleus (A6c). In addition, the diffuse locus coeruleus (A6d) appeared to contain very few tyrosine hydroxylase immunoreactive (TH+) neurons. The cholinergic system showed many features in common with that seen in both rodents and primates; however, there were three differences of note: (1) cholinergic neurons were observed in the anterior nuclei of the dorsal thalamus; (2) cholinergic parvocellular nerve cells, probably representing interneurons, forming subdivisions of the laterodorsal and pedunculopontine tegmental nuclei were observed at the midbrain/pons interface; and (3) a large number of cholinergic nerve cells in the periventricular grey of the medulla oblongata were observed. Thus, while there are many similarities to other mammalian species, the nuclear organization of these systems in the rock hyrax shows specific differences to what has been observed previously in other mammals. These differences are discussed in both a functional and phylogenetic perspective.

Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors tropomyosin-related kinase A and p75.

PubMed

Hoard, J L; Hoover, D B; Mabe, A M; Blakely, R D; Feng, N; Paolocci, N

2008-09-22

Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e. synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine beta-hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs), like those of humans, have a complex neurochemical phenotype that goes beyond the classical view of cardiac parasympathetic neurons. They also suggest that neurotrophins and local NE synthesis might have important effects on neurons of the mouse ICG.

Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors TrkA and p75

PubMed Central

Hoard, Jennifer L.; Hoover, Donald B.; Mabe, Abigail M.; Blakely, Randy D.; Feng, Ning; Paolocci, Nazareno

2008-01-01

Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart express enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e., synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine β-hydroxylase (DBH) and NE transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs), like those of humans, have a complex neurochemical phenotype that goes beyond the classical view of cardiac parasympathetic neurons. They also suggest that neurotrophins and local NE synthesis might have important effects on neurons of the mouse ICG. PMID:18674600

[Cholinergic anti-inflammatory pathway of some non-pharmacological therapies of complementary medicine: possible implications for treatment of rheumatic and autoimmune diseases].

PubMed

Gamus, Dorit

2011-08-01

Rheumatologic and autoimmune diseases are among foremost diseases for which patients seek complementary and integrative medicine options. Therefore, physicians should be informed on the advances in research of these therapies, in order to be able to discuss possible indications and contraindications for these treatment modalities with their patients. This review summarizes several therapeutic modalities of complementary medicine that may be involved in the cholinergic anti-inflammatory pathway. The analysis of systematic reviews of acupuncture for rheumatic conditions has concluded that the evidence is sufficiently sound to warrant positive recommendations of this therapy for osteoarthritis, low back pain and lateral elbow pain. There is relatively strong evidence to support the use of hypnosis in pain treatment, such as in cases of fibromyalgia. A recent controlled study that evaLuated tai-chi in fibromyalgia has reported reductions in pain, improvements in mood, quality of Life, self efficacy and exercise capacity. There is also cumulative evidence that acupuncture, hypnosis and tai-chi may decrease the high frequency of heart rate variability, suggesting enhancement of vagus nerve activity. Hence, it has been hypothesized that these modalities might impact the cholinergic anti-inflammatory pathway to modulate inflammation. Further clinical and basic research to confirm this hypothesis should be performed in order to validate integration of these therapies in comprehensive treatment for some inflammatory and autoimmune diseases.

Cholinergic signaling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits

PubMed Central

Jiang, Li; Kundu, Srikanya; Lederman, James D.; López-Hernández, Gretchen Y.; Ballinger, Elizabeth C.; Wang, Shaohua; Talmage, David A.; Role, Lorna W.

2016-01-01

Summary We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photo-stimulation of endogenous cholinergic input: (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs); (2) enhances glutamatergic synaptic transmission in the BLA and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories. PMID:27161525

Functional and structural microanatomy of the fetal sciatic nerve.

PubMed

Creze, Maud; Zaitouna, Mazen; Krystel, Nyangoh Timoh; Diallo, Djibril; Lebacle, Cédric; Bellin, Marie-France; Ducreux, Denis; Benoit, Gérard; Bessede, Thomas

2017-10-01

The ultrastructure of a nerve has implications for surgical nerve repair. The aim of our study was to characterize the fascicular versus fibrillar anatomy and the autonomic versus somatic nature of the fetal sciatic nerve (SN). Immunohistochemistry for vesicular acetylcholine transporter, tyrosine hydroxylase, and peripheral myelin protein 22 was performed to identify cholinergic, adrenergic, and somatic axons, respectively, in the human fetal SN. Two-dimensional (2D) analysis and 3D reconstructions were performed. The fetal SN is composed of one-third stromal tissue and two-thirds neural tissue. Autonomic fibers are predominant over somatic fibers within the neural tissue. The distribution of somatic fibers is initially random, but then become topographically organized after intra- and interfascicular rearrangements have occurred within the nerve. The fetal model presents limitations but enables illustration of the nature of the nerve fibers and the 3D fascicular anatomy of the SN. Muscle Nerve 56: 787-796, 2017. © 2017 Wiley Periodicals, Inc.

Copy number variations in patients with electrical status epilepticus in sleep.

PubMed

Kevelam, Sietske H G; Jansen, Floor E; Binsbergen, Ellen van; Braun, Kees P J; Verbeek, Nienke E; Lindhout, Dick; Poot, Martin; Brilstra, Eva H

2012-02-01

Electrical status epilepticus in sleep syndrome is the association of the electroencephalographic pattern and deficits in language or global cognitive function and behavioral problems. The etiology is often unknown, but genetic risk factors have been implicated. Array-based comparative genomic hybridization was used to identify copy number variations in 13 children with electrical status epilepticus in sleep syndrome to identify possible underlying risk factors. Seven copy number variations were detected in 4 of the 13 patients, which consisted of 6 novel gains and 1 loss, the recurrent 15q13.3 microdeletion. Two patients carried a probable pathogenic copy number variation containing a gene involved in the cholinergic pathway. Genetic aberrations in patients with electrical status epilepticus in sleep syndrome can provide an entry in the investigation of the etiology of electrical status epilepticus in sleep. However, further studies are needed to confirm our findings.

AN EMBRYONIC CHICK PANCREAS ORGAN CULTURE MODEL: CHARACTERIZATION AND NEURAL CONTROL OF EXOCRINE RELEASE

EPA Science Inventory

An embryonic chick (Gallus domesticus) whole-organ pancreas culture system was developed for use as an in vitro model to study cholinergic regulation of exocrine pancreatic function. The culture system was examined for characteristic exocrine function and viability by measuring e...

Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway.

PubMed

Venkatesan, Ramu; Subedi, Lalita; Yeo, Eui-Ju; Kim, Sun Yeou

2016-10-01

Cholinergic activity plays a vital role in cognitive function, and is reduced in individuals with neurodegenerative diseases. Scopolamine, a muscarinic cholinergic antagonist, has been employed in many studies to understand, identify, and characterize therapeutic targets for Alzheimer's disease (AD). Scopolamine-induced dementia is associated with impairments in memory and cognitive function, as seen in patients with AD. The current study aimed to investigate the molecular mechanisms underlying scopolamine-induced cholinergic neuronal dysfunction and the neuroprotective effect of lactucopicrin, an inhibitor of acetylcholine esterase (AChE). We investigated apoptotic cell death, caspase activation, generation of reactive oxygen species (ROS), mitochondrial dysfunction, and the expression levels of anti- and pro-apoptotic proteins in scopolamine-treated C6 cells. We also analyzed the expression levels of antioxidant enzymes and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in C6 cells and neurite outgrowth in N2a neuroblastoma cells. Our results revealed that 1 h scopolamine pre-treatment induced cytotoxicity by increasing apoptotic cell death via oxidative stress-mediated caspase 3 activation and mitochondrial dysfunction. Scopolamine also downregulated the expression the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, and the transcription factor NRF2. Lactucopicrin treatment protected C6 cells from scopolamine-induced toxicity by reversing the effects of scopolamine on those markers of toxicity. In addition, scopolamine attenuated the secretion of neurotrophic nerve growth factor (NGF) in C6 cells and neurite outgrowth in N2a cells. As expected, lactucopicrin treatment enhanced NGF secretion and neurite outgrowth. Our study is the first to show that lactucopicrin, a potential neuroprotective agent, ameliorates scopolamine-induced cholinergic dysfunction via NRF2 activation and subsequent expression of antioxidant enzymes. Copyright © 2016. Published by Elsevier Ltd.

The Trail Making Test elucidates neural substrates of specific post-stroke executive dysfunctions

PubMed Central

Muir, Ryan T.; Lam, Benjamin; Honjo, Kie; Harry, Robin D.; McNeely, Alicia A.; Gao, Fu-Qiang; Ramirez, Joel; Scott, Christopher J.M; Ganda, Anoop; Zhao, Jiali; Zhou, X. Joe; Graham, Simon J.; Rangwala, Novena; Gibson, Erin; Lobaugh, Nancy J.; Kiss, Alex; Stuss, Donald T.; Nyenhuis, David L.; Lee, Byung-Chul; Kang, Yeonwook; Black, Sandra E.

2015-01-01

Background and Purpose Post-stroke cognitive impairment (PSCI) is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. Methods One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set-shifting (TMT-B-A difference, proportion, quotient scores and TMT-B set-shifting errors). The TMT was administered to two overt ischemic stroke cohorts from a multinational study: (i) a chronic stroke cohort (N=61) and (ii) an acute-sub-acute stroke cohort (N=45). Volumetric quantification of ischemic stroke and White Matter HyperIntensities (WMH) was done on MRI, along with ratings of involvement of cholinergic projections, using the previously published Cholinergic Hyperintensities Projections Scale (CHIPS). Damage to the superior longitudinal fasciculus (SLF), which co-localizes with some cholinergic projections, was also documented. Results Multiple linear regression analyses were completed. While larger infarcts (β=0.37, p<0.0001) were associated with slower processing speed, CHIPS severity (β=0.39, p<0.0001) was associated with all metrics of set shifting. Left SLF damage, however, was only associated with the difference score (β=0.17, p=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set shifting errors also had greater CHIPS severity. Conclusions In this multinational stroke cohort study, damage to lateral cholinergic pathways and the SLF emerged as significant neuroanatomical correlates for executive deficits in set shifting. PMID:26382176

Acetylcholine modulates human working memory and subsequent familiarity based recognition via alpha oscillations.

PubMed

Eckart, Cindy; Woźniak-Kwaśniewska, Agata; Herweg, Nora A; Fuentemilla, Lluis; Bunzeck, Nico

2016-08-15

Working memory (WM) can be defined as the ability to maintain and process physically absent information for a short period of time. This vital cognitive function has been related to cholinergic neuromodulation and, in independent work, to theta (4-8Hz) and alpha (9-14Hz) band oscillations. However, the relationship between both aspects remains unclear. To fill this apparent gap, we used electroencephalography (EEG) and a within-subject design in healthy humans who either received the acetylcholinesterase inhibitor galantamine (8mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images were memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested according to a remember/know paradigm. As a main finding, we can show that both theta and alpha oscillations scale during WM maintenance as a function of WM load; this resembles the typical performance decrease. Importantly, cholinergic stimulation via galantamine administration slowed down retrieval speed during WM and reduced associated alpha but not theta power, suggesting a functional relationship between alpha oscillations and WM performance. At LTM, this pattern was accompanied by impaired familiarity based recognition. These findings show that stimulating the healthy cholinergic system impairs WM and subsequent recognition, which is in line with the notion of a quadratic relationship between acetylcholine levels and cognitive functions. Moreover, our data provide empirical evidence for a specific role of alpha oscillations in acetylcholine dependent WM and associated LTM formation. Copyright © 2016 Elsevier Inc. All rights reserved.

Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum

PubMed Central

Higley, Michael J.; Balthasar, Nina; Seal, Rebecca P.; Edwards, Robert H.; Lowell, Bradford B.; Kreitzer, Anatol C.; Sabatini, Bernardo L.

2011-01-01

The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity. PMID:21544206

Enzymes of acetylcholine metabolism in the rat cochlea.

PubMed

Godfrey, D A; Ross, C D

1985-01-01

The distributions within the rat cochlea of choline acetyltransferase and acetylcholinesterase activities were measured to evaluate the prominence of cholinergic mechanisms in cochlear function. Samples obtained by microdissection of freeze-dried bony labyrinths were assayed radiometrically. Activities of both enzymes were highest in regions containing olivocochlear fibers and terminals, especially the organ of Corti and spiral ganglion. Within the organ of Corti, activities of both enzymes were consistently higher in the vicinity of the inner hair cells than in that of the outer hair cells and were much lower in the apical turn than in middle or basal turns. Surgical cuts in the brain stem transecting the olivocochlear pathway on one side led within seven days to total loss of choline acetyltransferase activity in the ipsilateral organ of Corti. It is concluded that all cholinergic structures in the rat organ of Corti derive from the brain stem and that synapses on or near both inner and outer hair cells are cholinergic.

Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior

PubMed Central

Picciotto, Marina R.; Higley, Michael J.; Mineur, Yann S.

2012-01-01

Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss the consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on the site of release, the receptor subtypes, and the target neuronal population, however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. PMID:23040810

Capturing side-effect of medication to identify persons at risk of delirium.

PubMed

Lauretani, Fulvio; Ceda, Gian Paolo; Maggio, Marcello; Nardelli, Anna; Saccavini, Marsilio; Ferrucci, Luigi

2010-01-01

Delirium, an acute confusional state characterized by decline in attention and cognition, is a common, life-threatening, but potentially preventable clinical syndrome among older persons. Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. In particular, an imbalance between levels of acetylcholine and monoamine (such as dopamine) may cause delirium. We describe two cases of delirium in hospitalized older patients, supporting the "cholinergic deficiency hypothesis". In the first patient, hypo-reactive delirium developed a few hours after a dose of the long-acting opiate tramadol (a drug with anticholinergic effect) as analgesic for pain related to advanced peripheral artery disease. In the second patient, with vascular parkinsonism plus pre-frontal cortex vascular lesions, hyper-reactive delirium developed a few hours after a prescribed administration of L-dopa. These symptoms disappeared completely on the following day. These two "natural" experiments support the hypothesis that both hypo-reactive and hyper-active delirium may be caused by a reduction in cholinergic signaling.

Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats.

PubMed

Chen, Chen; Zheng, Yake; Wu, Tianwen; Wu, Chuanjie; Cheng, Xuan

2017-04-01

Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments.

A constitutively active G protein-coupled acetylcholine receptor regulates motility of larval Schistosoma mansoni.

PubMed

MacDonald, Kevin; Kimber, Michael J; Day, Tim A; Ribeiro, Paula

2015-07-01

The neuromuscular system of helminths controls a variety of essential biological processes and therefore represents a good source of novel drug targets. The neuroactive substance, acetylcholine controls movement of Schistosoma mansoni but the mode of action is poorly understood. Here, we present first evidence of a functional G protein-coupled acetylcholine receptor in S. mansoni, which we have named SmGAR. A bioinformatics analysis indicated that SmGAR belongs to a clade of invertebrate GAR-like receptors and is related to vertebrate muscarinic acetylcholine receptors. Functional expression studies in yeast showed that SmGAR is constitutively active but can be further activated by acetylcholine and, to a lesser extent, the cholinergic agonist, carbachol. Anti-cholinergic drugs, atropine and promethazine, were found to have inverse agonist activity towards SmGAR, causing a significant decrease in the receptor's basal activity. An RNAi phenotypic assay revealed that suppression of SmGAR activity in early-stage larval schistosomulae leads to a drastic reduction in larval motility. In sum, our results provide the first molecular evidence that cholinergic GAR-like receptors are present in schistosomes and are required for proper motor control in the larvae. The results further identify SmGAR as a possible candidate for antiparasitic drug targeting. Copyright © 2015 Elsevier B.V. All rights reserved.

Presynaptic muscarinic control of glutamatergic synaptic transmission.

PubMed

Buño, W; Cabezas, C; Fernández de Sevilla, D

2006-01-01

The hippocampus receives cholinergic projections from the medial septal nucleus and Broca's diagonal band that terminate in the CA1, CA3, and dentate gyrus regions (Frotscher and Leranth, 1985). Glutamatergic synapses between CA3 and CA1 pyramidal neurons are presynaptically inhibited by acetylcholine (ACh), via activation of muscarinic ACh receptors (mAChRs) at the terminals of Schaffer collaterals (SCs) (Hounsgaard, 1978; Fernández de Sevilla et al., 2002, 2003). There are two types of SC-CA1 pyramidal neuron synapses. One type, called functional synapse, shows postsynaptic alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor mediated currents at resting potential (Vm) and both AMPA and N-methyl-D-aspartate receptor (NMDAR)-mediated currents when depolarized. The other type, termed silent synapse, only displays postsynaptic NMDAR-mediated currents at depolarized Vms, but does not respond at the resting Vm (Isaac et al., 1995). Using hippocampal slices obtained from young Wistar rats, we examined the effects of activation of cholinergic afferents at the stratum oriens/alveus on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by stimulation of SCs. We also tested the action of the nonhydrolyzable cholinergic agonist carbamylcholine chloride (CCh) on EPSCs evoked by minimal stimulation of SCs (which activates a single or very few synapses) in functional and silent synapses.

Comparative effects of aluminum and ouabain on synaptosomal choline uptake, acetylcholine release and (Na+/K+)ATPase.

PubMed

Silva, Virgília S; Nunes, M Alexandra; Cordeiro, J Miguel; Calejo, Ana I; Santos, Sofia; Neves, Paulo; Sykes, António; Morgado, Fernando; Dunant, Yves; Gonçalves, Paula P

2007-07-17

Closing the gap between adverse health effects of aluminum and its mechanisms of action still represents a huge challenge. Cholinergic dysfunction has been implicated in neuronal injury induced by aluminum. Previously reported data also indicate that in vivo and in vitro exposure to aluminum inhibits the mammalian (Na(+)/K(+))ATPase, an ubiquitous plasma membrane pump. This study was undertaken with the specific aim of determining whether in vitro exposure to AlCl(3) and ouabain, the foremost utilized selective inhibitor of (Na(+)/K(+))ATPase, induce similar functional modifications of cholinergic presynaptic nerve terminals, by comparing their effects on choline uptake, acetylcholine release and (Na(+)/K(+))ATPase activity, on subcellular fractions enriched in synaptic nerve endings isolated from rat brain, cuttlefish optic lobe and torpedo electric organ. Results obtained show that choline uptake by rat synaptosomes was inhibited by submillimolar AlCl(3), whereas the amount of choline taken up by synaptosomes isolated from cuttlefish and torpedo remained unchanged. Conversely, choline uptake was reduced by ouabain to a large extent in all synaptosomal preparations analyzed. In contrast to ouabain, which modified the K(+) depolarization evoked release of acetylcholine by rat, cuttlefish and torpedo synaptosomal fractions, AlCl(3) induced reduction of stimulated acetylcholine release was only observed when rat synaptosomes were challenged. Finally, it was observed that the aluminum effect on cuttlefish and torpedo synaptosomal (Na(+)/K(+))ATPase activity was slight when compared to its inhibitory action on mammalian (Na(+)/K(+))ATPase. In conclusion, inhibition of (Na(+)/K(+))ATPase by AlCl(3) and ouabain jeopardized the high-affinity (Na(+)-dependent, hemicholinium-3 sensitive) uptake of choline and the Ca(2+)-dependent, K(+) depolarization evoked release of acetylcholine by rat, cuttlefish and torpedo synaptosomal fractions. The effects of submillimolar AlCl(3) on choline uptake and acetylcholine release only resembled those of ouabain when rat synaptosomes were assayed. Therefore, important differences were found between the species regarding the cholinotoxic action of aluminum. The variability of (Na(+)/K(+))ATPase sensitivity to aluminum of cholinergic neurons might contribute to their differential susceptibility to this neurotoxic agent.

Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats.

PubMed

Steidl, Stephan; Wang, Huiling; Wise, Roy A

2014-01-01

Cholinergic input to the ventral tegmental area (VTA) is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg) provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII), the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (±0.65)% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self-administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin.

Reactive oxygen species inactivate neuronal nicotinic acetylcholine receptors through a highly conserved cysteine near the intracellular mouth of the channel: implications for diseases that involve oxidative stress

PubMed Central

Krishnaswamy, Arjun; Cooper, Ellis

2012-01-01

Abstract An intriguing feature of several nicotinic acetylcholine receptors (nAChRs) on neurons is that their subunits contain a highly conserved cysteine residue located near the intracellular mouth of the receptor pore. The work summarized in this review indicates that α3β4-containing and α4β2-containing neuronal nAChRs, and possibly other subtypes, are inactivated by elevations in intracellular reactive oxygen species (ROS). This review discusses a model for the molecular mechanisms that underlie this inactivation. In addition, we explore the implications of this mechanism in the context of complications that arise from diabetes. We review the evidence that diabetes elevates cytosolic ROS in sympathetic neurons and inactivates postsynaptic α3β4-containing nAChRs shortly after the onset of diabetes, leading to a depression of synaptic transmission in sympathetic ganglia, an impairment of sympathetic reflexes. These effects of ROS on nAChR function are due to the highly conserved Cys residues in the receptors: replacing the cysteine residues in α3 allow ganglionic transmission and sympathetic reflexes to function normally in diabetes. This example from diabetes suggests that other diseases involving oxidative stress, such as Parkinson's disease, could lead to the inactivation of nAChRs on neurons and disrupt cholinergic nicotinic signalling. PMID:21969449

Cortical cholinergic signaling controls the detection of cues

PubMed Central

Gritton, Howard J.; Howe, William M.; Mallory, Caitlin S.; Hetrick, Vaughn L.; Berke, Joshua D.; Sarter, Martin

2016-01-01

The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses. PMID:26787867

Free energy, precision and learning: the role of cholinergic neuromodulation

PubMed Central

Moran, Rosalyn J.; Campo, Pablo; Symmonds, Mkael; Stephan, Klaas E.; Dolan, Raymond J.; Friston, Karl J.

2014-01-01

Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that acetylcholine enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimising the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore – using dynamic causal modelling – we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that acetylcholine adaptively enhances sensory precision by boosting bottom-up signalling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty. PMID:23658161

Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline.

PubMed

Kucinski, Aaron; Sarter, Martin

2015-04-01

In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex.

PubMed

Major, Alex J; Vijayraghavan, Susheel; Everling, Stefan

2018-01-31

Acetylcholine is released in the prefrontal cortex (PFC) and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of PFC during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades and antisaccades, a well established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers. SIGNIFICANCE STATEMENT The neurotransmitter acetylcholine is known to be important for cognitive processes in the prefrontal cortex. Removal of acetylcholine from prefrontal cortex can disrupt short-term memory performance and is reminiscent of Alzheimer's disease, which is characterized by degeneration of acetylcholine-producing neurons. Stimulation of cholinergic receptors is being explored to create cognitive enhancers for the treatment of Alzheimer's disease and other psychiatric diseases. Here, we stimulated cholinergic receptors in prefrontal cortex and examined its effects on neurons that are engaged in cognitive behavior. Surprisingly, cholinergic stimulation decreased neurons' ability to discriminate between rules. This work suggests that overstimulation of acetylcholine receptors could disrupt neuronal processing during cognition and is relevant to the design of cognitive enhancers based on stimulating the cholinergic system. Copyright © 2018 the authors 0270-6474/18/381137-14$15.00/0.

Tics and Tourette's: update on pathophysiology and tic control.

PubMed

Ganos, Christos

2016-08-01

To describe recent advances in the pathophysiology of tics and Tourette syndrome, and novel insights on tic control. The cortico-basal ganglia-thalamo-cortical loops are implicated in generation of tics. Disruption of GABAergic inhibition lies at the core of tic pathophysiology, but novel animal models also implicate cholinergic and histaminergic neurotransmission. Tourette syndrome patients have altered awareness of volition and enhanced formation of habits. Premonitory urges are not the driving force behind all tics. The intensity of premonitory urges depends on patients' capacity to perceive interoceptive signals. The insular cortex is a key structure in this process. The trait intensity of premonitory urges is not a prerequisite of voluntary tic inhibition, a distinct form of motor control. Voluntary tic inhibition is most efficient in the body parts that tic the least. The prefrontal cortex is associated with the capacity to inhibit tics. The management of tics includes behavioral, pharmacological and surgical interventions. Treatment recommendations differ based on patients' age. The study of Tourette syndrome pathophysiology involves different neural disciplines and provides novel, exciting insights of brain function in health and disease. These in turn provide the basis for innovative treatment approaches of tics and their associations.

Depressant effects of hypoxia and hypoglycaemia on neuro-effector transmission of guinea-pig intestine studied in vitro with a pharmacological model

PubMed Central

Corbett, A D; Lees, G M

1996-01-01

Since intermittent ischaemia may play an important role in the ætiology of Inflammatory Bowel Disease, particularly Crohn's Disease, a pharmacological model of neuronal ischaemia was applied to guinea-pig isolated intestinal preparations to mimic the acute effects of reduced blood flow on intestinal motility.Neuro-effector transmission and smooth muscle performance were examined in myenteric plexus-longitudinal muscle preparations of guinea-pig ileum exposed to sodium cyanide (NaCN), in order to inhibit oxidative phosphorylation, or to iodoacetic acid (IAA), to block glycolysis. Comparisons were made with the effects due to simple deprivation of oxygen or glucose.Depressions of cholinergic neuro-effector transmission induced by hypoxia or NaCN (effective concentration range 0.1–3 mM), given as separate treatments, singly or repetitively over 60–90 min, were apparent within 30 s and were reversible. The maximum inhibition was 90% and the IC50 for NaCN was 0.3 mM. A conspicuous component of these inhibitions was prejunctional.Non-cholinergic neuro-effector contractions were inhibited by up to 90% by anoxia or NaCN but recovery was incomplete and slower than with cholinergic contractions.Glucose-free solutions also caused a reversible failure of cholinergic neuro-effector transmission but of slower onset. In contrast, IAA (0.06–1 mM) abolished contractions irreversibly, apparently by a direct depressant effect on smooth muscle contraction. Unlike NaCN, IAA caused an initial potentiation of electrically-induced contractions, partly by a prejunctional potentiation of cholinergic neuro-effector transmission.It is concluded that a disruption of intestinal activity in pathological conditions associated with intestinal ischaemia may result from disturbances in the function of enteric neurones. PMID:9117084

Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes

PubMed Central

Bell, L. Andrew; Bell, Karen A.; McQuiston, A. Rory

2013-01-01

Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K+ channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function in the treatment of some neurodegenerative diseases. PMID:23747570

Scopolamine and amphetamine produce similar decision-making deficits on a rat gambling task via independent pathways.

PubMed

Silveira, Mason M; Malcolm, Emma; Shoaib, Mohammed; Winstanley, Catharine A

2015-03-15

Disorders characterized by disturbed cholinergic signaling, such as schizophrenia, exhibit impaired performance on measures of real-world cost/benefit decision-making. Whether the cholinergic system contributes to the choice deficits observed is currently unknown. We therefore determined the effects of broad-acting agonists and antagonists at the nicotinic and muscarinic receptor on decision making, as measured by the rodent gambling task (rGT). Given the anatomical and functional connectivity of the cholinergic and dopaminergic systems, we also sought to modulate amphetamine's previously reported effect on rGT performance via the cholinergic system. Male rats were trained on the rGT, during which animals chose from four different options. The optimal strategy on the rGT is to favor options associated with smaller immediate rewards and less punishment/loss. Impulsive action was also measured by recording the number of premature responses made. Performance on the rGT was assessed following acute treatment with the muscarinic receptor agonist oxotremorine, the muscarinic receptor antagonist scopolamine, nicotine, and the nicotinic receptor antagonist mecamylamine. Similar to the effect produced by amphetamine, muscarinic receptor antagonism with scopolamine (0.1mg/kg) impaired decision making, albeit to a lesser degree. Prior muscarinic agonism with oxotremorine was unable to attenuate amphetamine's effects on rGT performance. Oxotremorine, nicotine, and mecamylamine did not affect the choice profile. We therefore conclude that modulation of the muscarinic, but not nicotinic, receptor system can affect decision making under conditions of risk and uncertainty. Such findings contribute to a broader understanding of the cognitive deficits observed in disorders in which cholinergic signaling is compromised. Copyright © 2014 Elsevier B.V. All rights reserved.

Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors

PubMed Central

Zaghloul, Nahla; Addorisio, Meghan E.; Silverman, Harold A.; Patel, Hardik L.; Valdés-Ferrer, Sergio I.; Ayasolla, Kamesh R.; Lehner, Kurt R.; Olofsson, Peder S.; Nasim, Mansoor; Metz, Christine N.; Wang, Ping; Ahmed, Mohamed; Chavan, Sangeeta S.; Diamond, Betty; Tracey, Kevin J.; Pavlov, Valentin A.

2017-01-01

Sepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP)-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL)-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT)-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex) and increased Il1b and Il6 gene expression (in the cortex), and Il1b gene expression (in the hippocampus) were observed in mouse sepsis survivors. Furthermore, microglial activation was linked to decreased cortical ChAT protein expression and increased AChE activity. These results reinforce the notion of persistent inflammation-immunosuppression and catabolic syndrome in sepsis survivors and characterize a previously unrecognized relationship between forebrain cholinergic dysfunction and neuroinflammation in sepsis survivors. This insight is of interest for new therapeutic approaches that focus on brain cholinergic signaling for patients with chronic sepsis illness, a problem with no specific treatment. PMID:29326685

Interaction between basal ganglia and limbic circuits in learning and memory processes.

PubMed

Calabresi, Paolo; Picconi, Barbara; Tozzi, Alessandro; Ghiglieri, Veronica

2016-01-01

Hippocampus and striatum play distinctive roles in memory processes since declarative and non-declarative memory systems may act independently. However, hippocampus and striatum can also be engaged to function in parallel as part of a dynamic system to integrate previous experience and adjust behavioral responses. In these structures the formation, storage, and retrieval of memory require a synaptic mechanism that is able to integrate multiple signals and to translate them into persistent molecular traces at both the corticostriatal and hippocampal/limbic synapses. The best cellular candidate for this complex synthesis is represented by long-term potentiation (LTP). A common feature of LTP expressed in these two memory systems is the critical requirement of convergence and coincidence of glutamatergic and dopaminergic inputs to the dendritic spines of the neurons expressing this form of synaptic plasticity. In experimental models of Parkinson's disease abnormal accumulation of α-synuclein affects these two memory systems by altering two major synaptic mechanisms underlying cognitive functions in cholinergic striatal neurons, likely implicated in basal ganglia dependent operative memory, and in the CA1 hippocampal region, playing a central function in episodic/declarative memory processes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Early ionic and membrane potential changes caused by the pesticide rotenone in striatal cholinergic interneurons.

PubMed

Bonsi, P; Calabresi, P; De Persis, C; Papa, M; Centonze, D; Bernardi, G; Pisani, A

2004-01-01

Mitochondrial metabolism impairment has been implicated in the pathogenesis of several neurodegenerative disorders. In the present work, we combined electrophysiological recordings and microfluorometric measurements from cholinergic interneurons obtained from a rat neostriatal slice preparation. Acute application of the mitochondrial complex I inhibitor rotenone produced an early membrane hyperpolarization coupled to a fall in input resistance, followed by a late depolarizing response. Current-voltage relationship showed a reversal potential of -80 +/- 3 mV, suggesting the involvement of a potassium (K+) current. Simultaneous measurement of intracellular sodium [Na+]i or calcium [Ca2+]i concentrations revealed a striking correlation between [Na+]i elevation and the early membrane hyperpolarization, whereas a significant [Ca2+]i rise matched the depolarizing phase. Interestingly, ion and membrane potential changes were mimicked by ouabain, inhibitor of the Na+-K+ATPase, and were insensitive to tetrodotoxin (TTX) or to a combination of glutamate receptor antagonists. The rotenone effects were partially reduced by blockers of ATP-sensitive K+ channels, glibenclamide and tolbutamide, and largely attenuated by a low Na+-containing solution. Morphological analysis of the rotenone effects on striatal slices showed a significant decrease in the number of choline acetyltransferase (ChAT) immunoreactive cells. These results suggest that rotenone rapidly disrupts the ATP content, leading to a decreased Na+-K+ATPase function and, therefore, to [Na+]i overload. In turn, the hyperpolarizing response might be generated both by the opening of ATP-sensitive K+ channels and by Na+-activated K+ conductances. The increase in [Ca2+]i occurs lately and does not seem to influence the early events.

Carbachol induces burst firing of dopamine cells in the ventral tegmental area by promoting calcium entry through L-type channels in the rat

PubMed Central

Zhang, Lei; Liu, Yudan; Chen, Xihua

2005-01-01

Enhanced activity of the central dopamine system has been implicated in many psychiatric disorders including schizophrenia and addiction. Besides terminal mechanisms that boost dopamine levels at the synapse, the cell body of dopamine cells enhances terminal dopamine concentration through encoding action potentials in bursts. This paper presents evidence that burst firing of dopamine cells in the ventral tegmental area was under cholinergic control using nystatin-perforated patch clamp recording from slice preparations. The non-selective cholinergic agonist carbachol excited the majority of recorded neurones, an action that was not affected by blocking glutamate and GABA ionotropic receptors. Twenty per cent of dopamine cells responded to carbachol with robust bursting, an effect mediated by both muscarinic and nicotinic cholinoceptors postsynaptically. Burst firing induced as such was completely dependent on calcium entry as it could be blocked by cadmium and more specifically the L-type blocker nifedipine. In the presence of the sodium channel blocker tetrodotoxin, carbachol induced membrane potential oscillation that had similar kinetics and frequency as burst firing cycles and could also be blocked by cadmium and nifedipine. Direct activation of the L-type channel with Bay K8644 induced strong bursting which could be blocked by nifedipine but not by depleting internal calcium stores. These results indicate that carbachol increases calcium entry into the postsynaptic cell through L-type channels to generate calcium-dependent membrane potential oscillation and burst firing. This could establish the L-type channel as a target for modulating the function of the central dopamine system in disease conditions. PMID:16081481

Sulforaphane alleviates scopolamine-induced memory impairment in mice.

PubMed

Lee, Siyoung; Kim, Jisung; Seo, Sang Gwon; Choi, Bo-Ryoung; Han, Jung-Soo; Lee, Ki Won; Kim, Jiyoung

2014-07-01

Sulforaphane, an organosulfur compound present in cruciferous vegetables, has been shown to exert neuroprotective effects in experimental in vitro and in vivo models of neurodegeneration. To determine whether sulforaphane can preserve cognitive function, we examined its effects on scopolamine-induced memory impairment in mice using the Morris water maze test. Sulforaphane (10 or 50mg/kg) was administered to C57BL/6 mice by oral gavage for 14 days (days 1-14), and memory impairment was induced by intraperitoneal injection of scopolamine (1mg/kg) for 7 days (days 8-14). Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity in the hippocampus and frontal cortex, as indicated by a decreased acetylcholine (ACh) level and an increased acetylcholinesterase (AChE) activity. Sulforaphane significantly attenuated the scopolamine-induced memory impairment and improved cholinergic system reactivity, as indicated by an increased ACh level, decreased AChE activity, and increased choline acetyltransferase (ChAT) expression in the hippocampus and frontal cortex. These effects of sulforaphane on cholinergic system reactivity were confirmed in vitro. Sulforaphane (10 or 20μM) increased the ACh level, decreased the AChE activity, and increased ChAT expression in scopolamine-treated primary cortical neurons. These observations suggest that sulforaphane might exert a significant neuroprotective effect on cholinergic deficit and cognitive impairment. Copyright © 2014. Published by Elsevier Ltd.

Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice.

PubMed

Bazalakova, M H; Wright, J; Schneble, E J; McDonald, M P; Heilman, C J; Levey, A I; Blakely, R D

2007-07-01

Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (-/-) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/- mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/- mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/- mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity.

Cell type-specific long-range connections of basal forebrain circuit.

PubMed

Do, Johnny Phong; Xu, Min; Lee, Seung-Hee; Chang, Wei-Cheng; Zhang, Siyu; Chung, Shinjae; Yung, Tyler J; Fan, Jiang Lan; Miyamichi, Kazunari; Luo, Liqun; Dan, Yang

2016-09-19

The basal forebrain (BF) plays key roles in multiple brain functions, including sleep-wake regulation, attention, and learning/memory, but the long-range connections mediating these functions remain poorly characterized. Here we performed whole-brain mapping of both inputs and outputs of four BF cell types - cholinergic, glutamatergic, and parvalbumin-positive (PV+) and somatostatin-positive (SOM+) GABAergic neurons - in the mouse brain. Using rabies virus -mediated monosynaptic retrograde tracing to label the inputs and adeno-associated virus to trace axonal projections, we identified numerous brain areas connected to the BF. The inputs to different cell types were qualitatively similar, but the output projections showed marked differences. The connections to glutamatergic and SOM+ neurons were strongly reciprocal, while those to cholinergic and PV+ neurons were more unidirectional. These results reveal the long-range wiring diagram of the BF circuit with highly convergent inputs and divergent outputs and point to both functional commonality and specialization of different BF cell types.

Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions

PubMed Central

Klug, Jason R; Engelhardt, Max D; Cadman, Cara N; Li, Hao; Smith, Jared B; Ayala, Sarah; Williams, Elora W; Hoffman, Hilary

2018-01-01

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior. PMID:29714166

Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac.

PubMed

Paz, Rodrigo Manuel; Tubert, Cecilia; Stahl, Agostina; Díaz, Analía López; Etchenique, Roberto; Murer, Mario Gustavo; Rela, Lorena

2018-05-11

Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs. We found that autonomous firing of striatal cholinergic interneurons is not regulated by Kv7 channels. In contrast, Kv7 channels limit the summation of excitatory postsynaptic potentials in cholinergic interneurons through a postsynaptic mechanism. Striatal cholinergic interneurons have a high reserve of Kv7 channels, as their opening using pharmacological tools completely silenced the tonic firing and markedly reduced their intrinsic excitability. A strong inhibition of striatal cholinergic interneurons was also observed in response to the anti-inflammatory drugs diclofenac and meclofenamic acid, however, this effect was independent of Kv7 channels. These data bring attention to new potential molecular targets and pharmacological tools to control striatal cholinergic interneuron activity in pathological conditions where they are believed to be hyperactive, including Parkinson's disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Expression and Function of the Cholinergic System in Immune Cells

PubMed Central

Fujii, Takeshi; Mashimo, Masato; Moriwaki, Yasuhiro; Misawa, Hidemi; Ono, Shiro; Horiguchi, Kazuhide; Kawashima, Koichiro

2017-01-01

T and B cells express most cholinergic system components—e.g., acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase, and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Using ChATBAC-eGFP transgenic mice, ChAT expression has been confirmed in T and B cells, dendritic cells, and macrophages. Moreover, T cell activation via T-cell receptor/CD3-mediated pathways upregulates ChAT mRNA expression and ACh synthesis, suggesting that this lymphocytic cholinergic system contributes to the regulation of immune function. Immune cells express all five mAChRs (M1–M5). Combined M1/M5 mAChR-deficient (M1/M5-KO) mice produce less antigen-specific antibody than wild-type (WT) mice. Furthermore, spleen cells in M1/M5-KO mice produce less tumor necrosis factor (TNF)-α and interleukin (IL)-6, suggesting M1/M5 mAChRs are involved in regulating pro-inflammatory cytokine and antibody production. Immune cells also frequently express the α2, α5, α6, α7, α9, and α10 nAChR subunits. α7 nAChR-deficient (α7-KO) mice produce more antigen-specific antibody than WT mice, and spleen cells from α7-KO mice produce more TNF-α and IL-6 than WT cells. This suggests that α7 nAChRs are involved in regulating cytokine production and thus modulate antibody production. Evidence also indicates that nicotine modulates immune responses by altering cytokine production and that α7 nAChR signaling contributes to immunomodulation through modification of T cell differentiation. Together, these findings suggest the involvement of both mAChRs and nAChRs in the regulation of immune function. The observation that vagus nerve stimulation protects mice from lethal endotoxin shock led to the notion of a cholinergic anti-inflammatory reflex pathway, and the spleen is an essential component of this anti-inflammatory reflex. Because the spleen lacks direct vagus innervation, it has been postulated that ACh synthesized by a subset of CD4+ T cells relays vagal nerve signals to α7 nAChRs on splenic macrophages, which downregulates TNF-α synthesis and release, thereby modulating inflammatory responses. However, because the spleen is innervated solely by the noradrenergic splenic nerve, confirmation of an anti-inflammatory reflex pathway involving the spleen requires several more hypotheses to be addressed. We will review and discuss these issues in the context of the cholinergic system in immune cells. PMID:28932225

Simultaneous measurement of cholinergic tone and neuronal network dynamics in vivo in the rat brain using a novel choline oxidase based electrochemical biosensor.

PubMed

Santos, Ricardo M; Laranjinha, João; Barbosa, Rui M; Sirota, Anton

2015-07-15

Acetylcholine (ACh) modulates neuronal network activities implicated in cognition, including theta and gamma oscillations but the mechanisms remain poorly understood. Joint measurements of cholinergic activity and neuronal network dynamics with high spatio-temporal resolution are critical to understand ACh neuromodulation. However, current electrochemical biosensors are not optimized to measure nanomolar cholinergic signals across small regions like hippocampal sub-layers. Here, we report a novel oxidase-based electrochemical biosensor that matches these constraints. The approach is based on measurement of H2O2 generated by choline oxidase (ChOx) in the presence of choline (Ch). The microelectrode design consists of a twisted pair of 50µm diameter Pt/Ir wires (sensor and sentinel), which is scalable, provides high spatial resolution and optimizes common mode rejection. Microelectrode coating with ChOx in chitosan cross-linked with benzoquinone is simple, mechanically robust and provides high sensitivity (324±46nAµM(-1)cm(-2)), a limit of detection of 16nM and a t50 response time of 1.4s. Local field potential (LFP)-related currents dominate high-frequency component of electrochemical recordings in vivo. We significantly improved signal-to-noise-ratio compared to traditional sentinel subtraction by a novel frequency domain common mode rejection procedure that accounts for differential phase and amplitude of LFP-related currents on the two channels. We demonstrate measurements of spontaneous nanomolar Ch fluctuations, on top of which micromolar Ch increases occurred during periods of theta activity in anesthetized rats. Measurements were not affected by physiological O2 changes, in agreement with the low biosensor Km for O2 (2.6µM). Design and performance of the novel biosensor opens the way for multisite recordings of spontaneous cholinergic dynamics in behaving animals. Copyright © 2015 Elsevier B.V. All rights reserved.

Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain.

PubMed

Shelukhina, Irina; Mikhailov, Nikita; Abushik, Polina; Nurullin, Leniz; Nikolsky, Evgeny E; Giniatullin, Rashid

2017-01-01

Parasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown. Using electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Both ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca 2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.

Using motor behavior during an early critical period to restore skilled limb movement after damage to the corticospinal motor system during development

PubMed Central

Friel, KM; Chakrabarty, S; H-C, Kuo; Martin, JH

2012-01-01

This study investigated requirements for restoring motor function after corticospinal (CS) system damage during early postnatal development. Activity-dependent competition between the CS tracts (CST) of the two hemispheres is imperative for normal development. Blocking primary motor cortex (M1) activity unilaterally during a critical period (postnatal weeks-PW-5–7) produces permanent contralateral motor skill impairments, loss of M1 motor map, aberrant CS terminations, and decreases in CST presynaptic sites and spinal cholinergic interneuron numbers. To repair these motor systems impairments and restore function, we manipulated motor experience in three groups of cats after this CST injury produced by inactivation. One group wore a jacket restraining the limb ipsilateral to inactivation, forcing use of the contralateral, impaired, limb, for the month following M1 inactivation (PW8–13; “Restraint Alone”). A second group wore the restraint during PW8–13, and was also trained for 1 h/day in a reaching task with the contralateral forelimb (“Early Training”). To test the efficacy of intervention during adolescence, a third group wore the restraint and received reach training during PW20–24 (“Delayed Training”). Early training restored CST connections and the M1 motor map; increased cholinergic spinal interneurons numbers on the contralateral, relative to ipsilateral, side; and abrogated limb control impairments. Delayed training restored CST connectivity and the M1 motor map, but not contralateral spinal cholinergic cell counts or motor performance. Restraint alone only restored CST connectivity. Our findings stress the need to reestablish the integrated functions of the CS system at multiple hierarchical levels in restoring skilled motor function after developmental injury. PMID:22764234

Nicotinic receptor abnormalities in the cerebellar cortex in autism.

PubMed

Lee, M; Martin-Ruiz, C; Graham, A; Court, J; Jaros, E; Perry, R; Iversen, P; Bauman, M; Perry, E

2002-07-01

Autism is a common developmental disorder associated with structural and inferred neurochemical abnormalities of the brain. Cerebellar abnormalities frequently have been identified, based on neuroimaging or neuropathology. Recently, the cholinergic neurotransmitter system has been implicated on the basis of nicotinic receptor loss in the cerebral cortex. Cerebellar cholinergic activities were therefore investigated in autopsy tissue from a series of autistic individuals. The presynaptic cholinergic enzyme, choline acetyltransferase, together with nicotinic and muscarinic receptor subtypes were compared in the cerebellum from age-matched mentally retarded autistic (eight), normal control (10) and non-autistic mentally retarded individuals (11). The nicotinic receptor binding the agonist epibatidine (the high affinity receptor subtype, consisting primarily of alpha3 and alpha4, together with beta2 receptor subunits) was significantly reduced by 40-50% in the granule cell, Purkinje and molecular layers in the autistic compared with the normal group (P < 0.05). There was an opposite increase (3-fold) in the nicotinic receptor binding alpha-bungarotoxin (to the alpha7 subunit) which reached significance in the granule cell layer (P < 0.05). These receptor changes were paralleled by a significant reduction (P < 0.05) and non-significant increase, respectively, of alpha4 and alpha7 receptor subunit immunoreactivity measured using western blotting. Immunohistochemically loss of alpha(4 )reactivity was apparent from Purkinje and the other cell layers, with increased alpha7 reactivity in the granule cell layer. There were no significant changes in choline acetyltransferase activity, or in muscarinic M1 and M2 receptor subtypes in autism. In the non-autistic mentally retarded group, the only significant abnormality was a reduction in epibatidine binding in the granule cell and Purkinje layers. In two autistic cases examined histologically, Purkinje cell loss was observed in multiple lobules throughout the vermis and hemispheres. This was more severe in one case with epilepsy, which also showed vermis folial malformation. The case with less severe Purkinje cell loss also showed cerebellar white matter thinning and demyelination. These findings indicate a loss of the cerebellar nicotinic alpha4 receptor subunit in autism which may relate to the loss of Purkinje cells, and a compensatory increase in the alpha7 subunit. It remains to be determined how these receptor abnormalities are involved in neurodevelopment in autism and what is the relationship to mental function. Since nicotinic receptor agonists enhance attentional function and also induce an elevation in the high affinity receptor, nicotinic therapy in autism may be worth considering.

Neostigmine interactions with non steroidal anti-inflammatory drugs

PubMed Central

Miranda, Hugo F; Sierralta, Fernando; Pinardi, Gianni

2002-01-01

The common mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of the enzyme cyclo-oxygenase (COX), however, this inhibition is not enough to completely account for the efficacy of these agents in several models of acute pain. It has been demonstrated that cholinergic agents can induce antinociception, but the nature of the interaction between these agents and NSAIDs drugs has not been studied. The present work evaluates, by isobolographic analysis, the interactions between the cholinergic indirect agonist neostigmine (NEO) and NSAIDs drugs, using a chemical algesiometric test. Intraperitoneal (i.p.) or intrathecal (i.t.) administration of NEO and of the different NSAIDs produced dose-dependent antinociception in the acetic acid writhing test of the mouse. The i.p. or i.t. co-administration of fixed ratios of ED50 fractions of NSAIDs and NEO, resulted to be synergistic or supra-additive for the combinations ketoprofen (KETO) and NEO, paracetamol (PARA) and NEO) and diclofenac (DICLO) and NEO administered i.p. However, the same combinations administered i.t. were only additive. In addition, the combinations meloxicam (MELO) and NEO and piroxicam (PIRO) and NEO, administered either i.p. or i.t., were additive. The results suggest that the co-administration of NEO with some NSAIDs (e.g. KETO, PARA or DICLO) resulted in a synergistic interaction, which may provide evidence of supraspinal antinociception modulation by the increased acetylcholine concentration in the synaptic cleft of cholinergic interneurons. The interaction obtained between neostigmine and the NSAIDs could carry important clinical implications. PMID:11934798

Disruption of medial septum and diagonal bands of Broca cholinergic projections to the ventral hippocampus disrupt auditory fear memory.

PubMed

Staib, Jennifer M; Della Valle, Rebecca; Knox, Dayan K

2018-07-01

In classical fear conditioning, a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US), which leads to a fear memory. If the CS is repeatedly presented without the US after fear conditioning, the formation of an extinction memory occurs, which inhibits fear memory expression. A previous study has demonstrated that selective cholinergic lesions in the medial septum and vertical limb of the diagonal bands of Broca (MS/vDBB) prior to fear and extinction learning disrupt contextual fear memory discrimination and acquisition of extinction memory. MS/vDBB cholinergic neurons project to a number of substrates that are critical for fear and extinction memory. However, it is currently unknown which of these efferent projections are critical for contextual fear memory discrimination and extinction memory. To address this, we induced cholinergic lesions in efferent targets of MS/vDBB cholinergic neurons. These included the dorsal hippocampus (dHipp), ventral hippocampus (vHipp), medial prefrontal cortex (mPFC), and in the mPFC and dHipp combined. None of these lesion groups exhibited deficits in contextual fear memory discrimination or extinction memory. However, vHipp cholinergic lesions disrupted auditory fear memory. Because MS/vDBB cholinergic neurons are the sole source of acetylcholine in the vHipp, these results suggest that MS/vDBB cholinergic input to the vHipp is critical for auditory fear memory. Taken together with previous findings, the results of this study suggest that MS/vDBB cholinergic neurons are critical for fear and extinction memory, though further research is needed to elucidate the role of MS/vDBB cholinergic neurons in these types of emotional memory. Copyright © 2018 Elsevier Inc. All rights reserved.

Optogenetic stimulation of cholinergic projection neurons as an alternative for deep brain stimulation for Alzheimer's treatment

NASA Astrophysics Data System (ADS)

Mancuso, James; Chen, Yuanxin; Zhao, Zhen; Li, Xuping; Xue, Zhong; Wong, Stephen T. C.

2013-03-01

Deep brain stimulation (DBS) of the cholinergic nuclei has emerged as a powerful potential treatment for neurodegenerative disease and is currently in a clinical trial for Alzheimer's therapy. While effective in treatment for a number of conditions from depression to epilepsy, DBS remains somewhat unpredictable due to the heterogeneity of the projection neurons that are activated, including glutamatergic, GABAergic, and cholinergic neurons, leading to unacceptable side effects ranging from apathy to depression or even suicidal behavior. It would be highly advantageous to confine stimulation to specific populations of neurons, particularly in brain diseases involving complex network interactions such as Alzheimer's. Optogenetics, now firmly established as an effective approach to render genetically-defined populations of cells sensitive to light activation including mice expressing Channelrhodopsin-2 specifically in cholinergic neurons, provides just this opportunity. Here we characterize the light activation properties and cell density of cholinergic neurons in healthy mice and mouse models of Alzheimer's disease in order to evaluate the feasibility of using optogenetic modulation of cholinergic synaptic activity to slow or reverse neurodegeneration. This paper is one of the very first reports to suggest that, despite the anatomical depth of their cell bodies, cholinergic projection neurons provide a better target for systems level optogenetic modulation than cholinergic interneurons found in various brain regions including striatum and the cerebral cortex. Additionally, basal forebrain channelrhodopsin-expressing cholinergic neurons are shown to exhibit normal distribution at 60 days and normal light activation at 40 days, the latest timepoints observed. The data collected form the basis of ongoing computational modeling of light stimulation of entire populations of cholinergic neurons.

Selective effects of cholinergic modulation on task performance during selective attention.

PubMed

Furey, Maura L; Pietrini, Pietro; Haxby, James V; Drevets, Wayne C

2008-03-01

The cholinergic neurotransmitter system is critically linked to cognitive functions including attention. The current studies were designed to evaluate the effect of a cholinergic agonist and an antagonist on performance during a selective visual attention task where the inherent salience of attended/unattended stimuli was modulated. Two randomized, placebo-controlled, crossover studies were performed, one (n=9) with the anticholinesterase physostigmine (1.0 mg/h), and the other (n=30) with the anticholinergic scopolamine (0.4 mc/kg). During the task, two double-exposure pictures of faces and houses were presented side by side. Subjects were cued to attend to either the face or the house component of the stimuli, and were instructed to perform a matching task with the two exemplars from the attended category. The cue changed every 4-7 trials to instruct subjects to shift attention from one stimulus component to the other. During placebo in both studies, reaction time (RT) associated with the first trial following a cued shift in attention was longer than RT associated with later trials (p<0.05); RT also was significantly longer when attending to houses than to faces (p<0.05). Physostigmine decreased RT relative to placebo preferentially during trials greater than one (p<0.05), with no change during trial one; and decreased RT preferentially during the attention to houses condition (p<0.05) vs attention to faces. Scopolamine increased RT relative to placebo selectively during trials greater than one (p<0.05), and preferentially increased RT during the attention to faces condition (p<0.05). The results suggest that enhancement or impairment of cholinergic activity preferentially influences the maintenance of selective attention (ie trials greater than 1). Moreover, effects of cholinergic manipulation depend on the selective attention condition (ie faces vs houses), which may suggest that cholinergic activity interacts with stimulus salience. The findings are discussed within the context of the role of acetylcholine both in stimulus processing and stimulus salience, and in establishing attention biases through top-down and bottom-up mechanisms of attention.

Selective Effects of Cholinergic Modulation on Task Performance during Selective Attention

PubMed Central

Furey, Maura L; Pietrini, Pietro; Haxby, James V; Drevets, Wayne C

2010-01-01

The cholinergic neurotransmitter system is critically linked to cognitive functions including attention. The current studies were designed to evaluate the effect of a cholinergic agonist and an antagonist on performance during a selective visual attention task where the inherent salience of attended/unattended stimuli was modulated. Two randomized, placebo-controlled, crossover studies were performed, one (n = 9) with the anticholinesterase physostigmine (1.0 mg/h), and the other (n = 30) with the anticholinergic scopolamine (0.4 mc/kg). During the task, two double-exposure pictures of faces and houses were presented side by side. Subjects were cued to attend to either the face or the house component of the stimuli, and were instructed to perform a matching task with the two exemplars from the attended category. The cue changed every 4–7 trials to instruct subjects to shift attention from one stimulus component to the other. During placebo in both studies, reaction time (RT) associated with the first trial following a cued shift in attention was longer than RT associated with later trials (p<0.05); RT also was significantly longer when attending to houses than to faces (p<0.05). Physostigmine decreased RT relative to placebo preferentially during trials greater than one (p<0.05), with no change during trial one; and decreased RT preferentially during the attention to houses condition (p<0.05) vs attention to faces. Scopolamine increased RT relative to placebo selectively during trials greater than one (p<0.05), and preferentially increased RT during the attention to faces condition (p<0.05). The results suggest that enhancement or impairment of cholinergic activity preferentially influences the maintenance of selective attention (ie trials greater than 1). Moreover, effects of cholinergic manipulation depend on the selective attention condition (ie faces vs houses), which may suggest that cholinergic activity interacts with stimulus salience. The findings are discussed within the context of the role of acetylcholine both in stimulus processing and stimulus salience, and in establishing attention biases through top-down and bottom-up mechanisms of attention. PMID:17534379

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akhtar, R.A.; Abdel-Latif, A.A.

Muscarinic cholinergic and ..cap alpha../sub 1/-adrenergic agonists provoke hydrolysis of PIP/sub 2/ into diacylglycerol (DG) and inositol trisphosphate (IP/sub 3/) in a wide variety of tissue. Recently, IP/sub 3/ has been shown to mobilize Ca/sup 2 +/ from ER in several permeabilized tissue preparations. Although rabbit cornea is enriched in ACh and NE, the physiological function of these neurotransmitters is unclear. The present studies were initiated to determine the effects of cholinergic and adrenergic agonists on PIP/sub 2/ turnover in the cornea. Addition of ACh or NE (50 ..mu..M each) to the /sup 32/P-labeled corneas for 10 min decreased themore » radioactivity in PIP/sub 2/ by 33 and 36%, and increased the radioactivity in phosphatidic acid by 72 and 52%, respectively. When the corneas were labeled with myo-(/sup 3/H)inositol, ACh and NE increased the accumulation of IP/sub 3/ by 92 and 48%, respectively. The effects of ACh and NE on phospholipid labeling and IP/sub 3/ accumulation were specifically inhibited by atropine (10 ..mu..M) and prazosin (10 ..mu..M), respectively. The data suggest the presence of muscarinic cholinergic and ..cap alpha../sub 1/-adrenergic receptors in the rabbit cornea. Furthermore, activation of these receptors leads to cleavage of PIP/sub 2/ into DG and IP/sub 3/ which may function as second messengers in this tissue.« less

Comparison of non-invasive measures of cholinergic and allergic airway responsiveness in rats.

PubMed

Glaab, T; Hecker, H; Stephan, M; Baelder, R; Braun, A; Korolewitz, R; Krug, N; Hoymann, H G

2006-04-01

Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). First, dose-response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats.

Role of interstitial cells of Cajal in the generation and modulation of motor activity induced by cholinergic neurotransmission in the stomach.

PubMed

Zhang, R-X; Wang, X-Y; Chen, D; Huizinga, J D

2011-09-01

Interstitial cells of Cajal (ICC) are intimately linked to the enteric nervous system and a better understanding of the interactions between the two systems is going to advance our understanding of gut motor control. The objective of the present study was to investigate the role of ICC in the generation of gastric motor activity induced by cholinergic neurotransmission. Gastric motor activity was evoked through activation of intrinsic cholinergic neural activity, in in vitro muscle strips by electrical field stimulation, in the in vitro whole stomach by distension and in vivo by fluoroscopy after gavaging the stomach with barium sulfate. The cholinergic activity was assessed as that component of the effect of the stimulus that was sensitive to atropine. These experiments were carried out in wild-type and Ws/Ws rats that have few intramuscular ICC (ICC-IM) in the stomach. Under all three experimental conditions, cholinergic activity was prominent in both wild-type and W mutant rats providing evidence against the hypothesis that cholinergic neurotransmission to smooth muscle is primarily mediated by ICC-IM. Strong cholinergic activity in Ws/Ws rats was not due to upregulation of muscarinic receptors in ICC but possibly in smooth muscle of the antrum. Pacemaker ICC play a prominent role in the expression of motor activity induced by cholinergic activity and our data suggest that cholinergic neurotransmission to ICC affects the pacemaker frequency. © 2011 Blackwell Publishing Ltd.

Imaging: what can it tell us about parkinsonian gait?

PubMed Central

Bohnen, Nicolaas I.; Jahn, Klaus

2013-01-01

Functional neuroimaging has provided new tools to study cerebral gait control in Parkinson disease (PD). First, imaging of blood flow functions has identified a supraspinal locomotor network that includes the (frontal) cortex, basal ganglia, brainstem tegmentum and the cerebellum. These studies emphasize also the cognitive and attentional dependency of gait in PD. Furthermore, gait in PD and related syndromes like progressive supranuclear palsy may be associated with dysfunction of the indirect, modulatory prefrontal–subthalamic–pedunculopontine loop of locomotor control. The direct, stereotyped locomotor loop from the primary motor cortex to the spinal cord with rhythmic cerebellar input appears preserved and may contribute to the unflexible gait pattern in parkinsonian gait. Second, neurotransmitter and proteinopathy imaging studies are beginning to unravel novel mechanisms of parkinsonian gait and postural disturbances. Dopamine displacement imaging studies have shown evidence for a mesofrontal dopaminergic shift from a depleted striatum in parkinsonian gait. This may place additional burden on other brain systems mediating attention functions to perform previously automatic motor tasks. For example, our preliminary cholinergic imaging studies suggest significant slowing of gait speed when additional forebrain cholinergic denervation occurs in PD. Cholinergic denervation of the pedunculopontine nucleus and its thalamic projections have been associated with falls and impaired postural control. Deposition of β-amyloid may represent another non-dopaminergic correlate of gait disturbance in PD. These findings illustrate the emergence of dopamine non-responsive gait problems to reflect the transition from a predominantly hypodopaminergic disorder to a multisystem neurodegenerative disorder involving non-dopaminergic locomotor network structures and pathologies. PMID:24132837

Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions.

PubMed

Roy, Ashbeel; Dakroub, Mouhamed; Tezini, Geisa C S V; Liu, Yin; Guatimosim, Silvia; Feng, Qingping; Salgado, Helio C; Prado, Vania F; Prado, Marco A M; Gros, Robert

2016-02-01

Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24 ± 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure. © FASEB.

Nicotine recruits a local glutamatergic circuit to excite septohippocampal GABAergic neurons.

PubMed

Wu, Min; Hajszan, Tibor; Leranth, Csaba; Alreja, Meenakshi

2003-09-01

Tonic impulse flow in the septohippocampal GABAergic pathway is essential for normal cognitive functioning and is sustained, in part, by acetylcholine (ACh) that is released locally via axon collaterals of septohippocampal cholinergic neurons. Septohippocampal cholinergic neurons degenerate in Alzheimer's disease and other neurodegenerative disorders. While the importance of the muscarinic effects of ACh on septohippocampal GABAergic neurons is well recognized, the nicotinic effects of ACh remain unstudied despite the reported benefits of nicotine on cognitive functioning. In the present study, using electrophysiological recordings in a rat brain slice preparation, rapid applications of nicotine excited 90% of retrogradely labelled septohippocampal GABA-type neurons with an EC50 of 17 microm and increased the frequency of spontaneously occurring, impulse-dependent fast GABAergic and glutamatergic synaptic currents via the alpha4beta2-nicotinic receptor. Interestingly, tetrodotoxin blocked all effects of nicotine on septohippocampal GABAergic type neurons, suggesting involvement of indirect mechanisms. We demonstrate that the effects of nicotine on septohippocampal GABA-type neurons involve recruitment of a novel, local glutamatergic circuitry as (i). Group I metabotropic glutamatergic receptor antagonists reduced the effects of nicotine; (ii). the number of nicotine responsive neurons was significantly reduced in recordings from slices that had been trimmed so as to reduce the number of glutamate-containing neurons within the slice preparation; (iii). in light and ultrastructural double immunocytochemical labelling studies vesicular glutamate 2 transporter immunoreactive terminals made synaptic contacts with parvalbumin-immunoreactive septohippocampal GABAergic neurons. The discovery of a local glutamatergic circuit within the septum may provide another avenue for restoring septohippocampal GABAergic functions in neurodegenerative disorders associated with a loss of septohippocampal cholinergic neurons.

Neurochemical background and approaches in the understanding of motion sickness

NASA Technical Reports Server (NTRS)

Kohl, R. L.

1982-01-01

The problems and nature of space motion sickness were defined. The neurochemical and neurophysiological bases of vestibular system function and of the expression of motion sickness wre reviewed. Emphasis was given to the elucidation of the neuropharmacological mechanisms underlying the effects of scopolamine and amphetamine on motion sickness. Characterization of the ascending reticular activating system and the limbic system provided clues to the etiology of the side effects of scopolamine. The interrelationship between central cholinergic pathways and the peripheral (autonomic) expression of motion sickness was described. A correlation between the stress of excessive motion and a variety of hormonal responses to that stress was also detailed. The cholinergic system is involved in the efferent modulation of the vestibular hair cells, as an afferent modulator of the vestibular nuclei, in the activation of cortical and limbic structures, in the expression of motion sickness symptoms and most likely underscores a number of the hormonal changes that occur in stressful motion environments. The role of lecithin in the regulation of the levels of neurotransmitters was characterized as a possible means by which cholinergic neurochemistry can be modulated.

Effects of systemic cholinergic antagonism on reinforcer devaluation in macaques.

PubMed

Waguespack, Hannah F; Málková, Ludise; Forcelli, Patrick A; Turchi, Janita

2018-06-21

The capacity to adjust actions based on new information is a vital cognitive function. An animal's ability to adapt behavioral responses according to changes in reward value can be measured using a reinforcer devaluation task, wherein the desirability of a given object is reduced by decreasing the value of the associated food reinforcement. Elements of the neural circuits serving this ability have been studied in both rodents and nonhuman primates. Specifically, the basolateral amygdala, orbitofrontal cortex, nucleus accumbens, and mediodorsal thalamus have each been shown to play a critical role in the process of value updating, required for adaptive goal selection. As these regions receive dense cholinergic input, we investigated whether systemic injections of non-selective nicotinic or muscarinic acetylcholine receptor antagonists, mecamylamine and scopolamine, respectively, would impair performance on a reinforcer devaluation task. Here we demonstrate that in the presence of either a nicotinic or muscarinic antagonist, animals are able to shift their behavioral responses in an appropriate manner, suggesting that disruption of cholinergic neuromodulation is not sufficient to disrupt value updating, and subsequent goal selection, in rhesus macaques. Published by Elsevier B.V.

Tracking the origin and divergence of cholinesterases and neuroligins: the evolution of synaptic proteins.

PubMed

Lenfant, Nicolas; Hotelier, Thierry; Bourne, Yves; Marchot, Pascale; Chatonnet, Arnaud

2014-07-01

A cholinesterase activity can be found in all kingdoms of living organism, yet cholinesterases involved in cholinergic transmission appeared only recently in the animal phylum. Among various proteins homologous to cholinesterases, one finds neuroligins. These proteins, with an altered catalytic triad and no known hydrolytic activity, display well-identified cell adhesion properties. The availability of complete genomes of a few metazoans provides opportunities to evaluate when these two protein families emerged during evolution. In bilaterian animals, acetylcholinesterase co-localizes with proteins of cholinergic synapses while neuroligins co-localize and may interact with proteins of excitatory glutamatergic or inhibitory GABAergic/glycinergic synapses. To compare evolution of the cholinesterases and neuroligins with other proteins involved in the architecture and functioning of synapses, we devised a method to search for orthologs of these partners in genomes of model organisms representing distinct stages of metazoan evolution. Our data point to a progressive recruitment of synaptic components during evolution. This finding may shed light on the common or divergent developmental regulation events involved into the setting and maintenance of the cholinergic versus glutamatergic and GABAergic/glycinergic synapses.

Binding of /sup 3/H-acetylcholine to cholinergic receptors in bovine cerebral arteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shimohama, S.; Tsukahara, T.; Taniguchi, T.

Cholinergic receptor sites in bovine cerebral arteries were analyzed using radioligand binding techniques with the cholinergic agonist, /sup 3/H-acetylcholine (ACh), as the ligand. Specific binding of /sup 3/H-ACh to membrane preparations of bovine cerebral arteries was saturable, of two binding sites, with dissociation constant (K/sub D/) values of 0.32 and 23.7 nM, and maximum binding capacity (Bmax) values of 67 and 252 fmol/mg protein, respectively. Specific binding of /sup 3/H-ACh was displaced effectively by muscarinic cholinergic agents and less effectively by nicotinic cholinergic agents. IC/sub 50/ values of cholinergic drugs for /sup 3/H-ACh binding were as follows: atropine, 38.5 nM;more » ACh, 59.8 nM; oxotremorine, 293 nM; scopolamine 474 nM; carbamylcholine, 990 nM. IC/sub 50/ values of nicotinic cholinergic agents such as nicotine, cytisine and ..cap alpha..-bungarotoxin exceeded 50 ..mu..M. Choline acetyltransferase activity was 1.09 nmol/mg protein/hour in the cerebral arteries. These findings suggest that the cholinergic nerves innervate the bovine cerebral arteries and that there are at least two classes of ACh binding sites of different affinities on muscarinic reporters in these arteries. 18 references, 2 figures, 2 tables.« less

[Immunocytochemical study of cholinergic innervation in the neurosensory epithelia of human vestibule].

PubMed

Kong, W; Hussl, B; Schrott-Fischer, A

1998-02-01

To investigate the cholinergic innervation of the neurosensory epithelia of human vestibule. A modified preembedding immunostaining technique for immunoelectronmicroscopy was applied to this study. A polyclonal antibody to choline acetyltransferase (ChAT) was used as the marker of cholinergic fibers. ChAT-immunoreactive products were restricted to the nerve fibers and terminals which were rich in synaptic vesicles. The ChAT-immunoreactive fibers synaps with afferent chalice as well as with type II sensory hair cells. This study demonstrates that cholinergic fibers innervate the neurosensory epithelia of human vestible. The cholinergic fibers of human vestibular sensory epithelia belong to the vestibular efferent system.

The effects of caffeine on the cholinergic system.

PubMed

Pohanka, Miroslav

2014-01-01

Caffeine is a secondary metabolite of tea and coffee plants. It is the active psychostimulant ingredient of widely consumed beverages, chocolate and some drugs as well. The major pathways for caffeine including interaction with adenosine receptors have been identified but caffeine has several minor pathways as well that remain poorly understood including the cholinergic system. Given the role of caffeine in the cholinergic system, some molecular targets have been tracked and a mechanism of its action has been proposed in research studies. However, the biological effect of caffeine on the cholinergic system is not completely understood. The present review focuses on the role of caffeine in the cholinergic system.

Mood alterations during deanol therapy.

PubMed

Casey, D E

1979-04-11

An imbalance between central cholinergic and adrenergic influences may affect mood disorders. Of 38 patients taking high doses of deanol, a putative acetylcholine precursor, eight developed changes in mood: five became depressed and three became hypomanic. A predisposition is suggested as seven of these eight patients had histories of affective symptoms. There was no relationship between the changes in dyskinesias and mood. These observations have both practical and heuristic implications for the management of patients and for further research into the pharmacology of affective disorders and deanol.

Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats.

PubMed

Luine, V N

1985-08-01

Administration of estradiol to gonadectomized female, but not male rats, is associated with increased activity of choline acetyltransferase in the medial aspect of the horizontal diagonal band nucleus, the frontal cortex, and CA1 of the dorsal hippocampus. Four other basal forebrain cholinergic nuclei did not show changes in choline acetyltransferase activity after estradiol. These data have implications for possible benefits of estradiol administration to patients with senile dementia of the Alzheimer's type.

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

PubMed Central

Pavlov, Valentin A.; Ochani, Mahendar; Gallowitsch-Puerta, Margot; Ochani, Kanta; Huston, Jared M.; Czura, Christopher J.; Al-Abed, Yousef; Tracey, Kevin J.

2006-01-01

TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this “cholinergic antiinflammatory pathway” inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents. PMID:16549778

Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia.

PubMed

Román, Gustavo C; Kalaria, Raj N

2006-12-01

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.

[Involvement of cross interaction between central cholinergic and histaminergic systems in the nucleus tractus solitarius in regulating carotid sinus baroreceptor reflex].

PubMed

Hu, Li-Xun; Zhang, Guo-Xing; Zhang, Yu-Ying; Zhao, Hong-Fen; Yu, Kang-Ying; Wang, Guo-Qing

2013-12-25

The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and possible modulatory mechanism of preceding microinjection with different histaminergic receptor antagonists, the selective histaminergic H1 receptor antagonist, i.e., chlorpheniramine (CHL) or the H2 receptor antagonist, i.e., cimetidine (CIM) into the NTS on the changes in function of CSR resulted from the i.c.v. cholinesterase inhibitor, physostigmine (PHY) were also examined in order to confirm and to analyze effects of cross interaction between central histaminergic and cholinergic systems on CSR. The main results obtained are as follows. (1) Standalone microinjection of different selective cholinergic receptor antagonists (PRZ, MTR or HEX) or different selective histaminergic receptor antagonists (CHL or CIM) into the NTS with each given dose had no effects on the CSR function and on the basic levels of the artery blood pressure, respectively (P > 0.05). (2) The pretreatment of PRZ or MTR into the NTS with each corresponding dose could attenuate CSR resetting resulted from i.c.v. HA in some degrees, which remarkably moved the posterior half range of ISP-MAP relationship curve downwards (P < 0.05), shifted the middle part of ISP-Gain relationship curve upwards (P < 0.05), and increased reflex parameters such as the MAP range and maximum gain (P < 0.05), but decreased parameters such as saturation pressure and intracarotid sinus pressure at maximum gain (P < 0.05). The catabatic effects of pretreatment with MTR into the NTS on CSR resetting induced by i.c.v. HA were more obvious than those with PRZ (P < 0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P > 0.05). (3) The effects of pretreatment of CHL or CIM into the NTS with each corresponding dose on CSR resetting made by i.c.v. PHY were similar to those of pretreatment of PRZ or MTR into the NTS on CSR resetting resulted from i.c.v. HA, and the decreasing effects of pretreatment with CHL into the NTS on CSR resetting induced by i.c.v. PHY were more remarkable than those with CIM (P < 0.05). These findings suggest that CSR resetting resulted from either HA or PHY into the lateral ventricle may partly involve the descending histaminergic or cholinergic pathway from the hypothalamus to NTS, which might evoke a cross activation of the cholinergic system in the NTS, via cholinergic M1 and M2 receptors mediation, especially the M2 receptors showing actions, or trigger another cross activation of the histaminergic system in the NTS, by histaminergic H1 and H2 receptors mediation, especially the H1 receptors displaying effects.

Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation.

PubMed

Hulsey, Daniel R; Hays, Seth A; Khodaparast, Navid; Ruiz, Andrea; Das, Priyanka; Rennaker, Robert L; Kilgard, Michael P

2016-01-01

Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. The mechanisms that underlie VNS-dependent enhancement of map plasticity are largely unknown. The cholinergic nucleus basalis (NB) is a critical substrate in cortical plasticity, and several studies suggest that VNS activates cholinergic circuitry. We examined whether the NB is required for VNS-dependent enhancement of map plasticity in the motor cortex. Rats were trained to perform a lever pressing task and then received injections of the immunotoxin 192-IgG-saporin to selectively lesion cholinergic neurons of the NB. After lesion, rats underwent five days of motor training during which VNS was paired with successful trials. At the conclusion of behavioral training, intracortical microstimulation was used to document movement representations in motor cortex. VNS paired with forelimb training resulted in a substantial increase in the representation of proximal forelimb in rats with an intact NB compared to untrained controls. NB lesions prevent this VNS-dependent increase in proximal forelimb area and result in representations similar to untrained controls. Motor performance was similar between groups, suggesting that differences in forelimb function cannot account for the difference in proximal forelimb representation. Together, these findings indicate that the NB is required for VNS-dependent enhancement of plasticity in the motor cortex and may provide insight into the mechanisms that underlie the benefits of VNS therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice.

PubMed

Zhao, Qi; Murakami, Yukihisa; Tohda, Michihisa; Obi, Ryosuke; Shimada, Yutaka; Matsumoto, Kinzo

2007-04-01

We previously demonstrated that the Kampo formula chotosan (CTS) ameliorated spatial cognitive impairment via central cholinergic systems in a chronic cerebral hypoperfusion (P2VO) mouse model. In this study, the object discrimination tasks were used to determine if the ameliorative effects of CTS on P2VO-induced cognitive deficits are a characteristic pharmacological profile of this formula, with the aim of clarifying the mechanisms by which CTS enhances central cholinergic function in P2VO mice. The cholinesterase inhibitor tacrine (THA) and Kampo formula saikokeishito (SKT) were used as controls. P2VO impaired object discrimination performance in the object recognition, location, and context tests. Daily administration of CTS (750 mg/kg, p.o.) and THA (2.5 mg/kg, i.p.) improved the object discrimination deficits, whereas SKT (750 mg/kg, p.o.) did not. In ex vivo assays, tacrine but not CTS or SKT inhibited cortical cholinesterase activity. P2VO reduced the mRNA expression of m(3) and m(5) muscarinic receptors and choline acetyltransferase but not that of other muscarinic receptor subtypes in the cerebral cortex. Daily administration of CTS and THA but not SKT reversed these expression changes. These results suggest that CTS and THA improve P2VO-induced cognitive impairment by normalizing the deficit of central cholinergic systems and that the beneficial effect on P2VO-induced cognitive deficits is a distinctive pharmacological characteristic of CTS.

Cholinesterase Inhibitors Improve Both Memory and Complex Learning in Aged Beagle Dogs

PubMed Central

Araujo, Joseph A.; Greig, Nigel H.; Ingram, Donald K.; Sandin, Johan; de Rivera, Christina; Milgram, Norton W.

2016-01-01

Similar to patients with Alzheimer’s disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline. PMID:21593569

The cholinergic forebrain arousal system acts directly on the circadian pacemaker

PubMed Central

Yamakawa, Glenn R.; Basu, Priyoneel; Cortese, Filomeno; MacDonnell, Johanna; Whalley, Danica; Smith, Victoria M.

2016-01-01

Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7- to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system. PMID:27821764

Acetylcholine content and viability of cholinergic neurons are influenced by the activity of protein histidine phosphatase

PubMed Central

2012-01-01

Background The first mammalian protein histidine phosphatase (PHP) was discovered in the late 90s of the last century. One of the known substrates of PHP is ATP-citrate lyase (ACL), which is responsible - amongst other functions - for providing acetyl-CoA for acetylcholine synthesis in neuronal tissues. It has been shown in previous studies that PHP downregulates the activity of ACL by dephosphorylation. According to this our present work focused on the influence of PHP activity on the acetylcholine level in cholinergic neurons. Results The amount of PHP in SN56 cholinergic neuroblastoma cells was increased after overexpression of PHP by using pIRES2-AcGFP1-PHP as a vector. We demonstrated that PHP overexpression reduced the acetylcholine level and induced cell death. The acetylcholine content of SN56 cells was measured by fast liquid chromatography-tandem mass spectrometry method. Overexpression of the inactive H53A-PHP mutant also induced cell damage, but in a significantly reduced manner. However, this overexpression of the inactive PHP mutant did not change the acetylcholine content of SN56 cells significantly. In contrast, PHP downregulation, performed by RNAi-technique, did not induce cell death, but significantly increased the acetylcholine content in SN56 cells. Conclusions We could show for the first time that PHP downregulation increased the acetylcholine level in SN56 cells. This might be a potential therapeutic strategy for diseases involving cholinergic deficits like Alzheimer's disease. PMID:22436051

Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

PubMed Central

Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

2016-01-01

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated pools of neurons that may modulate specific cortical areas. PMID:27147975

Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

PubMed

Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

2016-01-01

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated pools of neurons that may modulate specific cortical areas.

Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity.

PubMed

Pitchers, Kyle K; Phillips, Kyra B; Jones, Jonte L; Robinson, Terry E; Sarter, Martin

2017-07-26

Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS + and a DS - , respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS + to reinstate cocaine seeking behavior. The DS + was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS + We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered. SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability. Copyright © 2017 the authors 0270-6474/17/377198-11$15.00/0.

CORRELATIONS OF PESTICIDE-INDUCED CHOLINESTERASE INHIBITION AND MOTOR ACTIVITY CHANGES IN ADULT RATS.

EPA Science Inventory

The acute neurobehavioral effects of acetylcholinesterase-inhibiting pesticides are primarily due to overstimulation of the cholinergic system. Lowered motor activity levels represent a sensitive endpoint with which to monitor functional changes in laboratory animals exposed to ...

Development of cardiac parasympathetic neurons, glial cells, and regional cholinergic innervation of the mouse heart.

PubMed

Fregoso, S P; Hoover, D B

2012-09-27

Very little is known about the development of cardiac parasympathetic ganglia and cholinergic innervation of the mouse heart. Accordingly, we evaluated the growth of cholinergic neurons and nerve fibers in mouse hearts from embryonic day 18.5 (E18.5) through postnatal day 21(P21). Cholinergic perikarya and varicose nerve fibers were identified in paraffin sections immunostained for the vesicular acetylcholine transporter (VAChT). Satellite cells and Schwann cells in adjacent sections were identified by immunostaining for S100β calcium binding protein (S100) and brain-fatty acid binding protein (B-FABP). We found that cardiac ganglia had formed in close association to the atria and cholinergic innervation of the atrioventricular junction had already begun by E18.5. However, most cholinergic innervation of the heart, including the sinoatrial node, developed postnatally (P0.5-P21) along with a doubling of the cross-sectional area of cholinergic perikarya. Satellite cells were present throughout neonatal cardiac ganglia and expressed primarily B-FABP. As they became more mature at P21, satellite cells stained strongly for both B-FABP and S100. Satellite cells appeared to surround most cardiac parasympathetic neurons, even in neonatal hearts. Mature Schwann cells, identified by morphology and strong staining for S100, were already present at E18.5 in atrial regions that receive cholinergic innervation at later developmental times. The abundance and distribution of S100-positive Schwann cells increased postnatally along with nerve density. While S100 staining of cardiac Schwann cells was maintained in P21 and older mice, Schwann cells did not show B-FABP staining at these times. Parallel development of satellite cells and cholinergic perikarya in the cardiac ganglia and the increase in abundance of Schwann cells and varicose cholinergic nerve fibers in the atria suggest that neuronal-glial interactions could be important for development of the parasympathetic nervous system in the heart. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care

PubMed Central

Hulse, Elspeth J.; Davies, James O. J.; Simpson, A. John; Sciuto, Alfred M.

2014-01-01

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities. PMID:25419614

Autoradiographic labeling of the cholinergic habenulo-interpeduncular projection.

PubMed

Villani, L; Contestabile, A; Fonnum, F

1983-12-11

The transmitter-specific autoradiographic method has been used to retrogradely trace the habenulo-interpeduncular cholinergic projection. [3H]Choline injection in the interpeduncular nucleus resulted in remarkable labeling of the fasciculus retroflexus and in very strong accumulation of silver grains in the medial habenula. Brainstem nuclei sending non-cholinergic projections to the interpeduncular nucleus were not labeled. The present findings strongly support the notion of a cholinergic medial habenula-interpeduncular nucleus projection in agreement with recent immunohistochemical evidence, but in contrast to previous immunocytochemical and pharmacohistochemical results.

Impact of Chronic Stress on the Spatial Learning and GR-PKAc-NF-κB Signaling in the Hippocampus and Cortex in Rats Following Cholinergic Depletion.

PubMed

Lee, Sun-Young; Cho, Woo-Hyun; Lee, Yo-Seob; Han, Jung-Soo

2018-05-01

Studies have shown that the removal of the cholinergic innervation to the hippocampus induces dysfunction of the hypothalamic-pituitary-adrenocortical axis and decreases the number of glucocorticoid receptors (GRs). Subsequent studies have revealed that the loss of cholinergic input to the hippocampus reduces the expression of GRs and activates nuclear factor-kappa B (NF-κB) signaling through interactions with the cytoplasmic catalytic subunit of protein kinase A (PKAc). We examined the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex. Male Sprague-Dawley rats received 192 IgG-saporin injections to selectively eliminate cholinergic neurons in their basal forebrain. Two weeks later, rats were subjected to 1 h of restraint stress per day for 14 days. Rats subjected to both chronic stress and cholinergic depletion showed more severe memory impairments compared to those that received either treatment alone. The reduction in nuclear GR levels induced by cholinergic depletion was unaffected by chronic stress. The activation of NF-κB signaling in the hippocampus and the cerebral cortex induced by cholinergic depletion was augmented by chronic stress, resulting in the increased expression of pro-inflammatory markers, such as inducible nitric oxide synthase and cyclooxygenase-2. The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer's disease to stress since activation of NF-κB is associated with stress.

Cholinergic neurodegeneration in an Alzheimer mouse model overexpressing amyloid-precursor protein with the Swedish-Dutch-Iowa mutations.

PubMed

Foidl, Bettina Maria; Do-Dinh, Patricia; Hutter-Schmid, Bianca; Bliem, Harald R; Humpel, Christian

2016-12-01

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is mainly characterized by beta-amyloid (Aβ) plaque deposition, Tau pathology and dysfunction of the cholinergic system causing memory impairment. The aim of the present study was to examine (1) anxiety and cognition, (2) Aβ plaque deposition and (3) degeneration of cholinergic neurons in the nucleus basalis of Meynert (nbM) and cortical cholinergic innervation in an Alzheimer mouse model (APP_SweDI; overexpressing amyloid precursor protein (APP) with the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations). Our results show that 12-month-old APP_SweDI mice were more anxious and had more memory impairment. A large number of Aβ plaques were already visible at the age of 6 months and increased with age. A significant decrease in cholinergic neurons was seen in the transgenic mouse model in comparison to the wild-type mice, identified by immunohistochemistry against choline acetyltransferase (ChAT) and p75 neurotrophin receptor as well as by in situ hybridization. Moreover, a significant decrease in cortical cholinergic fiber density was found in the transgenic mice as compared to the wild-type. In the cerebral cortex of APP_SweDI mice, swollen cholinergic varicosities were seen in the vicinity of Aβ plaques. In conclusion, the present study shows that in an AD mouse model (APP_SweDI mice) a high Aβ plaque load in the cortex causes damage to cholinergic axons in the cortex, followed by subsequent retrograde-induced cell death of cholinergic neurons and some forms of compensatory processes. This degeneration was accompanied by enhanced anxiety and impaired cognition. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of hydrogen sulphide on motility patterns in the rat colon

PubMed Central

Gil, V; Parsons, SP; Gallego, D; Huizinga, JD; Jimenez, M

2013-01-01

Background and Purpose Hydrogen sulphide (H2S) is an endogenous gaseous signalling molecule with putative functions in gastrointestinal motility regulation. Characterization of H2S effects on colonic motility is crucial to establish its potential use as therapeutic agent in the treatment of colonic disorders. Experimental Approach H2S effects on colonic motility were characterized using video recordings and construction of spatio-temporal maps. Microelectrode and muscle bath studies were performed to investigate the mechanisms underlying H2S effects. NaHS was used as the source of H2S. Key Results Rhythmic propulsive motor complexes (RPMCs) and ripples were observed in colonic spatio-temporal maps. Serosal addition of NaHS concentration-dependently inhibited RPMCs. In contrast, NaHS increased amplitude of the ripples without changing their frequency. Therefore, ripples became the predominant motor pattern. Neuronal blockade with lidocaine inhibited RPMCs, which were restored after administration of carbachol. Subsequent addition of NaHS inhibited RPMCs. Luminal addition of NaHS did not modify motility patterns. NaHS inhibited cholinergic excitatory junction potentials, carbachol-induced contractions and hyperpolarized smooth muscle cells, but did not modify slow wave activity. Conclusions and Implications H2S modulated colonic motility inhibiting propulsive contractile activity and enhancing the amplitude of ripples, promoting mixing. Muscle hyperpolarization and inhibition of neurally mediated cholinergic responses contributed to the inhibitory effect on propulsive activity. H2S effects were not related to changes in the frequency of slow wave activity originating in the network of interstitial cells of Cajal located near the submuscular plexus. Luminal H2S did not modify colonic motility probably because of epithelial detoxification. PMID:23297830

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age

PubMed Central

Crivello, Natalia A.; Blusztajn, Jan K.; Joseph, James A.; Shukitt-Hale, Barbara; Smith, Donald E.

2010-01-01

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). FD consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions. PMID:21056288

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age.

PubMed

Crivello, Natalia A; Blusztajn, Jan K; Joseph, James A; Shukitt-Hale, Barbara; Smith, Donald E

2010-10-01

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). Folate-deficient diet consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions. Copyright © 2010 Elsevier Inc. All rights reserved.

Plasticity of non-adrenergic non-cholinergic bladder contractions in rats after chronic spinal cord injury

PubMed Central

Lai, H. Henry; Munoz, Alvaro; Smith, Christopher P.; Boone, Timothy B.; Somogyi, George T.

2011-01-01

The purpose of this study was to examine the pharmacologic plasticity of cholinergic, non-adrenergic non-cholinergic (NANC), and purinergic contractions in neurogenic bladder strips from spinal cord injured (SCI) rats. Bladder strips were harvested from female rats three to four weeks after T9–T10 spinal cord transection. The strips were electrically stimulated using two experimental protocols to compare the contribution of muscarinic and NANC/purinergic contractions in the presence and the absence of carbachol or muscarine. The endpoints of the study were: (1) percent NANC contraction that was unmasked by the muscarinic antagonist 4-DAMP, and (2) P2X purinergic contraction that was evoked by α,β–methylene ATP. NANC contraction accounted for 78.5% of the neurally evoked contraction in SCI bladders. When SCI bladder strips were treated with carbachol (10 µM) prior to 4-DAMP (500 nM), the percent NANC contraction decreased dramatically to only 13.1% of the neurally evoked contraction (p=0.041). This was accompanied by a substantial decrease in α,β–methylene ATP evoked P2X contraction, and desensitization of purinergic receptors (the ratio of subsequent over initial P2X contraction decreased from 97.2% to 42.1%, p=0.0017). Sequential activation of the cholinergic receptors with carbachol (or with muscarine in neurally intact bladders) and unmasking of the NANC response with 4-DAMP switched the neurally evoked bladder contraction from predominantly NANC to predominantly cholinergic. We conclude that activation of muscarinic receptors (with carbachol or muscarine) blocks NANC and purinergic contractions in neurally intact or in SCI rat bladders. The carbachol-induced inhibition of the NANC contraction is expressed more in SCI bladders compared to neurally intact bladders. Along with receptor plasticity, this change in bladder function may involve P2X-independent mechanisms. PMID:21689735

Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys.

PubMed

Turchi, Janita; Saunders, Richard C; Mishkin, Mortimer

2005-02-08

Excitotoxic lesion studies have confirmed that the rhinal cortex is essential for visual recognition ability in monkeys. To evaluate the mnemonic role of cholinergic inputs to this cortical region, we compared the visual recognition performance of monkeys given rhinal cortex infusions of a selective cholinergic immunotoxin, ME20.4-SAP, with the performance of monkeys given control infusions into this same tissue. The immunotoxin, which leads to selective cholinergic deafferentation of the infused cortex, yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region, providing the most direct demonstration to date that cholinergic activation of the rhinal cortex is essential for storing the representations of new visual stimuli and thereby enabling their later recognition.

Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep

PubMed Central

Ni, Kun-Ming; Hou, Xiao-Jun; Yang, Ci-Hang; Dong, Ping; Li, Yue; Zhang, Ying; Jiang, Ping; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

2016-01-01

Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep. DOI: http://dx.doi.org/10.7554/eLife.10382.001 PMID:26880556

Differential Modulation of Spontaneous and Evoked Thalamocortical Network Activity by Acetylcholine Level In Vitro

PubMed Central

Wester, Jason C.

2013-01-01

Different levels of cholinergic neuromodulatory tone have been hypothesized to set the state of cortical circuits either to one dominated by local cortical recurrent activity (low ACh) or to one dependent on thalamic input (high ACh). High ACh levels depress intracortical but facilitate thalamocortical synapses, whereas low levels potentiate intracortical synapses. Furthermore, recent work has implicated the thalamus in controlling cortical network state during waking and attention, when ACh levels are highest. To test this hypothesis, we used rat thalamocortical slices maintained in medium to generate spontaneous up- and down-states and applied different ACh concentrations to slices in which thalamocortical connections were either maintained or severed. The effects on spontaneous and evoked up-states were measured using voltage-sensitive dye imaging, intracellular recordings, local field potentials, and single/multiunit activity. We found that high ACh can increase the frequency of spontaneous up-states, but reduces their duration in slices with intact thalamocortical connections. Strikingly, when thalamic connections are severed, high ACh instead greatly reduces or abolishes spontaneous up-states. Furthermore, high ACh reduces the spatial propagation, velocity, and depolarization amplitude of evoked up-states. In contrast, low ACh dramatically increases up-state frequency regardless of the presence or absence of intact thalamocortical connections and does not reduce the duration, spatial propagation, or velocity of evoked up-states. Therefore, our data support the hypothesis that strong cholinergic modulation increases the influence, and thus the signal-to-noise ratio, of afferent input over local cortical activity and that lower cholinergic tone enhances recurrent cortical activity regardless of thalamic input. PMID:24198382

Physical allergies and exercise. Clinical implications for those engaged in sports activities.

PubMed

Briner, W W

1993-06-01

There are several allergic responses that may occur in susceptible individuals as a result of exposure to physical stimuli. Most of these conditions are mediated by vasoactive substances and usually result in symptoms of urticaria and/or angioedema. There are 2 such conditions that may occur as a direct result from exercise. The first of these is cholinergic urticaria. Patients with cholinergic urticaria experience punctate (2 to 4mm) hives which occur reproducibly with exercise or with passive warming, such as might occur in a steam bath or hot pool. Life-threatening hypotension or angioedema usually do not occur with cholinergic urticaria. This condition usually responds well to oral hydroxyzine. Exercise-induced anaphylaxis (EIA) is a form of physical allergy that has been recognised with increasing frequency in recent years. This syndrome typically presents with generalised pruritus, a flushing sensation, a feeling of warmth and the development of conventional (10 to 15mm) urticaria in association with vigorous physical exertion only. Symptoms tend to occur variably with exposure to exercise and do not typically occur with passive warming. During symptomatic attacks, cutaneous mast cells degranulate and serum histamine levels increase. Treatment is problematic. Cessation of exercise with onset of symptoms and self-administration of epinephrine (adrenaline) are recommended. Other physical allergies that may affect exercising individuals include cold urticaria, localised heat urticaria, symptomatic dermatographism (dermographism), delayed pressure urticaria (angioedema), solar urticaria and aquagenic urticaria. Management of these conditions may include patient education, selective avoidance, antihistamines and, in some cases, induction of tolerance.

Neostigmine interactions with non steroidal anti-inflammatory drugs.

PubMed

Miranda, Hugo F; Sierralta, Fernando; Pinardi, Gianni

2002-04-01

1. The common mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of the enzyme cyclo-oxygenase (COX), however, this inhibition is not enough to completely account for the efficacy of these agents in several models of acute pain. 2. It has been demonstrated that cholinergic agents can induce antinociception, but the nature of the interaction between these agents and NSAIDs drugs has not been studied. The present work evaluates, by isobolographic analysis, the interactions between the cholinergic indirect agonist neostigmine (NEO) and NSAIDs drugs, using a chemical algesiometric test. 3. Intraperitoneal (i.p.) or intrathecal (i.t.) administration of NEO and of the different NSAIDs produced dose-dependent antinociception in the acetic acid writhing test of the mouse. 4. The i.p. or i.t. co-administration of fixed ratios of ED(50) fractions of NSAIDs and NEO, resulted to be synergistic or supra-additive for the combinations ketoprofen (KETO) and NEO, paracetamol (PARA) and NEO) and diclofenac (DICLO) and NEO administered i.p. However, the same combinations administered i.t. were only additive. In addition, the combinations meloxicam (MELO) and NEO and piroxicam (PIRO) and NEO, administered either i.p. or i.t., were additive. 5. The results suggest that the co-administration of NEO with some NSAIDs (e.g. KETO, PARA or DICLO) resulted in a synergistic interaction, which may provide evidence of supraspinal antinociception modulation by the increased acetylcholine concentration in the synaptic cleft of cholinergic interneurons. The interaction obtained between neostigmine and the NSAIDs could carry important clinical implications.

Abnormalities in the contractile properties of colonic smooth muscle in idiopathic slow transit constipation.

PubMed

Slater, B J; Varma, J S; Gillespie, J I

1997-02-01

The underlying pathophysiology of idiopathic slow transit constipation (ISTC) remains unclear. At present, there is little evidence to implicate a smooth muscle myopathy in the aetiology of this condition. This study compared the effect of cisapride on the cholinergic response of colonic muscle strips from patients with this condition with that of control tissue. Isometric tension production was recorded from circular smooth muscle strips taken from five patients undergoing colectomy for ISTC in response to cumulative concentrations of carbachol (100 nmol/1-100 mumol/l) alone and in the presence of cisapride 400 nmol/l. Similar dose-response activity was obtained for a control group consisting of six patients undergoing resection for colorectal carcinoma. In the absence of cisapride, smooth muscle from patients with carcinoma exhibited a significantly lower sensitivity to cholinergic stimulation (agonist concentration required to produce half-maximal activation (EC50) 4.83 mumol/l) than that from patients with ISTC (EC50 1.63 mumol/l, P = 0.036), and also a greater maximal frequency of the oscillatory activity associated with the increase in isometric tension (0.070 versus 0.049 Hz, P = 0.035). Cisapride had no effect on the sensitivity to carbachol of the carcinoma tissue but brought about a significant reduction in the sensitivity of smooth muscle from patients with ISTC (EC50 3.24 mumol/l, P = 0.043). These findings indicate that colonic smooth muscle from patients with ISTC is hypersensitive to cholinergic stimulation and suggest the existence of a smooth muscle myopathy in this condition.

Increased interactions between PKA and NF-κB signaling in the hippocampus following loss of cholinergic input.

PubMed

Lim, C S; Hwang, Y K; Kim, D; Cho, S H; Bañuelos, C; Bizon, J L; Han, J-S

2011-09-29

Neuropsychiatric disorders such as depression are frequently associated with Alzheimer's disease (AD) and the degeneration of cholinergic basal forebrain neurons and reductions in acetylcholine that occur in AD have been identified as potential mediators of these secondary neuropsychiatric symptomologies. Indeed, removal of cholinergic innervation to the hippocampus via selective immunolesions of septohippocampal cholinergic neurons induces dysfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis and decreases glucocorticoid receptor expression (GR). A subsequent study showed that loss of cholinergic input decreases the activity of the catalytic subunit of protein kinase A (PKAc) and lessens the interaction of protein kinase A (PKA) with GR. Because cross-coupling between nuclear factor-κB (NF-κB) p65 and GR depends on PKA signaling, the present study was conducted to evaluate the status of NF-κB as well as interactions of PKA with NF-κB in the hippocampus following cholinergic denervation. Expression of cytosolic NF-κB p65 was diminished and IκB was degraded in the hippocampus of cholinergic immunolesioned rats compared to the controls. Immunolesions also increased NF-κB p65 Ser276 phosphorylation, as well as interactions between PKAc and NF-κB p65. These results indicate that loss of cholinergic input to the hippocampus results in decreased PKA activity and increased NF-κB activity. Such altered signaling may contribute to psychiatric symptoms, including depression, in patients with AD. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Sex differences in brain cholinergic activity in MSG-obese rats submitted to exercise.

PubMed

Sagae, Sara Cristina; Grassiolli, Sabrina; Raineki, Charlis; Balbo, Sandra Lucinei; Marques da Silva, Ana Carla

2011-11-01

Obesity is an epidemic disease most commonly caused by a combination of increased energy intake and lack of physical activity. The cholinergic system has been shown to be involved in the regulation of food intake and energy expenditure. Moreover, physical exercise promotes a reduction of fat pads and body mass by increasing energy expenditure, but also influences the cholinergic system. The aim of this study is to evaluate the interaction between physical exercise (swimming) and central cholinergic activity in rats treated with monosodium glutamate (MSG, a model for obesity) during infancy. Our results show that MSG treatment is able to induce obesity in male and female rats. Specifically, MSG-treated rats presented a reduced body mass and nasoanal length, and increased perigonadal and retroperitoneal fat pads in relation to the body mass. Physical exercise was able to reduce body mass in both male and female rats, but did not change the fat pads in MSG-treated rats. Increased food intake was only seen in MSG-treated females submitted to exercise. Cholinergic activity was increased in the cortex of MSG-treated females and physical exercise was able to reduce this activity. Thalamic cholinergic activity was higher in sedentary MSG-treated females and exercised MSG-treated males. Hypothalamic cholinergic activity was higher in male and female MSG-treated rats, and was not reduced by exercise in the 2 sexes. Taken together, these results show that MSG treatment and physical exercise have different effects in the cholinergic activity of males and females.

Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

PubMed Central

Groessl, Florian; Jeong, Jae Hoon; Talmage, David A.; Role, Lorna W.; Jo, Young-Hwan

2013-01-01

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis. PMID:23585854

The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

PubMed

Chen, Tsan-Ju; Chen, Shun-Sheng; Wang, Dean-Chuan; Hung, Hui-Shan

2016-11-01

Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Role of the mesolimbic cholinergic projection to the septum in the production of 22 kHz alarm calls in rats.

PubMed

Bihari, Aurelia; Hrycyshyn, A W; Brudzynski, Stefan M

2003-05-15

The role of the ascending cholinergic projection from the laterodorsal tegmental nucleus (LDT) to septum in the production of 22 kHz ultrasonic vocalization was studied in adult rats, using behavioral-pharmacological and anatomical tracing methods. Direct application of carbachol, a muscarinic agonist, into the lateral septal region induced species-typical 22 kHz alarm calls. The septum receives cholinergic input from LDT, thus, activation with glutamate of predominantly cholinergic neurons of the LDT induced comparable 22 kHz alarm calls in the same animals. This glutamate-induced response from LDT was significantly reduced when the lateral septum was pretreated with scopolamine, a cholinergic antagonist. To investigate the localization of the cell groups projecting to septum, the fluorescent retrograde tracer, fluorogold, was pressure injected into the lateral septum and sections from these brains were also immunostained against choline acetyltransferase (ChAT) to visualize cholinergic cell bodies. Several ChAT-fluorogold double-labeled cells within the boundaries of the LDT were found, while other fluorogold-labeled regions did not contain double-labeled cells. These results provide both direct and indirect evidence that at least a part of the mesolimbic ascending cholinergic projection from LDT to septum is involved in the initiation of the 22 kHz vocalization. It is concluded that the septum is an integral part of the medial cholinoceptive vocalization strip and the 22 kHz alarm vocalization is triggered from septum by the cholinergic input from the LDT.

Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality and performance

PubMed Central

Paolone, Giovanna; Lee, Theresa M.; Sarter, Martin

2012-01-01

Although the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SAT time-stamped cholinergic activation occurred irrespective of whether the SAT was practiced during the light or dark phase or in constant light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark period but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed time performance and, if practiced during the light phase, contributes to a diurnal activity pattern. PMID:22933795

Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance.

PubMed

Paolone, Giovanna; Lee, Theresa M; Sarter, Martin

2012-08-29

Although the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed-time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here, we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SAT time-stamped cholinergic activation occurred regardless of whether the SAT was practiced during the light or dark phase or in constant-light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark phase but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed-time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed-time performance and, if practiced during the light phase, contributes to a diurnal activity pattern.

Identification of the Muscarinic Acetylcholine Receptor Subtype Mediating Cholinergic Vasodilation in Murine Retinal Arterioles

PubMed Central

Sniatecki, Jan J.; Goloborodko, Evgeny; Steege, Andreas; Zavaritskaya, Olga; Vetter, Jan M.; Grus, Franz H.; Patzak, Andreas; Wess, Jürgen; Pfeiffer, Norbert

2011-01-01

Purpose. To identify the muscarinic acetylcholine receptor subtype that mediates cholinergic vasodilation in murine retinal arterioles. Methods. Muscarinic receptor gene expression was determined in murine retinal arterioles using real-time PCR. To assess the functional relevance of muscarinic receptors for mediating vascular responses, retinal vascular preparations from muscarinic receptor–deficient mice were studied in vitro. Changes in luminal arteriole diameter in response to muscarinic and nonmuscarinic vasoactive substances were measured by video microscopy. Results. Only mRNA for the M3 receptor was detected in retinal arterioles. Thus, M3 receptor–deficient mice (M3R−/−) and respective wild-type controls were used for functional studies. Acetylcholine concentration-dependently dilated retinal arterioles from wild-type mice. In contrast, vasodilation to acetylcholine was almost completely abolished in retinal arterioles from M3R−/− mice, whereas responses to the nitric oxide (NO) donor nitroprusside were retained. Carbachol, an acetylcholinesterase-resistant analog of acetylcholine, also evoked dilation in retinal arterioles from wild-type, but not from M3R−/−, mice. Vasodilation responses from wild-type mice to acetylcholine were negligible after incubation with the non–subtype-selective muscarinic receptor blocker atropine or the NO synthase inhibitor Nω-nitro-l-arginine methyl ester, and were even reversed to contraction after endothelial damage with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. Conclusions. These findings provide evidence that endothelial M3 receptors mediate cholinergic vasodilation in murine retinal arterioles via activation of NO synthase. PMID:21873683

Basolateral Amygdala, Nicotinic Cholinergic Receptors, and Nicotine: pharmacological effects and addiction in animal models and humans.

PubMed

Sharp, B M

2018-05-26

The amygdala is involved in processing incoming information about rewarding stimuli and emotions that denote danger such as anxiety and fear. Bi-directional neural connections between basolateral amygdala (BLA) and brain regions such as nucleus accumbens, prefrontal cortex, hippocampus and hindbrain regions regulate motivation, cognition, and responses to stress. Altered local regulation of BLA excitability is pivotal to the behavioral disturbances characteristic of posttraumatic stress disorder (PTSD), and relapse to drug use induced by stress. Herein, we review the physiological regulation of BLA by cholinergic inputs, emphasizing the role of BLA nicotinic receptors. We review BLA-dependent effects of nicotine on cognition, motivated behaviors and emotional states, including memory, taking and seeking drugs, and anxiety and fear in humans and animal models. The alterations in BLA activity observed in animal studies inform human behavioral and brain imaging research by enabling a more exact understanding of altered BLA function. Converging evidence indicates that cholinergic signaling from basal forebrain projections to local nicotinic receptors is an important physiological regulator of BLA and that nicotine alters BLA function. In essence, BLA is necessary for: behavioral responses to stimuli that evoke anxiety and fear; reinstatement of cue-induced drug seeking; responding to second-order cues conditioned to abused drugs; reacquisition of amplified nicotine self-administration due to chronic stress during abstinence; and to promote responding for natural reward. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Action of cholinergic poisons on the central nervous system and effectiveness of potential antidotes. Annual report 1 Jul 81-30 Jun 82

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samson, F.; Nelson, S.

The research aim was to determine the effects of soman, related organophosphate toxins and potential antidotes on brain regional functions in rats: The (/sup 14/C)-2-deoxyglucose procedure (2-DG) was used for mapping brain regional glucose use. Quantitative autoradiography was used for muscarinic and nicotinic cholinergic receptors. The 2-DG procedure gives a quantitative measure of glucose utilization in brain regions and is in index of the 'functional activity' in brain regions and systems. Values were determined in controls, rats with soman induced seizures, seizures induced by convulsants (DFP, strychnine, picrotoxin, pentylenetetrazol, penicillin) and soman pretreated with TAB. Brain regional cholinergic receptor mapsmore » were prepared and some regional muscarinic and nicotinic receptor densities have been quantified. Soman (112 micrograms/kg i.m.) causes strong, continuous seizures and a dramatic (2-6 fold) increase in the rate of glucose use in 10 major brain regions. Most intense increases were in septum, substants nigra reticularis and outer layer of hippcampal dendata gyrus. The overt seizures of rats induced by convulsants DFP, strychnine, picrotoxin, pentylenetetrazol and penicillin (in hippocampus) were strikingly different from that of rats with soman seizures. High doses (2X LD50) of soman in rats protected with TAB caused a 50% depression of glucose use in most brain regions. The effects of repeated soman exposure on muscarinic and nicotinic receptors are under study.« less

An in vitro investigation of the effects of the nerve agent pretreatment pyridostigmine bromide on human peripheral blood T-cell function.

PubMed

Telford, Gary; Wilkinson, Lucy J; Hooi, Doreen S W; Worrall, Vivienne; Green, A Christopher; Cook, David L; Pritchard, David I; Griffiths, Gareth D

2004-11-01

The current pretreatment against nerve agent poisoning deployed by the UK and US armed forces is the acetylcholinesterase (EC 3.1.1.7) inhibitor pyridostigmine bromide (PB). At higher doses, PB is also used to treat the autoimmune disease myasthenia gravis. In both cases, the therapeutic effect is mediated by inhibition of acetylcholinesterase (AChE) at cholinergic synapses. However, the location of AChE is not restricted to these sites. AChE, acetylcholine (ACh) receptors and choline acetyltransferase have been reported to be expressed by T cells, suggesting that cholinergic signalling may exert some modulatory influence on T-cell function and consequently on the immune system. The aim of this study was to investigate the role of the T-cell cholinergic system in the immunological activation process and to examine whether inhibitors of AChE such as PB affect immune function. To investigate this, human peripheral blood mononuclear cells (PBMC) were stimulated using either mitogen, cross-linking of the T-cell receptor and co-receptors with antibodies (anti-CD3/CD28) or by antigen presentation in the presence of various AChE inhibitors and ACh receptor agonists or antagonist. Several indices were used to assess T-cell activation, including the secretion of IL-2, cell proliferation and expression of CD69. Treatment with PB had no significant effect on the immunological assays selected. Physostigmine (PHY), a carbamate compound similar to PB, consistently showed inhibition of T-cell activation, but only at concentrations in excess of those required to inhibit AChE. No evidence was found to support previously published findings showing muscarinic enhancement of cell proliferation or IL-2 secretion.

Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees

PubMed Central

Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

2013-01-01

Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

N(N)-nicotinic blockade as an acute human model of autonomic failure

NASA Technical Reports Server (NTRS)

Jordan, J.; Shannon, J. R.; Black, B. K.; Lance, R. H.; Squillante, M. D.; Costa, F.; Robertson, D.

1998-01-01

Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.

Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees.

PubMed

Williamson, Sally M; Moffat, Christopher; Gomersall, Martha A E; Saranzewa, Nastja; Connolly, Christopher N; Wright, Geraldine A

2013-01-01

Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival.

Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain

USDA-ARS?s Scientific Manuscript database

The cholinergic theory of aging states that dysfunction of cholinergic neurons arising from the basal forebrain and terminating in the cortex and hippocampus may be involved in the cognitive decline that occurs during aging and Alzheimer’s disease. Despite years of research, pharmacological interven...

Neuronal effects of nicotine during auditory selective attention.

PubMed

Smucny, Jason; Olincy, Ann; Eichman, Lindsay S; Tregellas, Jason R

2015-06-01

Although the attention-enhancing effects of nicotine have been behaviorally and neurophysiologically well-documented, its localized functional effects during selective attention are poorly understood. In this study, we examined the neuronal effects of nicotine during auditory selective attention in healthy human nonsmokers. We hypothesized to observe significant effects of nicotine in attention-associated brain areas, driven by nicotine-induced increases in activity as a function of increasing task demands. A single-blind, prospective, randomized crossover design was used to examine neuronal response associated with a go/no-go task after 7 mg nicotine or placebo patch administration in 20 individuals who underwent functional magnetic resonance imaging at 3T. The task design included two levels of difficulty (ordered vs. random stimuli) and two levels of auditory distraction (silence vs. noise). Significant treatment × difficulty × distraction interaction effects on neuronal response were observed in the hippocampus, ventral parietal cortex, and anterior cingulate. In contrast to our hypothesis, U and inverted U-shaped dependencies were observed between the effects of nicotine on response and task demands, depending on the brain area. These results suggest that nicotine may differentially affect neuronal response depending on task conditions. These results have important theoretical implications for understanding how cholinergic tone may influence the neurobiology of selective attention.

Cholinergic Interneurons Use Orbitofrontal Input to Track Beliefs about Current State.

PubMed

Stalnaker, Thomas A; Berg, Ben; Aujla, Navkiran; Schoenbaum, Geoffrey

2016-06-08

When conditions change, organisms need to learn about the changed conditions without interfering with what they already know. To do so, they can assign the new learning to a new "state" and the old learning to a previous state. This state assignment is fundamental to behavioral flexibility. Cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) are necessary for associative information to be compartmentalized in this way, but the mechanism by which they do so is unknown. Here we addressed this question by recording putative CINs from the DMS in rats performing a task consisting of a series of trial blocks, or states, that required the recall and application of contradictory associative information. We found that individual CINs in the DMS represented the current state throughout each trial. These state correlates were not observed in dorsolateral striatal CINs recorded in the same rats. Notably, DMS CIN ensembles tracked rats' beliefs about the current state such that, when states were miscoded, rats tended to make suboptimal choices reflecting the miscoding. State information held by the DMS CINs also depended completely on the orbitofrontal cortex, an area that has been proposed to signal environmental states. These results suggest that CINs set the stage for recalling associative information relevant to the current environment by maintaining a real-time representation of the current state. Such a role has novel implications for understanding the neural basis of a variety of psychiatric diseases, such as addiction or anxiety disorders, in which patients generalize inappropriately (or fail to generalize) between different environments. Striatal cholinergic interneurons (CINs) are thought to be identical to tonically active neurons. These neurons have long been thought to have an important influence on striatal processing during reward-related learning. Recently, a more specific function for striatal CINs has been suggested, which is that they are necessary for striatal learning to be compartmentalized into different states as the state of the environment changes. Here we report that putative CINs appear to track rats' beliefs about which environmental state is current. We further show that this property of CINs depends on orbitofrontal cortex input and is correlated with choices made by rats. These findings could provide new insight into neuropsychiatric diseases that involve improper generalization between different contexts. Copyright © 2016 the authors 0270-6474/16/366242-16$15.00/0.

Cholinergic inhibition of adrenergic neurosecretion in the rabbit iris-ciliary body

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jumblatt, J.E.; North, G.T.

The prejunctional effects of cholinergic agents on release of norepinephrine from sympathetic nerve endings were investigated in the isolated, superfused rabbit iris-ciliary body. Stimulation-evoked release of /sup 3/H-norepinephrine was inhibited by the cholinergic agonists methacholine, oxotremorine, muscarine, carbamylcholine and acetylcholine (plus eserine), but was unmodified by pilocarpine or nicotine. Agonist-induced inhibition was antagonized selectively by atropine, indicating a muscarinic response. Atropine alone markedly enhanced norepinephrine release, revealing considerable tonic activation of prejunctional cholinergic receptors in this system. Prejunctional inhibition by carbamylcholine was found to completely override the facilitative action of forskolin or 8-bromo-cyclic AMP on neurotransmitter release. Cholinergic and alphamore » 2-adrenergic effects on neurosecretion were non-additive, suggesting that the underlying receptors coexist at neurotransmitter release sites.« less

Relation between cognition and neural connection from injured cingulum to brainstem cholinergic nuclei in chronic patients with traumatic brain injury.

PubMed

Yoo, Jin-Sun; Kim, Oh Lyong; Kim, Seong Ho; Kim, Min Su; Jang, Sung Ho

2014-01-01

This study investigated the relation between cognition and the neural connection from injured cingulum to brainstem cholinergic nuclei in patients with traumatic brain injury (TBI), using diffusion tensor tractography (DTT). Among 353 patients with TBI, 20 chronic patients who showed discontinuation of both anterior cingulums from the basal forebrain on DTT were recruited for this study. The Wechsler Intelligence Scale and the Memory Assessment Scale (MAS; short-term, verbal, visual and total memory) were used for assessment of cognition. Patients were divided into two groups according to the presence of a neural connection between injured cingulum and brainstem cholinergic nuclei. Eight patients who had a neural connection between injured cingulum and brainstem cholinergic nuclei showed better short-term memory on MAS than 12 patients who did not (p < 0.05). However, other results of neuropsychological testing showed no significant difference (p > 0.05). Better short-term memory in patients who had the neural connection between injured cingulum and brainstem cholinergic nuclei appears to have been attributed to the presence of cholinergic innervation to the cerebral cortex through the neural connection instead of the injured anterior cingulum. The neural connection appears to compensate for the injured anterior cingulum in obtaining cholinergic innervation.

Behavioral characterization of mice lacking histamine H(3) receptors.

PubMed

Toyota, Hiroshi; Dugovic, Christine; Koehl, Muriel; Laposky, Aaron D; Weber, China; Ngo, Karen; Wu, Ying; Lee, Doo Hyun; Yanai, Kazuhiko; Sakurai, Eiko; Watanabe, Takehiko; Liu, Changlu; Chen, Jingcai; Barbier, Ann J; Turek, Fred W; Fung-Leung, Wai-Ping; Lovenberg, Timothy W

2002-08-01

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors. This paper provides the first description of the H(3) receptor-deficient mouse (H(3)(-/-)), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H(3)(-/-) mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H(3)(-/-) mice were insensitive to the wake-promoting effects of the H(3) receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.

Identification of cholinergic and non-cholinergic neurons in the pons expressing phosphorylated cyclic adenosine monophosphate response element-binding protein as a function of rapid eye movement sleep.

PubMed

Datta, S; Siwek, D F; Stack, E C

2009-09-29

Recent studies have shown that in the pedunculopontine tegmental nucleus (PPT), increased neuronal activity and kainate receptor-mediated activation of intracellular protein kinase A (PKA) are important physiological and molecular steps for the generation of rapid eye movement (REM) sleep. In the present study performed on rats, phosphorylated cyclic AMP response element-binding protein (pCREB) immunostaining was used as a marker for increased intracellular PKA activation and as a reflection of increased neuronal activity. To identify whether activated cells were either cholinergic or noncholinergic, the PPT and laterodorsal tegmental nucleus (LDT) cells were immunostained for choline acetyltransferase (ChAT) in combination with pCREB or c-Fos. The results demonstrated that during high rapid eye movement sleep (HR, approximately 27%), significantly higher numbers of cells expressed pCREB and c-Fos in the PPT, of which 95% of pCREB-expressing cells were ChAT-positive. With HR, the numbers of pCREB-positive cells were also significantly higher in the medial pontine reticular formation (mPRF), pontine reticular nucleus oral (PnO), and dorsal subcoeruleus nucleus (SubCD) but very few in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). Conversely, with low rapid eye movement sleep (LR, approximately 2%), the numbers of pCREB expressing cells were very few in the PPT, mPRF, PnO, and SubCD but significantly higher in the LC and DRN. The results of regression analyses revealed significant positive relationships between the total percentages of REM sleep and numbers of ChAT+/pCREB+ (Rsqr=0.98) cells in the PPT and pCREB+ cells in the mPRF (Rsqr=0.88), PnO (Rsqr=0.87), and SubCD (Rsqr=0.84); whereas significantly negative relationships were associated with the pCREB+ cells in the LC (Rsqr=0.70) and DRN (Rsqr=0.60). These results provide evidence supporting the hypothesis that during REM sleep, the PPT cholinergic neurons are active, whereas the LC and DRN neurons are inactive. More importantly, the regression analysis indicated that pCREB activation in approximately 98% of PPT cholinergic neurons, was caused by REM sleep. Moreover the results indicate that during REM sleep, PPT intracellular PKA activation and a transcriptional cascade involving pCREB occur exclusively in the cholinergic neurons.

Biflorin Ameliorates Memory Impairments Induced by Cholinergic Blockade in Mice

PubMed Central

Jeon, Se Jin; Kim, Boseong; Ryu, Byeol; Kim, Eunji; Lee, Sunhee; Jang, Dae Sik; Ryu, Jong Hoon

2017-01-01

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-ζ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-ζ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems. PMID:27829270

Penconazole alters redox status, cholinergic function, and membrane-bound ATPases in the cerebrum and cerebellum of adult rats.

PubMed

Chaâbane, M; Ghorbel, I; Elwej, A; Mnif, H; Boudawara, T; Chaâbouni, S Ellouze; Zeghal, N; Soudani, N

2017-08-01

Pesticides exposure causes usually harmful effects to the environment and human health. The present study aimed to investigate the potential toxic effects of penconazole, a triazole fungicide, on the cerebrum and cerebellum of adult rats. Penconazole was administered intraperitoneally to male Wistar rats at a dose of 67 mg kg -1 body weight every 2 days during 9 days. Results showed that penconazole induced oxidative stress in rat cerebrum and cerebellum tissues. In fact, we have found a significant increase in malondialdehyde, hydrogen peroxide, and advanced oxidation protein product levels, as well as an alteration of the antioxidant status, enzymatic (superoxide dismutase and catalase) and nonenzymatic (glutathione), the cholinergic function, and membrane-bound ATPases (Na + /K + -ATPase and Mg 2+ -ATPase). Penconazole also provoked histological alterations marked by pyknotic and vacuolated neurons in the cerebrum and apoptosis and edema in the cerebellum Purkinje cells' layer. Therefore, the use of this neurotoxicant fungicide must be regularly monitored in the environment.

Cholinergic modulation of dopaminergic neurons in the mouse olfactory bulb.

PubMed

Pignatelli, Angela; Belluzzi, Ottorino

2008-04-01

Considerable evidence exists for an extrinsic cholinergic influence in the maturation and function of the main olfactory bulb. In this study, we addressed the muscarinic modulation of dopaminergic neurons in this structure. We used different patch-clamp techniques to characterize the diverse roles of muscarinic agonists on identified dopaminergic neurons in a transgenic animal model expressing a reporter protein (green fluorescent protein) under the tyrosine hydroxylase promoter. Bath application of acetylcholine (1 mM) in slices and in enzymatically dissociated cells reduced the spontaneous firing of dopaminergic neurons recorded in cell-attached mode. In whole-cell configuration no effect of the agonist was observed, unless using the perforated patch technique, thus suggesting the involvement of a diffusible second messenger. The effect was mediated by metabotropic receptors as it was blocked by atropine and mimicked by the m2 agonist oxotremorine (10 muM). The reduction of periglomerular cell firing by muscarinic activation results from a membrane-potential hyperpolarization caused by activation of a potassium conductance. This modulation of dopaminergic interneurons may be important in the processing of sensory information and may be relevant to understand the mechanisms underlying the olfactory dysfunctions occurring in neurodegenerative diseases affecting the dopaminergic and/or cholinergic systems.

Azadirachtin blocks the calcium channel and modulates the cholinergic miniature synaptic current in the central nervous system of Drosophila.

PubMed

Qiao, Jingda; Zou, Xiaolu; Lai, Duo; Yan, Ying; Wang, Qi; Li, Weicong; Deng, Shengwen; Xu, Hanhong; Gu, Huaiyu

2014-07-01

Azadirachtin is a botanical pesticide, which possesses conspicuous biological actions such as insecticidal, anthelmintic, antifeedancy, antimalarial effects as well as insect growth regulation. Deterrent for chemoreceptor functions appears to be the main mechanism involved in the potent biological actions of Azadirachtin, although the cytotoxicity and subtle changes to skeletal muscle physiology may also contribute to its insecticide responses. In order to discover the effects of Azadirachtin on the central nervous system (CNS), patch-clamp recording was applied to Drosophila melanogaster, which has been widely used in neurological research. Here, we describe the electrophysiological properties of a local neuron located in the suboesophageal ganglion region of D. melanogaster using the whole brain. The patch-clamp recordings suggested that Azadirachtin modulates the properties of cholinergic miniature excitatory postsynaptic current (mEPSC) and calcium currents, which play important roles in neural activity of the CNS. The frequency of mEPSC and the peak amplitude of the calcium currents significantly decreased after application of Azadirachtin. Our study indicates that Azadirachtin can interfere with the insect's CNS via inhibition of excitatory cholinergic transmission and partly blocking the calcium channel. © 2013 Society of Chemical Industry.

Effects of short-term hormonal replacement on learning and on basal forebrain ChAT and TrkA content in ovariectomized rats.

PubMed

Espinosa-Raya, Judith; Plata-Cruz, Noemí; Neri-Gómez, Teresa; Camacho-Arroyo, Ignacio; Picazo, Ofir

2011-02-23

It has been proposed that sex steroid hormones improve performance in some cognitive tasks by regulating the basal forebrain cholinergic function. However, the molecular basis of such influence still remains unknown. Current study analyzed the performance of ovariectomized rats in an autoshaping learning task after a short-term treatment with 17β-estradiol (E2: 4 and 40μg/kg) and/or progesterone (P4: 4mg/kg). These results were correlated with basal forebrain choline acetyltransferase (ChAT) and TrkA protein content. The high dose of E2 enhanced both acquisition in the autoshaping task and the content of ChAT and TrkA. P4 treatment increased ChAT and TrkA content without affecting performance of rats in the autoshaping learning task. Interestingly, the continuous and simultaneous administration of E2 plus P4 did not significantly modify behavioral and biochemical evaluated parameters. These results address the influence of both E2 and P4 on cholinergic and TrkA activity and suggest that the effects of ovarian hormones on cognitive performance involve basal forebrain cholinergic neurons. Copyright © 2010 Elsevier B.V. All rights reserved.

Acetylcholinesterase is involved in apoptosis in the precursors of human muscle regeneration.

PubMed

Pegan, Katarina; Matkovic, Urska; Mars, Tomaz; Mis, Katarina; Pirkmajer, Sergej; Brecelj, Janez; Grubic, Zoran

2010-09-06

The best established role of acetylcholinesterase (EC 3.1.1.7, AChE) is termination of neurotransmission at cholinergic synapses. However, AChE is also located at sites, where no other cholinergic components are present and there is accumulating evidence for non-cholinergic functions of this protein. In the process of skeletal muscle formation, AChE is expressed already at the stage of mononuclear myoblast, which is long before other cholinergic components can be demonstrated in this tissue. Myoblast proliferation is an essential step in muscle regeneration and is always accompanied by apoptosis. Since there are several reports demonstrating AChE participation in apoptosis one can hypothesize that early AChE expression in myoblasts reflects the development of the apoptotic apparatus in these cells. Here we tested this hypothesis by following the effect of siRNA AChE silencing on apoptotic markers and by determination of AChE level after staurosporine-induced apoptosis in cultured human myoblasts. Decreased apoptosis in siRNA AChE silenced myoblasts and increased AChE expression in staurosporine-treated myoblasts confirmed AChE involvement in apoptosis. The three AChE splice variants were differently affected by staurosporine-induced apoptosis. The hydrophobic (H) variant appeared unaffected, a tendency towards increase of tailed (T) variant was detected, however the highest, 8-fold increase was observed for readthrough (R) variant. In the light of these findings AChE appears to be a potential therapeutic target at muscle injuries including organophosphate myopathy. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

The effects of dimethylaminoethanol (deanol) on cerebral cortical neurons.

PubMed

Kostopoulos, G K; Phillis, J W

1975-01-01

2-Dimethylaminoethanol and acetylcholine were iontophoretically tested on deep, spontaneously firing, neurons of the rat cerebral cortex. All identified corticospinal cells and 71% of the unidentified ones were excited by Deanol. Eight percent of the latter group were inhibited. All but one neuron responded similarly to ACh and Deanol, when both substances were tested on the same neuron. Atropine reversibly blocked these responses. The implications of these observations are discussed with regard to cholinergic synapses in the brain and the rationalization of the therapeutic use of Deanol.

Acetylcholinesterase activity in Clytia hemisphaerica (Cnidaria).

PubMed

Denker, Elsa; Chatonnet, Arnaud; Rabet, Nicolas

2008-09-25

Cholinesterase activity is known in representatives of all living organisms phyla but the origin of the cholinergic system as known in bilaterian animals is still undeciphered. In particular the implication of cholinesterases in the nervous system of non-bilaterian Metazoa is not well known. We thus chose to investigate this activity in the Clytia hemisphaerica (Cnidaria) medusa. In toto histochemical staining revealed an acetylcholinesterase activity in the tentacle bulbs but not in the nervous system. Sequences homologous to acetylcholinesterase were searched within Clytia ESTs and compared to other sequences found in public databases.

Decoding brain state transitions in the pedunculopontine nucleus: cooperative phasic and tonic mechanisms

PubMed Central

Petzold, Anne; Valencia, Miguel; Pál, Balázs; Mena-Segovia, Juan

2015-01-01

Cholinergic neurons of the pedunculopontine nucleus (PPN) are most active during the waking state. Their activation is deemed to cause a switch in the global brain activity from sleep to wakefulness, while their sustained discharge may contribute to upholding the waking state and enhancing arousal. Similarly, non-cholinergic PPN neurons are responsive to brain state transitions and their activation may influence some of the same targets of cholinergic neurons, suggesting that they operate in coordination. Yet, it is not clear how the discharge of distinct classes of PPN neurons organize during brain states. Here, we monitored the in vivo network activity of PPN neurons in the anesthetized rat across two distinct levels of cortical dynamics and their transitions. We identified a highly structured configuration in PPN network activity during slow-wave activity that was replaced by decorrelated activity during the activated state (AS). During the transition, neurons were predominantly excited (phasically or tonically), but some were inhibited. Identified cholinergic neurons displayed phasic and short latency responses to sensory stimulation, whereas the majority of non-cholinergic showed tonic responses and remained at high discharge rates beyond the state transition. In vitro recordings demonstrate that cholinergic neurons exhibit fast adaptation that prevents them from discharging at high rates over prolonged time periods. Our data shows that PPN neurons have distinct but complementary roles during brain state transitions, where cholinergic neurons provide a fast and transient response to sensory events that drive state transitions, whereas non-cholinergic neurons maintain an elevated firing rate during global activation. PMID:26582977

The Pedunculopontine Tegmental Nucleus as a Motor and Cognitive Interface between the Cerebellum and Basal Ganglia.

PubMed

Mori, Fumika; Okada, Ken-Ichi; Nomura, Taishin; Kobayashi, Yasushi

2016-01-01

As an important component of ascending activating systems, brainstem cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg) are involved in the regulation of motor control (locomotion, posture and gaze) and cognitive processes (attention, learning and memory). The PPTg is highly interconnected with several regions of the basal ganglia, and one of its key functions is to regulate and relay activity from the basal ganglia. Together, they have been implicated in the motor control system (such as voluntary movement initiation or inhibition), and modulate aspects of executive function (such as motivation). In addition to its intimate connection with the basal ganglia, projections from the PPTg to the cerebellum have been recently reported to synaptically activate the deep cerebellar nuclei. Classically, the cerebellum and basal ganglia were regarded as forming separated anatomical loops that play a distinct functional role in motor and cognitive behavioral control. Here, we suggest that the PPTg may also act as an interface device between the basal ganglia and cerebellum. As such, part of the therapeutic effect of PPTg deep brain stimulation (DBS) to relieve gait freezing and postural instability in advanced Parkinson's disease (PD) patients might also involve modulation of the cerebellum. We review the anatomical position and role of the PPTg in the pathway of basal ganglia and cerebellum in relation to motor control, cognitive function and PD.

Acetylcholine, Histamine, and Cognition: Two Sides of the Same Coin

ERIC Educational Resources Information Center

Blandina, Patrizio; Efoudebe, Marcel; Cenni, Gabriele; Mannaioni, Pierfrancesco; Passani, Maria Beatrice

2004-01-01

The forebrain cholinergic neurons are localized in the nucleus basalis magnocellularis (NBM), the major source of cholinergic innervation to the neocortex and to the amygdala, and in the medium septum-banda diagonalis complex, which provides cholinergic inputs to the hippocampus (Mesulam et al. 1983; Woolf et al. 1984; Nicoll 1985). Basic and…

Cholinergic modulation of activation sequence in the atrial myocardium of non-mammalian vertebrates.

PubMed

Abramochkin, Denis V; Kuzmin, Vladislav S; Sukhova, Galina S; Rosenshtraukh, Leonid V

2010-02-01

Cholinergic changes of electric activity were studied in isolated atrium preparations from fishes (cod and carp), amphibians (frog) and reptilians (lizard) using the microelectrode technique and high-resolution optical mapping. Perfusion of isolated atrium with acetylcholine (10(-6)-5.10(-5) M) caused gradual suppression of action potential generation and, eventually, completely blocked the excitation in a part of the preparation. Other regions of atrium, situated close to the sinoatrial and atrioventricular junctions, remained excitable. Such cholinergic suppression of electric activity was observed in the atrial myocardium of frog and in both fish species, but not in reptilians. Ba(2+) (10(-4) M), which blocks the acetylcholine-dependent potassium current (I(KACh)), prevented cholinergic reduction of action potential amplitude. In several preparations of frog atrium, cholinergic suppression of excitation coincided with episodes of atrial fibrillation. We conclude that the phenomenon of cholinergic suppression of electric activity is typical for atria of fishes and amphibians. It is likely to be caused by I(KACh) activation and may be important for initiation of atrial arrhythmias. 2009 Elsevier Inc. All rights reserved.

Nicotinic cholinergic antagonists: a novel approach for the treatment of autism.

PubMed

Lippiello, P M

2006-01-01

Evidence supports the hypothesis that normalization of cholinergic tone by selective antagonism of neuronal nicotinic acetylcholine receptors (NNRs) may ameliorate the core symptoms of autism. As often is the case, epidemiology has provided the first important clues. It is well recognized that psychiatric patients are significantly more often smokers than the general population. The only known exceptions are obsessive-compulsive disorder (OCD), catatonic schizophrenia and interestingly, autism. In this regard, clinical studies with nicotine have demonstrated amelioration of symptoms of a number of diseases and disorders, including Alzheimer's disease, Parkinson's disease, ADHD and Tourette's syndrome. Nicotine's agonist properties at CNS NNRs have been implicated in these effects and support the concept of self-medication as a strong motivation for smoking in cognitively compromised individuals. On the other hand, the inverse correlation between autism and smoking suggests that smoking does not provide symptomatic relief and may actually be indicative of an active avoidance of nicotine's agonist effects in this disorder. Neuroanatomical evidence is consistent with this idea based on the presence of hypercholinergic architecture in the autistic brain, particularly during the first few years of development, making the avoidance of further stimulation of an already hyperactive cholinergic system plausible. This may also explain why stimulants (known to increase dopamine levels as do NNR agonists) appear to aggravate autistic symptoms and why studies with cholinesterase inhibitors that increase acetylcholine levels in the brain have yielded variable effects in autism. Taken together, the evidence suggests the possibility that nicotinic cholinergic antagonism may in fact be palliative. Pharmacological evidence supports this hypothesis. For example, antidepressants, many of which are now known to be non-competitive NNR antagonists, have been used successfully to treat a number of autistic symptoms. More specifically, there is anecdotal evidence from at least one medical practitioner that mecamylamine, a non-selective NNR antagonist, is effective in treating many autistic symptoms, particularly those that are refractory to most other treatments. Clearly there is a need for carefully controlled clinical studies with novel selective NNR antagonists to explore their potential as a new and exciting approach for the treatment of autism.

Regulated Extracellular Choline Acetyltransferase Activity— The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway

PubMed Central

Aeinehband, Shahin; Behbahani, Homira; Grandien, Alf; Nilsson, Bo; Ekdahl, Kristina N.; Lindblom, Rickard P. F.; Piehl, Fredrik; Darreh-Shori, Taher

2013-01-01

Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer’s disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer’s disease and multiple sclerosis in particular. PMID:23840379

Cholinergic Plasticity of Oscillating Neuronal Assemblies in Mouse Hippocampal Slices

PubMed Central

Zylla, Maura M.; Zhang, Xiaomin; Reichinnek, Susanne; Draguhn, Andreas; Both, Martin

2013-01-01

The mammalian hippocampus expresses several types of network oscillations which entrain neurons into transiently stable assemblies. These groups of co-active neurons are believed to support the formation, consolidation and recall of context-dependent memories. Formation of new assemblies occurs during theta- and gamma-oscillations under conditions of high cholinergic activity. Memory consolidation is linked to sharp wave-ripple oscillations (SPW-R) during decreased cholinergic tone. We hypothesized that increased cholinergic tone supports plastic changes of assemblies while low cholinergic tone favors their stability. Coherent spatiotemporal network patterns were measured during SPW-R activity in mouse hippocampal slices. We compared neuronal activity within the oscillating assemblies before and after a transient phase of carbachol-induced gamma oscillations. Single units maintained their coupling to SPW-R throughout the experiment and could be re-identified after the transient phase of gamma oscillations. However, the frequency of SPW-R-related unit firing was enhanced after muscarinic stimulation. At the network level, these changes resulted in altered patterns of extracellularly recorded SPW-R waveforms. In contrast, recording of ongoing SPW-R activity without intermittent cholinergic stimulation revealed remarkably stable repetitive activation of assemblies. These results show that activation of cholinergic receptors induces plasticity at the level of oscillating hippocampal assemblies, in line with the different role of gamma- and SPW-R network activity for memory formation and –consolidation, respectively. PMID:24260462

Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

PubMed Central

Ramanathan, Dhakshin S.; Conner, James M.; Anilkumar, Arjun A.

2014-01-01

Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID:25505106

M Current-Based Therapies for Nerve Agent Seizures

DTIC Science & Technology

2013-07-01

Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS Seizures, status epilepticus Cholinergic, M Current...Channel openers in cholinergic overstimulation-induced status epilepticus . Body: We proposed to study the effects of organophosphates and muscarinic...test whether drugs that open M channels would terminate status epilepticus induced by an organophosphate and cholinergic agonist (Li/Pilocarpine). Two

Cholinergic medication for antipsychotic-induced tardive dyskinesia.

PubMed

Tammenmaa-Aho, Irina; Asher, Rosie; Soares-Weiser, Karla; Bergman, Hanna

2018-03-19

Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD. To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness. An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations. We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials. Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life. TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

PubMed

Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

5-HT4 receptors facilitate cholinergic neurotransmission throughout the murine gastrointestinal tract.

PubMed

Pauwelyn, V; Lefebvre, R A

2017-08-01

In the gastrointestinal tract of several species, facilitating 5-HT 4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5-HT 4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract. In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride. Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808. In the murine gastrointestinal tract, activation of 5-HT 4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species. © 2017 John Wiley & Sons Ltd.

Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

PubMed Central

Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

2014-01-01

The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically projecting GABAergic/PV neurons. PMID:24553925

Cholinergic Enhancement of Frontal Lobe Activity in Mild Cognitive Impairment

ERIC Educational Resources Information Center

Saykin, Andrew J.; Wishart, Heather A.; Rabin, Laura A.; Flashman, Laura A.; McHugh, Tara L.; Mamourian, Alexander C.; Santulli, Robert B.

2004-01-01

Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept[Registered sign]) on cognition and brain activity in patients with amnestic mild cognitive…

Choline metabolism as a basis for the selective vulnerability of cholinergic neurons

NASA Technical Reports Server (NTRS)

Wurtman, R. J.

1992-01-01

The unique propensity of cholinergic neurons to use choline for two purposes--ACh and membrane phosphatidylcholine synthesis--may contribute to their selective vulnerability in Alzheimer's disease and other cholinergic neurodegenerative disorders. When physiologically active, the neurons use free choline taken from the 'reservoir' in membrane phosphatidylcholine to synthesize ACh; this can lead to an actual decrease in the quantity of membrane per cell. Alzheimer's disease (but not Down's syndrome, or other neurodegenerative disorders) is associated with characteristic neurochemical lesions involving choline and ethanolamine: brain levels of these compounds are diminished, while those of glycerophosphocholine and glycerophosphoethanolamine (breakdown products of their respective membrane phosphatides) are increased, both in cholinergic and noncholinergic brain regions. Perhaps this metabolic disturbance and the tendency of cholinergic neurons to 'export' choline--in the form of ACh--underlie the selective vulnerability of the neurons. Resulting changes in membrane composition could abnormally expose intramembraneous proteins such as amyloid precursor protein to proteases.

Cholinergic neurotransmission seems not to be involved in depression but possibly in personality.

PubMed Central

Fritze, J; Lanczik, M; Sofic, E; Struck, M; Riederer, P

1995-01-01

Concordant with the adrenergic-cholinergic imbalance hypothesis of affective psychosis, there is a cholinergic supersensitivity in depression. Thus, the anticholinergic properties of some antidepressants might contribute to their efficacy. However, in the present double-blind studies (n = 20) with mianserin and viloxazine, respectively, which lack anticholinergic properties, adjunctive treatment with the anticholinergic biperiden versus placebo did not enhance the antidepressive efficacy. Therefore, we hypothesized that cholinergic supersensitivity might be linked to some possibly predisposing dimension of personality. Indeed, in healthy male volunteers (n = 11) the behavioral and cardiovascular sensitivity to physostigmine correlated significantly with "irritability" and "emotional lability" as well as with habitually passive strategies in stress coping. The rise in plasma cortisol and norepinephrine correlated with "retardation"; that of epinephrine with active coping. Thus, the cholinergic supersensitivity in affective psychoses might be linked to a personality dimension like stress sensitivity rather than to the diagnostic category itself. Images Fig. 2 PMID:7865500

Enhanced Control of Attention by Stimulating Mesolimbic-Corticopetal Cholinergic Circuitry

PubMed Central

St. Peters, Megan; Demeter, Elise; Lustig, Cindy; Bruno, John P.; Sarter, Martin

2011-01-01

Sustaining and recovering attentional performance requires interactions between the brain’s motivation and attention systems. The first experiment demonstrated that in rats performing a sustained attention task (SAT), presentation of a distractor (dSAT) augmented performance-associated increases in cholinergic neurotransmission in prefrontal cortex (PFC). Because stimulation of NMDA receptors in the shell of the nucleus accumbens (NAC) activates PFC cholinergic neurotransmission, a second experiment demonstrated that bilateral infusions of NMDA into the NAC shell, but not core, improved dSAT-performance to levels observed in the absence of a distractor. A third experiment demonstrated that removal of prefrontal or posterior parietal cholinergic inputs, by intra-cortical infusions of the cholinotoxin 192 IgG saporin, attenuated the beneficial effects of NMDA on dSAT perfomance. Mesolimbic activation of cholinergic projections to the cortex benefits the cognitive control of attentional performance by enhancing the detection of cues and the filtering of distractors. PMID:21715641

Agonist activation of cytosolic Ca2+ in subfornical organ cells projecting to the supraoptic nucleus

NASA Technical Reports Server (NTRS)

Johnson, R. F.; Beltz, T. G.; Sharma, R. V.; Xu, Z.; Bhatty, R. A.; Johnson, A. K.

2001-01-01

The subfornical organ (SFO) is sensitive to both ANG II and ACh, and local application of these agents produces dipsogenic responses and vasopressin release. The present study examined the effects of cholinergic drugs, ANG II, and increased extracellular osmolarity on dissociated, cultured cells of the SFO that were retrogradely labeled from the supraoptic nucleus. The effects were measured as changes in cytosolic calcium in fura 2-loaded cells by using a calcium imaging system. Both ACh and carbachol increased intracellular ionic calcium concentration ([Ca2+]i). However, in contrast to the effects of muscarinic receptor agonists on SFO neurons, manipulation of the extracellular osmolality produced no effects, and application of ANG II produced only moderate effects on [Ca2+]i in a few retrogradely labeled cells. The cholinergic effects on [Ca2+]i could be blocked with the muscarinic receptor antagonist atropine and with the more selective muscarinic receptor antagonists pirenzepine and 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP). In addition, the calcium in the extracellular fluid was required for the cholinergic-induced increase in [Ca2+]i. These findings indicate that ACh acts to induce a functional cellular response in SFO neurons through action on a muscarinic receptor, probably of the M1 subtype and that the increase of [Ca2+]i, at least initially, requires the entry of extracellular Ca2+. Also, consistent with a functional role of M1 receptors in the SFO are the results of immunohistochemical preparations demonstrating M1 muscarinic receptor-like protein present within this forebrain circumventricular organ.

Cholinergic modulation of cognitive processing: insights drawn from computational models

PubMed Central

Newman, Ehren L.; Gupta, Kishan; Climer, Jason R.; Monaghan, Caitlin K.; Hasselmo, Michael E.

2012-01-01

Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory, and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory, and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm plays a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers. PMID:22707936

The Prion Protein Modulates A-type K+ Currents Mediated by Kv4.2 Complexes through Dipeptidyl Aminopeptidase-like Protein 6*

PubMed Central

Mercer, Robert C. C.; Ma, Li; Watts, Joel C.; Strome, Robert; Wohlgemuth, Serene; Yang, Jing; Cashman, Neil R.; Coulthart, Michael B.; Schmitt-Ulms, Gerold; Jhamandas, Jack H.; Westaway, David

2013-01-01

Widely expressed in the adult central nervous system, the cellular prion protein (PrPC) is implicated in a variety of processes, including neuronal excitability. Dipeptidyl aminopeptidase-like protein 6 (DPP6) was first identified as a PrPC interactor using in vivo formaldehyde cross-linking of wild type (WT) mouse brain. This finding was confirmed in three cell lines and, because DPP6 directs the functional assembly of K+ channels, we assessed the impact of WT and mutant PrPC upon Kv4.2-based cell surface macromolecular complexes. Whereas a Gerstmann-Sträussler-Scheinker disease version of PrP with eight extra octarepeats was a loss of function both for complex formation and for modulation of Kv4.2 channels, WT PrPC, in a DPP6-dependent manner, modulated Kv4.2 channel properties, causing an increase in peak amplitude, a rightward shift of the voltage-dependent steady-state inactivation curve, a slower inactivation, and a faster recovery from steady-state inactivation. Thus, the net impact of wt PrPC was one of enhancement, which plays a critical role in the down-regulation of neuronal membrane excitability and is associated with a decreased susceptibility to seizures. Insofar as previous work has established a requirement for WT PrPC in the Aβ-dependent modulation of excitability in cholinergic basal forebrain neurons, our findings implicate PrPC regulation of Kv4.2 channels as a mechanism contributing to the effects of oligomeric Aβ upon neuronal excitability and viability. PMID:24225951

Role of cholinergic receptors in locomotion induced by scopolamine and oxotremorine-M.

PubMed

Chintoh, Araba; Fulton, James; Koziel, Nicole; Aziz, Mariam; Sud, Manu; Yeomans, John S

2003-08-01

Mesopontine cholinergic neurons activate dopamine neurons important for reward-seeking and locomotor activity. The present studies tested whether cholinergic receptor blockade in the ventral tegmental area (VTA) altered locomotion induced by scopolamine (3 mg/kg i.p.) or by oxotremorine-M (0.1 microg bilaterally in the VTA). It was predicted that cholinergic blockers in the VTA would attenuate these cholinergic-induced locomotor increases. Locomotor activity was increased by scopolamine and oxotremorine-M administration in all treatments. When dihydro-beta-erythroidine (DHBE), a nicotinic receptor antagonist, was applied in VTA prior to oxotremorine-M, locomotion was reduced to slightly above saline baseline levels, but atropine, a muscarinic antagonist, had no effect. This suggests that the locomotor effect of oxotremorine-M at this dose was mediated mainly via nicotinic, not muscarinic, receptors. Intra-VTA injections of DHBE, however, did not attenuate scopolamine-induced locomotion indicating that scopolamine-induced locomotion is not mediated mainly via VTA cholinergic receptors. In mutant mice with a deletion in the M5 muscarinic receptor gene, scopolamine-induced locomotion was increased versus wild type mice after scopolamine injection. This suggests that the M5 receptor has an inhibitory effect on scopolamine-induced locomotion.

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus.

PubMed

Vandecasteele, Marie; Varga, Viktor; Berényi, Antal; Papp, Edit; Barthó, Péter; Venance, Laurent; Freund, Tamás F; Buzsáki, György

2014-09-16

Theta oscillations in the limbic system depend on the integrity of the medial septum. The different populations of medial septal neurons (cholinergic and GABAergic) are assumed to affect different aspects of theta oscillations. Using optogenetic stimulation of cholinergic neurons in ChAT-Cre mice, we investigated their effects on hippocampal local field potentials in both anesthetized and behaving mice. Cholinergic stimulation completely blocked sharp wave ripples and strongly suppressed the power of both slow oscillations (0.5-2 Hz in anesthetized, 0.5-4 Hz in behaving animals) and supratheta (6-10 Hz in anesthetized, 10-25 Hz in behaving animals) bands. The same stimulation robustly increased both the power and coherence of theta oscillations (2-6 Hz) in urethane-anesthetized mice. In behaving mice, cholinergic stimulation was less effective in the theta (4-10 Hz) band yet it also increased the ratio of theta/slow oscillation and theta coherence. The effects on gamma oscillations largely mirrored those of theta. These findings show that medial septal cholinergic activation can both enhance theta rhythm and suppress peri-theta frequency bands, allowing theta oscillations to dominate.

The pedunculopontine nucleus is related to visual hallucinations in Parkinson's disease: preliminary results of a voxel-based morphometry study.

PubMed

Janzen, J; van 't Ent, D; Lemstra, A W; Berendse, H W; Barkhof, F; Foncke, E M J

2012-01-01

Visual hallucinations (VH) are common in Parkinson's disease (PD) and lead to a poor quality of life. For a long time, dopaminergic therapy was considered to be the most important risk factor for the development of VH in PD. Recently, the cholinergic system, including the pedunculopontine nucleus (PPN), has been implicated in the pathophysiology of VH. The aim of the present study was to investigate grey matter density of the PPN region and one of its projection areas, the thalamus. Thirteen non-demented PD patients with VH were compared to 16 non-demented PD patients without VH, 13 demented PD patients (PDD) with VH and 11 patients with dementia with Lewy bodies (DLB). Isotropic 3-D T1-weighted MRI images (3T) were analysed using voxel-based morphometry (VBM) with the PPN region and thalamus as ROIs. PD and PDD patients with VH showed grey matter reductions of the PPN region and the thalamus compared to PD patients without VH. VH in PD(D) patients are associated with atrophy of the PPN region and its thalamic target area, suggesting that a cholinergic deficit may be involved in the development of VH in PD(D).

Brain Region–Specific Alterations in the Gene Expression of Cytokines, Immune Cell Markers and Cholinergic System Components during Peripheral Endotoxin–Induced Inflammation

PubMed Central

Silverman, Harold A; Dancho, Meghan; Regnier-Golanov, Angelique; Nasim, Mansoor; Ochani, Mahendar; Olofsson, Peder S; Ahmed, Mohamed; Miller, Edmund J; Chavan, Sangeeta S; Golanov, Eugene; Metz, Christine N; Tracey, Kevin J; Pavlov, Valentin A

2014-01-01

Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune–brain communication, including the impact of peripheral inflammation on brain region–specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1β, IL-6 and other cytokines and brain region–specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches. PMID:25299421

Organization of the sleep-related neural systems in the brain of the harbour porpoise (Phocoena phocoena).

PubMed

Dell, Leigh-Anne; Patzke, Nina; Spocter, Muhammad A; Siegel, Jerome M; Manger, Paul R

2016-07-01

The present study provides the first systematic immunohistochemical neuroanatomical investigation of the systems involved in the control and regulation of sleep in an odontocete cetacean, the harbor porpoise (Phocoena phocoena). The odontocete cetaceans show an unusual form of mammalian sleep, with unihemispheric slow waves, suppressed REM sleep, and continuous bodily movement. All the neural elements involved in sleep regulation and control found in bihemispheric sleeping mammals were present in the harbor porpoise, with no specific nuclei being absent, and no novel nuclei being present. This qualitative similarity of nuclear organization relates to the cholinergic, noradrenergic, serotonergic, and orexinergic systems and is extended to the γ-aminobutyric acid (GABA)ergic elements involved with these nuclei. Quantitative analysis of the cholinergic and noradrenergic nuclei of the pontine region revealed that in comparison with other mammals, the numbers of pontine cholinergic (126,776) and noradrenergic (122,878) neurons are markedly higher than in other large-brained bihemispheric sleeping mammals. The diminutive telencephalic commissures (anterior commissure, corpus callosum, and hippocampal commissure) along with an enlarged posterior commissure and supernumerary pontine cholinergic and noradrenergic neurons indicate that the control of unihemispheric slow-wave sleep is likely to be a function of interpontine competition, facilitated through the posterior commissure, in response to unilateral telencephalic input related to the drive for sleep. In addition, an expanded peripheral division of the dorsal raphe nuclear complex appears likely to play a role in the suppression of REM sleep in odontocete cetaceans. Thus, the current study provides several clues to the understanding of the neural control of the unusual sleep phenomenology present in odontocete cetaceans. J. Comp. Neurol. 524:1999-2017, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome.

PubMed

Kelley, Christy M; Ash, Jessica A; Powers, Brian E; Velazquez, Ramon; Alldred, Melissa J; Ikonomovic, Milos D; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

2016-01-01

Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer's disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice compared to 2N mice sacrificed at 6-8 and 14-18 months of age. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6-8 and 14-18 mos were used for an aging study and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14-18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in Ts65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS.

Regional distribution of cholinergic, catecholaminergic, serotonergic and orexinergic neurons in the brain of two carnivore species: The feliform banded mongoose (Mungos mungo) and the caniform domestic ferret (Mustela putorius furo).

PubMed

Pillay, Sashrika; Bhagwandin, Adhil; Bertelsen, Mads F; Patzke, Nina; Engler, Gerhard; Engel, Andreas K; Manger, Paul R

2017-07-01

The nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic neurons in the brains of two species of carnivore, the banded mongoose (Mungos mungo) and domestic ferret (Mustela putorius furo), is presented. The banded mongoose belongs to the feliform suborder and the domestic ferret to the caniform suborder, having last shared a common ancestor approximately 53 million years ago; however, they have a very similar overall morphology and life history, presenting an interesting opportunity to examine the extent of evolutionary plasticity in these systems. The brains of the two carnivore species were coronally sectioned and immunohistochemically stained with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. The overall organization and complement of the nuclei of these systems was identical between the two species, although minor differences were noted. Moreover, this overall organization is identical to other studies undertaken in the domestic cat and dog. While for the most part the nuclei forming these systems are similar to those observed in other mammals, two species differences, which appear to be carnivore-specific, were noted. First, cholinergic neurons were observed in the lateral septal nucleus of both species, an apparently carnivore specific feature not recorded previously in other mammals. Second, the serotonergic neurons of the peripheral division of the dorsal raphe complex exhibited a significant caudad expansion, intermingling with the cholinergic and catecholaminergic nuclei of the pons, a carnivore specific feature. These carnivore specific features likely have functional consequences related to coping with stress and the expression of sleep. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of acidic fibroblast growth factor on cholinergic neurons of nucleus basalis magnocellularis and in a spatial memory task following cortical devascularization.

PubMed

Figueiredo, B C; Piccardo, P; Maysinger, D; Clarke, P B; Cuello, A C

1993-10-01

The ability of acidic fibroblast growth factor to elicit a trophic response in the nervous system of the rat was tested in vitro and in vivo. Treatment of cultured septal cells with acidic fibroblast growth factor resulted in an elongation of glial processes as assessed by immunostaining for glial fibrillary acidic protein. Increased choline acetyltransferase was also observed. The responses to acidic fibroblast growth factor in vivo were studied in rats trained in a spatial memory task, using the Morris water maze. Randomly selected animals were subjected to unilateral cortical devascularization. This lesion results in partial unilateral infarction of the neocortex, and in retrograde degeneration of the nucleus basalis magnocellularis. Animals were tested post-lesion for memory retention and were then killed for morphological studies. Intracerebroventricular administration of acidic fibroblast growth factor (0.6 microgram/h for seven days starting at surgery) prevented the lesion-induced impairment in this test, and reduced the nucleus basalis magnocellularis cholinergic degeneration, as assessed by morphometric choline acetyltransferase-like immunoreactivity and radioenzymatic assay for choline acetyltransferase activity. The preservation of the phenotype of injured cholinergic neurons of the nucleus basalis magnocellularis by acidic fibroblast growth factor was indicated by the maintenance of the cross-sectional area of cell bodies and mean length of neuritic processes one month after surgery. The effect of acidic fibroblast growth factor in non-cholinergic cells remains to be investigated. It is suggested that acidic fibroblast growth factor may alleviate the lesion-induced deficit in the memory retention task by preventing disruption of functional connections between nucleus basalis magnocellularis and intact cortical areas.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of acetylcholine in cocaine addiction.

PubMed

Williams, Mark J; Adinoff, Bryon

2008-07-01

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Neuronal somata and extrasomal compartments play distinct roles during synapse formation between Lymnaea neurons.

PubMed

Xu, Fenglian; Luk, Collin C; Wiersma-Meems, Ryanne; Baehre, Kelly; Herman, Cameron; Zaidi, Wali; Wong, Noelle; Syed, Naweed I

2014-08-20

Proper synapse formation is pivotal for all nervous system functions. However, the precise mechanisms remain elusive. Moreover, compared with the neuromuscular junction, steps regulating the synaptogenic program at central cholinergic synapses remain poorly defined. In this study, we identified different roles of neuronal compartments (somal vs extrasomal) in chemical and electrical synaptogenesis. Specifically, the electrically synapsed Lymnaea pedal dorsal A cluster neurons were used to study electrical synapses, whereas chemical synaptic partners, visceral dorsal 4 (presynaptic, cholinergic), and left pedal dorsal 1 (LPeD1; postsynaptic) were explored for chemical synapse formation. Neurons were cultured in a soma-soma or soma-axon configuration and synapses explored electrophysiologically. We provide the first direct evidence that electrical synapses develop in a soma-soma, but not soma-axon (removal of soma) configuration, indicating the requirement of gene transcription regulation in the somata of both synaptic partners. In addition, the soma-soma electrical coupling was contingent upon trophic factors present in Lymnaea brain-conditioned medium. Further, we demonstrate that chemical (cholinergic) synapses between soma-soma and soma-axon pairs were indistinguishable, with both exhibiting a high degree of contact site and target cell type specificity. We also provide direct evidence that presynaptic cell contact-mediated, clustering of postsynaptic cholinergic receptors at the synaptic site requires transmitter-receptor interaction, receptor internalization, and a protein kinase C-dependent lateral migration toward the contact site. This study provides novel insights into synaptogenesis between central neurons revealing both distinct and synergistic roles of cell-cell signaling and extrinsic trophic factors in executing the synaptogenic program. Copyright © 2014 the authors 0270-6474/14/3411304-12$15.00/0.

Botulinum toxin for pain.

PubMed

Casale, Roberto; Tugnoli, Valeria

2008-01-01

Botulinum toxin (BTX) injection is being increasingly used 'off label' in the management of chronic pain. Data support the hypothesis of a direct analgesic effect of BTX, different to that exerted on muscle. Although the pain-reducing effect of BTX is mainly due to its ability to block acetylcholine release at the synapse, other effects on the nervous system are also thought to be involved. BTX affects cholinergic transmission in both the somatic and the autonomic nervous systems. Proposed mechanisms of action of BTX for pain relief of trigger points, muscular spasms, fibromyalgia and myofascial pain include direct action on muscle and indirect effects via action at the neuromuscular junction. Invitro and invivo data have shown that BTX has specific antinociceptive activity relating to its effects on inflammation, axonal transport, ganglion inhibition, and spinal and suprasegmental level inhibition. Our review of the mechanisms of action, efficacy, administration techniques and therapeutic dosage of BTX for the management of chronic pain in a variety of conditions shows that although muscular tone and movement disorders remain the most important therapeutic applications for BTX, research suggests that BTX can also provide benefits related to effects on cholinergic control of the vascular system, autonomic function, and cholinergic control of nociceptive and antinociceptive systems. Furthermore, it appears that BTX may influence the peripheral and central nervous systems. The therapeutic potential of BTX depends mainly on the ability to deliver the toxin to the target structures, cholinergic or otherwise. Evidence suggests that BTX can be administered at standard dosages in pain disorders, where the objective is alteration of muscle tone. For conditions requiring an analgesic effect, the optimal therapeutic dosage of BTX remains to be defined.

Ethanol- and acetaldehyde-induced cholinergic imbalance in the hippocampus of Aldh2-knockout mice does not affect nerve growth factor or brain-derived neurotrophic factor.

PubMed

Jamal, Mostofa; Ameno, Kiyoshi; Ruby, Mostofa; Miki, Takanori; Tanaka, Naoko; Nakamura, Yu; Kinoshita, Hiroshi

2013-11-20

Neurotrophins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), play an important role in the maintenance of cholinergic-neuron function. The objective of this study was to investigate whether ethanol (EtOH)- and acetaldehyde (AcH)- induced cholinergic effects would cause neurotrophic alterations in the hippocampus of mice. We used Aldh2 knockout (Aldh2-KO) mice, a model of aldehyde dehydrogenase 2 (ALDH2)-deficiency in humans, to examine the effects of acute administration of EtOH and the role of AcH. Hippocampal slices were collected and the mRNA and protein levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), NGF and BDNF were analyzed 30 min after the i.p. administration of EtOH (0.5, 1.0, or 2.0 g/kg). We show that treatment with 2.0 g/kg of EtOH decreased ChAT mRNA and protein levels in Aldh2-KO mice but not in wild-type (WT) mice, which suggests a role for AcH in the mechanism of action of EtOH. The administration of 2.0 g/kg of EtOH increased AChE mRNA in both strains of mice. EtOH failed to change the levels of NGF or BDNF at any dose. Aldh2-KO mice exhibited a distinctly lower expression of ChAT and a higher expression of NGF both at mRNA and protein levels in the hippocampus compared with WT mice. Our observations suggest that administration of EtOH and elevated AcH can alter cholinergic markers in the hippocampus of mice, and this effect did not change the levels of NGF or BDNF. © 2013 Elsevier B.V. All rights reserved.

Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon.

PubMed

Jarvie, Emma M; Cellek, Selim; Sanger, Gareth J

2008-01-01

Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.01-1 microM; 754+/-337% facilitation at 1 microM); higher concentrations (1, 3 microM) also increased muscle tension. Donepezil increased EFS-evoked contractions gradually over the full range of concentrations (0.01-10 microM; maximum increase 516+/-20% at 10 microM). Itopride increased the contractions even more gradually, rising to 188+/-84% at 10 microM. The butyrylcholinesterase inhibitor iso-OMPA 0.01-10 microM also increased EFS-evoked contractions, to a maximum of 36+/-5.0% at 10 microM, similar to that caused by tegaserod (35+/-5.2% increase at 1 microM). The effects of tegaserod, but not itopride were inhibited by the 5-HT(4) receptor antagonist SB-204070A 0.3 microM. In rat isolated colon, neostigmine was again the most efficacious, causing a defined maximum increase in EFS-evoked contractions (343+/-82% at 10 microM), without changing muscle tension. Maximum increases caused by donepezil and itopride were, respectively, 57.6+/-20 and 43+/-15% at 10 microM. These data indicate that the abilities of different AChE inhibitors to increase GI cholinergic activity differ markedly. Understanding the reasons is essential if AChE inhibitors are to be optimally developed as GI prokinetics.

Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Kelley, Christy M.; Ash, Jessica A.; Powers, Brian E.; Velazquez, Ramon; Alldred, Melissa J.; Ikonomovic, Milos D.; Ginsberg, Stephen D.; Strupp, Barbara J.; Mufson, Elliott J.

2016-01-01

Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer’s disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6–8 and 14–18 mos were used for an aging study, and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14–18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in TS65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS. PMID:26391045

The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex

PubMed Central

Bajo, Victoria M; Leach, Nicholas D; Cordery, Patricia M; Nodal, Fernando R; King, Andrew J

2014-01-01

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en-passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing. PMID:24945075

Curcumin restores diabetes induced neurochemical changes in the brain stem of Wistar rats.

PubMed

Kumar, Peeyush T; George, Naijil; Antony, Sherin; Paulose, Cheramadathikudiyil Skaria

2013-02-28

Diabetes mellitus, when poorly controlled, leads to debilitating central nervous system (CNS) complications including cognitive deficits, somatosensory and motor dysfunction. The present study investigated curcumin's potential in modulating diabetes induced neurochemical changes in brainstem. Expression analysis of cholinergic, insulin receptor and GLUT-3 in the brainstem of streptozotocin (STZ) induced diabetic rats were studied. Radioreceptor binding assays, gene expression studies and immunohistochemical analysis were done in the brainstem of male Wistar rats. Our result showed that Bmax of total muscarinic and muscarinic M3 receptors were increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. mRNA level of muscarinic M3, α7-nicotinic acetylcholine, insulin receptors, acetylcholine esterase, choline acetyltransferase and GLUT-3 significantly increased and M1 receptor decreased in the brainstem of diabetic rats. Curcumin and insulin treatment restored the alterations and maintained all parameters to near control. The results show that diabetes is associated with significant reduction in brainstem function coupled with altered cholinergic, insulin receptor and GLUT-3 gene expression. The present study indicates beneficial effect of curcumin in diabetic rats by regulating the cholinergic, insulin receptor and GLUT-3 in the brainstem similar to the responses obtained with insulin therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

[Sex difference of functional and structural alterations in the myocardium of rats with hypothyroidism].

PubMed

Khara, M R; Pavlovych, S I; Mykhaĭliuk, V M

2013-01-01

In experiments on sexually mature rats we studied specific cholinergic regulations of the heart and the degree of its structural damage in hypothyroidism, depending on gender and hormone-productive activity of the gonads. Hypothyroidism in sexually mature males and females was modelled with mercazolil intragastric administration (75 mg/kg) daily during 15 days. We also studied the intensity of bradycardia, which occurred in response to electrical stimulation of vagus nerve and intravenous acetylcholine administration. The degree of structural heart damage was assessed by the percentage of damaged cardiomyocytes in the ventricles of myocardium. It was found that one of the mechanisms of bradycardia in merkazolil-induced hypothyroidism is an increase of the sensitivity of sinus node cholinergic receptors and release of more quanta of acetylcholine from stimulated nerves vagus endings, what was more intense in females. The intensity of bradycardia in hypothyroidism was more significant in gonadectomized animals than in individuals with preserved gonads. The mechanisms of its occurrence in males consist of release of greater amount of acetylcholine from the endings of the nerves vagus, and in females it was the result of significant increase of the sensitivity of sinus node cholinergic receptors. Regardless of the gonads activity, structural damage of the myocardium in merkazolil-induced hypothyroidism was more intensive in female rats.

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

PubMed Central

Jaunarajs, K.L. Eskow; Bonsi, P.; Chesselet, M.F.; Standaert, D.G.; Pisani, A.

2015-01-01

Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. PMID:25697043

Length-dependent modulation of cytoskeletal remodeling and mechanical energetics in airway smooth muscle.

PubMed

Kim, Hak Rim; Liu, Katrina; Roberts, Thomas J; Hai, Chi-Ming

2011-06-01

Actin cytoskeletal remodeling is an important mechanism of airway smooth muscle (ASM) contraction. We tested the hypothesis that mechanical strain modulates the cholinergic receptor-mediated cytoskeletal recruitment of actin-binding and integrin-binding proteins in intact airway smooth muscle, thereby regulating the mechanical energetics of airway smooth muscle. We found that the carbachol-stimulated cytoskeletal recruitment of actin-related protein-3 (Arp3), metavinculin, and talin were up-regulated at short muscle lengths and down-regulated at long muscle lengths, suggesting that the actin cytoskeleton--integrin complex becomes enriched in cross-linked and branched actin filaments in shortened ASM. The mechanical energy output/input ratio during sinusoidal length oscillation was dependent on muscle length, oscillatory amplitude, and cholinergic activation. The enhancing effect of cholinergic stimulation on mechanical energy output/input ratio at short and long muscle lengths may be explained by the length-dependent modulation of cytoskeletal recruitment and crossbridge cycling, respectively. We postulate that ASM functions as a hybrid biomaterial, capable of switching between operating as a cytoskeleton-based mechanical energy store at short muscle lengths to operating as an actomyosin-powered mechanical energy generator at long muscle lengths. This postulate predicts that targeting the signaling molecules involved in cytoskeletal recruitment may provide a novel approach to dilating collapsed airways in obstructive airway disease.

Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells.

PubMed Central

Gardner, J D; Conlon, T P; Kleveman, H L; Adams, T D; Ondetti, M A

1975-01-01

COOH-terminal octapeptide of cholecystokinin (CCK-octapeptide) and the cholinergic agent carbamylcholine each produced a fourfold stimulation of calcium outflux in guinea pig isolated pancreatic acinar cells. Neither agent altered calcium influx. Stimulation of calcium outflux was rapid and specific, was abolished by reducing the incubation temperature to 4 degrees C, and was a saturable function of the secretagogue concentration. The concentrations of CCK-octapeptide and carbamylcholine that produced half-maximal stimulation of calcium outflux were 3.1 x 10(-10) M and 4.9 x 10(-5) M, respectively. The cholinergic antagonist antropine competitively inhibited carbamylcholine stimulation of calcium outflux but did not alter stimulation produced by CCK-octapeptide. Stimulation of calcium outflux by maximal concentrations of carbamycholine plus CCK-octapeptide was the same as that produced by a maximal concentration of either agent alone.Calcium outflux became refractory to stimulation by secretagogues, and incubation with either CCK-ostapeptide or carbamylcholine produced a refractoriness to both agents. The relative potencies with CCK and its related fragments stimulated calcium outflux were CCK-octapeptide greater than heptapeptide greater than CCK greater than hexapeptide = gastrin. Secretin, glucagon, and vasoactive intestinal peptide, at concentrations as high as 10(-5) M, failed to alter calcium outflux and did not affect stimulation by CCK-octapeptide or by carbamycholine. Images PMID:1150877

The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract.

PubMed

Babalola, P A; Fitz, N F; Gibbs, R B; Flaherty, P T; Li, P-K; Johnson, D A

2012-10-01

Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo-hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (p<0.05). However, in the DMP task, steroid sulfatase inhibition impaired acquisition in lesioned rats while having no effect on intact animals. These results suggest that steroid sulfatase inhibition facilitates memory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract. Copyright © 2012 Elsevier Inc. All rights reserved.

Presynaptic Neuronal Nicotinic Receptors Differentially Shape Select Inputs to Auditory Thalamus and Are Negatively Impacted by Aging.

PubMed

Sottile, Sarah Y; Hackett, Troy A; Cai, Rui; Ling, Lynne; Llano, Daniel A; Caspary, Donald M

2017-11-22

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal. SIGNIFICANCE STATEMENT The pedunculopontine tegmental nucleus is the source of cholinergic innervation for sensory thalamus and is a critical part of an ascending arousal system that controls the firing mode of thalamic cells based on attentional demand. The present study describes the location and impact of aging on presynaptic neuronal nicotinic acetylcholine receptors (nAChRs) within the circuitry of the auditory thalamus (medial geniculate body, MGB). We show that nAChRs are located on ascending inhibitory and descending excitatory presynaptic inputs onto MGB neurons, likely increasing gain selectively and improving temporal clarity. In addition, we show that aging has a deleterious effect on nAChR efficacy. Cholinergic dysfunction at the level of MGB may affect speech understanding negatively in the elderly population. Copyright © 2017 the authors 0270-6474/17/3711378-13$15.00/0.

Presynaptic Neuronal Nicotinic Receptors Differentially Shape Select Inputs to Auditory Thalamus and Are Negatively Impacted by Aging

PubMed Central

Sottile, Sarah Y.; Hackett, Troy A.

2017-01-01

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal. SIGNIFICANCE STATEMENT The pedunculopontine tegmental nucleus is the source of cholinergic innervation for sensory thalamus and is a critical part of an ascending arousal system that controls the firing mode of thalamic cells based on attentional demand. The present study describes the location and impact of aging on presynaptic neuronal nicotinic acetylcholine receptors (nAChRs) within the circuitry of the auditory thalamus (medial geniculate body, MGB). We show that nAChRs are located on ascending inhibitory and descending excitatory presynaptic inputs onto MGB neurons, likely increasing gain selectively and improving temporal clarity. In addition, we show that aging has a deleterious effect on nAChR efficacy. Cholinergic dysfunction at the level of MGB may affect speech understanding negatively in the elderly population. PMID:29061702

Side effects in preventive maintenance therapy with neuroleptics with special emphasis on tardive dyskinesia.

PubMed

Logothetis, J; Paraschos, A; Frangos, E

1981-01-01

Neuroleptics induce hypersensitivity reactions, and toxic, systemic and extrapyramidal manifestations. The latter mainly include acute dystonic reactions, other early dyskinesias, akathisia, parkinsonism and TD. These drugs have been implicated for DA antagonism exerted by an adenylate cyclase inhibition. Prolonged blockade of DA receptors is considered as the motivation for a counterbalancing mechanism inducing the DA supersensitivity from which TD results. Recent reports suggest cholinergic and GABA ergic insufficiency as secondary participants. The increasing frequency of TD calls for prevention by modifying treatment practices and searching for effective measures to combat the symptoms.

Muscarinic agonists for the treatment of cognition in schizophrenia.

PubMed

Sellin, Angela K; Shad, Mujeeb; Tamminga, Carol

2008-11-01

It is widely accepted that cholinergic activity at muscarinic receptors is required to maintain cognitive functions, including learning and memory. Memory domains are especially impaired in schizophrenia, which may explain difficulties in psychosocial rehabilitation of individuals with this illness. However, little is known about the mechanism of this impairment. To understand our current knowledge, we reviewed the literature since 1990 via a PubMed search for the terms "muscarinic", "schizophrenia", "cognition", "memory", "learning", and "agonist" in combination. We found 89 basic science/laboratory studies, case reports/series, case-control studies, cross-sectional studies, standardized controlled animal trials, standardized controlled human trials, and reviews. Although further research is required to fully understand the neuropharmacology of the cholinergic system in cognitive function in schizophrenia, we have examined the data currently available. In general, these data suggest that agonist activity at acetylcholine muscarinic type 1 (M1) receptors would enhance memory and learning in schizophrenia. We present an overview of likely side effects of muscarinic agonists. We outline the anticholinergic activity of several available antipsychotics and review the available M1 muscarinic agonists.

Control of cerebral cortical blood flow by stimulation of basal forebrain cholinergic areas in mice.

PubMed

Hotta, Harumi; Uchida, Sae; Kagitani, Fusako; Maruyama, Naoki

2011-05-01

We examined whether activity of the nucleus basalis of Meynert (NBM) regulates regional cerebral cortical blood flow (rCBF) in mice, using laser speckle and laser Doppler flowmetry. In anesthetized mice, unilateral focal stimulation, either electrical or chemical, of the NBM increased rCBF of the ipsilateral cerebral cortex in the frontal, parietal and occipital lobes, independent of changes in systemic blood pressure. Most of vasodilative responses to low intensity stimuli (2 times threshold intensity: 2T) were abolished by atropine (a muscarinic cholinergic blocker), whereas responses to higher intensity stimuli (3T) were abolished by atropine and mecamylamine (a nicotinic cholinergic blocker). Blood flow changes were largest when the tip of the electrode was located within the area containing cholinergic neurons shown by choline acetyltransferase-immunocytochemistry. These results suggest that cholinergic projections from basal forebrain neurons in mice cause vasodilation in the ipsilateral cerebral cortex by a combination of muscarinic and nicotinic mechanisms, as previously found in rats and cats.

Effects of Chemical Agents on the Cholinergic Neurotransmitter System: Mechanisms of Adaptation.

DTIC Science & Technology

1984-06-20

DFP; 19h cholinergic agonist, oxotremorine ; oxotremorine analogs, A ~ mustards BM 123 and BM 130; pharmacological, (see reverse i - = V u M pan...anticholinesterase, DFP; a cholinergic agonist, oxotremorine ; and two oxotremorine mustards, BM 123 and BM 130. The studies were of four major kinds...findings. The general pharmacological investigations were directed primarily toward the mustard analogs of oxotremorine and used in vitro and in vivo

Eccrine sweat gland development and sweat secretion

PubMed Central

Cui, Chang-Yi; Schlessinger, David

2017-01-01

Eccrine sweat glands help to maintain homoeostasis, primarily by stabilizing body temperature. Derived from embryonic ectoderm, millions of eccrine glands are distributed across human skin and secrete litres of sweat per day. Their easy accessibility has facilitated the start of analyses of their development and function. Mouse genetic models find sweat gland development regulated sequentially by Wnt, Eda and Shh pathways, although precise subpathways and additional regulators require further elucidation. Mature glands have two secretory cell types, clear and dark cells, whose comparative development and functional interactions remain largely unknown. Clear cells have long been known as the major secretory cells, but recent studies suggest that dark cells are also indispensable for sweat secretion. Dark cell-specific Foxa1 expression was shown to regulate a Ca2+-dependent Best2 anion channel that is the candidate driver for the required ion currents. Overall, it was shown that cholinergic impulses trigger sweat secretion in mature glands through second messengers – for example InsP3 and Ca2+ – and downstream ion channels/transporters in the framework of a Na+-K+-Cl− cotransporter model. Notably, the microenvironment surrounding secretory cells, including acid–base balance, was implicated to be important for proper sweat secretion, which requires further clarification. Furthermore, multiple ion channels have been shown to be expressed in clear and dark cells, but the degree to which various ion channels function redundantly or indispensably also remains to be determined. PMID:26014472

Improvements in Memory after Medial Septum Stimulation Are Associated with Changes in Hippocampal Cholinergic Activity and Neurogenesis

PubMed Central

Jeong, Da Un; Lee, Ji Eun; Lee, Sung Eun; Chang, Won Seok; Kim, Sung June; Chang, Jin Woo

2014-01-01

Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis. PMID:25101288

Intracellular Aß triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease.

PubMed

Christensen, Ditte Z; Bayer, Thomas A; Wirths, Oliver

2010-07-01

Loss of cholinergic neurons in the Nucleus Basalis of Meynert in Alzheimer's disease (AD) patients was one of the first discoveries of neuron loss in AD. Despite an intense focus on the cholinergic system in AD, the reason for this cholinergic neuron loss is yet unknown. In the present study we examined Abeta-induced pathology and neuron loss in the cholinergic system of the bigenic APP/PS1KI mouse model. Expression of the APP transgene was found in ChAT-positive neurons of motor nuclei accompanied by robust intracellular Abeta accumulation, whereas no APP expressing neurons and thus no intracellular Abeta accumulation were found in neither the forebrain or pons complexes, nor in the caudate putamen. This expression pattern was used as a model system to study the effect of intra- and extracellular Abeta accumulation on neuron loss in the cholinergic system. Stereological quantification revealed a loss of ChAT-positive neurons in APP/PS1KI mice only in the motor nuclei Mo5 and 7N accumulating intracellular Abeta. This study supports the hypothesis of intracellular Abeta accumulation as an early pathological alteration contributing to cell death in AD. Copyright 2008 Elsevier Inc. All rights reserved.

Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-Inflammatory Processes: A Role for Cholinergic α7 Nicotinic Receptors

PubMed Central

Morris, John S.; Karelina, Kate; Weil, Zachary M.; Zhang, Ning; Al-Abed, Yousef; Brothers, Holly M.; Wenk, Gary L.; Pavlov, Valentin A.; Tracey, Kevin J.; DeVries, A. Courtney

2011-01-01

Cardiac arrest is a leading cause of death worldwide. While survival rates following sudden cardiac arrest remain relatively low, recent advancements in patient care have begun to increase the proportion of individuals who survive cardiac arrest. However, many of these individuals subsequently develop physiological and psychiatric conditions that likely result from ongoing neuroinflammation and neuronal death. The present study was conducted to better understand the pathophysiological effects of cardiac arrest on neuronal cell death and inflammation, and their modulation by the cholinergic system. Using a well validated model of cardiac arrest, here we show that global cerebral ischemia increases microglial activation, proinflammatory cytokine mRNA expression (interleukin-1β, interleukin-6, tumor necrosis factor-α), and neuronal damage. Cardiac arrest also induces alterations in numerous cellular components of central cholinergic signaling, including a reduction in choline acetyltransferase enzymatic activity and the number of choline acetyltransferase-positive neurons, as well as, reduced acetylcholinesterase and vesicular acetylcholine transporter mRNA. However, treatment with a selective agonist of the α7 nicotinic acetylcholine receptor, the primary receptor mediating the cholinergic anti-inflammatory pathway, significantly decreases the neuroinflammation and neuronal damage resulting from cardiac arrest. These data suggest that global cerebral ischemia results in significant declines in central cholinergic signaling, which may in turn diminish the capacity of the cholinergic anti-inflammatory pathway to control inflammation. Furthermore, we provide evidence that pharmacological activation of α7 nicotinic acetylcholine receptors provide significant protection against ischemia-related cell death and inflammation within a clinically relevant time frame. PMID:21368056

Control of heart rate during thermoregulation in the heliothermic lizard Pogona barbata: importance of cholinergic and adrenergic mechanisms.

PubMed

Seebacher, F; Franklin, C E

2001-12-01

During thermoregulation in the bearded dragon Pogona barbata, heart rate when heating is significantly faster than when cooling at any given body temperature (heart rate hysteresis), resulting in faster rates of heating than cooling. However, the mechanisms that control heart rate during heating and cooling are unknown. The aim of this study was to test the hypothesis that changes in cholinergic and adrenergic tone on the heart are responsible for the heart rate hysteresis during heating and cooling in P. barbata. Heating and cooling trials were conducted before and after the administration of atropine, a muscarinic antagonist, and sotalol, a beta-adrenergic antagonist. Cholinergic and beta-adrenergic blockade did not abolish the heart rate hysteresis, as the heart rate during heating was significantly faster than during cooling in all cases. Adrenergic tone was extremely high (92.3 %) at the commencement of heating, and decreased to 30.7 % at the end of the cooling period. Moreover, in four lizards there was an instantaneous drop in heart rate (up to 15 beats min(-1)) as the heat source was switched off, and this drop in heart rate coincided with either a drop in beta-adrenergic tone or an increase in cholinergic tone. Rates of heating were significantly faster during the cholinergic blockade, and least with a combined cholinergic and beta-adrenergic blockade. The results showed that cholinergic and beta-adrenergic systems are not the only control mechanisms acting on the heart during heating and cooling, but they do have a significant effect on heart rate and on rates of heating and cooling.

Identification of the origin of adrenergic and cholinergic nerve fibers within the superior hypogastric plexus of the human fetus

PubMed Central

Zaitouna, Mazen; Alsaid, Bayan; Diallo, Djibril; Benoit, Gérard; Bessede, Thomas

2013-01-01

Nerve fibers contributing to the superior hypogastric plexus (SHP) and the hypogastric nerves (HN) are currently considered to comprise an adrenergic part of the autonomic nervous system located between vertebrae (T1 and L2), with cholinergic aspects originating from the second to fourth sacral spinal segments (S2, S3 and S4). The aim of this study was to identify the origin and the nature of the nerve fibers within the SHP and the HN, especially the cholinergic fibers, using computer-assisted anatomic dissection (CAAD). Serial histological sections were performed at the level of the lumbar spine and pelvis in five human fetuses between 14 and 30 weeks of gestation. Sections were treated with histological staining [hematoxylin-eosin (HE) and Masson's trichrome (TriM)] and with immunohistochemical methods to detect nerve fibers (anti-S100), adrenergic fibers (anti-TH), cholinergic fibers (anti-VAChT) and nitrergic fibers (anti-nNOS). The sections were then digitalized using a high-resolution scanner and the 3D images were reconstructed using winsurf software. These experiments revealed the coexistence of adrenergic and cholinergic fibers within the SHP and the HNs. One-third of these cholinergic fibers were nitrergic fibers [anti-VACHT (+)/anti-NOS (+)] and potentially pro-erectile, while the others were non-nitrergic [anti-VACHT (+)/anti-NOS (−)]. We found these cholinergic fibers arose from the lumbar nerve roots. This study described the nature of the SHP nerve fibers which gives a better understanding of the urinary and sexual dysfunctions after surgical injuries. PMID:23668336

Acetylcholine-induced seizure-like activity and modified cholinergic gene expression in chronically epileptic rats.

PubMed

Zimmerman, Gabriel; Njunting, Marleisje; Ivens, Sebastian; Tolner, Else A; Tolner, Elsa; Behrens, Christoph J; Gross, Miriam; Soreq, Hermona; Heinemann, Uwe; Friedman, Alon

2008-02-01

The entorhinal cortex (EC) plays an important role in temporal lobe epilepsy. Under normal conditions, the enriched cholinergic innervation of the EC modulates local synchronized oscillatory activity; however, its role in epilepsy is unknown. Enhanced neuronal activation has been shown to induce transcriptional changes of key cholinergic genes and thus alter cholinergic responses. To examine cholinergic modulations in epileptic tissue we studied molecular and electrophysiological cholinergic responses in the EC of chronically epileptic rats following exposure to pilocarpine or kainic acid. We confirmed that while the total activity of the acetylcholine (ACh)-hydrolysing enzyme, acetylcholinesterase (AChE) was not altered, epileptic rats showed alternative splicing of AChE pre-mRNA transcripts, accompanied by a shift from membrane-bound AChE tetramers to soluble monomers. This was associated with increased sensitivity to ACh application: thus, in control rats, ACh (10-100 microm) induced slow (< 1Hz), periodic events confined to the EC; however, in epileptic rats, ACh evoked seconds-long seizure-like events with initial appearance in the EC, and frequent propagation to neighbouring cortical regions. ACh-induced seizure-like events could be completely blocked by the non-specific muscarinic antagonist, atropine, and were partially blocked by the muscarinic-1 receptor antagonist, pirenzepine; but were not affected by the non-specific nicotinic antagonist, mecamylamine. Epileptic rats presented reduced transcript levels of muscarinic receptors with no evidence of mRNA editing or altered mRNA levels for nicotinic ACh receptors. Our findings suggest that altered cholinergic modulation may initiate seizure events in the epileptic temporal cortex.

The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex.

PubMed

Bajo, Victoria M; Leach, Nicholas D; Cordery, Patricia M; Nodal, Fernando R; King, Andrew J

2014-09-01

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en-passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing. © 2014 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Novel Fast Adapting Interneurons Mediate Cholinergic-Induced Fast GABAA IPSCs In Striatal Spiny Neurons

PubMed Central

Faust, Thomas W.; Assous, Maxime; Shah, Fulva; Tepper, James M.; Koós, Tibor

2015-01-01

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism only one such cell type, the neuropeptide-Y expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained in vitro slice recordings from double transgenic mice in which Channelrhodopsin-2 was natively expressed in cholinergic neurons and a population of serotonin receptor-3a-Cre expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast-adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast-adapting interneurons receive a powerful supra-threshold nicotinic cholinergic input in vitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABAA receptor mediated inhibitory postsynaptic responses. The nicotinic receptor mediated activation of fast-adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli. PMID:25865337

20(S)-protopanaxadiol (PPD) alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of Egr-1, c-Fos and c-Jun in mice.

PubMed

Lu, Cong; Dong, Liming; Lv, Jingwei; Wang, Yan; Fan, Bei; Wang, Fengzhong; Liu, Xinmin

2018-01-05

20(S)-protopanaxadiol (PPD) possesses various biological properties, including anti-inflammatory, antitumor and anti-fatigue properties. Recent studies found that PPD functioned as a neurotrophic agent to ameliorate the sensory deficit caused by glutamate-induced excitotoxicity through its antioxidant effects and exhibited strong antidepressant-like effects in vivo. The objective of the present study was first to investigate the effect of PPD in scopolamine (SCOP)-induced memory deficit in mice and the potential mechanisms involved. In this study, mice were pretreated with PPD (20 and 40 μmol/kg) and donepezil (1.6 mg/kg) intraperitoneally (i.p) for 14 days. Then, open field test was used to assess the effect of PPD on the locomotor activity and mice were daily injected with SCOP (0.75 mg/kg) to induce cognitive deficits and then subjected to behavioral tests by object location recognition (OLR) experiment and Morris water maze (MWM) task. The cholinergic system function, oxidative stress biomarkers and protein expression of Egr-1, c-Fos, and c-Jun in mouse hippocampus were examined. PPD was found to significantly improve the performance of amnesia mice in OLR and MWM tests. PPD regulated cholinergic function by inhibiting SCOP-induced elevation of acetylcholinesterase (AChE) activity, decline of choline acetyltransferase (ChAT) activity and decrease of acetylcholine (Ach) level. PPD suppressed oxidative stress by increasing activities of antioxidant enzymes such as superoxide dismutase (SOD) and lowering maleic diadehyde (MDA) level. Additionally, PPD significantly elevated the expression of Egr-1, c-Fos, and c-Jun in hippocampus at protein level. Taken together, all these results suggested that 20(S)-protopanaxadiol (PPD) may be a candidate compound for the prevention against memory loss in some neurodegenerative diseases such as Alzheimer's disease (AD). Copyright © 2017. Published by Elsevier B.V.

Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia.

PubMed

Benes, Francine M

2012-01-01

Studies of the hippocampus in postmortem brains from patients with schizophrenia and bipolar disorder have provided evidence for a defect of GABAergic interneurons. Significant decreases in the expression of GAD67, a marker for GABA cell function, have been found repeatedly in several different brain regions that include the hippocampus. In this region, nicotinic receptors are thought to play an important role in modulating the activity of GABAergic interneurons by influences of excitatory cholinergic afferents on their activity. In bipolar disorder, this influence appears to be particularly prominent in the stratum oriens of sectors CA3/2 and CA1, two sites where these cells constitute the exclusive neuronal cell type. In sector CA3/2, this layer receives a robust excitatory projection from the basolateral amygdala (BLA) and this is thought to play a central role in regulating GABA cells at this locus. Using laser microdissection, recent studies have focused selectively on these two layers and their associated GABA cells using microarray technology. The results have provided support for the idea that nicotinic cholinergic receptors play a particularly important role in regulating the activity of GABA neurons at these loci by regulating the progression of cell cycle and the repair of damaged DNA. In bipolar disorder, there is a prominent reduction in the expression of mRNAs for several different nicotinic subunit isoforms. These decreases could reflect a diminished influence of this receptor system on these GABA cells, particularly in sector CA3/2 where a preponderance of abnormalities have been observed in postmortem studies. In patients with bipolar disorder, excitatory nicotinic cholinergic fibers from the medial septum may converge with glutamatergic fibers from the BLA on GABAergic interneurons in the stratum oriens of CA3/2 and result in disturbances of their genomic and functional integrity, ones that may induce disruptions of the integration of microcircuitry within this region.

Two neuropeptides colocalized in a command-like neuron use distinct mechanisms to enhance its fast synaptic connection.

PubMed

Koh, H Y; Vilim, F S; Jing, J; Weiss, K R

2003-09-01

In many neurons more than one peptide is colocalized with a classical neurotransmitter. The functional consequence of such an arrangement has been rarely investigated. Here, within the feeding circuit of Aplysia, we investigate at a single synapse the actions of two modulatory neuropeptides that are present in a cholinergic interneuron. In combination with previous work, our study shows that the command-like neuron for feeding, CBI-2, contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that high-frequency prestimulation or repeated stimulation of CBI-2 increases the size of CBI-2 to B61/62 excitatory postsynaptic potentials (EPSPs) and shortens the latency of firing of neuron B61/62 in response to CBI-2 stimulation. We find that both FCAP and CP2 mimic these two effects. The variance method of quantal analysis indicates that FCAP increases the calculated quantal size (q) and CP2 increases the calculated quantal content (m) of EPSPs. Since the PSP amplitude represents the product of q and m, the joint action of the two peptides is expected to be cooperative. This observation suggests a possible functional implication for multiple neuropeptides colocalized with a classical neurotransmitter in one neuron.

Evidence for non-acetylcholinesterase mechanisms in ...

EPA Pesticide Factsheets

Acetyicholinesterase inhibition is a well-established mode of action for adverse effects of organophosphorus and carbamate pesticides, and the use of this endpoint in regulatory considerations has been assumed to be protective of downstream cholinergic effects. It has been questioned whether neurodevelopmental outcomes are also a consequence of this enzyme inhibition, or whether there are alternative non-cholinesterase mechanisms by which these chemicals alter key events in nervous system development. There is a growing body of literature in laboratory animals indicating that gestational and/or postnatal exposure may cause persistent behavioral effects into adulthood, as well as emerging epidemiological reports of neurodevelopmental outcomes in children. Common experimental findings are alterations in motor activity, cognitive function, and affective and social behaviors in rats or mice, as well as disrupted neuromotor and cognitive development in children. However, the data do not provide evidence for a characteristic pattern of effects. This may suggest nonspecific alterations in neurobehavioral function, but it may also be the result of considerable differences in exposure parameters, experimental designs, test methods and equipment, populations and animal models, and a host of other variables. A number of pesticides have been implicated, but the database for chiorpyrifos is the largest and thus those studies influence any evaluations of trend. Specific attri

Evidence for non-acetylcholinesterase mechanisms in ...

EPA Pesticide Factsheets

Acetylcholinesterase inhibition is a well-established mode of action for adverse effects of organophosphorus and carbamate pesticides, and the use of this endpoint in regulatory considerations has been assumed to be protective of downstream cholinergic effects. It has been questioned whether neurodevelopmental outcomes are also a consequence of this enzyme inhibition, or whether there are alternative non-cholinesterase mechanisms by which these chemicals alter key events in nervous system development. There is a growing body of literature in laboratory animals indicating that gestational and/or postnatal exposure may cause persistent behavioral effects into adulthood, as well as emerging epidemiological reports of neurodevelopmental outcomes in children. Common experimental findings are alterations in motor activity, cognitive function, and affective and social behaviors in rats or mice, as well as disrupted neuromotor and cognitive development in children. However, the data do not provide evidence for a characteristic pattern of effects. This may suggest nonspecific alterations in neurobehavioral function, but it may also be the result of considerable differences in exposure parameters, experimental designs, test methods and equipment, populations and animal models, and a host of other variables. A number of pesticides have been implicated, but the database for chlorpyrifos is the largest and thus those studies influence any evaluations of trend. Specific attri

Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases-An Overview of Imaging Studies.

PubMed

Peterson, Andrew C; Li, Chiang-Shan R

2018-01-01

Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD.

Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents.

PubMed

Dohanich, G P; Cada, D A

1989-12-01

Androgens have been found to inhibit lordosis activated by estrogen treatment of ovariectomized female rats. In the present experiments, dihydrotestosterone propionate (200 micrograms for 3 days) inhibited the incidence of lordosis in ovariectomized females treated with estradiol benzoate (1 microgram for 3 days). This inhibition of lordosis was reversed 15 min after bilateral intraventricular infusion of physostigmine (10 micrograms/cannula), an acetylcholinesterase inhibitor, or carbachol (0.5 microgram/cannula), a cholinergic receptor agonist. This reversal of inhibition appears to be mediated by cholinergic muscarinic receptors since pretreatment with scopolamine (4 mg/kg, ip), a muscarinic receptor blocker, prevented the reversal of androgen inhibition by physostigmine. These results indicate that androgens may inhibit estrogen-activated lordosis through interference with central cholinergic muscarinic mechanisms.

Islet-1 Controls the Differentiation of Retinal Bipolar and Cholinergic Amacrine Cells

PubMed Central

Elshatory, Yasser; Everhart, Drew; Deng, Min; Xie, Xiaoling; Barlow, Robert B.; Gan, Lin

2010-01-01

Whereas the mammalian retina possesses a repertoire of factors known to establish general retinal cell types, these factors alone cannot explain the vast diversity of neuronal subtypes. In other CNS regions, the differentiation of diverse neuronal pools is governed by coordinately acting LIM-homeodomain proteins including the Islet-class factor Islet-1 (Isl1). We report that deletion of Isl1 profoundly disrupts retinal function as assessed by electroretinograms and vision as assessed by optomotor behavior. These deficits are coupled with marked reductions in mature ON- and OFF-bipolar (>76%), cholinergic amacrine (93%), and ganglion (71%) cells. Mosaic deletion of Isl1 permitted a chimeric analysis of “wild-type” cells in a predominantly Isl1-null environment, demonstrating a cell-autonomous role for Isl1 in rod bipolar and cholinergic amacrine development. Furthermore, the effects on bipolar cell development appear to be dissociable from the preceding retinal ganglion cell loss, because Pou4f2-null mice are devoid of similar defects in bipolar cell marker expression. Expression of the ON- and OFF-bipolar cell differentiation factors Bhlhb4 and Vsx1, respectively, requires the presence of Isl1, whereas the early bipolar cell marker Prox1 initially did not. Thus, Isl1 is required for engaging bipolar differentiation pathways but not for general bipolar cell specification. Spatiotemporal expression analysis of additional LIM-homeobox genes identifies a LIM-homeobox gene network during bipolar cell development that includes Lhx3 and Lhx4. We conclude that Isl1 has an indispensable role in retinal neuron differentiation within restricted cell populations and this function may reflect a broader role for other LIM-homeobox genes in retinal development, and perhaps in establishing neuronal subtypes. PMID:18003851

Muscarinic Acetylcholine Receptor Localization and Activation Effects on Ganglion Response Properties

PubMed Central

Renna, Jordan M.; Amthor, Franklin R.; Keyser, Kent T.

2010-01-01

Purpose. The activation and blockade of muscarinic acetylcholine receptors (mAChRs) affects retinal ganglion cell light responses and firing rates. This study was undertaken to identify the full complement of mAChRs expressed in the rabbit retina and to assess mAChR distribution and the functional effects of mAChR activation and blockade on retinal response properties. Methods. RT-PCR, Western blot analysis, and immunohistochemistry were used to identify the complement and distribution of mAChRs in the rabbit retina. Extracellular electrophysiology was used to determine the effects of the activation or blockade of mAChRs on ganglion cell response properties. Results. RT-PCR of whole neural retina resulted in the amplification of mRNA transcripts for the m1 to m5 mAChR subtypes. Western blot and immunohistochemical analyses confirmed that all five mAChR subtypes were expressed by subpopulations of bipolar, amacrine, and ganglion cells in the rabbit retina, including subsets of cells in cholinergic and glycinergic circuits. Nonspecific muscarinic activation and blockade resulted in the class-specific modulation of maintained ganglion cell firing rates and light responses. Conclusions. The expression of mAChR subtypes on subsets of bipolar, amacrine, and ganglion cells provides a substrate for both enhancement and suppression of retinal responses via activation by cholinergic agents. Thus, the muscarinic cholinergic system in the retina may contribute to the modulation of complex stimuli. Understanding the distribution and function of mAChRs in the retina has the potential to provide important insights into the visual changes that are caused by decreased ACh in the retinas of Alzheimer's patients and the potential visual effects of anticholinergic treatments for ocular diseases. PMID:20042645

Assessment of the expression and role of the α1-nAChR subunit in efferent cholinergic function during the development of the mammalian cochlea.

PubMed

Roux, Isabelle; Wu, Jingjing Sherry; McIntosh, J Michael; Glowatzki, Elisabeth

2016-08-01

Hair cell (HC) activity in the mammalian cochlea is modulated by cholinergic efferent inputs from the brainstem. These inhibitory inputs are mediated by calcium-permeable nicotinic acetylcholine receptors (nAChRs) containing α9- and α10-subunits and by subsequent activation of calcium-dependent potassium channels. Intriguingly, mRNAs of α1- and γ-nAChRs, subunits of the "muscle-type" nAChR have also been found in developing HCs (Cai T, Jen HI, Kang H, Klisch TJ, Zoghbi HY, Groves AK. J Neurosci 35: 5870-5883, 2015; Scheffer D, Sage C, Plazas PV, Huang M, Wedemeyer C, Zhang DS, Chen ZY, Elgoyhen AB, Corey DP, Pingault V. J Neurochem 103: 2651-2664, 2007; Sinkkonen ST, Chai R, Jan TA, Hartman BH, Laske RD, Gahlen F, Sinkkonen W, Cheng AG, Oshima K, Heller S. Sci Rep 1: 26, 2011) prompting proposals that another type of nAChR is present and may be critical during early synaptic development. Mouse genetics, histochemistry, pharmacology, and whole cell recording approaches were combined to test the role of α1-nAChR subunit in HC efferent synapse formation and cholinergic function. The onset of α1-mRNA expression in mouse HCs was found to coincide with the onset of the ACh response and efferent synaptic function. However, in mouse inner hair cells (IHCs) no response to the muscle-type nAChR agonists (±)-anatoxin A, (±)-epibatidine, (-)-nicotine, or 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was detected, arguing against the presence of an independent functional α1-containing muscle-type nAChR in IHCs. In α1-deficient mice, no obvious change of IHC efferent innervation was detected at embryonic day 18, contrary to the hyperinnervation observed at the neuromuscular junction. Additionally, ACh response and efferent synaptic activity were detectable in α1-deficient IHCs, suggesting that α1 is not necessary for assembly and membrane targeting of nAChRs or for efferent synapse formation in IHCs.

Assessment of the expression and role of the α1-nAChR subunit in efferent cholinergic function during the development of the mammalian cochlea

PubMed Central

Wu (武靜靜), Jingjing Sherry; McIntosh, J. Michael; Glowatzki, Elisabeth

2016-01-01

Hair cell (HC) activity in the mammalian cochlea is modulated by cholinergic efferent inputs from the brainstem. These inhibitory inputs are mediated by calcium-permeable nicotinic acetylcholine receptors (nAChRs) containing α9- and α10-subunits and by subsequent activation of calcium-dependent potassium channels. Intriguingly, mRNAs of α1- and γ-nAChRs, subunits of the “muscle-type” nAChR have also been found in developing HCs (Cai T, Jen HI, Kang H, Klisch TJ, Zoghbi HY, Groves AK. J Neurosci 35: 5870–5883, 2015; Scheffer D, Sage C, Plazas PV, Huang M, Wedemeyer C, Zhang DS, Chen ZY, Elgoyhen AB, Corey DP, Pingault V. J Neurochem 103: 2651–2664, 2007; Sinkkonen ST, Chai R, Jan TA, Hartman BH, Laske RD, Gahlen F, Sinkkonen W, Cheng AG, Oshima K, Heller S. Sci Rep 1: 26, 2011) prompting proposals that another type of nAChR is present and may be critical during early synaptic development. Mouse genetics, histochemistry, pharmacology, and whole cell recording approaches were combined to test the role of α1-nAChR subunit in HC efferent synapse formation and cholinergic function. The onset of α1-mRNA expression in mouse HCs was found to coincide with the onset of the ACh response and efferent synaptic function. However, in mouse inner hair cells (IHCs) no response to the muscle-type nAChR agonists (±)-anatoxin A, (±)-epibatidine, (−)-nicotine, or 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was detected, arguing against the presence of an independent functional α1-containing muscle-type nAChR in IHCs. In α1-deficient mice, no obvious change of IHC efferent innervation was detected at embryonic day 18, contrary to the hyperinnervation observed at the neuromuscular junction. Additionally, ACh response and efferent synaptic activity were detectable in α1-deficient IHCs, suggesting that α1 is not necessary for assembly and membrane targeting of nAChRs or for efferent synapse formation in IHCs. PMID:27098031

Thiamine Deficiency Induced Neurochemical, Neuroanatomical, and Neuropsychological Alterations: A Reappraisal

PubMed Central

Höller, Yvonne; Storti, Monica; Christova, Monica; Tezzon, Frediano; Golaszewski, Stefan; Trinka, Eugen

2013-01-01

Nutritional deficiency can cause, mainly in chronic alcoholic subjects, the Wernicke encephalopathy and its chronic neurological sequela, the Wernicke-Korsakoff syndrome (WKS). Long-term chronic ethanol abuse results in hippocampal and cortical cell loss. Thiamine deficiency also alters principally hippocampal- and frontal cortical-dependent neurochemistry; moreover in WKS patients, important pathological damage to the diencephalon can occur. In fact, the amnesic syndrome typical for WKS is mainly due to the damage in the diencephalic-hippocampal circuitry, including thalamic nuclei and mammillary bodies. The loss of cholinergic cells in the basal forebrain region results in decreased cholinergic input to the hippocampus and the cortex and reduced choline acetyltransferase and acetylcholinesterase activities and function, as well as in acetylcholine receptor downregulation within these brain regions. In this narrative review, we will focus on the neurochemical, neuroanatomical, and neuropsychological studies shedding light on the effects of thiamine deficiency in experimental models and in humans. PMID:24235882

Pioglitazone Improves Cognitive Function via Increasing Insulin Sensitivity and Strengthening Antioxidant Defense System in Fructose-Drinking Insulin Resistance Rats

PubMed Central

Yin, Qing-Qing; Pei, Jin-Jing; Xu, Song; Luo, Ding-Zhen; Dong, Si-Qing; Sun, Meng-Han; You, Li; Sun, Zhi-Jian; Liu, Xue-Ping

2013-01-01

Insulin resistance (IR) links Alzheimer’s disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance. PMID:23527159

[Antagonistic effects of cholinergic drugs on xylazine induced sedation].

PubMed

Ding, R G; Huang, S J; Yang, J S

1993-01-01

Xylazine induced sedation in mice was observed as a kind of inhibition of exploratory activity. The reversible cholinesterase inhibitor cui xing ning (0.25-1.0 m.kg-1), the precursor of acetylcholine, choline bromide (100-300 mg.kg-1), and the M-receptor agonist arecoline (1.0-5.0 mg.kg-1) were shown to significantly antagonize xylazine (5.0 mg.kg-1) induced sedation. While cui xing ning (0.25 mg.kg-1) shifted the dose-response curve of xylazine induced sedation to the right, hemicholinum-3 (3 micrograms icv), which inhibits the synthesis of acetylcholine, shifted the dose-response curve to the left. These results suggest that the xylazine induced sedation may be partly due to a reduced central cholinergic function. Cui xing ning may have some value in the treatment of xylazine overdose and antagonize the anesthesia induced by anesthetics combined with xylazine.

Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

PubMed Central

Murray, Ana Paula; Faraoni, María Belén; Castro, María Julia; Alza, Natalia Paola; Cavallaro, Valeria

2013-01-01

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. PMID:24381530

Evaluation of the inhibitory effect of abamectin on mammalian butyrylcholinesterase: Enzyme kinetic and molecular docking studies.

PubMed

Teralı, Kerem; Dalmizrak, Ozlem; Hoti, Qendresa; Ozer, Nazmi

2018-06-08

Abamectin, a blend of the natural avermectins B 1a and B 1b , is a widely-used insecticide/miticide with relatively low toxicity to mammals. Exposure to high doses of it, however, leads to cholinergic-like neurotoxic effects. Butyrylcholinesterase, which is best known for its abundant presence in plasma, is a serine hydrolase loosely coupled with the cholinergic system. It protects and supports the neurotransmitter function of its sister enzyme acetylcholinesterase. Here, using experimental and computational studies, we provide evidence demonstrating that abamectin is a potent (IC 50 = 10.6 μM; K i = 2.26 ± 0.35 μM) inhibitor of horse serum butyrylcholinesterase and that it interacts with the enzyme in a reversible, competitive manner predictively to block the mouth of the active-site gorge of the enzyme and to bind to several critical residues that normally bind/hydrolyze choline esters.

Elevated Hippocampal Cholinergic Neurostimulating Peptide precursor protein (HCNP-pp) mRNA in the amygdala in major depression.

PubMed

Bassi, Sabrina; Seney, Marianne L; Argibay, Pablo; Sibille, Etienne

2015-04-01

The amygdala is innervated by the cholinergic system and is involved in major depressive disorder (MDD). Evidence suggests a hyper-activate cholinergic system in MDD. Hippocampal Cholinergic Neurostimulating Peptide (HCNP) regulates acetylcholine synthesis. The aim of the present work was to investigate expression levels of HCNP-precursor protein (HCNP-pp) mRNA and other cholinergic-related genes in the postmortem amygdala of MDD patients and matched controls (females: N = 16 pairs; males: N = 12 pairs), and in the mouse unpredictable chronic mild stress (UCMS) model that induced elevated anxiety-/depressive-like behaviors (females: N = 6 pairs; males: N = 6 pairs). Results indicate an up-regulation of HCNP-pp mRNA in the amygdala of women with MDD (p < 0.0001), but not males, and of UCMS-exposed mice (males and females; p = 0.037). HCNP-pp protein levels were investigated in the human female cohort, but no difference was found. There were no differences in gene expression of acetylcholinesterase (AChE), muscarinic (mAChRs) or nicotinic receptors (nAChRs) between MDD subjects and controls or UCMS and control mice, except for an up-regulation of AChE in UCMS-exposed mice (males and females; p = 0.044). Exploratory analyses revealed a baseline expression difference of cholinergic signaling-related genes between women and men (p < 0.0001). In conclusion, elevated amygdala HCNP-pp expression may contribute to mechanisms of MDD in women, potentially independently from regulating the cholinergic system. The differential expression of genes between women and men could also contribute to the increased vulnerability of females to develop MDD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate.

PubMed

Lelkes, Zoltán; Abdurakhmanova, Shamsiiat; Porkka-Heiskanen, Tarja

2017-09-18

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23 μg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3 h with 0.3 mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24 h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate. © 2017 European Sleep Research Society.

Organization of the sleep-related neural systems in the brain of the river hippopotamus (Hippopotamus amphibius): A most unusual cetartiodactyl species.

PubMed

Dell, Leigh-Anne; Patzke, Nina; Spocter, Muhammad A; Bertelsen, Mads F; Siegel, Jerome M; Manger, Paul R

2016-07-01

This study provides the first systematic analysis of the nuclear organization of the neural systems related to sleep and wake in the basal forebrain, diencephalon, midbrain, and pons of the river hippopotamus, one of the closest extant terrestrial relatives of the cetaceans. All nuclei involved in sleep regulation and control found in other mammals, including cetaceans, were present in the river hippopotamus, with no specific nuclei being absent, but novel features of the cholinergic system, including novel nuclei, were present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic, and orexinergic systems and is extended to the γ-aminobutyric acid (GABA)ergic elements of these nuclei. Quantitative analysis reveals that the numbers of pontine cholinergic (259,578) and noradrenergic (127,752) neurons, and hypothalamic orexinergic neurons (68,398) are markedly higher than in other large-brained mammals. These features, along with novel cholinergic nuclei in the intralaminar nuclei of the dorsal thalamus and the ventral tegmental area of the midbrain, as well as a major expansion of the hypothalamic cholinergic nuclei and a large laterodorsal tegmental nucleus of the pons that has both parvocellular and magnocellular cholinergic neurons, indicates an unusual sleep phenomenology for the hippopotamus. Our observations indicate that the hippopotamus is likely to be a bihemispheric sleeper that expresses REM sleep. The novel features of the cholinergic system suggest the presence of an undescribed sleep state in the hippopotamus, as well as the possibility that this animal could, more rapidly than other mammals, switch cortical electroencephalographic activity from one state to another. J. Comp. Neurol. 524:2036-2058, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Chaoborus and gasterosteus anti-predator responses in Daphnia pulex are mediated by independent cholinergic and gabaergic neuronal signals.

PubMed

Weiss, Linda C; Kruppert, Sebastian; Laforsch, Christian; Tollrian, Ralph

2012-01-01

Many prey species evolved inducible defense strategies that protect effectively against predation threats. Especially the crustacean Daphnia emerged as a model system for studying the ecology and evolution of inducible defenses. Daphnia pulex e.g. shows different phenotypic adaptations against vertebrate and invertebrate predators. In response to the invertebrate phantom midge larvae Chaoborus (Diptera) D. pulex develops defensive morphological defenses (neckteeth). Cues originating from predatory fish result in life history changes in which resources are allocated from somatic growth to reproduction. While there are hints that responses against Chaoborus cues are transmitted involving cholinergic neuronal pathways, nothing is known about the neurophysiology underlying the transmission of fish related cues. We investigated the neurophysiological basis underlying the activation of inducible defenses in D. pulex using induction assays with the invertebrate predator Chaoborus and the three-spined stickleback Gasterosteus aculeatus. Predator-specific cues were combined with neuro-effective substances that stimulated or inhibited the cholinergic and gabaergic nervous system. We show that cholinergic-dependent pathways are involved in the perception and transmission of Chaoborus cues, while GABA was not involved. Thus, the cholinergic nervous system independently mediates the development of morphological defenses in response to Chaoborus cues. In contrast, only the inhibitory effect of GABA significantly influence fish-induced life history changes, while the application of cholinergic stimulants had no effect in combination with fish related cues. Our results show that cholinergic stimulation mediates signal transmission of Chaoborus cues leading to morphological defenses. Fish cues, which are responsible for predator-specific life history adaptations involve gabaergic control. Our study shows that both pathways are independent and thus potentially allow for adjustment of responses to variable predation regimes.

Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-β peptide oligomers.

PubMed

Nunes-Tavares, Nilson; Santos, Luís Eduardo; Stutz, Bernardo; Brito-Moreira, Jordano; Klein, William L; Ferreira, Sérgio T; de Mello, Fernando G

2012-06-01

Dysregulated cholinergic signaling is an early hallmark of Alzheimer disease (AD), usually ascribed to degeneration of cholinergic neurons induced by the amyloid-β peptide (Aβ). It is now generally accepted that neuronal dysfunction and memory deficits in the early stages of AD are caused by the neuronal impact of soluble Aβ oligomers (AβOs). AβOs build up in AD brain and specifically attach to excitatory synapses, leading to synapse dysfunction. Here, we have investigated the possibility that AβOs could impact cholinergic signaling. The activity of choline acetyltransferase (ChAT, the enzyme that carries out ACh production) was inhibited by ~50% in cultured cholinergic neurons exposed to low nanomolar concentrations of AβOs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, lactate dehydrogenase release, and [(3)H]choline uptake assays showed no evidence of neuronal damage or loss of viability that could account for reduced ChAT activity under these conditions. Glutamate receptor antagonists fully blocked ChAT inhibition and oxidative stress induced by AβOs. Antioxidant polyunsaturated fatty acids had similar effects, indicating that oxidative damage may be involved in ChAT inhibition. Treatment with insulin, previously shown to down-regulate neuronal AβO binding sites, fully prevented AβO-induced inhibition of ChAT. Interestingly, we found that AβOs selectively bind to ~50% of cultured cholinergic neurons, suggesting that ChAT is fully inhibited in AβO-targeted neurons. Reduction in ChAT activity instigated by AβOs may thus be a relevant event in early stage AD pathology, preceding the loss of cholinergic neurons commonly observed in AD brains.

Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties

PubMed Central

Hornick, Ariane; Schwaiger, Stefan; Rollinger, Judith M.; Vo, Nguyen Phung; Prast, Helmut; Stuppner, Hermann

2012-01-01

Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits. PMID:18541221

In utero methanesulfonyl fluoride differentially affects learning and maze performance in the absence of long-lasting cholinergic changes in the adult rat.

PubMed

Carcoba, Luis M; Santiago, Miguel; Moss, Donald E; Cabeza, Rafael

2008-02-01

There is increasing evidence that acetylcholinesterase (AChE) may have various specific developmental roles in brain development. Nevertheless, specific effects of AChE inhibition during early brain development have not been adequately described. Therefore, methanesulfonyl fluoride (MSF), an irreversible AChE inhibitor that shows high selectivity for the CNS was used to produce AChE inhibition in utero to study subsequent adult behaviors, sleep, and cholinergic markers. Rats exposed to MSF in utero showed a deficit in spatial learning tasks using appetitive motivation but, surprisingly, they performed equally well or better than controls when aversive motivation was used. One hypothesis was that MSF treatment in utero affected the response to stress. Tests of anxiety however showed no differences in basal levels of anxiety. Studies of sleep behavior, however, indicated a higher level of REM sleep which is only seen during the light phase of male rats exposed to MSF in utero as compared to controls. No differences in cholinergic markers in the brains of adults were found except that females exposed to MSF in utero had a higher level of ChAT activity in the synaptosomal fraction of the hippocampus. Even so, whether cholinergic alterations accompany the in utero MSF exposure remains to be determined. The failure to find widespread changes in cholinergic markers in the adult brains suggests changes in behaviors should be further investigated by testing the participation of postsynaptic mechanisms, measuring of cholinergic markers during earlier development periods and the possible participation of other neurotransmitter systems to clearly reveal the role of the cholinergic system following in utero MSF exposure.

In utero methanesulfonyl fluoride differentially affects learning and maze performance in the absence of long-lasting cholinergic changes in the adult rat

PubMed Central

Carcoba, Luis M .; Santiago, Miguel; Moss, Donald E.; Cabeza, Rafael

2008-01-01

There is increasing evidence that acetylcholinesterase (AChE) may have various specific developmental roles in brain development. Nevertheless, specific effects of AChE inhibition during early brain development have not been adequately described. Therefore, methanesulfonyl fluoride (MSF), an irreversible AChE inhibitor that shows high selectivity for the CNS was used to produce AChE inhibition in utero to study subsequent adult behaviors, sleep, and cholinergic markers. Rats exposed to MSF in utero showed a deficit in spatial learning tasks using appetitive motivation but, surprisingly, they performed equally well or better than controls when aversive motivation was used. One hypothesis was that MSF treatment in utero affected the response to stress. Tests of anxiety however showed no differences in basal levels of anxiety. Studies of sleep behavior, however, indicated a higher level of REM sleep which is only seen during the light phase of male rats exposed to MSF in utero as compared to controls. No differences in cholinergic markers in the brains of adults were found except that females exposed to MSF in utero had a higher level of ChAT activity in the synaptosomal fraction of the hippocampus. Even so, whether cholinergic alterations accompany the in utero MSF exposure remains to be determined. The failure to find widespread changes in cholinergic markers in the adult brains suggests changes in behaviors should be further investigated by testing the participation of postsynaptic mechanisms, measuring of cholinergic markers during earlier development periods and the possible participation of other neurotransmitter systems to clearly reveal the role of the cholinergic system following in utero MSF exposure. PMID:17920111

Prefrontal gray matter morphology mediates the association between serum anticholinergicity and cognitive functioning in early course schizophrenia.

PubMed

Wojtalik, Jessica A; Eack, Shaun M; Pollock, Bruce G; Keshavan, Matcheri S

2012-11-30

Antipsychotic and other medications used in the treatment of schizophrenia place a burden on the cholinergic subsystems of the brain, which have been associated with increased cognitive impairment in the disorder. This study sought to examine the neurobiologic correlates of the association between serum anticholinergic activity (SAA) and cognitive impairments in early schizophrenia. Neurocognitive performance on measures of memory and executive function, structural magnetic resonance imaging (MRI) scans, and SAA assays were collected from 47 early course, stabilized outpatients with schizophrenia or schizoaffective disorder. Voxel-based morphometry analyses employing general linear models, adjusting for demographic and illness-related confounds, were used to investigate the associations between SAA, gray matter morphology, and neurocognitive impairment. SAA was related to working memory and executive function impairments. Higher SAA was significantly associated with lower gray matter density in broad regions of the frontal and medial-temporal lobes, including the dorsolateral prefrontal cortex (DLPFC), hippocampus, and striatum. Lower gray matter volume in the left DLPFC was found to significantly mediate the association between SAA and working memory impairment. Disease- and/or medication-related cholinergic dysfunction may be associated with brain volume abnormalities in early course schizophrenia, which may account for the association between SAA and cognitive dysfunction in the disorder. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Neuroanatomical organization of the cholinergic system in the central nervous system of a basal actinopterygian fish, the senegal bichir Polypterus senegalus.

PubMed

López, Jesús M; Perlado, Jorge; Morona, Ruth; Northcutt, R Glenn; González, Agustín

2013-01-01

Polypterid bony fishes are believed to be basal to other living ray-finned fishes, and their brain organization is therefore critical in providing information as to primitive neural characters that existed in the earliest ray-finned fishes. The cholinergic system has been characterized in more advanced ray-finned fishes, but not in polypterids. In order to establish which cholinergic neural centers characterized the earliest ray-finned fishes, the distribution of choline acetyltransferase (ChAT) is described in Polypterus and compared with the distribution of this molecule in other ray-finned fishes. Cell groups immunoreactive for ChAT were observed in the hypothalamus, the habenula, the optic tectum, the isthmus, the cranial motor nuclei, and the spinal motor column. Cholinergic fibers were observed in both the telencephalic pallium and the subpallium, in the thalamus and pretectum, in the optic tectum and torus semicircularis, in the mesencephalic tegmentum, in the cerebellar crest, in the solitary nucleus, and in the dorsal column nuclei. Comparison of the data within a segmental neuromeric context indicates that the cholinergic system in polypterid fishes is generally similar to that in other ray-finned fishes, but cholinergic-positive neurons in the pallium and subpallium, and in the thalamus and cerebellum, of teleosts appear to have evolved following the separation of polypterids and other ray-finned fishes. Copyright © 2012 Wiley Periodicals, Inc.

Nicotinic and muscarinic cholinergic receptors are recruited by acetylcholine-mediated neurotransmission within the locus coeruleus during the organisation of post-ictal antinociception.

PubMed

de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Biagioni, Audrey Franceschi; Falconi-Sobrinho, Luiz Luciano; Dos Anjos-Garcia, Tayllon; Coimbra, Norberto Cysne

2016-10-01

Post-ictal antinociception is characterised by an increase in the nociceptive threshold that accompanies tonic and tonic-clonic seizures (TCS). The locus coeruleus (LC) receives profuse cholinergic inputs from the pedunculopontine tegmental nucleus. Different concentrations (1μg, 3μg and 5μg/0.2μL) of the muscarinic cholinergic receptor antagonist atropine and the nicotinic cholinergic receptor antagonist mecamylamine were microinjected into the LC of Wistar rats to investigate the role of cholinergic mechanisms in the severity of TCS and the post-ictal antinociceptive response. Five minutes later, TCS were induced by systemic administration of pentylenetetrazole (PTZ) (64mg/kg). Seizures were recorded inside the open field apparatus for an average of 10min. Immediately after seizures, the nociceptive threshold was recorded for 130min using the tail-flick test. Pre-treatment of the LC with 1μg, 3μg and 5μg/0.2μL concentrations of both atropine and mecamylamine did not cause a significant effect on seizure severity. However, the same treatments decreased the post-ictal antinociceptive phenomenon. In addition, mecamylamine caused an earlier decrease in the post-ictal antinociception compared to atropine. These results suggest that muscarinic and mainly nicotinic cholinergic receptors of the LC are recruited to organise tonic-clonic seizure-induced antinociception. Copyright © 2016 Elsevier Inc. All rights reserved.

Endogenous Cholinergic Neurotransmission Contributes to Behavioral Sensitization to Morphine

PubMed Central

Bajic, Dusica; Soiza-Reilly, Mariano; Spalding, Allegra L.; Berde, Charles B.; Commons, Kathryn G.

2015-01-01

Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg), a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter) in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg) dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg. PMID:25647082

Key role of striatal cholinergic interneurons in processes leading to arrest of motor stereotypies.

PubMed

Aliane, Verena; Pérez, Sylvie; Bohren, Yohann; Deniau, Jean-Michel; Kemel, Marie-Louise

2011-01-01

Motor stereotypy is a key symptom of various disorders such as Tourette's syndrome and punding. Administration of nicotine or cholinesterase inhibitors is effective in treating some of these symptoms. However, the role of cholinergic transmission in motor stereotypy remains unknown. During strong cocaine-induced motor stereotypy, we showed earlier that increased dopamine release results in decreased acetylcholine release in the territory of the dorsal striatum related to the prefrontal cortex. Here, we investigated the role of striatal cholinergic transmission in the arrest of motor stereotypy. Analysis of N-methyl-d-aspartic acid-evoked release of dopamine and acetylcholine during declining intensity of motor stereotypy revealed a dissociation between dopamine and acetylcholine release. Whereas dopamine release remained increased, the inhibition of acetylcholine release decreased, mirroring the time course of motor stereotypy. Furthermore, pharmacological treatments restoring striatal acetylcholine release (raclopride, dopamine D2 antagonist; intraperitoneal or local injection in prefrontal territory of the dorsal striatum) rapidly stopped motor stereotypy. In contrast, pharmacological treatments that blocked the post-synaptic effects of acetylcholine (scopolamine, muscarinic antagonist; intraperitoneal or striatal local injection) or induced degeneration of cholinergic interneurons (AF64A, cholinergic toxin) in the prefrontal territory of the dorsal striatum robustly prolonged the duration of strong motor stereotypy. Thus, we propose that restoration of cholinergic transmission in the prefrontal territory of the dorsal striatum plays a key role in the arrest of motor stereotypy.

A non-neuronal cholinergic system regulates cellular ATP levels to maintain cell viability.

PubMed

Oikawa, Shino; Iketani, Mitsue; Kakinuma, Yoshihiko

2014-01-01

We previously suggested that a non-neuronal cholinergic system modulates energy metabolism through the mitochondria. However, the mechanisms responsible for making this system crucial remained undetermined. In this study, we developed a fusion protein expression vector containing a luciferase gene fused to the folic acid receptor-α gene. This protein of the vector was confirmed to target the plasma membrane of transfected HEK293 cells, and vector-derived luciferase activities and ATP levels in viable cells were positively correlated (r = 0.599). Using this luciferase vector, choline acetyltransferase (ChAT)-expressing cells (i.e., cells with an activated non-neuronal cholinergic system) had increased cellular ATP levels. ChAT-expressing cells also had upregulated IGF-1R and Glut-1 protein expressions as well as increased glucose uptake. This activated non-neuronal cholinergic system with efficient glucose metabolism rendered cells resistant to serum depletion-induced cell death. Our results indicate that a non-neuronal cholinergic system is involved in sustaining ATP levels to render cells resistant to a nutrient-deficient environment. © 2014 S. Karger AG, Basel.

Involvement of the basolateral amygdala in muscarinic cholinergic modulation of extinction memory consolidation

PubMed Central

Boccia, Mariano M.; Blake, Mariano G.; Baratti, Carlos M.; McGaugh, James L.

2009-01-01

Previous studies have reported that drugs affecting neuromodulatory systems within the basolateral amygdala (BLA), including drugs affecting muscarinic cholinergic receptors, modulate the consolidation of many kinds of training, including contextual fear conditioning (CFC). The present experiments investigated the involvement of muscarinic cholinergic influences within the BLA in modulating the consolidation of CFC extinction memory. Male Sprague Dawley rats implanted with unilateral cannula aimed at the BLA were trained on a CFC task, using footshock stimulation, and 24 and 48 h later were given extinction training by replacing them in the apparatus without footshock. Following each extinction session they received intra-BLA infusions of the cholinergic agonist oxotremorine (10 ng). Immediate post-extinction BLA infusions significantly enhanced extinction but infusions administered 180 min after extinction training did not influence extinction. Thus the oxotremorine effects were time-dependent and not attributable to non-specific effects on retention performance. These findings provide evidence that, as previously found with original CFC learning, cholinergic activation within the BLA modulates the consolidation of CFC extinction. PMID:18706510

Hippocampal acetylcholine depletion has no effect on anxiety, spatial novelty preference, or differential reward for low rates of responding (DRL) performance in rats.

PubMed

McHugh, Stephen B; Francis, Anna; McAuley, J Devin; Stewart, Amanda L; Baxter, Mark G; Bannerman, David M

2015-08-01

We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50-97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL. (c) 2015 APA, all rights reserved).

Hippocampal Acetylcholine Depletion Has No Effect on Anxiety, Spatial Novelty Preference, or Differential Reward for Low Rates of Responding (DRL) Performance in Rats

PubMed Central

2015-01-01

We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50–97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL. PMID:26214215

Prenatal choline deficiency decreases the cross-sectional area of cholinergic neurons in the medial septal nucleus.

PubMed

McKeon-O'Malley, Catherine; Siwek, Donald; Lamoureux, Jeffrey A; Williams, Christina L; Kowall, Neil W

2003-07-11

Levels of dietary choline in utero influence postnatal cognitive performance. To better understand this phenomenon, forebrain cholinergic neurons were studied in the 8-9 month old offspring of dams fed a control or choline-deficient diet from EDs 11-17. Serial sections were immunostained with antibodies against p75, a cholinergic marker. Neuronal morphology was analyzed in the basal forebrain, a heterogeneous area composed of several structures including the medial septal nucleus (MSN), nucleus of the diagonal band (DB), and the nucleus basalis of Meynert (NB). Neuronal cross-sectional areas were selectively reduced in the MSN of choline-deficient animals, compared to controls, but cell counts were not altered. Our findings suggest that cholinergic medial septal neurons may be selectively vulnerable to in utero choline deficiency.

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

PubMed

Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

2017-11-17

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats

PubMed Central

Fortress, Ashley M.; Buhusi, Mona; Helke, Kris L.; Granholm, Ann-Charlotte E.

2011-01-01

Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors. PMID:21785728

Involvement of Cholinergic Dysfunction and Oxidative Damage in the Effects of Simulated Weightlessness on Learning and Memory in Rats

PubMed Central

Wang, Qiong; Lv, Ke; Wang, Tingmei; Wang, Yanli; Ji, Guohua; Cao, Hongqing; Kan, Guanghan

2018-01-01

The present study aimed to determine how the learning and memory gradually change with the prolonged hindlimb unloading (HU) treatment in rats. Different HU durations (7 d, 14 d, 21 d, and 28 d) in Sprague-Dawley (SD) rats were implemented. Cognitive function was assessed using the Morris water maze (MWM) and the shuttle box test. Additionally, parameters about cholinergic activity and oxidative stress were tested. Results showed that longer-than-14 d HU led to the inferior performances in the behavioral tasks. Besides, acetylcholine esterase (AChE) activity, malondialdehyde (MDA) level in brain, reactive oxygen species (ROS), and 8-hydroxy-2-deoxyguanosine (8-OHdG) concentrations of HU rats were significantly increased. Furthermore, choline acetyltransferase (ChAT), superoxide dismutase (SOD), and catalase (CAT) activity in brain were notably attenuated. Most of these effects were more pronounced after longer exposure (21 d and 28 d) to HU, although some indicators had their own characteristics of change. These results indicate that cholinergic dysfunction and oxidative damage were involved in the learning and memory impairments induced by longer-than-14 d HU. Moreover, the negative effects of HU tend to be augmented as the HU duration becomes longer. The results may be helpful to present possible biochemical targets for countermeasures development regarding the memory deficits under extreme environmental conditions. PMID:29581965

High affinity choline uptake (HACU) and choline acetyltransferase (ChAT) activity in neuronal cultures for mechanistic and drug discovery studies

PubMed Central

Ray, Balmiki; Bailey, Jason A.; Simon, Jay R.; Lahiri, Debomoy K.

2012-01-01

Acetylcholine (ACh) is the neurotransmitter used by cholinergic neurons at the neuromuscular junction and in parasympathetic nerve terminals in the periphery, as well as important memory-related circuits in the brain and also takes part in several critical functions. ACh is synthesized from choline and acetyl coenzyme-A by the enzyme choline acetyltransferase (ChAT). The formation of acetylcholine in cholinergic nerve terminals requires both the transport of choline into the cells from the extracellular space, and the activity of ChAT. High affinity choline uptake (HACU) represents the majority of choline uptake into the nerve terminal, and is the acutely regulated, rate-limiting step in ACh synthesis. The HACU component of choline uptake can be differentiated from non-specific choline uptake by inhibition of the choline transporter with hemicholinium. Several methods have been described previously to measure HACU and ChAT simultaneously in synaptosomes, but a well-documented protocol for cultured cells is lacking. We describe a procedure to simultaneously measure HACU and ChAT in cultured cells by simple radionuclide-based techniques. In this procedure we have quantitatively determined HACU and ChAT activity in cholinergically differentiated human neuroblastoma (SK-N-SH) cells. These simple methods can be used for neurochemical and drug discovery studies relevant to several disorders including Alzheimer’s disease, myasthenia gravis, and cardiovascular disease. PMID:22752895

A positive relationship between harm avoidance and brain nicotinic acetylcholine receptor availability.

PubMed

Storage, Steven; Mandelkern, Mark A; Phuong, Jonathan; Kozman, Maggie; Neary, Meaghan K; Brody, Arthur L

2013-12-30

Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm-avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high α4β2* nicotinic acetylcholine receptor (nAChR) availability. Healthy adults (n=105; 47 non-smokers and 58 smokers) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI. The central study analysis revealed a significant association between total HA and mean nAChR availability, with higher total HA scores being linked with greater nAChR availability. In examining HA subscales, both 'Fear of Uncertainty' and 'Fatigability' were significant, based on higher levels of these characteristics being associated with greater nAChR availabilities. This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics to HA. Study findings may indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits. Published by Elsevier Ireland Ltd.

A positive relationship between harm avoidance and brain nicotinic acetylcholine receptor availability

PubMed Central

Storage, Steven; Mandelkern, Mark A.; Phuong, Jonathan; Kozman, Maggie; Neary, Meaghan K.; Brody, Arthur L.

2013-01-01

Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm-avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high α4β2* nicotinic acetylcholine receptor (nAChR) availability. Healthy adults (n = 105; 47 non-smokers and 58 smokers) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI. The central study analysis revealed a significant association between total HA and mean nAChR availability, with higher total HA scores being linked with greater nAChR availability. In examining HA subscales, both ‘Fear of Uncertainty’ and ‘Fatigability’ were significant, based on higher levels of these characteristics being associated with greater nAChR availabilities. This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics to HA. Study findings may indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits. PMID:24148908

Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system.

PubMed

Marks, G A; Sachs, O W; Birabil, C G

2008-09-22

The brainstem reticular formation is an area important to the control of rapid eye movement (REM) sleep. The antagonist of GABA-type A (GABA(A)) receptors, bicuculline methiodide (BMI), injected into the rat nucleus pontis oralis (PnO) of the reticular formation resulted in a long-lasting increase in REM sleep. Thus, one factor controlling REM sleep appears to be the number of functional GABA(A) receptors in the PnO. The long-lasting effect produced by BMI may result from secondary influences on other neurotransmitter systems known to have long-lasting effects. To study this question, rats were surgically prepared for chronic sleep recording and additionally implanted with guide cannulas aimed at sites in the PnO. Multiple, 60 nl, unilateral injections were made either singly or in combination. GABA(A) receptor antagonists, BMI and gabazine (GBZ), produced dose-dependent increases in REM sleep with GBZ being approximately 35 times more potent than BMI. GBZ and the cholinergic agonist, carbachol, produced very similar results, both increasing REM sleep for about 8 h, mainly through increased period frequency, with little reduction in REM latency. Pre-injection of the muscarinic antagonist, atropine, completely blocked the REM sleep-increase by GBZ. GABAergic control of REM sleep in the PnO requires the cholinergic system and may be acting through presynaptic modulation of acetylcholine release.

Cholinergic Mechanisms, Early Brain Development, and Risk for Schizophrenia

PubMed Central

Ross, Randal G; Stevens, Karen E; Proctor, William R; Leonard, Sherry; Kisley, Michael A; Hunter, Sharon K; Freedman, Robert; Adams, Catherine E

2009-01-01

Neuropsychiatric diseases are complex illnesses where the onset of diagnostic symptomology is often the end result of a decades-long process of aberrant brain development. The identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal; however, there are few models for how this goal might be achieved. This report uses the attentional deficits of schizophrenia as an example and reviews data from genetic, anatomical, physiological, and pharmacologic studies to hypothesize a developmental model with translational primary prevention implications. Specifically, the model suggests that an early interaction between α7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Translational implications, including perinatal dietary choline supplementation, are discussed. It is hoped that presentation of this model will stimulate other efforts to develop empirically-driven primary prevention strategies. PMID:19925602

Subcellular Distribution of M2-muscarinic Receptors in Relation to Dopaminergic Neurons of the Rat Ventral Tegmental Area

PubMed Central

Garzón, Miguel; Pickel, Virginia M.

2008-01-01

Acetylcholine can affect cognitive functions and reward, in part, through activation of muscarinic receptors in the ventral tegmental area (VTA) to evoke changes in mesocorticolimbic dopaminergic transmission. Of the known muscarinic receptor subtypes present in the VTA, the M2 receptor (M2R) is most implicated in autoregulation, and also may play a heteroreceptor role in regulation of the output of the dopaminergic neurons. We sought to determine the functionally relevant sites for M2R activation in relation to VTA dopaminergic neurons by examining the electron microscopic immunolabeling of M2R and the dopamine transporter (DAT) in the VTA of rat brain. The M2R was localized to endomembranes in DAT-containing somatodendritic profiles, but showed a more prominent, size-dependent plasmalemmal location in non-dopaminergic dendrites. M2R also was located on the plasma membrane of morphologically heterogenous axon terminals contacting unlabeled as well as M2R or DAT-labeled dendrites. Some of these terminals formed asymmetric synapses resembling those of cholinergic terminals in the VTA. The majority, however, formed symmetric, inhibitory-type synapses, or were apposed without recognized junctions. Our results provide the first ultrastructural evidence that the M2R is expressed, but largely not available for local activation, on the plasma membrane of VTA dopaminergic neurons. Instead, the M2R in this region has a distribution suggesting more indirect regulation of mesocorticolimbic transmission through autoregulation of acetylcholine release and changes in the physiological activity or release of other, largely inhibitory transmitters. These findings could have implications for understanding the muscarinic control of cognitive and goal-directed behaviors within the VTA. PMID:16927256

Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: A review of human brain oscillations as effective endophenotypes

PubMed Central

Rangaswamy, Madhavi; Porjesz, Bernice

2010-01-01

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders. PMID:18634760

Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes.

PubMed

Rangaswamy, Madhavi; Porjesz, Bernice

2008-10-15

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders.

The Role of Basal Forebrain in Rat Somatosensory Cortex: Impact on Cholinergic Innervation, Sensory Information Processing, and Tactile Discrimination

DTIC Science & Technology

1993-05-28

1993 Dissertation and Abstract Approved: Commit tee Chairperson . ,a..w ember ~tee Member tli:u., ;2 9" PQ3 bate Date bate The author...1982; Mesulam et al., 1983; Rye et al., 1984; Saper, 1984). I will refer to the region of the basal forebrain that supplies cholinergic innervation to...topographical organization has been observed for cholinergic projection patterns, with more rostral and medial basal forebrain cell groups supplying

Catecholamines alter the intrinsic variability of cortical population activity and perception

PubMed Central

Avramiea, Arthur-Ervin; Nolte, Guido; Engel, Andreas K.; Linkenkaer-Hansen, Klaus; Donner, Tobias H.

2018-01-01

The ascending modulatory systems of the brain stem are powerful regulators of global brain state. Disturbances of these systems are implicated in several major neuropsychiatric disorders. Yet, how these systems interact with specific neural computations in the cerebral cortex to shape perception, cognition, and behavior remains poorly understood. Here, we probed into the effect of two such systems, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems, on an important aspect of cortical computation: its intrinsic variability. To this end, we combined placebo-controlled pharmacological intervention in humans, recordings of cortical population activity using magnetoencephalography (MEG), and psychophysical measurements of the perception of ambiguous visual input. A low-dose catecholaminergic, but not cholinergic, manipulation altered the rate of spontaneous perceptual fluctuations as well as the temporal structure of “scale-free” population activity of large swaths of the visual and parietal cortices. Computational analyses indicate that both effects were consistent with an increase in excitatory relative to inhibitory activity in the cortical areas underlying visual perceptual inference. We propose that catecholamines regulate the variability of perception and cognition through dynamically changing the cortical excitation–inhibition ratio. The combined readout of fluctuations in perception and cortical activity we established here may prove useful as an efficient and easily accessible marker of altered cortical computation in neuropsychiatric disorders. PMID:29420565

Schizophrenia and the alpha7 nicotinic acetylcholine receptor.

PubMed

Martin, Laura F; Freedman, Robert

2007-01-01

In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.

Hierarchical prediction errors in midbrain and septum during social learning.

PubMed

Diaconescu, Andreea O; Mathys, Christoph; Weber, Lilian A E; Kasper, Lars; Mauer, Jan; Stephan, Klaas E

2017-04-01

Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser's intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser's trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support 'theory of mind', but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs ('expected uncertainty') about the adviser's fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others. © The Author (2017). Published by Oxford University Press.

Hierarchical prediction errors in midbrain and septum during social learning

PubMed Central

Mathys, Christoph; Weber, Lilian A. E.; Kasper, Lars; Mauer, Jan; Stephan, Klaas E.

2017-01-01

Abstract Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser’s intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser’s trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support ‘theory of mind’, but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs (‘expected uncertainty’) about the adviser’s fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others. PMID:28119508

The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory.

PubMed

Giovannini, Maria Grazia; Lana, Daniele; Pepeu, Giancarlo

2015-03-01

The purpose of this review is to summarize the present knowledge on the interplay among the cholinergic system, Extracellular signal-Regulated Kinase (ERK) and Mammalian Target of Rapamycin (mTOR) pathways in the development of short and long term memories during the acquisition and recall of the step-down inhibitory avoidance in the hippocampus. The step-down inhibitory avoidance is a form of associative learning that is acquired in a relatively simple one-trial test through several sensorial inputs. Inhibitory avoidance depends on the integrated activity of hippocampal CA1 and other brain areas. Recall can be performed at different times after acquisition, thus allowing for the study of both short and long term memory. Among the many neurotransmitter systems involved, the cholinergic neurons that originate in the basal forebrain and project to the hippocampus are of crucial importance in inhibitory avoidance processes. Acetylcholine released from cholinergic fibers during acquisition and/or recall of behavioural tasks activates muscarinic and nicotinic acetylcholine receptors and brings about a long-lasting potentiation of the postsynaptic membrane followed by downstream activation of intracellular pathway (ERK, among others) that create conditions favourable for neuronal plasticity. ERK appears to be salient not only in long term memory, but also in the molecular mechanisms underlying short term memory formation in the hippocampus. Since ERK can function as a biochemical coincidence detector in response to extracellular signals in neurons, the activation of ERK-dependent downstream effectors is determined, in part, by the duration of ERK phosphorylation itself. Long term memories require protein synthesis, that in the synapto-dendritic compartment represents a direct mechanism that can produce rapid changes in protein content in response to synaptic activity. mTOR in the brain regulates protein translation in response to neuronal activity, thereby modulating synaptic plasticity and long term memory formation. Some studies demonstrate a complex interplay among the cholinergic system, ERK and mTOR. It has been shown that co-activation of muscarinic acetylcholine receptors and β-adrenergic receptors facilitates the conversion of short term to long term synaptic plasticity through an ERK- and mTOR-dependent mechanism which requires translation initiation. It seems therefore that the complex interplay among the cholinergic system, ERK and mTOR is crucial in the development of new inhibitory avoidance memories in the hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

The vanadium (IV) compound rescues septo-hippocampal cholinergic neurons from neurodegeneration in olfactory bulbectomized mice.

PubMed

Han, F; Shioda, N; Moriguchi, S; Qin, Z-H; Fukunaga, K

2008-02-06

The bilateral olfactory bulbectomy (OBX) mouse exhibits neurodegeneration of cholinergic neurons in the medial septum with concomitant cognitive deficits. Consistent with our previous observations, choline acetyltransferase (ChAT) protein levels in the medial septum decreased by 43.5% 2 weeks after OBX without changes in glutamic acid decarboxylase-65 (GAD65) levels. Interestingly, levels of the vesicular acetylcholine transporter (VAChT), which is localized at cholinergic neuron terminals, decreased both in hippocampal CA1 and CA3 regions following OBX. Confocal microscopy showed that VAChT expression was more severely reduced in CA3 14 days after OBX compared with CA1. Intriguingly, chronic treatment with a vanadium (IV) compound, VO(OPT) [bis(1-N-oxide-pyridine-2-thiolato)oxovanadium(IV)] (0.5-1 mg as vanadium (V)/kg/day, i.p.), significantly rescued cholinergic neurons in the medial septum in a dose-dependent manner. VO(OPT) treatment also prevented decreased VAChT immunoreactivity both in CA1 and CA3 regions in the hippocampus. Consistent with these findings, an impaired hippocampal long-term potentiation (LTP) and memory deficits seen in OBX mice were significantly prevented by VO(OPT) treatment. Taken together, OBX induces neurodegeneration of septo-hippocampal cholinergic neurons and impairment of memory-related behaviors. The neuroprotective effect of VO(OPT) could lead to novel therapeutic strategies to ameliorate cognitive deficits associated with cholinergic neuron degeneration in Alzheimer's disease and other neurodegenerative disorders.

GABAergic terminals are a source of galanin to modulate cholinergic neuron development in the neonatal forebrain.

PubMed

Keimpema, Erik; Zheng, Kang; Barde, Swapnali Shantaram; Berghuis, Paul; Dobszay, Márton B; Schnell, Robert; Mulder, Jan; Luiten, Paul G M; Xu, Zhiqing David; Runesson, Johan; Langel, Ülo; Lu, Bai; Hökfelt, Tomas; Harkany, Tibor

2014-12-01

The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Mechanism of action of ionizing radiation on hexokinase and cholinesterase activity in the rat brain, in the presence of altered function of M-cholinergic structures. [X radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khripchenko, I.P.; Kukulyanskaya, M.F.; Markina, V.L.

1977-01-01

Data are submitted on activity of hexokinase and isozymes thereof, and cholinesterase in subcellular fractions of the brain in the case of inhibition and stimulation of M-cholinoreactive structures under the influence of a relatively small dose, 40 R, of ionizing radiation.

Cost-benefit decision circuitry: proposed modulatory role for acetylcholine.

PubMed

Fobbs, Wambura C; Mizumori, Sheri J Y

2014-01-01

In order to select which action should be taken, an animal must weigh the costs and benefits of possible outcomes associate with each action. Such decisions, called cost-benefit decisions, likely involve several cognitive processes (including memory) and a vast neural circuitry. Rodent models have allowed research to begin to probe the neural basis of three forms of cost-benefit decision making: effort-, delay-, and risk-based decision making. In this review, we detail the current understanding of the functional circuits that subserve each form of decision making. We highlight the extensive literature by detailing the ability of dopamine to influence decisions by modulating structures within these circuits. Since acetylcholine projects to all of the same important structures, we propose several ways in which the cholinergic system may play a local modulatory role that will allow it to shape these behaviors. A greater understanding of the contribution of the cholinergic system to cost-benefit decisions will permit us to better link the decision and memory processes, and this will help us to better understand and/or treat individuals with deficits in a number of higher cognitive functions including decision making, learning, memory, and language. © 2014 Elsevier Inc. All rights reserved.

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome

PubMed Central

Powers, Brian E.; Velazquez, Ramon; Kelley, Christy M.; Ash, Jessica A.; Strawderman, Myla S.; Alldred, Melissa J.; Ginsberg, Stephen D.; Mufson, Elliott J.

2016-01-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs. PMID:26719290

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome.

PubMed

Powers, Brian E; Velazquez, Ramon; Kelley, Christy M; Ash, Jessica A; Strawderman, Myla S; Alldred, Melissa J; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2016-12-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.

The cell adhesion molecule L1 regulates the expression of choline acetyltransferase and the development of septal cholinergic neurons

PubMed Central

Cui, Xuezhi; Weng, Ying-Qi; Frappé, Isabelle; Burgess, Alison; Girão da Cruz, M Teresa; Schachner, Melitta; Aubert, Isabelle

2011-01-01

Mutations in the L1 gene cause severe brain malformations and mental retardation. We investigated the potential roles of L1 in the regulation of choline acetyltransferase (ChAT) and in the development of septal cholinergic neurons, which are known to project to the hippocampus and play key roles in cognitive functions. Using stereological approaches, we detected significantly fewer ChAT-positive cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB) of 2-week-old L1-deficient mice compared to wild-type littermates (1644 ± 137 vs. 2051 ± 165, P = 0.038). ChAT protein levels in the septum were 53% lower in 2-week-old L1-deficient mice compared to wild-type littermates. ChAT activity in the septum was significantly reduced in L1-deficient mice compared to wild-type littermates at 1 (34%) and 2 (40%) weeks of age. In vitro, increasing doses of L1-Fc induced ChAT activity in septal neurons with a significant linear trend (*P = 0.0065). At 4 weeks of age in the septum and at all time points investigated in the caudate-putamen (CPu), the number of ChAT-positive neurons and the levels of ChAT activity were not statistically different between L1-deficient mice and wild-type littermates. The total number of cells positive for the neuronal nuclear antigen (NeuN) in the MS/VDB and CPu was not statistically different in L1-deficient mice compared to wild-type littermates, and comparable expression of the cell cycle marker Ki67 was observed. Our results indicate that L1 is required for the timely maturation of septal cholinergic neurons and that L1 promotes the expression and activity of ChAT in septal neurons. PMID:22399087

Cannabinoid 1 (CB1) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon

PubMed Central

Hinds, Nicholas M; Ullrich, Katja; Smid, Scott D

2006-01-01

The effects of cannabinoid subtype 1 (CB1) receptor activation were determined on smooth muscle, inhibitory and excitatory motorneuronal function in strips of human colonic longitudinal muscle (LM) and circular muscle (CM) in vitro. Electrical field stimulation (EFS; 0.5–20 Hz, 50 V) evoked a relaxation in LM and CM precontracted with a neurokinin-2 (NK-2) selective receptor agonist (β-ala8-neurokinin A; 10−6 M) in the presence of atropine (10−6 M); this was unaltered following pretreatment with the CB1-receptor selective agonist arachidonyl-2-chloroethylamide (ACEA; 10−6 M). In the presence of nitric oxide synthase blockade with N-nitro-L-arginine (10−4 M), EFS evoked a frequency-dependent ‘on-contraction' during stimulation and an ‘off-contraction' following stimulus cessation. On-contractions were significantly inhibited in CM strips by pretreatment with ACEA (10−6 M). These inhibitory effects were reversed in the presence of the CB1 receptor-selective antagonist N-(piperidine-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (10−7 M). ACEA did not alter LM or CM contractile responses to acetylcholine or NK-2 receptor-evoked contraction. Immunohistochemical studies revealed a colocalisation of CB1 receptors to cholinergic neurones in the human colon based on colabelling with choline acetyltransferase, in addition to CB1 receptor labelling in unidentified structures in the CM. In conclusion, activation of CB1 receptors coupled to cholinergic motorneurones selectively and reversibly inhibits excitatory nerve transmission in colonic human colonic CM. These results provide evidence of a direct role for cannabinoids in the modulation of motor activity in the human colon by coupling to cholinergic motorneurones. PMID:16520743

Cholinergic modulation of visual and attentional brain responses in Alzheimer's disease and in health

PubMed Central

Bentley, P.; Driver, J.; Dolan, R.J.

2008-01-01

Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visual attentional processing would be impaired relative to controls, yet partially susceptible to improvement with cholinesterase inhibition. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of the effects of physostigmine on stimulus- and attention-related brain activations, and to allow between-group comparisons for these. Subjects viewed stimuli comprising faces or buildings while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed poorer than controls in both tasks, while physostigmine benefited AD patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in AD relative to controls but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed enhanced stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. Our results demonstrate cholinergic-mediated improvements for both stimulus- and attention-dependent responses in functionally affected extrastriate and frontoparietal regions for AD. We also show that normal stimulus- and task-dependent activity patterns can be perturbed in the healthy brain by cholinergic stimulation. PMID:18077465

Endochondral Ossification Is Accelerated in Cholinesterase-Deficient Mice and in Avian Mesenchymal Micromass Cultures

PubMed Central

Spieker, Janine; Mudersbach, Thomas; Vogel-Höpker, Astrid; Layer, Paul G.

2017-01-01

Most components of the cholinergic system are detected in skeletogenic cell types in vitro, yet the function of this system in skeletogenesis remains unclear. Here, we analyzed endochondral ossification in mutant murine fetuses, in which genes of the rate-limiting cholinergic enzymes acetyl- (AChE), or butyrylcholinesterase (BChE), or both were deleted (called here A-B+, A+B-, A-B-, respectively). In all mutant embryos bone growth and cartilage remodeling into mineralizing bone were accelerated, as revealed by Alcian blue (A-blu) and Alizarin red (A-red) staining. In A+B- and A-B- onset of mineralization was observed before E13.5, about 2 days earlier than in wild type and A-B+ mice. In all mutants between E18.5 to birth A-blu staining disappeared from epiphyses prematurely. Instead, A-blu+ cells were dislocated into diaphyses, most pronounced so in A-B- mutants, indicating additive effects of both missing ChEs in A-B- mutant mice. The remodeling effects were supported by in situ hybridization (ISH) experiments performed on cryosections from A-B- mice, in which Ihh, Runx2, MMP-13, ALP, Col-II and Col-X were considerably decreased, or had disappeared between E18.5 and P0. With a second approach, we applied an improved in vitro micromass model from chicken limb buds that allowed histological distinction between areas of cartilage, apoptosis and mineralization. When treated with the AChE inhibitor BW284c51, or with nicotine, there was decrease in cartilage and accelerated mineralization, suggesting that these effects were mediated through nicotinic receptors (α7-nAChR). We conclude that due to absence of either one or both cholinesterases in KO mice, or inhibition of AChE in chicken micromass cultures, there is increase in cholinergic signalling, which leads to increased chondroblast production and premature mineralization, at the expense of incomplete chondrogenic differentiation. This emphasizes the importance of cholinergic signalling in cartilage and bone formation. PMID:28118357

Nicotine increases impulsivity and decreases willingness to exert cognitive effort despite improving attention in "slacker" rats: insights into cholinergic regulation of cost/benefit decision making.

PubMed

Hosking, Jay G; Lam, Fred C W; Winstanley, Catharine A

2014-01-01

Successful decision making in our daily lives requires weighing an option's costs against its associated benefits. The neuromodulator acetylcholine underlies both the etiology and treatment of a number of illnesses in which decision making is perturbed, including Alzheimer's disease, attention-deficit/hyperactivity disorder, and schizophrenia. Nicotine acts on the cholinergic system and has been touted as a cognitive enhancer by both smokers and some researchers for its attention-boosting effects; however, it is unclear whether treatments that have a beneficial effect on attention would also have a beneficial effect on decision making. Here we utilize the rodent Cognitive Effort Task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, to examine cholinergic contributions to both attentional performance and choice based on attentional demand. Following the establishment of baseline behavior, four drug challenges were administered: nicotine, mecamylamine, scopolamine, and oxotremorine (saline plus three doses for each). As per previous rCET studies, animals were divided by their baseline preferences, with "worker" rats choosing high-effort/high-reward options more than their "slacker" counterparts. Nicotine caused slackers to choose even fewer high-effort trials than at baseline, but had no effect on workers' choice. Despite slackers' decreased willingness to expend effort, nicotine improved their attentional performance on the task. Nicotine also increased measures of motor impulsivity in all animals. In contrast, scopolamine decreased animals' choice of high-effort trials, especially for workers, while oxotremorine decreased motor impulsivity for all animals. In sum, the cholinergic system appears to contribute to decision making, and in part these contributions can be understood as a function of individual differences. While nicotine has been considered as a cognitive enhancer, these data suggest that its modest benefits to attention may be coupled with impulsiveness and decreased willingness to work hard, especially in individuals who are particularly sensitive to effort costs (i.e. slackers).

Nicotine Increases Impulsivity and Decreases Willingness to Exert Cognitive Effort despite Improving Attention in “Slacker” Rats: Insights into Cholinergic Regulation of Cost/Benefit Decision Making

PubMed Central

Hosking, Jay G.; Lam, Fred C. W.; Winstanley, Catharine A.

2014-01-01

Successful decision making in our daily lives requires weighing an option’s costs against its associated benefits. The neuromodulator acetylcholine underlies both the etiology and treatment of a number of illnesses in which decision making is perturbed, including Alzheimer’s disease, attention-deficit/hyperactivity disorder, and schizophrenia. Nicotine acts on the cholinergic system and has been touted as a cognitive enhancer by both smokers and some researchers for its attention-boosting effects; however, it is unclear whether treatments that have a beneficial effect on attention would also have a beneficial effect on decision making. Here we utilize the rodent Cognitive Effort Task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, to examine cholinergic contributions to both attentional performance and choice based on attentional demand. Following the establishment of baseline behavior, four drug challenges were administered: nicotine, mecamylamine, scopolamine, and oxotremorine (saline plus three doses for each). As per previous rCET studies, animals were divided by their baseline preferences, with “worker” rats choosing high-effort/high-reward options more than their “slacker” counterparts. Nicotine caused slackers to choose even fewer high-effort trials than at baseline, but had no effect on workers’ choice. Despite slackers’ decreased willingness to expend effort, nicotine improved their attentional performance on the task. Nicotine also increased measures of motor impulsivity in all animals. In contrast, scopolamine decreased animals’ choice of high-effort trials, especially for workers, while oxotremorine decreased motor impulsivity for all animals. In sum, the cholinergic system appears to contribute to decision making, and in part these contributions can be understood as a function of individual differences. While nicotine has been considered as a cognitive enhancer, these data suggest that its modest benefits to attention may be coupled with impulsiveness and decreased willingness to work hard, especially in individuals who are particularly sensitive to effort costs (i.e. slackers). PMID:25353339