Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

PubMed

Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

2017-06-01

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Effects of Aged Garlic Extract on Cholinergic, Glutamatergic and GABAergic Systems with Regard to Cognitive Impairment in Aβ-Induced Rats

PubMed Central

Thorajak, Piyaporn; Pannangrong, Wanassanun; Umka Welbat, Jariya; Chaijaroonkhanarak, Wunnee; Sripanidkulchai, Kittisak; Sripanidkulchai, Bungorn

2017-01-01

Alzheimer’s disease (AD) has been linked to the degeneration of central cholinergic and glutamatergic transmission, which correlates with progressive memory loss and the accumulation of amyloid-β (Aβ). It has been claimed that aged garlic extract (AGE) has a beneficial effect in preventing neurodegeneration in AD. Therefore, the objective of this study was to investigate the effects of AGE on Aβ-induced cognitive dysfunction with a biochemical basis in the cholinergic, glutamatergic, and GABAergic systems in rats. Adult male Wistar rats were orally administered three doses of AGE (125, 250, and 500 mg/kg) daily for 65 days. At day 56, they were injected with 1 μL of aggregated Aβ (1–42) into each lateral ventricle, bilaterally. After six days of Aβ injection, the rats’ working and reference memory was tested using a radial arm maze. The rats were then euthanized to investigate any changes to the cholinergic neurons, vesicular glutamate transporter 1 and 2 proteins (VGLUT1 and VGLUT2), and glutamate decarboxylase (GAD) in the hippocampus. The results showed that AGE significantly improved the working memory and tended to improve the reference memory in cognitively-impaired rats. In addition, AGE significantly ameliorated the loss of cholinergic neurons and increased the VGLUT1 and GAD levels in the hippocampus of rat brains with Aβ-induced toxicity. In contrast, the VGLUT2 protein levels did not change in any of the treated groups. We concluded that AGE was able to attenuate the impairment of working memory via the modification of cholinergic neurons, VGLUT1, and GAD in the hippocampus of Aβ-induced rats. PMID:28671572

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

Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage.

PubMed

Mandel, R J; Gage, F H; Thal, L J

1989-06-01

Rats display an acquisition deficit in a circular water maze following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). Experiments were therefore performed to determine if acquisition behavior on this task could predict the degree of cortical cholinergic deafferentation and if the acquisition deficit could be pharmacologically reversed. Performance on acquisition was highly correlated with the lesion-induced reduction in cortical choline acetyltransferase (ChAT) activity. Accuracy of spatial behavior was highly correlated to percentage ChAT depletion (r = 0.75). Neither lesioned rats nor controls displayed a retention deficit after a 9-day interval, nor did either group display a passive-avoidance retention deficit. To test the causal relationship between cholinergic dysfunction and spatial behavior, the central nervous system cholinergic enhancer nerve growth factor (NGF) was intraventricularly infused for 4 weeks. NGF infusion resulted in improved acquisition of the water maze task compared to NBM-lesioned rats receiving vehicle infusion and untreated rats with NBM lesions. These studies indicate that the decrease in cortical ChAT activity is likely to be responsible for the observed acquisition deficit and that pharmacological manipulations can be successfully used to improve behavior following NBM lesions.

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.

Red Dermographism in Autism Spectrum Disorders: A Clinical Sign of Cholinergic Dysfunction?

ERIC Educational Resources Information Center

Lemonnier, E.; Grandgeorge, M.; Jacobzone-Leveque, C.; Bessaguet, C.; Peudenier, S.; Misery, L.

2013-01-01

The authors hypothesised that red dermographism--a skin reaction involving the cholinergic system--is more frequent in children with autism spectrum disorders (ASDs) than in children exhibiting typical development. We used a dermatological examination to study red dermographism in this transverse study, which compared forty six children with ASDs…

Acteoside and Isoacteoside Protect Amyloid β Peptide Induced Cytotoxicity, Cognitive Deficit and Neurochemical Disturbances In Vitro and In Vivo

PubMed Central

Shiao, Young-Ji; Su, Muh-Hwan; Lin, Hang-Ching; Wu, Chi-Rei

2017-01-01

Acteoside and isoacteoside, two phenylethanoid glycosides, coexist in some plants. This study investigates the memory-improving and cytoprotective effects of acteoside and isoacteoside in amyloid β peptide 1-42 (Aβ 1-42)-infused rats and Aβ 1-42-treated SH-SY5Y cells. It further elucidates the role of amyloid cascade and central neuronal function in these effects. Acteoside and isoacteoside ameliorated cognitive deficits, decreased amyloid deposition, and reversed central cholinergic dysfunction that were caused by Aβ 1-42 in rats. Acteoside and isoacteoside further decreased extracellular Aβ 1-40 production and restored the cell viability that was decreased by Aβ 1-42 in SH-SY5Y cells. Acteoside and isoacteoside also promoted Aβ 1-40 degradation and inhibited Aβ 1-42 oligomerization in vitro. However, the memory-improving and cytoprotective effects of isoacteoside exceeded those of acteoside. Isoacteoside promoted exploratory behavior and restored cortical and hippocampal dopamine levels, but acteoside did not. We suggest that acteoside and isoacteoside ameliorated the cognitive dysfunction that was caused by Aβ 1-42 by blocking amyloid deposition via preventing amyloid oligomerization, and reversing central neuronal function via counteracting amyloid cytotoxicity. PMID:28441758

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.

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.

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.

Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer's disease

PubMed Central

Kar, Satyabrata; Slowikowski, Stephen P.M.; Westaway, David; Mount, Howard T.J.

2004-01-01

Alzheimer's disease is an age-related neurodegenerative disorder that is characterized by a progressive loss of memory and deterioration of higher cognitive functions. The brain of an individual with Alzheimer's disease exhibits extracellular plaques of aggregated β-amyloid protein (Aβ), intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Aβ accumulation may trigger or contribute to the process of neurodegeneration. However, the mechanisms whereby Aβ induces basal forebrain cholinergic cell loss and cognitive impairment remain obscure. Physiologically relevant concentrations of Aβ-related peptides have acute, negative effects on multiple aspects of acetylcholine (ACh) synthesis and release, without inducing toxicity. These data suggest a neuromodulatory influence of the peptides on central cholinergic functions. Long-term exposure to micromolar Aβ induces cholinergic cell toxicity, possibly via hyperphosphorylation of tau protein. Conversely, activation of selected cholinergic receptors has been shown to alter the processing of the amyloid precursor protein as well as phosphorylation of tau protein. A direct interaction between Aβ and nicotinic ACh receptors has also been demonstrated. This review addresses the role of Aβ-related peptides in regulating the function and survival of central cholinergic neurons and the relevance of these effects to cholinergic deficits in Alzheimer's disease. Understanding the functional interrelations between Aβ peptides, cholinergic neurons and tau phosphorylation will unravel the biologic events that precede neurodegeneration and may lead to the development of more effective pharmacotherapies for Alzheimer's disease. PMID:15644984

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.

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

Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.

PubMed

Tozzi, Alessandro; de Iure, Antonio; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Di Filippo, Massimiliano; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Wegrzynowicz, Michal; Decressac, Mickael; Giampà, Carmela; Dalley, Jeffrey W; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; El-Agnaf, Omar Mukhtar; Ardah, Mustafa Taleb; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo

2016-03-01

Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves.

PubMed

Everaert, K; de Waard, W I Q; Van Hoof, T; Kiekens, C; Mulliez, T; D'herde, C

2010-03-01

Review article. The neuroanatomy and physiology of psychogenic erection, cholinergic versus adrenergic innervation of emission and the predictability of outcome of vibration and electroejaculation require a review and synthesis. University Hospital Belgium. We reviewed the literature with PubMed 1973-2008. Erection, emission and ejaculation are separate phenomena and have different innervations. It is important to realize, which are the afferents and efferents and where the motor neuron of the end organ is located. When interpreting a specific lesion it is important to understand if postsynaptic fibres are intact or not. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. For vibratory-evoked ejaculation, the reflex arch must be complete; for electroejaculation, the postsynaptic neurons (paravertebral ganglia) must be intact. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. In neurogenic disease, a good knowledge of neuroanatomy and physiology makes understanding of sexual dysfunction possible and predictable. The minimal requirement for the success of penile vibration is a preserved reflex arch and the minimal requirement for the success of electroejaculation is the existence of intact post-ganglionic fibres.

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

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

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.

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.

Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats.

PubMed

Yadav, Rajesh S; Chandravanshi, Lalit P; Shukla, Rajendra K; Sankhwar, Madhu L; Ansari, Reyaz W; Shukla, Pradeep K; Pant, Aditya B; Khanna, Vinay K

2011-12-01

Our recent studies have shown that curcumin protects arsenic induced neurotoxicity by modulating oxidative stress, neurotransmitter levels and dopaminergic system in rats. As chronic exposure to arsenic has been associated with cognitive deficits in humans, the present study has been carried out to implore the neuroprotective potential of curcumin in arsenic induced cholinergic dysfunctions in rats. Rats treated with arsenic (sodium arsenite, 20mg/kg body weight, p.o., 28 days) exhibited a significant decrease in the learning activity, assessed by passive avoidance response associated with decreased binding of (3)H-QNB, known to label muscarinic-cholinergic receptors in hippocampus (54%) and frontal cortex (27%) as compared to controls. Decrease in the activity of acetylcholinesterase in hippocampus (46%) and frontal cortex (33%), staining of Nissl body, immunoreactivity of choline acetyltransferase (ChAT) and expression of ChAT protein in hippocampal region was also observed in arsenic treated rats as compared to controls. Simultaneous treatment with arsenic and curcumin (100mg/kg body weight, p.o., 28 days) increased learning and memory performance associated with increased binding of (3)H-QNB in hippocampus (54%), frontal cortex (25%) and activity of acetylcholinesterase in hippocampus (41%) and frontal cortex (29%) as compared to arsenic treated rats. Increase in the expression of ChAT protein, immunoreactivity of ChAT and staining of Nissl body in hippocampal region was also observed in rats simultaneously treated with arsenic and curcumin as compared to those treated with arsenic alone. The results of the present study suggest that curcumin significantly modulates arsenic induced cholinergic dysfunctions in brain and also exhibits neuroprotective efficacy of curcumin. Copyright © 2011 Elsevier Inc. All rights reserved.

[Physiopathology of overactive bladder syndrome].

PubMed

Sacco, Emilio

2012-01-01

The pathophysiology of OAB is complex, multifactorial and still largely unknown. Several pathophysiological mechanisms have been highlighted that may play a different role in different patient groups. There are now experimental evidences that support both the myogenic and neurogenic hypothesis, but in recent years the "integrative" hypothesis has been gaining more and more acceptance, where a disruption in the multiple interactions between different cell types (neurons, urothelium, interstitial cells, myocytes) and network functions represent a central element of lower urinary tract dysfunctions. Of utmost importance, a disorder in the urothelial sensory function and in the urothelial/suburothelial non-neural cholinergic system, favored by age and comorbidities, appears to be crucial for the development of the OAB. Neuroplastic and detrusor changes in OAB are broadly similar to those observed in bladders exposed to outlet obstruction, neuropathies, inflammation or aging, and may be driven by a common urothelial dysfunction. Several signaling substances and their receptors were found to be involved in central pathways of bidirectional communication between the different cell types in the bladder, and were shown to be modified in several animal models of OAB as well as in human models, indicating new potential therapeutic targets.

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.

Huperzine A, but not tacrine, stimulates S100B secretion in astrocyte cultures.

PubMed

Lunardi, Paula; Nardin, Patrícia; Guerra, Maria Cristina; Abib, Renata; Leite, Marina Concli; Gonçalves, Carlos-Alberto

2013-04-09

The loss of cholinergic function in the central nervous system contributes significantly to the cognitive decline associated with advanced age and dementias. Huperzine A (HupA) is a selective inhibitor of acetylcholinesterase (AChE) and has been shown to significantly reduce cognitive impairment in animal models of dementia. Based on the importance of astrocytes in physiological and pathological brain activities, we investigated the effect of HupA and tacrine on S100B secretion in primary astrocyte cultures. S100B is an astrocyte-derived protein that has been proposed to be a marker of brain injury. Primary astrocyte cultures were exposed to HupA, tacrine, cholinergic agonists, and S100B secretion was measured by enzyme-linked immunosorbent assay (ELISA) at 1 and 24h. HupA, but not tacrine, at 100μM significantly increased S100B secretion in astrocyte cultures. Nicotine (at 100 and 1000μM) was able to stimulate S100B secretion in astrocyte cultures. Our data reinforce the idea that AChE inhibitors, particularly HupA, do not act exclusively on the acetylcholine balance. This effect of HupA could contribute to improve the cognitive deficit observed in patients, which are attributed to cholinergic dysfunction. In addition, for the first time, to our knowledge, these data indicate that S100B secretion can be modulated by nicotinic receptors, in addition to glutamate, dopamine and serotonin receptors. Copyright © 2013 Elsevier Inc. All rights reserved.

Idiopathic pure sudomotor failure and cholinergic urticaria in a patient after acute infectious mononucleosis infection.

PubMed

Chin, Y-Y; Chang, T C-C; Chang, C-H

2013-03-01

Idiopathic pure sudomotor failure (IPSF) is a subgroup of acquired idiopathic generalized anhidrosis, which is characterized by early age of onset, acute or sudden onset, concomitant sharp pain or cholinergic urticaria over the entire body, absence of autonomic dysfunction other than generalized anhidrosis, raised serum IgE level, and marked response to steroid. The aetiology of IPSF is still not well understood, but is thought to be caused by interference in cholinergic transmission in the eccrine glands of skin. IPSF after viral infection has rarely been reported in the literature. We describe a patient who developed generalized anhidrosis and cholinergic urticaria accompanied by heat intolerance after infectious mononucleosis infection. This is the first such case, to our knowledge, and the patient was successfully treated with steroid pulse therapy. © The Author(s). CED © 2012 British Association of Dermatologists.

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.

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 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

Oxotremorine-induced hypothermia as a method for evaluating long-term neuronal changes following poisoning by cholinesterase inhibitors in rats.

PubMed

Grauer, E; Levy, A

2007-12-05

Severe poisoning by inhibitors of cholinesterase (ChE) enzymes is often associated with prolonged central or peripheral neuronal damage. Oxotremorine is a cholinergic agonist known to induce acute hypothermia. Central and peripheral cholinergic signaling is involved in the induction of hypothermia as well as in its recovery. These processes were used in the present study to reveal prolonged neuronal abnormalities in poisoned rats, using oxotremorine with and without concomitant administration of the peripheral muscarinic antagonist methyl scopolamine. In non-poisoned naïve rats, the hypothermic effect of oxotremorine appeared faster while its recovery was delayed following co-administration of methyl scopolamine, suggesting predominantly peripheral processes in counteracting the hypothermia. One month after exposure to approximately 1LD(50) of the carbamates aldicarb and oxamyl, the hypothermic effect of oxotremorine was similar to that found in saline-treated control group. However, the effect of methyl scopolamine on the recovery process was significantly diminished, indicating that the impaired cholinergic mechanisms were predominantly peripheral. In contrast, 1 month following organophosphate (OP) poisoning by the nerve agents sarin and VX, oxotremorine-induced hypothermia was reduced, indicating mainly impaired central cholinergic mechanisms. The development of severe convulsions during nerve agent poisoning may explain the central neuronal damage in OP-poisoned rats, displayed as reduced hypothermia. As convulsions were not part of the poisoning symptoms with the carbamates tested, their long-term damage was displayed at the recovery stage. This method might be used as a relatively simple means for detecting differential long-term central and peripheral cholinergic injuries, long after toxicity signs have receded.

The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed rats.

PubMed

Srikumar, B N; Raju, T R; Shankaranarayana Rao, B S

2006-12-01

Chronic stress in rats has been shown to impair learning and memory, and precipitate several affective disorders like depression and anxiety. The mechanisms involved in these stress-induced disorders and the possible reversal are poorly understood, thus limiting the number of drugs available for their treatment. Our earlier studies suggest cholinergic dysfunction as the underlying cause in the behavioral deficits following stress. Muscarinic cholinergic agonist, oxotremorine is demonstrated to have a beneficial effect in reversing brain injury-induced behavioral dysfunction. In this study, we have evaluated the effect of oxotremorine treatment on chronic restraint stress-induced cognitive deficits. Rats were subjected to restraint stress (6 h/day) for 21 days followed by oxotremorine treatment for 10 days. Spatial learning and memory was assessed in a partially baited eight-arm radial maze task. Stressed rats exhibited impairment in performance, with decreased percentage of correct choices and an increase in the number of reference memory errors (RMEs). Oxotremorine treatment (0.1 or 0.2 mg/kg, i.p.) to stressed rats resulted in a significant increase in the percent correct choices and a decrease in the number of RMEs compared with stress as well as the stress+vehicle-treated groups. In the retention test, oxotremorine treated rats committed less RMEs compared with the stress group. Chronic restraint stress decreased acetylcholinesterase (AChE) activity in the hippocampus, frontal cortex and septum, which was reversed by both the doses of oxotremorine. Further, oxotremorine treatment also restored the norepinephrine levels in the hippocampus and frontal cortex. Thus, this study demonstrates the potential of cholinergic muscarinic agonists and the involvement of both cholinergic and noradrenergic systems in the reversal of stress-induced learning and memory deficits.

Cholinergic autonomic dysfunction in veterans with Gulf War illness: confirmation in a population-based sample.

PubMed

Haley, Robert W; Charuvastra, Elizabeth; Shell, William E; Buhner, David M; Marshall, W Wesley; Biggs, Melanie M; Hopkins, Steve C; Wolfe, Gil I; Vernino, Steven

2013-02-01

The authors of prior small studies raised the hypothesis that symptoms in veterans of the 1991 Gulf War, such as chronic diarrhea, dizziness, fatigue, and sexual dysfunction, are due to cholinergic autonomic dysfunction. To perform a confirmatory test of this prestated hypothesis in a larger, representative sample of Gulf War veterans. Nested case-control study. Clinical and Translational Research Center, University of Texas Southwestern Medical Center, Dallas. Representative samples of Gulf War veterans meeting a validated case definition of Gulf War illness with 3 variants (called syndromes 1-3) and a control group, all selected randomly from the US Military Health Survey. Validated domain scales from the Autonomic Symptom Profile questionnaire, the Composite Autonomic Severity Score, and high-frequency heart rate variability from a 24-hour electrocardiogram. The Autonomic Symptom Profile scales were significantly elevated in all 3 syndrome groups (P< .001), primarily due to elevation of the orthostatic intolerance, secretomotor, upper gastrointestinal dysmotility, sleep dysfunction, urinary, and autonomic diarrhea symptom domains. The Composite Autonomic Severity Score was also higher in the 3 syndrome groups (P= .045), especially in syndrome 2, primarily due to a significant reduction in sudomotor function as measured by the Quantitative Sudomotor Axon Reflex Test, most significantly in the foot; the score was intermediate in the ankle and upper leg and was nonsignificant in the arm, indicating a peripheral nerve length-related deficit. The normal increase in high-frequency heart rate variability at night was absent or blunted in all 3 syndrome groups (P< .001). Autonomic symptoms are associated with objective, predominantly cholinergic autonomic deficits in the population of Gulf War veterans.

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.

Incidence of the WAIS-R Fuld profile in HIV-1 infection.

PubMed

van Gorp, W G; Tulin, S J; Evans, G; Satz, P

1990-10-01

The incidence of a WAIS-R subtest "marker" sensitive to cholinergic dysfunction was assessed in a sample 116 homosexual males infected with HIV (Acquired Immunodeficiency Syndrome [AIDS] N = 40; AIDS Related Complex [ARC], N = 76). The incidence of positive profiles was low in the overall sample (11/116, 9%), and significantly lower than incidence rates reported for known cholinergic deficient groups (Alzheimer's disease; scopolamine). However, significantly more AIDS patients (8/40, 20%) than ARC patients (3/76, 4%) demonstrated positive profiles. These results suggest that, as a group, persons with ARC or AIDS do not show an increased incidence of the Fuld profile associated with cholinergic disruption, and offer continued support for diagnostic specificity of the Fuld formula for Alzheimer's disease.

Extinction and recovery of an avoidance memory impaired by scopolamine.

PubMed

Navarro, N M; Krawczyk, M C; Boccia, M M; Blake, M G

2017-03-15

Pre-training administration of scopolamine (SCP) resembles situations of cholinergic dysfunction, leading to memory impairment of mice trained in an inhibitory avoidance task. We suggest here that SCP does not impair memory formation, but acquisition is affected in a way that reduces the strength of the stored memory, thus making this memory less able to control behavior when tested. Hence, a memory trace is stored, but is poorly expressed during the test. Although weakly expressed, this memory shows extinction during successive tests, and can be strengthened by using a reminder. Our results indicate that memories stored under cholinergic dysfunction conditions seem absent or lost, but are in fact present and experience common memory processes, such as extinction, and could be even recovered by using appropriate protocols. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

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.

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.

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

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

Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects.

PubMed

Wezenberg, E; Verkes, R J; Sabbe, B G C; Ruigt, G S F; Hulstijn, W

2005-09-01

The central cholinergic system is implicated in cognitive functioning. The dysfunction of this system is expressed in many diseases like Alzheimer's disease, dementia of Lewy body, Parkinson's disease and vascular dementia. In recent animal studies, it was found that selective cholinergic modulation affects visuospatial processes even more than memory function. In the current study, we tried to replicate those findings. In order to investigate the acute effects of cholinergic drugs on memory and visuospatial functions, a selective anticholinergic drug, biperiden, was compared to a selective acetylcholinesterase-inhibiting drug, rivastigmine, in healthy elderly subjects. A double-blind, placebo-controlled, randomised, cross-over study was performed in 16 healthy, elderly volunteers (eight men, eight women; mean age 66.1, SD 4.46 years). All subjects received biperiden (2 mg), rivastigmine (3 mg) and placebo with an interval of 7 days between them. Testing took place 1 h after drug intake (which was around Tmax for both drugs). Subjects were presented with tests for episodic memory (wordlist and picture memory), working memory tasks (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Visuospatial abilities were assessed by tests with high visual scanning components (tangled lines and Symbol Digit Substitution Test). Episodic memory was impaired by biperiden. Rivastigmine impaired recognition parts of the episodic memory performance. Working memory was non-significantly impaired by biperiden and not affected by rivastigmine. Motor learning as well as visuospatial processes were impaired by biperiden and improved by rivastigmine. These results implicate acetylcholine as a modulator not only of memory but also of visuospatial abilities.

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

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.

Immunolocalization of choline acetyltransferase of common type in the central brain mass of Octopus vulgaris

PubMed Central

Casini, A.; Vaccaro, R.; D'Este, L.; Sakaue, Y.; Bellier, J.P.; Kimura, H.; Renda, T.G.

2012-01-01

Acetylcholine, the first neurotransmitter to be identified in the vertebrate frog, is widely distributed among the animal kingdom. The presence of a large amount of acetylcholine in the nervous system of cephalopods is well known from several biochemical and physiological studies. However, little is known about the precise distribution of cholinergic structures due to a lack of a suitable histochemical technique for detecting acetylcholine. The most reliable method to visualize the cholinergic neurons is the immunohistochemical localization of the enzyme choline acetyltransferase, the synthetic enzyme of acetylcholine. Following our previous study on the distribution patterns of cholinergic neurons in the Octopus vulgaris visual system, using a novel antibody that recognizes choline acetyltransferase of the common type (cChAT), now we extend our investigation on the octopus central brain mass. When applied on sections of octopus central ganglia, immunoreactivity for cChAT was detected in cell bodies of all central brain mass lobes with the notable exception of the subfrontal and subvertical lobes. Positive varicosed nerves fibers where observed in the neuropil of all central brain mass lobes. PMID:23027350

Immunolocalization of choline acetyltransferase of common type in the central brain mass of Octopus vulgaris.

PubMed

Casini, A; Vaccaro, R; D'Este, L; Sakaue, Y; Bellier, J P; Kimura, H; Renda, T G

2012-07-19

Acetylcholine, the first neurotransmitter to be identified in the vertebrate frog, is widely distributed among the animal kingdom. The presence of a large amount of acetylcholine in the nervous system of cephalopods is well known from several biochemical and physiological studies. However, little is known about the precise distribution of cholinergic structures due to a lack of a suitable histochemical technique for detecting acetylcholine. The most reliable method to visualize the cholinergic neurons is the immunohistochemical localization of the enzyme choline acetyltransferase, the synthetic enzyme of acetylcholine. Following our previous study on the distribution patterns of cholinergic neurons in the Octopus vulgaris visual system, using a novel antibody that recognizes choline acetyltransferase of the common type (cChAT), now we extend our investigation on the octopus central brain mass. When applied on sections of octopus central ganglia, immunoreactivity for cChAT was detected in cell bodies of all central brain mass lobes with the notable exception of the subfrontal and subvertical lobes. Positive varicosed nerves fibers where observed in the neuropil of all central brain mass lobes.

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

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.

Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge

PubMed Central

Li, Xiufeng; Spence, Jeffrey S.; Buhner, David M.; Hart, John; Cullum, C. Munro; Biggs, Melanie M.; Hester, Andrea L.; Odegard, Timothy N.; Carmack, Patrick S.; Haley, Robert W.

2011-01-01

Purpose: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. Materials and Methods: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups—syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)—and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. Results: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. Conclusion: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101715/-/DC1 PMID:21914840

Central cholinergic regulation of respiration: nicotinic receptors

PubMed Central

Shao, Xuesi M; Feldman, Jack L

2009-01-01

Nicotinic acetylcholine receptors (nAChRs) are expressed in brainstem and spinal cord regions involved in the control of breathing. These receptors mediate central cholinergic regulation of respiration and effects of the exogenous ligand nicotine on respiratory pattern. Activation of α4* nAChRs in the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic α4* nAChRs on hypoglossal (XII) motoneurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity. As perinatal nicotine exposure may contribute to the pathogenesis of sudden infant death syndrome (SIDS), we discuss the effects of perinatal nicotine exposure on development of the cholinergic and other neurotransmitter systems involved in control of breathing. Advances in understanding of the mechanisms underlying central cholinergic/nicotinic modulation of respiration provide a pharmacological basis for exploiting nAChRs as therapeutic targets for neurological disorders related to neural control of breathing such as sleep apnea and SIDS. PMID:19498418

Parkinson's: a syndrome rather than a disease?

PubMed

Titova, Nataliya; Padmakumar, C; Lewis, Simon J G; Chaudhuri, K Ray

2017-08-01

Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder. The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease.

The memory-ameliorating effects of Artemisia princeps var. orientalis against cholinergic dysfunction in mice.

PubMed

Liu, Xiaotong; Kim, Dong Hyun; Kim, Jong Min; Park, Se Jin; Cai, Mudan; Jang, Dae Sik; Ryu, Jong Hoon

2012-01-01

Artemisia princeps var. orientalis (Compositae) is widely distributed in China, Japan and Korea and is known to have anti-inflammatory and anti-oxidative activities. The ethyl acetate fraction of ethanolic extract of A. princeps var. orientalis (AEA) was found to inhibit acetylcholinesterase activity in a dose-dependent manner in vitro (IC(50) value: 541.4 ± 67.5 μg/ml). Therefore, we investigated the effects of AEA on scopolamine-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. AEA (100 or 200 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (p < 0.05). In the Morris water maze task, AEA (200 mg/kg, p.o.) significantly shortened escape latencies in training trials and increased both swimming time spent in the target zone and probe crossing numbers during the probe trial as compared with scopolamine-treated mice (p < 0.05). Additionally, the ameliorating effect of AEA on scopolamine-induced memory impairment was antagonized by a subeffective dose of MK-801. These results suggest that AEA could be an effective treatment against cholinergic dysfunction and its effect is mediated by the enhancement of the cholinergic neurotransmitter system via NMDA receptor signaling or acetylcholinesterase inhibition.

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.

Thyroid function, Alzheimer's disease and postoperative cognitive dysfunction: a tale of dangerous liaisons?

PubMed

Mafrica, Federica; Fodale, Vincenzo

2008-05-01

Hypothyroidism and hyperthyroidism are commonly present conditions in adults, leading to neurological symptoms, affecting the central and peripheral nervous system, and to neurocognitive impairment. Several studies investigated a possible association between Alzheimer's disease (AD) and thyroid dysfunctions. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Moreover, thyroid hormones negatively regulate expression of the amyloid-beta protein precursor (AbetaPP), which plays a key role in the development of AD. A condition, the so called euthyroid sick syndrome (ESS), characterized by reduced serum T_{3} and T_{4} concentrations without increased serum thyroid stimulation hormone secretion, occurs within hours after major surgery. After surgery, elderly patients often exhibit a transient, reversible state of cognitive alterations. Delirium occurs in 10-26% of general medical patients over 65, and it is associated with a significant increase in morbidity and mortality. Modifications in thyroid hormone functioning may take place as a consequence of psycho-physical stress caused by surgery, and probably as a consequence of reduced conversion of T4 into T3 by the liver engaged in metabolizing anesthetic drugs. Therefore, modifications of thyroid hormones post-surgery, might play a role in the pathogenesis of postoperative cognitive dysfunction.

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

Recovery of diminished mealtime-associated anticipatory behavior by aniracetam in aged rats.

PubMed

Tanaka, Y; Kurasawa, M; Nakamura, K

2000-08-01

Disease- or age-related neuropsychiatric symptoms and cognitive and chronobiological impairments greatly aggravate the activities of daily living (ADL) in patients. The present study evaluates the effects of aniracetam on a decline in mealtime-associated anticipatory behavior in aged rats, as an animal model of temporally regulated behaviors or habitual daily activities. Aged rats showed a lower but typical nocturnal motor activity rhythm than young rats when the animals were fed ad lib. Mealtime-associated anticipatory behavior emerged in young rats when the rats were fed at a fixed time for 6 days, but the activity in aged rats was diminished. Repeated administration of aniracetam (100 mg/kg PO) or physostigmine (0.1 mg/kg SC) for 7 days ameliorated the impaired anticipatory behavior in aged rats. Nefiracetam (10 mg/kg PO) was ineffective. All compounds tested had no effect on appetite or motor ability. These results indicate that aging disturbs the timing or temporal regulation of anticipatory behavior, probably resulting from dysfunction in a food-entrainable oscillator linked to central cholinergic systems. The restoration of the time-keeping ability by aniracetam may be mediated by the facilitation of reticulothalamic cholinergic neurotransmission, and the action may lead to the improvement of declined ADL in stroke patients.

Inhibition of choline acetyltransferase by excitatory amino acids as a possible mechanism for cholinergic dysfunction in the central nervous system.

PubMed

Loureiro-Dos-Santos, N E; Reis, R A; Kubrusly, R C; de Almeida, O M; Gardino, P F; de Mello, M C; de Mello, F G

2001-05-01

Choline acetyltransferase (ChAT) activity was reduced by more than 85% in cultured retina cells after 16 h treatment with 150 microM kainate (T(1/2) : 3.5 h). Glutamate, AMPA and quisqualate also inhibited the enzyme in equivalent proportion. Cell lesion measured by lactate dehydrogenase (LDH) release, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide - thiazolyl blue (MTT) reduction and microscopic observation was not detected even after 48 h with kainate. Other retina neurochemical markers were not affected by kainate and full recovery of the enzyme was achieved 9 days after kainate removal. Moreover, hemicolinium-3 sensitive choline uptake and hemicolinium-3 binding sites were maintained intact after kainate treatment. The immunoblot and immunohistochemical analysis of the enzyme revealed that ChAT molecules were maintained in cholinergic neurons. The use of antagonists showed that ionotropic and group 1 metabotropic receptors mediated the effect of glutamate on ChAT inhibition, in a calcium dependent manner. The quisqualate mediated ChAT inhibition and part of the kainate effect (30%) was prevented by 5 mM N(G)-nitro-L-arginine methyl ester (L-NAME). Veratridine (3 microM) also reduced ChAT by a Ca(2+) dependent, but glutamate independent mechanism and was prevented by 1 microM tetrodotoxin.

Disruption of trace conditioning of the nictitating membrane response in rabbits by central cholinergic blockade.

PubMed

Kaneko, T; Thompson, R F

1997-05-01

Central muscarinic cholinergic involvement in classical conditioning of eyeblink responses was determined in trace and delay paradigms. Rabbits were trained on a trace procedure in which a 250-ms tone conditioned stimulus (CS) and a 100-ms air-puff unconditioned stimulus (UCS) were presented with a 500-ms trace interval. Each training session day consisted of ten tone alone, ten air-puff alone and 80 paired CS-UCS trials. Scopolamine hydrochloride at doses of 0.03 and 0.1 mg/0.5 ml per kg, s.c. dose-dependently disrupted acquisition of conditioned responses. Rabbits that were treated with scopolamine and failed to learn showed a gradual increase in conditioned responses during an additional training period with saline injections and no transfer from earlier training. Scopolamine methyl bromide, which does not appreciably cross the blood-brain barrier, showed no effects in the trace conditioning paradigm at a dose of 0.1 mg/kg, s.c., indicating central cholinergic blockade is responsible for the suppressive effect of scopolamine. Scopolamine hydrochloride at a dose of 0.1 mg/kg, s.c. did not block acquisition in the delay procedure with a 250-ms inter-stimulus interval, although the rate of acquisition was somewhat reduced by the drug. These data are the first to demonstrate that classical conditioning of the eyeblink response in the trace procedure is highly sensitive to central cholinergic deficits.

Regional Blood-Brain Barrier Responses to Central Cholinergic Activity

DTIC Science & Technology

1989-07-30

i.e., oxotremorine, pilocarpine, carbachol , physostigmine [Olney et al., 1983]). These are some of the same regions affected by soman-induced...Diehl et al., 1984). Carbachol kindling also has been reported (Wasterlain, 1989), linking the cholinergic system to an increase in the sensitivity to

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.

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

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.

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

Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs

NASA Technical Reports Server (NTRS)

Kandasamy, S. B.; Williaes, B. A.

1983-01-01

It is shown that the intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP) induced hyperthermia in guinea pigs which was not mediated through prostaglandins or norepinephrine since a prostaglandin synthesis inhibitor and an alpha-adrenergic receptor blocking agent did not antagonize the hyperthermia. However, the hyperthermic response to Db-cAMP was attenuated by the central administration of a beta-adrenergic receptor antagonist, which indicates that cAMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production and conservation. The central administration of Db-cGMP produced hypothermia which was not mediated via histamine H1 or H2 receptors and serotonin. The antagonism of hypothermia induced by Db-cGMP and acetylcholine + physostigmine by central administration of a cholinergic muscarine receptor antagonist and not by a cholinergic nicotinic receptor antagonist suggests that cholinoceptive neurons and endogenous cGMP may regulate heat loss through cholinergic muscarine receptors. It is concluded that these results indicate a regulatory role in thermoregulation provided by a balance between opposing actions of cAMP and cGMP in guinea pigs.

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

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

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.

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 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.

Effects of [6]-shogaol on cholinergic signaling in HT22 cells following neuronal damage induced by hydrogen peroxide.

PubMed

Shim, Sehwan; Kwon, Jungkee

2012-05-01

Cholinergic neurons play a major role in memory and attention. The dysfunction and death of these neurons, especially in the hippocampus, are thought to contribute to the pathophysiology of memory deficits associated with Alzheimer's disease (AD). Therefore, studying the cholinergic properties and cell survival may help in treating this disease. We investigated the possible effects of [6]-shogaol on cholinergic signaling in HT22 hippocampal neuronal cells. HT22 cells express essential cholinergic markers, including choline acetyltransferase (ChAT) and choline transporter (ChTp). HT22 cells treated with H(2)O(2) for 3h showed an increase in ROS production (35%). These features were partly recovered by [6]-shogaol. Treating H(2)O(2)-treated HT22 cells with [6]-shogaol markedly increased the expression of ChAT and ChTp, an effect similar to that of brain-derived neurotrophic factor (BDNF). Furthermore, K-252a, an inhibitor of the BDNF receptor Trk B, attenuated the effects of both [6]-shogaol and BDNF. These data suggest that [6]-shogaol protects neurons by increasing ChAT and ChTp expression through a BDNF increase and thus may be useful for treating neurodegenerative diseases. Copyright © 2012 Elsevier Ltd. 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.

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

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.

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.

Event-Related Potential Patterns Associated with Hyperarousal in Gulf War Illness Syndrome Groups

PubMed Central

Tillman, Gail D.; Calley, Clifford S.; Green, Timothy A.; Buhl, Virginia I.; Biggs, Melanie M.; Spence, Jeffrey S.; Briggs, Richard W.; Haley, Robert W.; Hart, John; Kraut, Michael A.

2012-01-01

An exaggerated response to emotional stimuli is one of several symptoms widely reported by veterans of the 1991 Persian Gulf War. Many have attributed these symptoms to post-war stress; others have attributed the symptoms to deployment-related exposures and associated damage to cholinergic, dopaminergic, and white matter systems. We collected event-related potential (ERP) data from 20 veterans meeting Haley criteria for Gulf War Syndromes 1–3 and from 8 matched Gulf War veteran controls, who were deployed but not symptomatic, while they performed an auditory three-condition oddball task with gunshot and lion roar sounds as the distractor stimuli. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans; different ERP profiles emerged to account for their hyperarousability. Syndromes 2 and 3, who have previously shown brainstem abnormalities, show significantly stronger auditory P1 amplitudes, purported to indicate compromised cholinergic inhibitory gating in the reticular activating system. Syndromes 1 and 2, who have previously shown basal ganglia dysfunction, show significantly weaker P3a response to distractor stimuli, purported to indicate dysfunction of the dopaminergic contribution to their ability to inhibit distraction by irrelevant stimuli. All three syndrome groups showed an attenuated P3b to target stimuli, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity. PMID:22691951

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

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

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

Galantamine Facilitates Acquisition of Hippocampus-Dependent Trace Eyeblink Conditioning in Aged Rabbits

ERIC Educational Resources Information Center

Weible, Aldis P.; Oh, M. Matthew; Lee, Grace; Disterhoft, John F.

2004-01-01

Cholinergic systems are critical to the neural mechanisms mediating learning. Reduced nicotinic cholinergic receptor (nAChR) binding is a hallmark of normal aging. These reductions are markedly more severe in some dementias, such as Alzheimer's disease. Pharmacological central nervous system therapies are a means to ameliorate the cognitive…

Effects of muscarinic blockade in perirhinal cortex during visual recognition

PubMed Central

Tang, Yi; Mishkin, Mortimer; Aigner, Thomas G.

1997-01-01

Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored. PMID:9356507

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.

Cholinesterase inhibitors, donepezil and rivastigmine, attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats.

PubMed

Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Filarowska, Joanna; Silberring, Jerzy; Kotlinska, Jolanta H

2016-10-01

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

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.

Neonatal treatment with scopolamine butylbromide prevents metabolic dysfunction in male rats

PubMed Central

Malta, Ananda; Souza, Aline Amenencia de; Ribeiro, Tatiane Aparecida; Francisco, Flávio Andrade; Pavanello, Audrei; Prates, Kelly Valério; Tófolo, Laize Peron; Miranda, Rosiane Aparecida; Oliveira, Júlio Cezar de; Martins, Isabela Peixoto; Previate, Carina; Gomes, Rodrigo Mello; Franco, Claudinéia Conationi da Silva; Natali, Maria Raquel Marçal; Palma-Rigo, Kesia; Mathias, Paulo Cezar de Freitas

2016-01-01

We tested whether treatment with a cholinergic antagonist could reduce insulin levels in early postnatal life and attenuate metabolic dysfunctions induced by early overfeeding in adult male rats. Wistar rats raised in small litters (SLs, 3 pups/dam) and normal litters (NLs, 9 pups/dam) were used in models of early overfeeding and normal feeding, respectively. During the first 12 days of lactation, animals in the SL and NL groups received scopolamine butylbromide (B), while the controls received saline (S) injections. The drug treatment decreased insulin levels in pups from both groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, vagus nerve activity, fat tissue accretion, insulinemia, leptinemia, body weight gain and food intake. Low glucose and cholinergic insulinotropic effects were observed in pancreatic islets from both groups. Low protein expression was observed for the muscarinic M3 acetylcholine receptor subtype (M3mAChR), although M2mAChR subtype expression was increased in SL-B islets. In addition, beta-cell density was reduced in drug-treated rats. These results indicate that early postnatal scopolamine butylbromide treatment inhibits early overfeeding-induced metabolic dysfunctions in adult rats, which might be caused by insulin decreases during lactation, associated with reduced parasympathetic activity and expression of M3mAChR in pancreatic islets. PMID:27561682

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…

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.

Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: Relationship with spatial impairment

PubMed Central

Bañuelos, C.; LaSarge, C. L.; McQuail, J. A.; Hartman, J. J.; Gilbert, R. J.; Ormerod, B. K.; Bizon, J. L.

2013-01-01

Both cholinergic and GABAergic projections from the rostral basal forebrain have been implicated in hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in co-distributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase (ChAT) immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 (GAD67) immunopositive) neurons, and total (NeuN immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline. PMID:22817834

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.

Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity.

PubMed

Kaur, Shamsherjit; Singh, Satinderpal; Chahal, Karan Singh; Prakash, Atish

2014-11-01

Organophosphates (OP) are highly toxic compounds that cause cholinergic neuronal excitotoxicity and dysfunction by irreversible inhibition of acetylcholinesterase, resulting in delayed brain damage. This delayed secondary neuronal destruction, which arises primarily in the cholinergic areas of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, could be largely responsible for persistent profound neuropsychiatric and neurological impairments such as memory, cognitive, mental, emotional, motor, and sensory deficits in the victims of OP poisoning. The therapeutic strategies for reducing neuronal brain damage must adopt a multifunctional approach to the various steps of brain deterioration: (i) standard treatment with atropine and related anticholinergic compounds; (ii) anti-excitotoxic therapies to prevent cerebral edema, blockage of calcium influx, inhibition of apoptosis, and allow for the control of seizure; (iii) neuroprotection by aid of antioxidants and N-methyl-d-aspartate (NMDA) antagonists (multifunctional drug therapy), to inhibit/limit the secondary neuronal damage; and (iv) therapies targeting chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may prevent secondary neuronal damage in both early and late stages of OP poisoning, and thus may be a beneficial approach to treating the neuropsychological and neuronal impairments resulting from OP toxicity.

Activation of the reticulothalamic cholinergic pathway by the major metabolites of aniracetam.

PubMed

Nakamura, K; Shirane, M

1999-09-10

The aim of the study was to further investigate the effects of aniracetam, a cognition enhancer, and its metabolites on the brain cholinergic system. We measured choline acetyltransferase activity and acetylcholine release using in vivo brain microdialysis in stroke-prone spontaneously hypertensive rats (SHRSP). The enzyme activity in the pons-midbrain and hippocampus, and basal acetylcholine release in the nucleus reticularis thalami were lower in SHRSP than in age-matched Wistar Kyoto rats, indicating central cholinergic deficits in SHRSP. Repeated treatment of aniracetam (50 mg/kg p.o. x 11 for 6 days) preferentially increased the enzyme activity in the thalamus, whereas decreased it in the striatum. Among the metabolites of aniracetam, local perfusion of N-anisoyl-gamma-aminobutyric acid (GABA, 0.1 and/or 1 microM) and p-anisic acid (1 microM) into the nucleus reticularis thalami, dorsal hippocampus and prefrontal cortex of SHRSP produced a significant but delayed increase of acetylcholine release. We failed, however, to find any effect of aniracetam itself. A direct injection of N-anisoyl-GABA (1 nmol) into the pedunculopontine tegmental nucleus of SHRSP enhanced the release in the nucleus reticularis thalami. Thus, these data prove that aniracetam can facilitate central cholinergic neurotransmission via both metabolites. Based on its pharmacokinetic profile, N-anisoyl-GABA may contribute to the clinical effects of aniracetam, mainly by acting on the reticulothalamic cholinergic pathway.

Immunostaining to visualize murine enteric nervous system development.

PubMed

Barlow-Anacker, Amanda J; Erickson, Christopher S; Epstein, Miles L; Gosain, Ankush

2015-04-29

The enteric nervous system is formed by neural crest cells that proliferate, migrate and colonize the gut. Following colonization, neural crest cells must then differentiate into neurons with markers specific for their neurotransmitter phenotype. Cholinergic neurons, a major neurotransmitter phenotype in the enteric nervous system, are identified by staining for choline acetyltransferase (ChAT), the synthesizing enzyme for acetylcholine. Historical efforts to visualize cholinergic neurons have been hampered by antibodies with differing specificities to central nervous system versus peripheral nervous system ChAT. We and others have overcome this limitation by using an antibody against placental ChAT, which recognizes both central and peripheral ChAT, to successfully visualize embryonic enteric cholinergic neurons. Additionally, we have compared this antibody to genetic reporters for ChAT and shown that the antibody is more reliable during embryogenesis. This protocol describes a technique for dissecting, fixing and immunostaining of the murine embryonic gastrointestinal tract to visualize enteric nervous system neurotransmitter expression.

Neuropharmacology of memory consolidation and reconsolidation: Insights on central cholinergic mechanisms.

PubMed

Blake, M G; Krawczyk, M C; Baratti, C M; Boccia, M M

2014-01-01

Central cholinergic system is critically involved in all known memory processes. Endogenous acetylcholine release by cholinergic neurons is necessary for modulation of acquisition, encoding, consolidation, reconsolidation, extinction, retrieval and expression. Experiments from our laboratory are mainly focused on elucidating the mechanisms by which acetylcholine modulates memory processes. Blockade of hippocampal alpha-7-nicotinic receptors (α7-nAChRs) with the antagonist methyllycaconitine impairs memory reconsolidation. However, the administration of a α7-nAChR agonist (choline) produce a paradoxical modulation, causing memory enhancement in mice trained with a weak footshock, but memory impairment in animals trained with a strong footshock. All these effects are long-lasting, and depend on the age of the memory trace. This review summarizes and discusses some of our recent findings, particularly regarding the involvement of α7-nAChRs on memory reconsolidation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mitochondrial dysfunction and organophosphorus compounds

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

Karami-Mohajeri, Somayyeh; Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Kerman University of Medical Sciences, Kerman; Abdollahi, Mohammad, E-mail: Mohammad.Abdollahi@UToronto.Ca

2013-07-01

Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen frommore » dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.« less

Modulation of cholinergic functions by serotonin and possible implications in memory: general data and focus on 5-HT(1A) receptors of the medial septum.

PubMed

Jeltsch-David, Hélène; Koenig, Julie; Cassel, Jean-Christophe

2008-12-16

Cholinergic systems were linked to cognitive processes like attention and memory. Other neurotransmitter systems having minor influence on cognitive functions - as shown by the weakness of the effects of their selective lesions - modulate cholinergic functions. The serotonergic system is such a system. Conjoined functional changes in cholinergic and serotonergic systems may have marked cognitive consequences [Cassel JC, Jeltsch H. Serotoninergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69(1):1-41; Steckler T, Sahgal A. The role of serotoninergic-cholinergic interactions in the mediation of cognitive behaviour. Behav Brain Res 1995;67:165-99]. A crucial issue in that concern is the identification of the neuroanatomical and neuropharmacological substrates where functional effects of serotonergic/cholinergic interactions originate. Approaches relying on lesions and intracerebral cell grafting, on systemic drug-cocktail injections, or even on intracerebral drug infusions represent the main avenues on which our knowledge about the role of serotonergic/cholinergic interactions has progressed. The present review will visit some of these avenues and discuss their contribution to what is currently known on the potential or established implication(s) into memory functions of serotonergic/cholinergic interactions. It will then focus on a brain region and a neuropharmacological substrate that have been poorly studied as regards serotonergic modulation of memory functions, namely the medial septum and its 5-HT(1A) receptors. Based on recent findings of our laboratory, we suggest that these receptors, located on both cholinergic and GABAergic septal neurons, take part in a mechanism that controls encoding, to some extent consolidation, but not retrieval, of hippocampal-dependent memories. This control, however, does not occur by the way of an exclusive action of serotonin on cholinergic neurons.

The Ror receptor tyrosine kinase CAM-1 is required for ACR-16-mediated synaptic transmission at the C. elegans neuromuscular junction.

PubMed

Francis, Michael M; Evans, Susan P; Jensen, Michael; Madsen, David M; Mancuso, Joel; Norman, Kenneth R; Maricq, Andres Villu

2005-05-19

Nicotinic (cholinergic) neurotransmission plays a critical role in the vertebrate nervous system, underlies nicotine addiction, and nicotinic receptor dysfunction leads to neurological disorders. The C. elegans neuromuscular junction (NMJ) shares many characteristics with neuronal synapses, including multiple classes of postsynaptic currents. Here, we identify two genes required for the major excitatory current found at the C. elegans NMJ: acr-16, which encodes a nicotinic AChR subunit homologous to the vertebrate alpha7 subunit, and cam-1, which encodes a Ror receptor tyrosine kinase. acr-16 mutants lack fast cholinergic current at the NMJ and exhibit synthetic behavioral deficits with other known AChR mutants. In cam-1 mutants, ACR-16 is mislocalized and ACR-16-dependent currents are disrupted. The postsynaptic deficit in cam-1 mutants is accompanied by alterations in the distribution of cholinergic vesicles and associated synaptic proteins. We hypothesize that CAM-1 contributes to the localization or stabilization of postsynaptic ACR-16 receptors and presynaptic release sites.

Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats.

PubMed

Dwivedi, Nidhi; Flora, Govinder; Kushwaha, Pramod; Flora, Swaran J S

2014-01-01

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid. Copyright © 2013 Elsevier B.V. All rights reserved.

Medications influencing central cholinergic pathways affect fixation stability, saccadic response time and associated eye movement dynamics during a temporally-cued visual reaction time task.

PubMed

Naicker, Preshanta; Anoopkumar-Dukie, Shailendra; Grant, Gary D; Modenese, Luca; Kavanagh, Justin J

2017-02-01

Anticholinergic medications largely exert their effects due to actions on the muscarinic receptor, which mediates the functions of acetylcholine in the peripheral and central nervous systems. In the central nervous system, acetylcholine plays an important role in the modulation of movement. This study investigated the effects of over-the-counter medications with varying degrees of central anticholinergic properties on fixation stability, saccadic response time and the dynamics associated with this eye movement during a temporally-cued visual reaction time task, in order to establish the significance of central cholinergic pathways in influencing eye movements during reaction time tasks. Twenty-two participants were recruited into the placebo-controlled, human double-blind, four-way crossover investigation. Eye tracking technology recorded eye movements while participants reacted to visual stimuli following temporally informative and uninformative cues. The task was performed pre-ingestion as well as 0.5 and 2 h post-ingestion of promethazine hydrochloride (strong centrally acting anticholinergic), hyoscine hydrobromide (moderate centrally acting anticholinergic), hyoscine butylbromide (anticholinergic devoid of central properties) and a placebo. Promethazine decreased fixation stability during the reaction time task. In addition, promethazine was the only drug to increase saccadic response time during temporally informative and uninformative cued trials, whereby effects on response time were more pronounced following temporally informative cues. Promethazine also decreased saccadic amplitude and increased saccadic duration during the temporally-cued reaction time task. Collectively, the results of the study highlight the significant role that central cholinergic pathways play in the control of eye movements during tasks that involve stimulus identification and motor responses following temporal cues.

Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: A Chronic Effects of Neurotrauma Consortium Study

PubMed Central

Mufson, Elliott J.; Perez, Sylvia E.; Nadeem, Muhammad; Mahady, Laura; Kanaan, Nicholas M.; Abrahamson, Eric E.; Ikonomovic, Milos D.; Crawford, Fiona; Alvarez, Victor; Stein, Thor; McKee, Ann C.

2017-01-01

Objective To test the hypothesis that the nucleus basalis of Meynert (nbM), a cholinergic basal forebrain (CBF) cortical projection system, develops neurofibrillary tangles (NFTs) during the progressive pathological stages of chronic traumatic encephalopathy (CTE) in the brain of athletes. Method To characterize NFT pathology we used tau- antibodies marking early, intermediate, and late stages of NFT development in cholinergic basal forebrain tissue obtained at autopsy from eighteen former athletes and veterans with a history of repetitive mild traumatic brain injury (TBI). Results We found evidence that cholinergic nbM neurons develop intracellular tau-immunoreactive changes progressively across the pathological stages of CTE. In particular, there was an increase in pretangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The nbM neurons also displayed pathologic TDP-43 inclusions and diffuse extracellular and vascular amyloid-β (Aβ) deposits in CTE. A higher percent of pS422/p75NTR, pS422 and TNT1 labeled neurons were significantly correlated with age at symptom onset, interval between symptom onset and death and age at death. Conclusion The development of NFTs within the nbM neurons could contribute to the basal forebrain cortical cholinergic disconnection in CTE. Further studies are needed to determine the mechanism driving NFT formation in the nbM neurons and its relation to chronic cognitive dysfunction in CTE. PMID:27834536

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.

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.

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.

Cholinergic abnormalities in autism: is there a rationale for selective nicotinic agonist interventions?

PubMed

Deutsch, Stephen I; Urbano, Maria R; Neumann, Serina A; Burket, Jessica A; Katz, Elionora

2010-05-01

The core dysfunctions of autism spectrum disorders, which include autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified, include deficits in socialization and communication and a need for the preservation of "sameness;" intellectual impairment and epilepsy are common comorbidities. Data suggest that pathological involvement of cholinergic nuclei and altered expression of acetylcholine receptors, particularly nicotinic acetylcholine receptors, occur in brain of persons with autistic disorder. However, many of these studies involved postmortem tissue from small samples of primarily adult persons. Thus, the findings may reflect compensatory changes and may relate more closely to intellectual impairment and the confounding effects of seizures and medications, as opposed to the core dysfunctions of autism. Nonetheless, because of the roles played by acetylcholine receptors in general, and nicotinic acetylcholine receptors in particular, in normal processes of attention, cognition, and memory, selective cholinergic interventions should be explored for possible therapeutic effects. Additionally, there are electrophysiological data that complement the clinical observations of frequent comorbid seizure disorders in these patients, suggesting a disturbance in the balance of excitatory and inhibitory tone in the brains of persons with autistic disorders. Conceivably, because the alpha7 nicotinic acetylcholine receptor is located on the surface of gamma-aminobutyric acid inhibitory neurons, selective stimulation of this receptor would promote gamma-aminobutyric acid's release and restore diminished inhibitory tone. The development of agonists and partial agonists for nicotinic acetylcholine receptors and positive allosteric modulators that enhance the efficiency of coupling between the binding of agonist and channel opening should facilitate consideration of clinical trials.

Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-β aggregation.

PubMed

Simoni, Elena; Bartolini, Manuela; Abu, Izuddin F; Blockley, Alix; Gotti, Cecilia; Bottegoni, Giovanni; Caporaso, Roberta; Bergamini, Christian; Andrisano, Vincenza; Cavalli, Andrea; Mellor, Ian R; Minarini, Anna; Rosini, Michela

2017-06-01

Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways. The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation. The compounds emerged as a suitable starting point for a further optimization process.

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.

ChAT-ChR2-EYFP mice have enhanced motor endurance but show deficits in attention and several additional cognitive domains.

PubMed

Kolisnyk, Benjamin; Guzman, Monica S; Raulic, Sanda; Fan, Jue; Magalhães, Ana C; Feng, Guoping; Gros, Robert; Prado, Vania F; Prado, Marco A M

2013-06-19

Acetylcholine (ACh) is an important neuromodulator in the nervous system implicated in many forms of cognitive and motor processing. Recent studies have used bacterial artificial chromosome (BAC) transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2-EYFP) to dissect cholinergic circuit connectivity and function using optogenetic approaches. We report that a mouse line used for this purpose also carries several copies of the vesicular acetylcholine transporter gene (VAChT), which leads to overexpression of functional VAChT and consequently increased cholinergic tone. We demonstrate that these mice have marked improvement in motor endurance. However, they also present severe cognitive deficits, including attention deficits and dysfunction in working memory and spatial memory. These results suggest that increased VAChT expression may disrupt critical steps in information processing. Our studies demonstrate that ChAT-ChR2-EYFP mice show altered cholinergic tone that fundamentally differentiates them from wild-type mice.

Neuroprotective Effects of Agomelatine and Vinpocetine Against Chronic Cerebral Hypoperfusion Induced Vascular Dementia.

PubMed

Gupta, Surbhi; Singh, Prabhat; Sharma, Brij Mohan; Sharma, Bhupesh

2015-01-01

Chronic cerebral hypoperfusion (CCH) has been considered as a critical cause for the development of cognitive decline and dementia of vascular origin. Melatonin receptors have been reported to be beneficial in improving memory deterioration. Phosphodiesterase-1 (PDE1) enzyme offers protection against cognitive impairments and cerebrovascular disorders. Aim of this study is to explore the role of agomelatine (a dual MT1 and MT2 melatonin receptor agonist) and vinpocetine (selective PDE1 inhibitor) in CCH induced vascular dementia (VaD). Two vessel occlusion (2VO) or bilateral common carotid arteries ligation method was performed to initiate a phase of chronic hypoperfusion in mice. 2VO animals have shown significant cognitive deficits (Morris water maze), cholinergic dysfunction (increased acetyl cholinesterase -AChE) activity alongwith increased brain oxidative stress (decreased brain catalase, glutathione, as well as superoxide dismutase with an increase in malondialdehyde levels), and significant increase in brain infarct size (2,3,5- triphenylterazolium chloride-TTC staining). Treatment of agomelatine and vinpocetine reduced CCH induced learning and memory deficits and limited cholinergic dysfunction, oxidative stress, and tissue damage, suggesting that agomelatine and vinpocetine may provide benefits in CCH induced VaD.

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.

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.

Effects of alpha-lipoic acid on spatial learning and memory, oxidative stress, and central cholinergic system in a rat model of vascular dementia.

PubMed

Zhao, Ran-Ran; Xu, Fei; Xu, Xiao-Chen; Tan, Guo-Jun; Liu, Liang-Min; Wu, Ning; Zhang, Wen-Zhong; Liu, Ji-Xiang

2015-02-05

Brain oxidative stress due to chronic cerebral hypoperfusion was considered to be the major risk factor in the pathogenesis of vascular dementia. In this study, we investigated the protective efficacy of alpha-lipoic acid, an antioxidant, against vascular dementia in rats, as well as the potential mechanism. Bilateral common carotid arteries occlusion (BCCAO) induced severe cognitive deficits tested by Morris water maze (MWM), along with oxidative stress and disturbance of central cholinergic system. However, administration of alpha-lipoic acid (50mg/kg, i.p.) for 28 days significantly restored cognitive deficits induced by BCCAO. Biochemical determination revealed that alpha-lipoic acid markedly decreased the production of malondialdehyde (MDA) and the generation of reactive oxidative species (ROS), and increased the level of reduced glutathione (GSH) in the hippocampal tissue. Additionally, alpha-lipoic acid raised the level of acetylcholine (ACh) and choline acetyltransferase (ChAT) and decreased the activity of acetycholinesterase (AChE) in the hippocampus. These results indicated that treatment with alpha-lipoic acid significantly improved behavioral alterations, protected against oxidative stress, and restored central cholinergic system in the rat model of vascular dementia induced by BCCAO. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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.

Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system.

PubMed

Chi, Laiting; Du, Kairong; Liu, Dongdong; Bo, Yulong; Li, Wenzhi

2018-03-01

The demand for using parasympathetic activation for stroke therapy is unmet. In the current study, we investigated whether the neuroprotection provided by electroacupuncture (EA) in an experimental stroke model was associated with activation of the parasympathetic nervous system (PNS). The results showed that parasympathetic dysfunction (PD), performed as unilateral vagotomy combined with peripheral atropine, attenuated both the functional benefits of EA and its effects in improving cerebral perfusion, reducing infarct volume, and hindering apoptosis, neuronal and peripheral inflammation, and oxidative stress. Most importantly, EA rats showed a dramatically less reduction in the mRNA level of choline acetyltransferase, five subtypes of muscarinic receptors and α7nAChR, suggesting the inhibition of the impairment of the central cholinergic system; EA also activated dorsal motor nucleus of the vagus, the largest source of parasympathetic pre-ganglionic neurons in the lower brainstem (detected by c-fos immunohistochemistry), and PD suppressed these changes. These findings indicated EA may serve as an alternative modality of PNS activation for stroke therapy.

Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice.

PubMed

Takuma, K; Mizoguchi, H; Funatsu, Y; Hoshina, Y; Himeno, Y; Fukuzaki, E; Kitahara, Y; Arai, S; Ibi, D; Kamei, H; Matsuda, T; Koike, K; Inoue, M; Nagai, T; Yamada, K

2012-04-05

We have recently found that the combination of ovariectomy (OVX) and chronic restraint stress (CS) causes hippocampal pyramidal cell loss and cognitive dysfunction in female rats and that estrogen replacement prevents the OVX/CS-induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the OVX/CS-mediated memory impairment further, we examined the roles of cholinergic systems in the OVX/CS-induced memory impairment in mice. Female Slc:ICR strain mice were randomly divided into two groups: OVX and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to CS (6 h/day) or non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, and context- and tone-dependent memory tests were conducted 1 or 24 h after the conditioning. Overburden with 3 weeks of CS from 2 weeks after OVX impaired context- and tone-dependent freezing and the OVX/CS caused significant Nissl-stained neuron-like cell loss in the hippocampal CA3 region, although OVX and CS alone did not cause such behavioral and histological changes. Replacement of 17β-estradiol for 5 weeks after OVX suppressed OVX/CS-induced memory impairment and hippocampal Nissl-positive cell loss. Furthermore, the OVX/CS mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with other groups. The cholinesterase inhibitors donepezil and galantamine ameliorated OVX/CS-induced memory impairment. These data suggest that cholinergic dysfunction may be involved in the OVX/CS-induced conditioned fear memory impairment. Overall, our findings suggest that the OVX/CS mouse model is useful to study the mechanisms underlying estrogen loss-induced memory deficits. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

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.

Nerve growth factor metabolic dysfunction in Down’s syndrome brains

PubMed Central

Iulita, M. Florencia; Do Carmo, Sonia; Ower, Alison K.; Fortress, Ashley M.; Aguilar, Lisi Flores; Hanna, Michael; Wisniewski, Thomas; Granholm, Ann-Charlotte; Buhusi, Mona; Busciglio, Jorge

2014-01-01

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer’s disease and Down’s syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer’s disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF’s extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down’s syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down’s syndrome and age-matched controls (age range 31–68 years). We further examined primary cultures of human foetal Down’s syndrome cortex (17–21 gestational age weeks) and brains from Ts65Dn mice (12–22 months), a widely used animal model of Down’s syndrome. We report a significant increase in proNGF levels in human and mouse Down’s syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down’s syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down’s syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down’s syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer’s disease and Down’s syndrome. PMID:24519975

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

Peripheral choline acetyltransferase in rat skin demonstrated by immunohistochemistry.

PubMed

Hanada, Keiji; Kishimoto, Saburo; Bellier, Jean-Pierre; Kimura, Hiroshi

2013-03-01

Conventional choline acetyltransferase immunohistochemistry has been used widely for visualizing central cholinergic neurons and fibers but not often for labeling peripheral structures, probably because of their poor staining. The recent identification of the peripheral type of choline acetyltransferase (pChAT) has enabled the clear immunohistochemical detection of many known peripheral cholinergic elements. Here, we report the presence of pChAT-immunoreactive nerve fibers in rat skin. Intensely stained nerve fibers were distributed in association with eccrine sweat glands, blood vessels, hair follicles and portions just beneath the epidermis. These results suggest that pChAT-positive nerves participate in the sympathetic cholinergic innervation of eccrine sweat glands. Moreover, pChAT also appears to play a role in cutaneous sensory nerve endings. These findings are supported by the presence of many pChAT-positive neuronal cells in the sympathetic ganglion and dorsal root ganglion. Thus, pChAT immunohistochemistry should provide a novel and unique tool for studying cholinergic nerves in the skin.

Cholinergic symptoms with low serum cholinesterase from therapeutic cholinesterase inhibitor toxicity.

PubMed

Leikin, Jerrold B; Braund, Victoria; DesLauris, Carol

2014-07-01

Although cholinesterase inhibitors have been frequently used in the treatment of Alzheimer disease, its effects on serum cholinesterase concentrations have been rarely described. We described significant depression of serum cholinesterase levels due to cholinesterase inhibitor toxicity from redundant use of donepezil and rivastigmine in a 78-year-old man. Recovery of serum cholinesterase level was noted upon drug discontinuation and cholinergic symptom resolution. Serum cholinesterase level can be used as a biomarker for central cholinesterase inhibitor toxicity.

Glucocorticoid Programing of the Mesopontine Cholinergic System

PubMed Central

Borges, Sónia; Coimbra, Bárbara; Soares-Cunha, Carina; Ventura-Silva, Ana P.; Pinto, Luisa; Carvalho, Miguel M.; Pêgo, José-Miguel; Rodrigues, Ana João; Sousa, Nuno

2013-01-01

Stress perception, response, adaptation, and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids (GCs) is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programing intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety, and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to GCs (in utero glucocorticoid exposure, iuGC) present hyperanxiety, increased fear behavior, and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22 kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT), in the initiation of 22 kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT) expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individual stress vulnerability threshold. PMID:24379803

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.

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.

The effect of prenatal nicotine on mRNA of central cholinergic markers and hematological parameters in rat fetuses

PubMed Central

Mao, Caiping; Yuan, Xin; Zhang, Hong; Lv, Juanxiu; Guan, Junchang; Miao, Liyan; Chen, Linqi; Zhang, Yuying; Zhang, Lubo; Xu, Zhice

2009-01-01

A number of studies have demonstrated the influence of nicotine on fetal development. This study determined the expression of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and high-affinity choline transporter (CHT1) in the forebrain and hindbrain following chronic prenatal nicotine exposure in the rat fetus (maternal rats were subcutaneously injected with nicotine at different gestation periods). We also measured the effect of chronic nicotine exposure on fetal blood pO2, pCO2, pH, Na+ and K+ concentrations, as well as lactic acid levels. Maternal nicotine exposure during pregnancy was associated with a decrease in fetal pO2 coupled with a significant increase in pCO2 and lactic acid as well as restricted fetal growth. Additionally, maternal nicotine administration also reduced ChAT, VAChT, and CHT1 mRNA levels in the fetal brain. Nicotine-induced fetal hypoxic responses and reduced cholinergic marker expression in the brain were more severe when nicotine was started in early gestation. Our results provide new information about the effects of repeated exposure to nicotine in utero on the expression of central ChAT, VAChT, and CHT1 in the rat fetus. These results indicate that repeated hypoxic episodes or/and a direct effect of nicotine on the central cholinergic system during pregnancy may contribute to brain developmental problems in fetal origin. PMID:18407449

Neurochemical correlates of autistic disorder: a review of the literature.

PubMed

Lam, Kristen S L; Aman, Michael G; Arnold, L Eugene

2006-01-01

Review of neurochemical investigations in autistic disorder revealed that a wide array of transmitter systems have been studied, including serotonin, dopamine, norepinephrine, acetylcholine, oxytocin, endogenous opioids, cortisol, glutamate, and gamma-aminobutyric acid (GABA). These studies have been complicated by the fact that autism is a very heterogeneous disorder which often presents with comorbid behavioral problems. In addition, many of these studies employed very small samples and inappropriate control groups, making it difficult to draw conclusions with confidence. Overall, serotonin appears to have the most empirical evidence for a role in autism, but this requires further investigation and replication. There is little support for the notion that a dysfunction of norepinephrine or the endogenous opioids are related to autism. The role of dopaminergic functioning has not been compelling thus far, though conflicting findings on central dopamine turnover require further study. Promising new areas of study may include possible dysfunction of the cholinergic system, oxytocin, and amino acid neurotransmitters. Implications for pharmacotherapy are briefly discussed for each neurotransmitter system with brief research examples. Review of this work emphasizes the need for future studies to control for subject variables, such as race, sex, pubertal status, and distress associated with blood draws, which can affect measures of neurochemical function. In addition, research in neurochemistry must continue to work in concert with other subspecialties to form a more comprehensive and theory-based approach to the neurobiological correlates of autistic disorder.

Canagliflozin prevents scopolamine-induced memory impairment in rats: Comparison with galantamine hydrobromide action.

PubMed

Arafa, Nadia M S; Ali, Elham H A; Hassan, Mohamed Kamel

2017-11-01

Canagliflozin (CAN) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated to improve glycemic control in adults with type 2 diabetes mellitus. There is a little information about its effect on the cholinergic system that proposed mechanism for memory improvement occurring by SGLT2 drugs. This study aimed to estimate the effect of CAN as compared to galantamine (GAL) treatments for two weeks on scopolamine hydrobromide (SCO)-induced memory dysfunction in experimental rats. Animals divided into six groups; control (CON), CAN, GAL, SCO, SCO + CAN and SCO + GAL. Results indicated significant decrease in body weights of the CAN groups as compared to control values. Moreover, in the SCO + CAN and SCO + GAL the number of arm entry and number of correct alternation in Y maze task increased and showed improvement in the water maze task, acetylcholinesterase (AChE) activities decreased significantly, while monoamines levels significantly increased compared with the SCO group values. Results also recorded acetylcholine M1 receptor (M1 mAChR) in SCO + CAN or SCO + GAL groups in comparison with the SCO group. The study suggested that canagliflozin might improve memory dysfunction induced by scopolamine hydrobromide via cholinergic and monoamines system. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Dual autonomic inhibitory action of central Apelin on gastric motor functions in rats.

PubMed

Bülbül, Mehmet; Sinen, Osman

2018-07-01

Centrally administered apelin has been shown to inhibit gastric emptying (GE) in rodents, however, the relevant mechanism has been investigated incompletely. Using male Wistar rats, we investigated the efferent pathways involved in gastroinhibitory action of central apelin. Stereotaxic intracerebroventricular (icv) cannulation, subdiaphragmatic vagotomy (VGX) and/or celiac ganglionectomy (CGX) were performed 7 days prior to the experiments. Apelin-13 was administered (30 nmol, icv) 90 min prior to GE measurement. Nitric oxide synthase inhibitor L-NAME (100 mg/kg), sympatholytic agent guanethidine (5 mg/kg) and/or muscarinic receptor agonist bethanechol (1 mg/kg) were administered intraperitoneally 30 min prior to the central apelin-13 injection. Two strain gages were implanted serosally onto antrum and pylorus to monitor gastric postprandial motility. Heart rate variability (HRV) analysis was performed before and after central vehicle or apelin-13 administration. Apelin-13 delayed solid GE significantly by disturbing coordinated antral and pyloric postprandial contractions. The apelin-induced delayed GE was attenuated partially by CGX or VGX, whereas it was restored completely in rats underwent both CGX and VGX. L-NAME did not change the apelin-induced alterations. Guanethidine or bethanechol restored the apelin-induced gastroinhibition partially, while it was abolished completely in rats received both agents. Apelin-13 decreased the HRV spectral activity in high-frequency range by increasing low-frequency component and the ratio of LF:HF. The present data suggest that (1) both vagal parasympathetic and sympathetic pathways play a role in apelin-induced gastroinhibition, (2) central apelin attenuates vagal cholinergic pathway rather than activating nonadrenergic-noncholinergic pathway. Apelin/APJ receptor system might be candidate for the treatment of autonomic dysfunction and gastrointestinal motor disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

The effect of centrally injected CDP-choline on respiratory system; involvement of phospholipase to thromboxane signaling pathway.

PubMed

Topuz, Bora B; Altinbas, Burcin; Yilmaz, Mustafa S; Saha, Sikha; Batten, Trevor F; Savci, Vahide; Yalcin, Murat

2014-05-01

CDP-choline is an endogenous metabolite in phosphatidylcholine biosynthesis. Exogenous administration of CDP-choline has been shown to affect brain metabolism and to exhibit cardiovascular, neuroendocrine neuroprotective actions. On the other hand, little is known regarding its respiratory actions and/or central mechanism of its respiratory effect. Therefore the current study was designed to investigate the possible effects of centrally injected CDP-choline on respiratory system and the mediation of the central cholinergic receptors and phospholipase to thromboxane signaling pathway on CDP-choline-induced respiratory effects in anaesthetized rats. Intracerebroventricularly (i.c.v.) administration of CDP-choline induced dose- and time-dependent increased respiratory rates, tidal volume and minute ventilation of male anaesthetized Spraque Dawley rats. İ.c.v. pretreatment with atropine failed to alter the hyperventilation responses to CDP-choline whereas mecamylamine, cholinergic nicotinic receptor antagonist, mepacrine, phospholipase A2 inhibitor, and neomycin phospholipase C inhibitor, blocked completely the hyperventilation induced by CDP-choline. In addition, central pretreatment with furegrelate, thromboxane A2 synthesis inhibitor, also partially blocked CDP-choline-evoked hyperventilation effects. These data show that centrally administered CDP-choline induces hyperventilation which is mediated by activation of central nicotinic receptors and phospholipase to thromboxane signaling pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

[Modulation of the cholinergic system during inflammation].

PubMed

Nezhinskaia, G I; Vladykin, A L; Sapronov, N S

2008-01-01

This review describes the effects of realization of the central and peripheral "cholinergic antiinflammatory pathway" in a model of endotoxic and anaphylactic shock. Under endotoxic shock conditions, a pharmacological correction by means of the central m-cholinomimetic action (electrical stimulation of the distal ends of nervus vagus after bilateral cervical vagotomy, surgical implantation of the stimulant devise, activation of efferent vagal neurons by means of muscarinic agonist) is directed toward the elimination of LPS-induced hypotension. During the anaphylaxis, peripheral effects of the cholinergic system induced by blocking m-AChR on the target cells (neuronal and non-neuronal lung cells) and acetylcholinesterase inhibition are related to suppression of the bronchoconstrictor response. The role of immune system in the pathogenesis of endotoxic shock is associated with the production of proinflammatory cytokines by macrophages, increase in IgM concentration, and complement activation, while the role in the pathogenesis of anaphylactic shock is associated with IgE, IgG1 augmentation. Effects of B cell stimulation may be important in hypoxia and in the prophylaxis of stress ulcers and other diseases. Plasma proteins can influence the effects of the muscarinic antagonist methacine: IgG enhance its action while albumin and CRP abolish it.

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.

[Condition of neurohumoral regulation of bronchial tone and gallbladder in patients with chronic cholecystitis and chronic obstructive pulmonary disease].

PubMed

Dudka, T V; Khukhlina, O S; Dudka, I V

2014-01-01

SUMMARY The paper presents data from a study of the neuroendocrine regulation of nonstriated muscles, bronchial tree and the gallbladder tones by means of an assessment of the adrenergic and cholinergic systems state in patients, suffering from chronic obstructive pulmonary disease and chronic acalculous cholecystitis. Adrenergic and cholinergic activities as well as cortisol secretion have significantly changed. To study the features of adrenergic and cholinergic regulations of bronchial tone and that of the gallbladder in patients with combined course of chronic acalculous cholecystitis and chronic obstructive pulmonary disease. 92 patients were involved in the study: 30 patients with COPD (1st group), 30 patients with COPD of comorbid CAC in the acute phase (2nd group), 32 patients with CAC in the acute phase (3rd group) and a control group--30 practically healthy individuals (PHI) of the respective age. All the patients with COPD and COPD combined with CAC had a marked predominance of the parasympathetic nervous system, as evidenced by the established significant decrease of CDE (Table) in patients with isolated COPD is 1.4 times (p < 0.05), in patients with COPD combined with CAC--there was more intense inhibition of enzyme activity--in 1.8 times (p < 0.05) and in patients with CAC of the 3rd group there were identical changes--a decreased activity of CDE in 1.6 times (p < 0.05) with significant intergroup differences between the groups (p < 0.05). An analysis of the studies showed significant changes in the CDE of the surveyed individuals. For instance, the CDA in the individuals of groups 1 and 2 was lower by 1.6 and 2.4 times respectively (p < 0.001) than in the group of PHI; in the patients of the 3rd group--the changes were minor--a decline of 14.6% (p < 0.05) compared with practically healthy individuals (Table). Participation of sympathoadrenal system in the pathogenesis of COPD occurrence has been proved, however, in patients with COPD and CAC, the ability to deposit CA, when combined with CAC has significantly dropped. The study of cortisol density in the blood serum of the patients under examination showed its significant drop in all groups observed. For instance, the first group patients' blood contained 2.7 times (p < 0.05) less cortisol than that of PHI; in the patients of the second group the inhibition of the functional state of the adrenal cortex was even more intense--cortisol was lower than its index in the control group by 3.7 times (p < 0.05); the 3d group patients had the maximum drop in cortisol secretion by 1.7 times (p < 0.05) with reliable intergroup difference. The base of regulatory neuroendocrine and paracrine mecganisms imbalance, contributing to a development of COPD, is the cholinergic imbalance (reduction in blood acetylcholinesterase activity, hypertensive sphincter of Oddi dysfunction), adrenergic imbalance, reduction in catecholamine-depositing erythrocytes function, hypokinetic gallbladder dysfunction, adrenal dysfunction (decreased cortisol levels) that contribute to the development and progression of chronic cholecystitis against a background of hypokinetic gallbladder dysfunction.

C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation

PubMed Central

Matsui, Toshiyasu; Hongo, Yu; Haizuka, Yoshinori; Kaida, Kenichi; Matsumura, George; Martin, Donna M.; Kobayashi, Yasushi

2013-01-01

Large cholinergic synaptic boutons called "C-terminals" contact motoneurons and regulate their excitability. C-terminals in the spinal somatic motor nuclei originate from cholinergic interneurons in laminae VII and X that express a transcription factor Pitx2. Cranial motor nuclei contain another type of motoneuron: branchiomotor neurons. Although branchiomotor neurons receive abundant C-terminal projections, the neural source of these C-terminals remains unknown. In the present study, we first examined whether cholinergic neurons express Pitx2 in the reticular formation of the adult mouse brainstem, as in the spinal cord. Although Pitx2-positive cholinergic neurons were observed in the magnocellular reticular formation and region around the central canal in the caudal medulla, none was present more rostrally in the brainstem tegmentum. We next explored the origin of C-terminals in the branchiomotor nuclei by using biotinylated dextran amine (BDA). BDA injections into the magnocellular reticular formation of the medulla and pons resulted in the labeling of numerous C-terminals in the branchiomotor nuclei: the ambiguous, facial, and trigeminal motor nuclei. Our results revealed that the origins of C-terminals in the branchiomotor nuclei are cholinergic neurons in the magnocellular reticular formation not only in the caudal medulla, but also at more rostral levels of the brainstem, which lacks Pitx2-positive neurons. PMID:23756176

The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study.

PubMed

Liu, Shu-Ying; Wile, Daryl J; Fu, Jessie Fanglu; Valerio, Jason; Shahinfard, Elham; McCormick, Siobhan; Mabrouk, Rostom; Vafai, Nasim; McKenzie, Jess; Neilson, Nicole; Perez-Soriano, Alexandra; Arena, Julieta E; Cherkasova, Mariya; Chan, Piu; Zhang, Jing; Zabetian, Cyrus P; Aasly, Jan O; Wszolek, Zbigniew K; McKeown, Martin J; Adam, Michael J; Ruth, Thomas J; Schulzer, Michael; Sossi, Vesna; Stoessl, A Jon

2018-04-01

Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N- 11 C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

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.

Transient cardiac effects in a child with acute cholinergic syndrome due to rivastigmine poisoning.

PubMed

Raucci, Umberto; Vanacore, Nicola; Cecchetti, Corrado; Russo, Mario Salvatore; Rossi, Rossella; Pirozzi, Nicola

2014-07-01

We report a case of rivastigmine poisoning resulting in a full cholinergic syndrome with nicotinic, muscarinic, and central effects requiring supportive or intensive care in a pediatric patient. A 3-year-old girl was admitted to the Emergency Department suspected of having ingested one or two pills of rivastigmine. The child was hyporeactive, with symptoms of altered mental status, sialorrhea, sweating, and diarrhea. Subsequently, she started showing signs of respiratory failure, severe tracheobronchial involvement, and gastric and abdominal distension. An electrocardiogram recorded frequent monomorphic ventricular ectopic beats with bigeminy and trigeminy. Long-term follow-up showed a transient dysrhythmia. Poisoning with rivastigmine can be a life-threatening condition. Timely identification and appropriate management of the toxic effects of this drug are essential and often life-saving. This is particularly true in cases of cholinergic syndrome subsequent to drug poisoning. Patients with cholinergic syndrome should also be assessed for possible cardiac complications such as dysrhythmias. The main factors predisposing to the development of such complications are autonomic disorder, hypoxemia, acidosis, and electrolyte imbalance. Copyright © 2014 Elsevier Inc. All rights reserved.

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

PubMed

Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

2016-12-01

Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

PubMed Central

Wonnacott, Susan

2011-01-01

Parkinson's disease is a debilitating movement disorder characterized by a generalized dysfunction of the nervous system, with a particularly prominent decline in the nigrostriatal dopaminergic pathway. Although there is currently no cure, drugs targeting the dopaminergic system provide major symptomatic relief. As well, agents directed to other neurotransmitter systems are of therapeutic benefit. Such drugs may act by directly improving functional deficits in these other systems, or they may restore aberrant motor activity that arises as a result of a dopaminergic imbalance. Recent research attention has focused on a role for drugs targeting the nicotinic cholinergic systems. The rationale for such work stems from basic research findings that there is an extensive overlap in the organization and function of the nicotinic cholinergic and dopaminergic systems in the basal ganglia. In addition, nicotinic acetylcholine receptor (nAChR) drugs could have clinical potential for Parkinson's disease. Evidence for this proposition stems from studies with experimental animal models showing that nicotine protects against neurotoxin-induced nigrostriatal damage and improves motor complications associated with l-DOPA, the “gold standard” for Parkinson's disease treatment. Nicotine interacts with multiple central nervous system receptors to generate therapeutic responses but also produces side effects. It is important therefore to identify the nAChR subtypes most beneficial for treating Parkinson's disease. Here we review nAChRs with particular emphasis on the subtypes that contribute to basal ganglia function. Accumulating evidence suggests that drugs targeting α6β2* and α4β2* nAChR may prove useful in the management of Parkinson's disease. PMID:21969327

Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits.

PubMed

Davie, Briana J; Christopoulos, Arthur; Scammells, Peter J

2013-07-17

Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues.

Chronic Neuropsychological Sequelae of Cholinesterase Inhibitors in the Absence of Structural Brain Damage: Two Cases of Acute Poisoning

PubMed Central

Roldán-Tapia, Lola; Leyva, Antonia; Laynez, Francisco; Santed, Fernando Sánchez

2005-01-01

Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers. PMID:15929901

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.

N-Benzoyl-D-phenylalanine attenuates brain acetylcholinesterase in neonatal streptozotocin-diabetic rats.

PubMed

Ashokkumar, Natarajan; Pari, Leelavinothan; Ramkumar, Kunga Mohan

2006-09-01

The effect of hyperglycaemia due to experimental diabetes in male Wistar rats causes a decrease in the level of acetylcholinesterase (AChE) with significant increase in lipid peroxidative markers: thiobarbituric acid-reactive substances (TBARS) and hydroperoxides in brains of experimental animals. The decreased activity of both salt soluble and detergent soluble acetylcholinesterase observed in diabetes may be attributed to lack of insulin which causes specific alterations in the level of neurotransmitter, thus causing brain dysfunction. Administration of non-sulfonylurea drug N-benzoyl-D-phenylalanine (NBDP) could protect against direct action of lipid peroxidation on brain AChE and in this way it might be useful in the prevention of cholinergic neural dysfunction, which is one of the major complications in diabetes.

Brain cholinergic involvement during the rapid development of tolerance to morphine

NASA Technical Reports Server (NTRS)

Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

1987-01-01

The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

Cholinergic, serotoninergic and peptidergic components of the nervous system of Discocotyle sagittata (Monogenea:Polyopisthocotylea).

PubMed

Cable, J; Marks, N J; Halton, D W; Shaw, C; Johnston, C F; Tinsley, R C; Gannicott, A M

1996-12-01

Cholinergic, serotoninergic (5-HT) and peptidergic neuronal pathways have been demonstrated in both central and peripheral nervous systems of adult Discocotyle sagittata, using enzyme histochemistry and indirect immunocytochemistry in conjunction with confocal scanning laser microscopy. Antisera to 2 native flatworm neuropeptides, neuropeptide F and the FMRFamide-related peptide (FaRP), GNFFRFamide, were employed to detect peptide immunoreactivity. The CNS is composed of paired cerebral ganglia and connecting dorsal commissure, together with several paired longitudinal nerve cords. The main longitudinal nerve cords (lateral, ventral and dorsal) are interconnected at intervals by a series of annular cross-connectives, producing a ladder-like arrangement typical of the platyhelminth nervous system. At the level of the haptor, the ventral cords provide nerve roots which innervate each of the 9 clamps. Cholinergic and peptidergic neuronal organisation was similar, but distinct from that of the serotoninergic components. The PNS and reproductive system are predominantly innervated by peptidergic neurones.

Tiliacora triandra, an Anti-Intoxication Plant, Improves Memory Impairment, Neurodegeneration, Cholinergic Function, and Oxidative Stress in Hippocampus of Ethanol Dependence Rats.

PubMed

Phunchago, Nattaporn; Wattanathorn, Jintanaporn; Chaisiwamongkol, Kowit

2015-01-01

Oxidative stress plays an important role in brain dysfunctions induced by alcohol. Since less therapeutic agent against cognitive deficit and brain damage induced by chronic alcohol consumption is less available, we aimed to assess the effect of Tiliacora triandra extract, a plant possessing antioxidant activity, on memory impairment, neuron density, cholinergic function, and oxidative stress in hippocampus of alcoholic rats. Male Wistar rats were induced ethanol dependence condition by semivoluntary intake of alcohol for 15 weeks. Alcoholic rats were orally given T. triandra at doses of 100, 200, and 400 mg·kg(-1)BW for 14 days. Memory assessment was performed every 7 days while neuron density, activities of AChE, SOD, CAT, and GSH-Px and, MDA level in hippocampus were assessed at the end of study. Interestingly, the extract mitigated the increased escape latency, AChE and MDA level. The extract also mitigated the decreased retention time, SOD, CAT, and GSH-Px activities, and neurons density in hippocampus induced by alcohol. These data suggested that the extract improved memory deficit in alcoholic rats partly via the decreased oxidative stress and the suppression of AChE. Therefore, T. triandra is the potential reagent for treating brain dysfunction induced by alcohol. However, further researches are necessary to understand the detail mechanism and possible active ingredient.

Slow Cholinergic Modulation of Spike Probability in Ultra-Fast Time-Coding Sensory Neurons

PubMed Central

Goyer, David; Kurth, Stefanie; Rübsamen, Rudolf

2016-01-01

Abstract Sensory processing in the lower auditory pathway is generally considered to be rigid and thus less subject to modulation than central processing. However, in addition to the powerful bottom-up excitation by auditory nerve fibers, the ventral cochlear nucleus also receives efferent cholinergic innervation from both auditory and nonauditory top–down sources. We thus tested the influence of cholinergic modulation on highly precise time-coding neurons in the cochlear nucleus of the Mongolian gerbil. By combining electrophysiological recordings with pharmacological application in vitro and in vivo, we found 55–72% of spherical bushy cells (SBCs) to be depolarized by carbachol on two time scales, ranging from hundreds of milliseconds to minutes. These effects were mediated by nicotinic and muscarinic acetylcholine receptors, respectively. Pharmacological block of muscarinic receptors hyperpolarized the resting membrane potential, suggesting a novel mechanism of setting the resting membrane potential for SBC. The cholinergic depolarization led to an increase of spike probability in SBCs without compromising the temporal precision of the SBC output in vitro. In vivo, iontophoretic application of carbachol resulted in an increase in spontaneous SBC activity. The inclusion of cholinergic modulation in an SBC model predicted an expansion of the dynamic range of sound responses and increased temporal acuity. Our results thus suggest of a top–down modulatory system mediated by acetylcholine which influences temporally precise information processing in the lower auditory pathway. PMID:27699207

C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation.

PubMed

Matsui, Toshiyasu; Hongo, Yu; Haizuka, Yoshinori; Kaida, Kenichi; Matsumura, George; Martin, Donna M; Kobayashi, Yasushi

2013-08-26

Large cholinergic synaptic boutons called "C-terminals" contact motoneurons and regulate their excitability. C-terminals in the spinal somatic motor nuclei originate from cholinergic interneurons in laminae VII and X that express a transcription factor Pitx2. Cranial motor nuclei contain another type of motoneuron: branchiomotor neurons. Although branchiomotor neurons receive abundant C-terminal projections, the neural source of these C-terminals remains unknown. In the present study, we first examined whether cholinergic neurons express Pitx2 in the reticular formation of the adult mouse brainstem, as in the spinal cord. Although Pitx2-positive cholinergic neurons were observed in the magnocellular reticular formation and region around the central canal in the caudal medulla, none was present more rostrally in the brainstem tegmentum. We next explored the origin of C-terminals in the branchiomotor nuclei by using biotinylated dextran amine (BDA). BDA injections into the magnocellular reticular formation of the medulla and pons resulted in the labeling of numerous C-terminals in the branchiomotor nuclei: the ambiguous, facial, and trigeminal motor nuclei. Our results revealed that the origins of C-terminals in the branchiomotor nuclei are cholinergic neurons in the magnocellular reticular formation not only in the caudal medulla, but also at more rostral levels of the brainstem, which lacks Pitx2-positive neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats.

PubMed

Kenny, Jonathan D; Chemali, Jessica J; Cotten, Joseph F; Van Dort, Christa J; Kim, Seong-Eun; Ba, Demba; Taylor, Norman E; Brown, Emery N; Solt, Ken

2016-11-01

Although emergence from general anesthesia is clinically treated as a passive process driven by the pharmacokinetics of drug clearance, agents that hasten recovery from general anesthesia may be useful for treating delayed emergence, emergence delirium, and postoperative cognitive dysfunction. Activation of central monoaminergic neurotransmission with methylphenidate has been shown to induce reanimation (active emergence) from general anesthesia. Cholinergic neurons in the brainstem and basal forebrain are also known to promote arousal. The objective of this study was to test the hypothesis that physostigmine, a centrally acting cholinesterase inhibitor, induces reanimation from isoflurane anesthesia in adult rats. The dose-dependent effects of physostigmine on time to emergence from a standardized isoflurane general anesthetic were tested. It was then determined whether physostigmine restores righting during continuous isoflurane anesthesia. In a separate group of rats with implanted extradural electrodes, physostigmine was administered during continuous inhalation of 1.0% isoflurane, and the electroencephalogram changes were recorded. Finally, 2.0% isoflurane was used to induce burst suppression, and the effects of physostigmine and methylphenidate on burst suppression probability (BSP) were tested. Physostigmine delayed time to emergence from isoflurane anesthesia at doses ≥0.2 mg/kg (n = 9). During continuous isoflurane anesthesia (0.9% ± 0.1%), physostigmine did not restore righting (n = 9). Blocking the peripheral side effects of physostigmine with the coadministration of glycopyrrolate (a muscarinic antagonist that does not cross the blood-brain barrier) produced similar results (n = 9 each). However, during inhalation of 1.0% isoflurane, physostigmine shifted peak electroencephalogram power from δ (<4 Hz) to θ (4-8 Hz) in 6 of 6 rats. During continuous 2.0% isoflurane anesthesia, physostigmine induced large, statistically significant decreases in BSP in 6 of 6 rats, whereas methylphenidate did not. Unlike methylphenidate, physostigmine does not accelerate time to emergence from isoflurane anesthesia and does not restore righting during continuous isoflurane anesthesia. However, physostigmine consistently decreases BSP during deep isoflurane anesthesia, whereas methylphenidate does not. These findings suggest that activation of cholinergic neurotransmission during isoflurane anesthesia produces arousal states that are distinct from those induced by monoaminergic activation.

The effect of aniracetam on cerebral glucose metabolism in rats after lesioning of the basal forebrain measured by PET.

PubMed

Ouchi, Y; Kakiuchi, T; Okada, H; Nishiyama, S; Tsukada, H

1999-03-15

To evaluate the effect of aniracetam, a potent modulator of the glutamatergic and cholinergic systems, on the altered cerebral glucose metabolism after lesioning of the basal forebrain, we measured the cerebral metabolic rate of glucose (CMRGlc) with positron emission tomography and the choline acetyltransferase (ChAT) activity in the frontal cortex of the lesioned rats after treating them with aniracetam. Continuous administration of aniracetam for 7 days after the surgery prevented CMRGlc reduction in the frontal cortex ipsilateral to the lesion while the lesioned rats without aniracetam showed significant CMRGlc reduction in the frontal cortex. The level of CMRGlc in the lesion-side basal forebrain was lower in all rats regardless of the aniracetam treatment. Biochemical studies showed that aniracetam did not alter the reduction in the frontal ChAT activity. These results showed that aniracetam prevents glucose metabolic reduction in the cholinergically denervated frontal cortex with little effect on the cortical cholinergic system. The present study suggested that a neurotransmitter system other than the cholinergic system, e.g. the glutamatergic system, plays a central role in the cortical metabolic recovery after lesioning of the basal forebrain.

Effects of Pro-Cholinergic Treatment in Patients Suffering from Spatial Neglect

PubMed Central

Lucas, N.; Saj, A.; Schwartz, S.; Ptak, R.; Thomas, C.; Conne, P.; Leroy, R.; Pavin, S.; Diserens, K.; Vuilleumier, Patrik

2013-01-01

Spatial neglect is a neurological condition characterized by a breakdown of spatial cognition contralateral to hemispheric damage. Deficits in spatial attention toward the contralesional side are considered to be central to this syndrome. Brain lesions typically involve right fronto-parietal cortices mediating attentional functions and subcortical connections in underlying white matter. Convergent findings from neuroimaging and behavioral studies in both animals and humans suggest that the cholinergic system might also be critically implicated in selective attention by modulating cortical function via widespread projections from the basal forebrain. Here we asked whether deficits in spatial attention associated with neglect could partly result from a cholinergic deafferentation of cortical areas subserving attentional functions, and whether such disturbances could be alleviated by pro-cholinergic therapy. We examined the effect of a single-dose transdermal nicotine treatment on spatial neglect in 10 stroke patients in a double-blind placebo-controlled protocol, using a standardized battery of neglect tests. Nicotine-induced systematic improvement on cancellation tasks and facilitated orienting to single visual targets, but had no significant effect on other tests. These results support a global effect of nicotine on attention and arousal, but no effect on other spatial mechanisms impaired in neglect. PMID:24062674

Alzheimer's Disease: Targeting the Cholinergic System

PubMed Central

Ferreira-Vieira, Talita H.; Guimaraes, Isabella M.; Silva, Flavia R.; Ribeiro, Fabiola M.

2016-01-01

Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer’s disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients. PMID:26813123

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.

Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning.

PubMed

Masson, Patrick; Nachon, Florian

2017-08-01

Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for post-exposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre- and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

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.

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.

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

Inhaled ammonium persulphate inhibits non-adrenergic, non-cholinergic relaxations in the guinea pig isolated trachea.

PubMed

Dellabianca, A; Faniglione, M; De Angelis, S; Colucci, M; Cervio, M; Balestra, B; Tonini, S; Candura, S M

2010-01-01

Persulphates can act both as irritants and sensitizers in inducing occupational asthma. A dysfunction of nervous control regulating the airway tone has been hypothesized as a mechanism underlying bronchoconstriction in asthma. It was the aim of this study to investigate whether inhaled ammonium persulphate affects the non-adrenergic, non-cholinergic (NANC) inhibitory innervation, the cholinergic nerve-mediated contraction or the muscular response to the spasmogens, carbachol or histamine, in the guinea pig epithelium-free, isolated trachea. Male guinea pigs inhaled aerosols containing ammonium persulphate (10 mg/m(3) for 30 min for 5 days during 3 weeks). Control animals inhaled saline aerosol. NANC relaxations to electrical field stimulation at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Drugs inactivating peptide transmission, nitric oxide synthase, carbon monoxide production by haem oxygenase-2 and soluble guanylyl cyclase were used to assess the involvement of various inhibitory neurotransmitters. Carbachol and histamine cumulative concentration-response curves were obtained. In both groups, nitric oxide and carbon monoxide participated to the same extent as inhibitory neurotransmitters. In exposed animals, the tracheal NANC relaxations were reduced to 45.9 +/- 12.1% (p < 0.01). The cholinergic nerve-mediated contractions to electrical field stimulation and the muscular response to histamine were not modified by ammonium persulphate exposure. The muscular response to carbachol was unaffected up to 1 microM. Conversely, the response to the maximal concentration of carbachol (3 microM) was increased (p < 0.01). Ammonium persulphate inhalation at high concentrations impairs the nervous NANC inhibitory control in the guinea pig airways. This may represent a novel mechanism contributing to persulphate-induced asthma. Copyright 2009 S. Karger AG, Basel.

SN56 neuronal cell death after 24 h and 14 days chlorpyrifos exposure through glutamate transmission dysfunction, increase of GSK-3β enzyme, β-amyloid and tau protein levels.

PubMed

Moyano, Paula; Frejo, María Teresa; Anadon, María José; García, José Manuel; Díaz, María Jesús; Lobo, Margarita; Sola, Emma; García, Jimena; Del Pino, Javier

2018-06-01

Chlorpyrifos (CPF) is an organophosphate insecticide described to induce cognitive disorders, both after acute and repeated administration. However, the mechanisms through which it induces these effects are unknown. CPF has been reported to produce basal forebrain cholinergic neuronal cell death, involved on learning and memory regulation, which could be the cause of such cognitive disorders. Neuronal cell death was partially mediated by oxidative stress generation, P75 NTR and α 7 -nAChRs gene expression alteration triggered through acetylcholinesterase (AChE) variants disruption, suggesting other mechanisms are involved. In this regard, CPF induces Aβ and tau proteins production and activation of GSK3β enzyme and alters glutamatergic transmission, which have been related with basal forebrain cholinergic neuronal cell death and development of cognitive disorders. According to these data, we hypothesized that CPF induces basal forebrain cholinergic neuronal cell death through induction of Aβ and tau proteins production, activation of GSK-3β enzyme and disruption of glutamatergic transmission. We evaluated this hypothesis in septal SN56 basal forebrain cholinergic neurons, after 24 h and 14 days CPF exposure. This study shows that CPF increases glutamate levels, upregulates GSK-3β gene expression, and increases the production of Aβ and phosphorylated tau proteins and all these effects reduced cell viability. CPF increases glutaminase activity and upregulates the VGLUT1 gene expression, which could mediate the disruption of glutamatergic transmission. Our present results provide new understanding of the mechanisms contributing to the harmful effects of CPF, and its possible relevance in the pathogenesis of neurodegenerative diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.

DTIC Science & Technology

1983-09-30

Pathways; GABAergic Pathway; Atropine; Reserpine; Alphamethylparatyrosine; Oxotremorine ; Feedback 20 ABSTRACT (Continue on reverse side It necessary and...see Preface). The purpose was the compare the regional distribution of the effect of anticholinesterases with oxotremorine ),a selective centrally...hippocampus, differently from oxotremorine which was ineffective. In the other two regions, physostigmine and oxotremorine were equally active. At the

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

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

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.

An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment

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

Pauly, J.R.; Marks, M.J.; Gross, S.D.

1991-09-01

Quantitative autoradiographic procedures were used to examine the effects of chronic nicotine infusion on the number of central nervous system nicotinic cholinergic receptors. Female DBA mice were implanted with jugular cannulas and infused with saline or various doses of nicotine (0.25, 0.5, 1.0 or 2.0 mg/kg/hr) for 10 days. The animals were then sacrificed and the brains were removed and frozen in isopentane. Cryostat sections were collected and prepared for autoradiographic procedures as previously described. Nicotinic cholinergic receptors were labeled with L-(3H)nicotine or alpha-(125I)bungarotoxin; (3H)quinuclidinyl benzilate was used to measure muscarinic cholinergic receptor binding. Chronic nicotine infusion increased the numbermore » of sites labeled by (3H)nicotine in most brain areas. However, the extent of the increase in binding as well as the dose-response curves for the increase were widely different among brain regions. After the highest treatment dose, binding was increased in 67 of 86 regions measured. Septal and thalamic regions were most resistant to change. Nicotinic binding measured by alpha-(125I)bungarotoxin also increased after chronic treatment, but in a less robust fashion. At the highest treatment dose, only 26 of 80 regions were significantly changes. Muscarinic binding was not altered after chronic nicotine treatment. These data suggest that brain regions are not equivalent in the mechanisms that regulate alterations in nicotinic cholinergic receptor binding after chronic nicotine treatment.« less

Possible role of acetylcholine in regulating spatial novelty effects on theta rhythm and grid cells

PubMed Central

Barry, Caswell; Heys, James G.; Hasselmo, Michael E.

2012-01-01

Existing pharmacological and lesion data indicate that acetylcholine plays an important role in memory formation. For example, increased levels of acetylcholine in the hippocampal formation are known to be associated with successful encoding while disruption of the cholinergic system leads to impairments on a range of mnemonic tasks. However, cholinergic signaling from the medial septum also plays a central role in generating and pacing theta-band oscillations throughout the hippocampal formation. Recent experimental results suggest a potential link between these distinct phenomena. Environmental novelty, a condition associated with strong cholinergic drive, has been shown to induce an expansion in the firing pattern of entorhinal grid cells and a reduction in the frequency of theta measured from the LFP. Computational modeling suggests the spatial activity of grid cells is produced by interference between neuronal oscillators; scale being determined by theta-band oscillations impinging on entorhinal stellate cells, the frequency of which is modulated by acetylcholine. Here we propose that increased cholinergic signaling in response to environmental novelty triggers grid expansion by reducing the frequency of the oscillations. Furthermore, we argue that cholinergic induced grid expansion may enhance, or even induce, encoding by producing a mismatch between expanded grid cells and other spatial inputs to the hippocampus, such as boundary vector cells. Indeed, a further source of mismatch is likely to occur between grid cells of different native scales which may expand by different relative amounts. PMID:22363266

Cholinergic modulation of event-related oscillations (ERO)

PubMed Central

Sanchez-Alavez, Manuel; Robledo, Patricia; Wills, Derek N.; Havstad, James; Ehlers, Cindy L.

2014-01-01

The cholinergic system in the brain modulates patterns of activity involved in general arousal, attention processing, memory and consciousness. In the present study we determined the effects of selective cholinergic lesions of the medial septum area (MS) or nucleus basalis magnocellularis (NBM) on amplitude and phase characteristics of event related oscillations (EROs). A time–frequency based representation was used to determine ERO energy, phase synchronization across trials, recorded within a structure (phase lock index, PLI), and phase synchronization across trials, recorded between brain structures (phase difference lock index, PDLI), in the frontal cortex (Fctx), dorsal hippocampus (DHPC) and central amygdala (Amyg). Lesions in MS produced: (1) decreases in ERO energy in delta, theta, alpha, beta and gamma frequencies in Amyg, (2) reductions in gamma ERO energy and PLI in Fctx, (3) decreases in PDLI between the Fctx–Amyg in the theta, alpha, beta and gamma frequencies, and (4) decreases in PDLI between the DHPC–Amyg and Fctx–DHPC in the theta frequency bands. Lesions in NBM resulted in: (1) increased ERO energy in delta and theta frequency bands in Fctx, (2) reduced gamma ERO energy in Fctx and Amyg, (3) reductions in PLI in the theta, beta and gamma frequency ranges in Fctx, (4) reductions in gamma PLI in DHPC and (5) reduced beta PLI in Amyg. These studies suggest that the MS cholinergic system can alter phase synchronization between brain areas whereas the NBM cholinergic system modifies phase synchronization/phase resetting within a brain area. PMID:24594019

INCREASED SUSCEPTIBILITY OF THE SPONTANEOUSLY HYPERTENSIVE RAT TO CHLORPYRIFOS, AN ORGANOPHOSPHATE PESTICIDE.

EPA Science Inventory

Hypertension and hypothermia are common symptoms in rats exposed to chlorpyrifos (CHP), an organophosphate (OP)-based pesticide. CHP inhibits acetylcholinesterase (AChE) activity resulting in central and peripheral stimulation of cholinergic pathways involved in blood pressure ...

6,7,4'-Trihydroxyisoflavone, a major metabolite of daidzein, improves learning and memory via the cholinergic system and the p-CREB/BDNF signaling pathway in mice.

PubMed

Ko, Yong-Hyun; Kim, Sun Yeou; Lee, Seok-Yong; Jang, Choon-Gon

2018-05-05

Daidzein is one of the major isoflavfones found in soy food and plants. Following ingestion, daidzein is readily converted to hydroxylated metabolites in the human body. 6,7,4'-Trihydroxyisoflavone (THIF), one of the metabolites of daidzein, has several pharmacological activities, including anti-cancer and anti-obesity properties. However, no reports exist on the effects of 6,7,4'-THIF for cognitive function in mice. The present study aimed to investigate the effects of 6,7,4'-THIF against scopolamine-induced learning and memory impairments using the Y-maze and passive avoidance test. A single administration of 6,7,4'-THIF significantly improved scopolamine-induced cognitive dysfunction in these in vivo tests. Moreover, treatment with 6,7,4'-THIF alone enhanced learning and memory performance in the same behavioral tests. Molecular studies showed that 6,7,4'-THIF significantly inhibited acetylcholinesterase and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus of scopolamine-induced mice. In addition, immunohistochemistry and Western blot results revealed that 6,7,4'-THIF significantly increased brain-derived neurotrophic factor (BDNF) and phosphor cAMP response element binding (CREB) in the hippocampus of mice. Taken together, these findings suggest that 6,7,4'-THIF improves cognitive dysfunction induced by scopolamine and enhances learning and memory by activation of the cholinergic system and the p-CREB/BDNF signaling pathway in mice. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

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.

Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.

PubMed

Das, Devsmita; Phillips, Cristy; Hsieh, Wayne; Sumanth, Krithika; Dang, Van; Salehi, Ahmad

2014-10-03

Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer's disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration. Published by Elsevier Inc.

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.

Commissural NTS lesions enhance the pressor response to central cholinergic and adrenergic activation.

PubMed

Vieira, Alexandre A; De Luca, Laurival A; Colombari, Eduardo; Colombari, Debora S A; Menani, José V

2012-07-11

Electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) in rats enhance the pressor response to bilateral carotid occlusion or to intravenous infusion of hypertonic NaCl without changing baroreflex responses. In an opposite direction, commNTS lesions abolish the pressor responses to peripheral chemoreflex activation. These opposite effects of commNTS lesions apparently result from an impairment of sympathetic activation in one case and in a facilitation of vasopressin secretion in the others. In the present study, we investigated the effects of the electrolytic lesions of the commNTS in the pressor responses that depend on sympathetic activation and vasopressin secretion produced by central cholinergic or adrenergic activation with intracerebroventricular (i.c.v.) injections of carbachol or noradrenaline, respectively, in unanesthetized rats. Male Holtzman rats (280-320 g, n=8-15/group) with acute (1 day) or chronic (21 days) sham or commNTS lesions (1 mA×10 s) and a stainless steel cannula implanted in the lateral ventricle were used. Acute commNTS lesions increased the pressor response to i.c.v. injection of carbachol (0.5 nmol/1μ1) (52 ± 2, vs. sham: 37 ± 2mm Hg) or noradrenaline (80 nmol/1μl) (45 ± 6, vs. sham: 30 ± 3 mm Hg), whereas chronic commNTS lesions did not affect the pressor responses to the same treatments. Lesions of the commNTS impaired chemoreflex responses produced by intravenous KCN, without changing baroreflex responses. The results suggest that commNTS-dependent inhibitory signals are involved in the modulation of the pressor responses to central cholinergic and adrenergic activation, probably limiting vasopressin secretion. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.

PubMed

Alvarez-Jimenez, Ricardo; Groeneveld, Geert Jan; van Gerven, Joop M A; Goulooze, Sebastiaan C; Baakman, Anne Catrien; Hay, Justin L; Stevens, Jasper

2016-10-01

Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min(-1) . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels. © 2016 The British Pharmacological Society.

Model‐based exposure‐response analysis to quantify age related differences in the response to scopolamine in healthy subjects

PubMed Central

Groeneveld, Geert Jan; van Gerven, Joop M. A.; Goulooze, Sebastiaan C.; Baakman, Anne Catrien; Hay, Justin L.; Stevens, Jasper

2016-01-01

Aim Subjects with increasing age are more sensitive to the effects of the anti‐muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age‐dependent pharmacodynamic neuro‐physiologic effects of scopolamine after correcting for differences in individual exposure. Methods We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. Results A two‐compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min−1. Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. Conclusions Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels. PMID:27273555

The nature of neuroendocrine abnormalities in depression: a controversial issue in contemporary psychiatry.

PubMed

von Zerssen, D; Berger, M; Dose, M; Doerr, P; Krieg, C; Bossert, S; Riemann, D; Pirke, K M; Dolhofer, R; Müller, O A

1986-01-01

Neuroendocrine abnormalities in depression have been regarded, by many authors, as relatively specific markers of nosological subtypes of the disorder, e.g. primary vs. secondary, endogenous vs. non-endogenous or unipolar vs. bipolar depression. They should reflect the same changes in central neurotransmitters (e.g. noradrenergic insufficiency and/or cholinergic hyperactivity) that were hypothesized as the cause of clinical symptoms. This view is challenged on the basis of our own neuroendocrine investigations in 317 psychiatric patients and 103 normal controls. According to these studies the abnormalities are nosologically rather unspecific. They are induced by a large variety of factors, e.g. emotional stress associated with the clinical symptomatology, weight loss due to malnutrition as a consequence of reduced appetite, medication and drug withdrawal. Stress-induced hypercortisolism appears to be the most common abnormality that may trigger other neuroendocrine dysfunctions, such as a blunted TSH response to TRH. Differences in neuroendocrine abnormalities of depressives are probably due to variations in the manifold factors influencing the hormonal axes involved, to temporal changes in hormonal patterns (e.g. one abnormality triggering another) and to individual differences in the basic activity and the responsiveness of the various axes.

Choline as an agonist: determination of its agonistic potency on cholinergic receptors.

PubMed

Ulus, I H; Millington, W R; Buyukuysal, R L; Kiran, B K

1988-07-15

These experiments examined the potency of choline as a cholinergic agonist at both muscarinic and nicotinic receptors in rat brain and peripheral tissues. Choline stimulated the contraction of isolated smooth muscle preparations of the stomach fundus, urinary bladder and trachea and reduced the frequency of spontaneous contractions of the right atrium at high micromolar and low millimolar concentrations. The potency of choline to elicit a biological response varied markedly among these tissues; EC50 values ranged between 0.41 mM in the fundus to 14.45 mM in the atrium. Choline also displaced [3H]quinuclidinyl benzilate binding in a concentration-dependent manner although, again, its potency varied among different brain regions (Ki = 1.2 to 3.5 mM) and peripheral tissues (Ki = 0.28 to 3.00 mM). Choline exhibited a comparable affinity for nicotinic receptors. It stimulated catecholamine release from the vascularly perfused adrenal gland (EC50 = 1.3 mM) and displaced L-[3H]nicotine binding to membrane preparations of brain and peripheral tissues (Ki = 0.38 to 1.17 mM). However, the concentration of choline required to bind to cholinergic receptors in most tissues was considerably higher than serum levels either in controls (8-13 microM) or following the administration of choline chloride (200 microM). These results clearly demonstrate that choline is a weak cholinergic agonist. Its potency is too low to account for the central nervous system effects produced by choline administration, although the direct activation of cholinergic receptors in several peripheral tissues may explain some of its side effects.

Antibodies in Cerebrospinal Fluid of Some Alzheimer Disease Patients Recognize Cholinergic Neurons in the Rat Central Nervous System

NASA Astrophysics Data System (ADS)

McRae-Degueurce, Amanda; Booj, Serney; Haglid, Kenneth; Rosengren, Lars; Karlsson, Jan Erik; Karlsson, Ingvar; Wallin, Anders; Svennerholm, Lars; Gottfries, Carl-Gerhard; Dahlstrom, Annica

1987-12-01

The etiology of Alzheimer disease is unclear. However, immunological aberrations have been suggested to be critical factors in the pathogenesis of this neurodegenerative disease. This study was carried out to investigate if cerebrospinal fluid (CSF) from Alzheimer disease patients contains antibodies that recognize specific neuronal populations in the rat central nervous system. The results indicate that in a subgroup of patients this is indeed the case. The antibodies reported in this study have the following properties: (i) they recognize neuronal populations and components in the medial septum and spinal motor neurons in rats perfused with a mixture that fixes small neurotransmitter molecules; (ii) adsorption of the patient CSF with staphylococcal protein A-Sepharose and using a polyclonal antiserum against human IgG3 indicates that the immunocytochemical reaction in these brain regions is mainly due to the subclass IgG3; and (iii) the CSF immunocytochemical reaction is blocked by preincubation of the sections with a rabbit anti-acetylcholine antiserum. These results provide evidence that antibodies in the CSF of some, but not all, Alzheimer disease patients recognize acetylcholine-like epitopes in cholinergic neurons in the rat central nervous system.

Effects of a neurotensin analogue (PD149163) and antagonist (SR142948A) on the scopolamine-induced deficits in a novel object discrimination task.

PubMed

Azmi, Norazrina; Norman, Christine; Spicer, Clare H; Bennett, Geoffrey W

2006-06-01

Various lines of evidence suggest a role in cognition for the endogenous neuropeptide, neurotensin, involving an interaction with the central nervous system cholinergic pathways. A preliminary study has shown that central administration of neurotensin enhances spatial and nonspatial working memory in the presence of scopolamine, a muscarinic receptor antagonist which induces memory deficits. Utilizing similar methods, the present study employed a two-trial novel object discrimination task to determine the acute effect of a neurotensin peptide analogue with improved metabolic stability, PD149163, on recognition memory in Lister hooded rats. Consistent with previous findings with neurotensin, animals receiving an intracerebroventricular injection of PD149163 (3 microg) significantly discriminated the novel from familiar object during the choice trial. In addition, a similar dose of PD149163 restored the scopolamine-induced deficit in novelty recognition. The restoration effect on scopolamine-induced amnesia produced by PD149163 was blocked by SR142948A, a nonselective neurotensin receptor antagonist, at a dose of 1 mg/kg (intraperitonial) but not at 0.1 mg/kg. In conclusion, the present results confirm a role for neurotensin in mediating memory processes, possibly via central cholinergic mechanisms.

Comparative analysis of the organization of the cholinergic system in the brains of two holostean fishes, the Florida gar Lepisosteus platyrhincus and the bowfin Amia calva.

PubMed

Morona, Ruth; López, Jesús M; Northcutt, R Glenn; González, Agustín

2013-01-01

The cholinergic system in the brain has been widely studied in most vertebrate groups, but there is no information available about this neurotransmission system in the brains of holostean fishes, a primitive and poorly understood group of actinopterygian fishes. The present study provides the first detailed information on the distribution of cholinergic cell bodies and fibers in the central nervous system in two holostean species, the Florida gar, Lepisosteus platyrhincus, and the bowfin, Amia calva. Immmunohistochemistry against the enzyme choline acetyltransferase (ChAT) revealed distinct groups of ChAT-immunoreactive (ChAT-ir) cells in the habenula, isthmic nucleus, laterodorsal tegmental nucleus, octavolateral area, reticular formation, cranial nerve motor nuclei and the motor column of the spinal cord, all of which seem to be highly conserved among vertebrates. Some ChAT-ir cells were detected in the basal telencephalon that appear in actinopterygians for the first time in the evolution of this neurotransmission system, whereas the remarkable cholinergic population in the optic tectum is a peculiar characteristic, the presence of which varies throughout evolution, although it is present in all teleosts studied. Abundant cholinergic fibers were found in the pretectal region and optic tectum, where they probably modulate vision, and in the hypothalamus and the interpeduncular neuropil. Some interspecific differences were also observed, such as the presence of ChAT-ir cells in the supraoptoparaventricular band only in Lepisosteus and in in the nucleus subglomerulosus only in Amia. In addition, ChAT-ir fibers in the olfactory bulb were detected only in Amia. Comparison of these results with those from other classes of vertebrates, and a segmental analysis to correlate cell populations, reveal that the pattern of the cholinergic system in holosteans is very close to that in ancestral actinopterygian fishes, as recently described in the bichir (Cladistia), although an important evolutionary novelty in holosteans is the presence of cholinergic cells in the basal telencephalon. Copyright © 2013 S. Karger AG, Basel.

The Brainstem Tau Cytoskeletal Pathology of Alzheimer's Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance.

PubMed

Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Turco, Domenico Del; Seidel, Kay; Dunnen, Wilfred den; Korf, Horst-Werner

2016-01-01

The human brainstem is involved in the regulation of the sleep/waking cycle and normal sleep architectonics and is crucial for the performance of a variety of somatomotor, vital autonomic, oculomotor, vestibular, auditory, ingestive and somatosensory functions. It harbors the origins of the ascending dopaminergic, cholinergic, noradrenergic, serotonergic systems, as well the home base of the descending serotonergic system. In contrast to the cerebral cortex the affection of the brainstem in Alzheimer's disease (AD) by the neurofibrillary or tau cytoskeletal pathology was recognized only approximately fourty years ago in initial brainstem studies. Detailed pathoanatomical investigations of silver stained or tau immunostained brainstem tissue sections revealed nerve cell loss and prominent ADrelated cytoskeletal changes in the raphe nuclei, locus coeruleus, and in the compact parts of the substantia nigra and pedunculopontine nucleus. An additional conspicuous AD-related cytoskeletal pathology was also detected in the auditory brainstem system of AD patients (i.e. inferior colliculus, superior olive, dorsal cochlear nucleus), in the oculomotor brainstem network (i.e. rostral interstitial nucleus of the medial longitudinal fascicle, Edinger-Westphal nucleus, reticulotegmental nucleus of pons), autonomic system (i.e. central and periaqueductal grays, parabrachial nuclei, gigantocellular reticular nucleus, dorsal motor vagal and solitary nuclei, intermediate reticular zone). The alterations in these brainstem nuclei offered for the first time adequate explanations for a variety of less understood disease symptoms of AD patients: Parkinsonian extrapyramidal motor signs, depression, hallucinations, dysfunctions of the sleep/wake cycle, changes in sleeping patterns, attentional deficits, exaggerated pupil dilatation, autonomic dysfunctions, impairments of horizontal and vertical saccades, dysfunctional smooth pursuits. The very early occurrence of the AD-related cytoskeletal pathology in some of these brainstem nuclei points to a major and strategic role of the brainstem in the induction and brain spread of the AD-related cytoskeletal pathology.

Central Processing Dysfunctions in Children: A Review of Research.

ERIC Educational Resources Information Center

Chalfant, James C.; Scheffelin, Margaret A.

Research on central processing dysfunctions in children is reviewed in three major areas. The first, dysfunctions in the analysis of sensory information, includes auditory, visual, and haptic processing. The second, dysfunction in the synthesis of sensory information, covers multiple stimulus integration and short-term memory. The third area of…

Interactions between the Central Nervous System and Pancreatic Islet Secretions: A Historical Perspective

ERIC Educational Resources Information Center

Begg, Denovan P.; Woods, Stephen C.

2013-01-01

The endocrine pancreas is richly innervated with sympathetic and parasympathetic projections from the brain. In the mid-20th century, it was established that alpha-adrenergic activation inhibits, whereas cholinergic stimulation promotes, insulin secretion; this demonstrated the importance of the sympathetic and parasympathetic systems in…

A PERIPHERAL CHOLINERGIC PATHWAY MODULATES STRESS-INDUCED HYPERTHERMIA IN THE RAT EXPOSED TO AN OPEN FIELD.

EPA Science Inventory

Exposure to an open-field is psychologically stressful and leads to an elevation in core temperature (Tc). This increase in Tc associated with open-field is usually referred to as stress-induced hyperthermia (SIH) and can be blocked centrally with cyclooxygenase inhibitors suc...

Orexigenic Hormone Ghrelin Attenuates Local and Remote Organ Injury after Intestinal Ischemia-Reperfusion

PubMed Central

Wu, Rongqian; Dong, Weifeng; Ji, Youxin; Zhou, Mian; Marini, Corrado P.; Ravikumar, Thanjavur S.; Wang, Ping

2008-01-01

Background Gut ischemia/reperfusion (I/R) injury is a serious condition in intensive care patients. Activation of immune cells adjacent to the huge endothelial cell surface area of the intestinal microvasculature produces initially local and then systemic inflammatory responses. Stimulation of the vagus nerve can rapidly attenuate systemic inflammatory responses through inhibiting the activation of macrophages and endothelial cells. Ghrelin, a novel orexigenic hormone, is produced predominately in the gastrointestinal system. Ghrelin receptors are expressed at a high density in the dorsal vagal complex of the brain stem. In this study, we investigated the regulation of the cholinergic anti-inflammatory pathway by the novel gastrointestinal hormone, ghrelin, after gut I/R. Methods and Findings Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery for 90 min in male adult rats. Our results showed that ghrelin levels were significantly reduced after gut I/R and that ghrelin administration inhibited pro-inflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated organ injury, and improved survival after gut I/R. Administration of a specific ghrelin receptor antagonist worsened gut I/R-induced organ injury and mortality. To determine whether ghrelin's beneficial effects after gut I/R require the intact vagus nerve, vagotomy was performed in sham and gut I/R animals immediately prior to the induction of gut ischemia. Our result showed that vagotomy completely eliminated ghrelin's beneficial effect after gut I/R. To further confirm that ghrelin's beneficial effects after gut I/R are mediated through the central nervous system, intracerebroventricular administration of ghrelin was performed at the beginning of reperfusion after 90-min gut ischemia. Our result showed that intracerebroventricular injection of ghrelin also protected the rats from gut I/R injury. Conclusions These findings suggest that ghrelin attenuates excessive inflammation and reduces organ injury after gut I/R through activation of the cholinergic anti-inflammatory pathway. PMID:18431503

Cholinergic Dysfunction in Fragile X Syndrome and Potential Intervention

PubMed Central

Kesler, Shelli R; Lightbody, Amy A; Reiss, Allan L

2009-01-01

Males with fragile X syndrome are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X syndrome and 9 age-matched typically developing controls using 1H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with fragile X syndrome participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for fragile X syndrome and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy. PMID:19215057

Acupuncture Stimulation Alleviates Corticosterone-Induced Impairments of Spatial Memory and Cholinergic Neurons in Rats

PubMed Central

Lee, Bombi; Sur, Bong-Jun; Kwon, Sunoh; Jung, Euntaek; Shim, Insop; Lee, Hyejung; Hahm, Dae-Hyun

2012-01-01

The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT) administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg) once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun) acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36%) and hippocampal CORT level (+204%) compared with saline-treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction. PMID:22216057

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.

Patterns of fast synaptic cholinergic activation of neurons in the celiac ganglia of cats.

PubMed

Niel, J P; Clerc, N; Jule, Y

1988-12-01

Fast nicotinic transmission was studied in vitro in neurons of isolated cat celiac ganglia. In the absence of nerve stimulation, neurons could be classified into three types: silent neurons, synaptically activated neurons, and spontaneously discharging neurons. In all three types, fast synaptic activation could be obtained in single neurons by stimulating with a single pulse both the splanchnic nerves or one of the peripheral nerves connected to the ganglia. During repetitive nerve stimulation, a gradual depression of the central and peripheral fast nicotinic activation occurred, which was not affected by phentolamine plus propranolol, domperidone, atropine, or naloxone. Repetitive nerve stimulation was followed by a long lasting discharge of excitatory postsynaptic potentials and action potentials that decreased gradually with time. This discharge, which was probably due to presynaptic or prejunctional facilitation of acetylcholine release from cholinergic terminals, was reduced by the application of phentolamine plus propranolol, domperidone, or atropine and increased with naloxone. The existence of the mechanisms described in this study reflects the complexity of the integrative processes at work in neurons of the cat celiac ganglia that involve fast synaptic cholinergic activation.

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

A non-invasive system for delivering neural growth factors across the blood-brain barrier: a review.

PubMed

Granholm, A C; Albeck, D; Bäckman, C; Curtis, M; Ebendal, T; Friden, P; Henry, M; Hoffer, B; Kordower, J; Rose, G M; Söderström, S; Bartus, R T

1998-01-01

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment, as well as protect these neurons against a variety of perturbations. Since neurotrophins do not pass the blood-brain barrier (BBB) in significant amounts, a non-invasive delivery system for this group of therapeutic molecules needs to be developed. We have utilized a carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. The biological activity of this carrier system was tested using in vitro bioassays and intraocular transplants; we were able to demonstrate that cholinergic markers in both developing and aged intraocular septal grafts were enhanced by intravenous delivery of the OX-26-NGF conjugate. In subsequent experiments, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate for 6 weeks, resulting in a significant improvement in spatial learning in previously impaired rats, but disrupting the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size as well as an upregulation of both low and high affinity NGF receptors in the medial septal region of rats initially impaired in spatial learning. Finally, OX-26-NGF was able to protect striatal cholinergic neurons against excitotoxicity and basal forebrain cholinergic neurons from degeneration associated with chemically-induced loss of target neurons. These results indicate the potential utility of the transferrin receptor antibody delivery system for treatment of neurodegenerative disorders with neurotrophic substances.

Cholinergic modulation of neuronal excitability in the rat suprachiasmatic nucleus.

PubMed

Yang, Jyh-Jeen; Wang, Yu-Ting; Cheng, Pi-Cheng; Kuo, Yeh-Jung; Huang, Rong-Chi

2010-03-01

The central cholinergic system regulates both the circadian clock and sleep-wake cycle and may participate in the feedback control of vigilance states on neural excitability in the suprachiasmatic nucleus (SCN) that houses the circadian clock. Here we investigate the mechanisms for cholinergic modulation of SCN neuron excitability. Cell-attached recordings indicate that the nonspecific cholinergic agonist carbachol (CCh) inhibited 55% and excited 21% SCN neurons, leaving 24% nonresponsive. Similar response proportions were produced by two muscarinic receptor [muscarinic acetylcholine receptor (mAChR)] agonists, muscarine and McN-A-343 (M1/4 agonist), but not by two nicotinic receptor (nAChR) agonists, nicotine and choline (alpha7-nAChR agonist), which, however, produced similar response proportions. Whole cell and perforated-patch recordings indicate that CCh inhibition of firing was mediated by membrane hyperpolarization due to activation of background K(+) currents, which were sensitive to submillimolar concentrations of Ba(2+) and to millimolar concentrations of TEA. RT-PCR analysis demonstrated the presence of mRNA for M1 to M5 mAChRs in SCN. The CCh-induced hyperpolarization and activation of background K(+) currents were blocked by M4 antagonists and to a lesser degree by M1 antagonists but were insensitive to the antagonists for M2 or M3, suggesting the involvement of M4 and M1 mAChRs in mediating CCh inhibition of firing. CCh enhancement of firing was mediated by membrane depolarization, as a result of postsynaptic inhibition of background K(+) currents. The multiple actions of cholinergic modulation via multiple receptors and ion channels may allow acetylcholine to finely control SCN neuron excitability in different physiological settings.

Effects of acute administration of nicotinic and muscarinic cholinergic agonists and antagonists on performance in different cost–benefit decision making tasks in rats

PubMed Central

Mendez, Ian A.; Gilbert, Ryan J.; Bizon, Jennifer L.

2012-01-01

Rationale Alterations in cost–benefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost–benefit decision making. Objectives The goal of these experiments was to determine how cholinergic signaling is involved in cost–benefit decision making, using a behavioral pharmacological approach. Methods Male Long-Evans rats were trained in either “probability discounting” or “delay discounting” tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task. Results In the probability discounting task, acute nicotine administration (1.0 mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3 mg/kg) and atropine (0.3 mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks. Conclusions These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes. PMID:22760484

Effects of acute administration of nicotinic and muscarinic cholinergic agonists and antagonists on performance in different cost-benefit decision making tasks in rats.

PubMed

Mendez, Ian A; Gilbert, Ryan J; Bizon, Jennifer L; Setlow, Barry

2012-12-01

Alterations in cost-benefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost-benefit decision making. The goal of these experiments was to determine how cholinergic signaling is involved in cost-benefit decision making, using a behavioral pharmacological approach. Male Long-Evans rats were trained in either "probability discounting" or "delay discounting" tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task. In the probability discounting task, acute nicotine administration (1.0 mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3 mg/kg) and atropine (0.3 mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks. These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes.

Rotenone and elevated extracellular potassium concentration induce cell-specific fibrillation of α-synuclein in axons of cholinergic enteric neurons in the guinea-pig ileum.

PubMed

Sharrad, D F; Chen, B N; Gai, W P; Vaikath, N; El-Agnaf, O M; Brookes, S J H

2017-04-01

Parkinson's disease is a progressive neurodegenerative disorder that results in the widespread loss of select classes of neurons throughout the nervous system. The pathological hallmarks of Parkinson's disease are Lewy bodies and neurites, of which α-synuclein fibrils are the major component. α-Synuclein aggregation has been reported in the gut of Parkinson's disease patients, even up to a decade before motor symptoms, and similar observations have been made in animal models of disease. However, unlike the central nervous system, the nature of α-synuclein species that form these aggregates and the classes of neurons affected in the gut are unclear. We have previously reported selective expression of α-synuclein in cholinergic neurons in the gut (J Comp Neurol. 2013; 521:657), suggesting they may be particularly vulnerable to degeneration in Parkinson's disease. In this study, we used immunohistochemistry to detect α-synuclein oligomers and fibrils via conformation-specific antibodies after rotenone treatment or prolonged exposure to high [K + ] in ex vivo segments of guinea-pig ileum maintained in organotypic culture. Rotenone and prolonged raising of [K + ] caused accumulation of α-synuclein fibrils in the axons of cholinergic enteric neurons. This took place in a time- and, in the case of rotenone, concentration-dependent manner. Rotenone also caused selective necrosis, indicated by increased cellular autofluorescence, of cholinergic enteric neurons, labeled by ChAT-immunoreactivity, also in a concentration-dependent manner. To our knowledge, this is the first report of rotenone causing selective loss of a neurochemical class in the enteric nervous system. Cholinergic enteric neurons may be particularly susceptible to Lewy pathology and degeneration in Parkinson's disease. © 2016 John Wiley & Sons Ltd.

Activation of the cholinergic anti-inflammatory pathway by GTS-21 attenuates cisplatin-induced acute kidney injury in mice

PubMed Central

Chatterjee, Prodyot K.; Yeboah, Michael M.; Solanki, Malvika H.; Kumar, Gopal; Xue, Xiangying; Pavlov, Valentin A.; Al-Abed, Yousef

2017-01-01

Acute kidney injury (AKI) is the most common side effect of cisplatin, a widely used chemotherapy drug. Although AKI occurs in up to one third of cancer patients receiving cisplatin, effective renal protective strategies are lacking. Cisplatin targets renal proximal tubular epithelial cells leading to inflammation, reactive oxygen species, tubular cell injury, and eventually cell death. The cholinergic anti-inflammatory pathway is a vagus nerve-mediated reflex that suppresses inflammation via α7 nicotinic acetylcholine receptors (α7nAChRs). Our previous studies demonstrated the renoprotective and anti-inflammatory effects of cholinergic agonists, including GTS-21. Therefore, we examined the effect of GTS-21 on cisplatin-induced AKI. Male C57BL/6 mice received either saline or GTS-21 (4mg/kg, i.p.) twice daily for 4 days before cisplatin and treatment continued through euthanasia; 3 days post-cisplatin mice were euthanized and analyzed for markers of renal injury. GTS-21 significantly reduced cisplatin-induced renal dysfunction and injury (p<0.05). GTS-21 significantly attenuated renal Ptgs2/COX-2 mRNA and IL-6, IL-1β, and CXCL1 protein expression, as well as neutrophil infiltration after cisplatin. GTS-21 blunted cisplatin-induced renal ERK1/2 activation, as well as renal ATP depletion and apoptosis (p<0.05). GTS-21 suppressed the expression of CTR1, a cisplatin influx transporter and enhanced the expression of cisplatin efflux transporters MRP2, MRP4, and MRP6 (p<0.05). Using breast, colon, and lung cancer cell lines we showed that GTS-21 did not inhibit cisplatin’s tumor cell killing activity. GTS-21 protects against cisplatin-AKI by attenuating renal inflammation, ATP depletion and apoptosis, as well as by decreasing renal cisplatin influx and increasing efflux, without impairing cisplatin-mediated tumor cell killing. Our results support further exploring the cholinergic anti-inflammatory pathway for preventing cisplatin-induced AKI. PMID:29190774

Maternal Fructose Exposure Programs Metabolic Syndrome-Associated Bladder Overactivity in Young Adult Offspring

PubMed Central

Lee, Wei-Chia; Tain, You-Lin; Wu, Kay L. H.; Leu, Steve; Chan, Julie Y. H.

2016-01-01

Maternal fructose exposure (MFE) programs the development of metabolic syndrome (MetS) in young adult offspring. Epidemiological data indicate that MetS may increase the risks of overactive bladder (OAB) symptoms. However, it remains unknown whether MFE programs MetS-associated bladder dysfunction in adult offspring. Using Sprague-Dawley rats, we investigated the effects of MFE during pregnancy and lactation on developmental programming of MetS-associated bladder dysfunction. In addition, next generation sequencing technology was used to identify potential transcripts involved in the programmed bladder dysfunction in adult male offspring to MFE. We found that MFE programmed the MetS-associated OAB symptoms (i.e., an increase in micturition frequency and a shortened mean inter-contractile interval) in young adult male offspring, alongside significant alterations in bladder transcripts, including Chrm2, Chrm3, P2rx1, Trpv4, and Vipr2 gene expression. At protein level, the expressions of M2-, M3-muscarinic and P2X1 receptor proteins were upregulated in the MFE bladder. Functionally, the carbachol-induced detrusor contractility was reduced in the MFE offspring. These data suggest that alterations in the bladder transcripts and impairment of the bladder cholinergic pathways may underlie the pathophysiology of programmed bladder dysfunction in adult offspring to MFE. PMID:27703194

Maternal Fructose Exposure Programs Metabolic Syndrome-Associated Bladder Overactivity in Young Adult Offspring.

PubMed

Lee, Wei-Chia; Tain, You-Lin; Wu, Kay L H; Leu, Steve; Chan, Julie Y H

2016-10-05

Maternal fructose exposure (MFE) programs the development of metabolic syndrome (MetS) in young adult offspring. Epidemiological data indicate that MetS may increase the risks of overactive bladder (OAB) symptoms. However, it remains unknown whether MFE programs MetS-associated bladder dysfunction in adult offspring. Using Sprague-Dawley rats, we investigated the effects of MFE during pregnancy and lactation on developmental programming of MetS-associated bladder dysfunction. In addition, next generation sequencing technology was used to identify potential transcripts involved in the programmed bladder dysfunction in adult male offspring to MFE. We found that MFE programmed the MetS-associated OAB symptoms (i.e., an increase in micturition frequency and a shortened mean inter-contractile interval) in young adult male offspring, alongside significant alterations in bladder transcripts, including Chrm2, Chrm3, P2rx1, Trpv4, and Vipr2 gene expression. At protein level, the expressions of M 2 -, M 3 -muscarinic and P2X 1 receptor proteins were upregulated in the MFE bladder. Functionally, the carbachol-induced detrusor contractility was reduced in the MFE offspring. These data suggest that alterations in the bladder transcripts and impairment of the bladder cholinergic pathways may underlie the pathophysiology of programmed bladder dysfunction in adult offspring to MFE.

INHIBITION OF BRAIN CHOLINESTERASE AND THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS PRODUCED BY CARBARYL IN LONG EVANS RATS.

EPA Science Inventory

Carbaryl is a widely used N-methyl carbamate pesticide that acts by inhibiting cholinesterases (ChE), which may lead to cholinergic toxicity. Flash evoked potentials (FEPs) are a neurophysiological response often used to detect central nervous system (CNS) changes following expos...

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders.

PubMed

McLean, Samantha L; Grayson, Ben; Marsh, Samuel; Zarroug, Samah H O; Harte, Michael K; Neill, Jo C

2016-04-01

Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, these remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female Hooded Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6h inter-trial interval (ITI). In all treatment groups, there was no preference for the left or right identical objects in the acquisition trial. Risperidone failed to enhance recognition memory in this paradigm whereas donepezil was effective such that rats discriminated between the novel and familiar object in the retention trial following a 6h ITI. Although a narrow dose range of PNU-282987 and RJR-2403 was tested, only one dose of each increased recognition memory, the highest dose of PNU-282987 (10mg/kg) and the lowest dose of RJR-2403 (0.1mg/kg), indicative of enhanced cognitive performance. Interestingly, these compounds were also efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory. Copyright © 2016. Published by Elsevier B.V.

NORADRENERGIC INNERVATION OF THE RAT SPINAL CORD CAUDAL TO A COMPLETE SPINAL CORD TRANSECTION: EFFECTS OF OLFACTORY ENSHEATHING GLIA

PubMed Central

Takeoka, Aya; Kubasak, Marc D.; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R.; Phelps, Patricia E.

2010-01-01

Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG- than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now we report that NA axons are present throughout the caudal stump of both media- and OEG-injected spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This effect could be mediated through direct association with SMNs and/or indirectly via cholinergic interneurons. PMID:20025875

Wasp venom blocks central cholinergic synapses to induce transient paralysis in cockroach prey.

PubMed

Haspel, G; Libersat, F

2003-03-01

The parasitoid wasp Ampulex compressa induces a set of unique behavioral effects upon stinging its prey, the cockroach. It stings into the first thoracic segment inducing 2 to 3 min of transient flaccid paralysis of the front legs. This facilitates a second sting in the cockroach's head that induces 30 min of excessive grooming followed by a 2 to 5-week long lethargic state. In the present study, we examine the immediate effect of the first sting, which is a transient paralysis of the front legs. Using radiolabeled wasps, we demonstrate that the wasp injects its venom directly into the cockroach's first thoracic ganglion. The artificial injection of milked venom into a thoracic ganglion abolishes spontaneous and evoked responses of the motoneurons associated with leg movements. To investigate the physiological mechanism of action of the venom, we injected venom into the last abdominal ganglion of the cockroach, which houses a well-characterized cholinergic synapse. Injected venom abolishes both sensory-evoked and agonist-evoked postsynaptic potentials recorded in the postsynaptic neuron for 2 to 3 min without affecting action potential propagation. Thus, the venom blocking effect has a postsynaptic component that follows the same time course as the transient paralysis induced by the thoracic sting. Finally, injection of a nicotinic antagonist in the front thoracic ganglion induces paralysis of the front legs. We conclude that the transient paralytic effect of the thoracic sting can be mainly accounted for by the presence of a venom active component that induces a postsynaptic block of central cholinergic synaptic transmission. Copyright 2003 Wiley Periodicals, Inc. J Neurobiol 54: 628-637, 2003

The role of the central ghrelin system in reward from food and chemical drugs.

PubMed

Dickson, Suzanne L; Egecioglu, Emil; Landgren, Sara; Skibicka, Karolina P; Engel, Jörgen A; Jerlhag, Elisabet

2011-06-20

Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergic-dopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine. Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. Thus, the central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the treatment of substance use disorder. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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.

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.

Atropa belladonna intoxication: a case report.

PubMed

Berdai, Mohamed Adnane; Labib, Smael; Chetouani, Khadija; Harandou, Mustapha

2012-01-01

Atropa belladonna is a poisonous plant also called deadly nightshade. Its roots, leaves and fruits contain alkaloids: atropine, hyocyamine and scopolamine. The risk of poisoning in children is important because of possible confusion with other berries. Atropa belladonna acute intoxication is a severe condition, it's should be considered in the presence of anti-cholinergic toxidrome, the differential diagnosis include other plants or psychoactive drugs containing atropine. The treatment is mainly symptomatic including gastrointestinal decontamination with activated charcoal. In severe cases, physostigmine can be used as an antidote. We report the case of 11 year old girl with Atropa belladonna poisoning which was administrated in a therapeutic purpose as a remedy to jaundice. The child presented essentially a central anti-cholinergic syndrome. She was admitted in the intensive care unit, the progression was favorable with symptomatic treatment.

Perinatal exposure to methadone affects central cholinergic activity in the weanling rat.

PubMed

Robinson, S E; Mo, Q; Maher, J R; Wallace, M J; Kunko, P M

1996-06-01

Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. Perinatal methadone exposure disrupted cholinergic activity on postnatal day 21 as measured by the turnover rate of acetylcholine (TRACh) in both female and male rats, although there were some sexually-dimorphic responses. The most profoundly affected brain region was the striatum, where prenatal exposure to methadone increased ACh turnover, whether or not the rats continued to be exposed to methadone postnatally. It appears unlikely that neonatal withdrawal contributes to brain regional changes in ACh turnover, as continued postnatal exposure to methadone did not prevent the prenatal methadone induced changes.

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

PubMed Central

Pohanka, Miroslav

2014-01-01

Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

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

Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

PubMed Central

Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

2012-01-01

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

Knockdown of Myo-Inositol Transporter SMIT1 Normalizes Cholinergic and Glutamatergic Function in an Immortalized Cell Line Established from the Cerebral Cortex of a Trisomy 16 Fetal Mouse, an Animal Model of Human Trisomy 21 (Down Syndrome).

PubMed

Cárdenas, Ana María; Fernández-Olivares, Paola; Díaz-Franulic, Ignacio; González-Jamett, Arlek M; Shimahara, Takeshi; Segura-Aguilar, Juan; Caviedes, Raúl; Caviedes, Pablo

2017-11-01

The Na + /myo-inositol cotransporter (SMIT1) is overexpressed in human Down syndrome (DS) and in trisomy 16 fetal mice (Ts16), an animal model of the human condition. SMIT1 overexpression determines increased levels of intracellular myo-inositol, a precursor of phophoinositide synthesis. SMIT1 is overexpressed in CTb cells, an immortalized cell line established from the cerebral cortex of a Ts16 mouse fetus. CTb cells exhibit impaired cytosolic Ca 2+ signals in response to glutamatergic and cholinergic stimuli (increased amplitude and delayed time-dependent kinetics in the decay post-stimulation), compared to our CNh cell line, derived from the cerebral cortex of a euploid animal. Considering the role of myo-inositol in intracellular signaling, we normalized SMIT1 expression in CTb cells using specific mRNA antisenses. Forty-eight hours post-transfection, SMIT1 levels in CTb cells reached values comparable to those of CNh cells. At this time, decay kinetics of Ca 2+ signals induced by either glutamate, nicotine, or muscarine were accelerated in transfected CTb cells, to values similar to those of CNh cells. The amplitude of glutamate-induced cytosolic Ca 2+ signals in CTb cells was also normalized. The results suggest that SMIT1 overexpression contributes to abnormal cholinergic and glutamatergic Ca 2+ signals in the trisomic condition, and knockdown of DS-related genes in our Ts16-derived cell line could constitute a relevant tool to study DS-related neuronal dysfunction.

Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway.

PubMed

Mesquita, Thássio R R; de Jesus, Itamar C G; Dos Santos, Jucilene F; de Almeida, Grace K M; de Vasconcelos, Carla M L; Guatimosim, Silvia; Macedo, Fabrício N; Dos Santos, Robervan V; de Menezes-Filho, José E R; Miguel-Dos-Santos, Rodrigo; Matos, Paulo T D; Scalzo, Sérgio; Santana-Filho, Valter J; Albuquerque-Júnior, Ricardo L C; Pereira-Filho, Rose N; Lauton-Santos, Sandra

2017-01-01

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba -mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M 2 ) and downregulation of β 1 -AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo , we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M 2 /NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba .

Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway

PubMed Central

Mesquita, Thássio R. R.; de Jesus, Itamar C. G.; dos Santos, Jucilene F.; de Almeida, Grace K. M.; de Vasconcelos, Carla M. L.; Guatimosim, Silvia; Macedo, Fabrício N.; dos Santos, Robervan V.; de Menezes-Filho, José E. R.; Miguel-dos-Santos, Rodrigo; Matos, Paulo T. D.; Scalzo, Sérgio; Santana-Filho, Valter J.; Albuquerque-Júnior, Ricardo L. C.; Pereira-Filho, Rose N.; Lauton-Santos, Sandra

2017-01-01

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba. PMID:28553225

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

Specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats.

PubMed

Cansev, Mehmet; van Wijk, Nick; Turkyilmaz, Mesut; Orhan, Fulya; Sijben, John W C; Broersen, Laus M

2015-01-01

Fortasyn Connect (FC) is a specific nutrient combination designed to target synaptic dysfunction in Alzheimer's disease by providing neuronal membrane precursors and other supportive nutrients. The aim of the present study was to investigate the effects of FC on hippocampal cholinergic neurotransmission in association with its effects on synaptic membrane formation in aged rats. Eighteen-month-old male Wistar rats were randomized to receive a control diet for 4 weeks or an FC-enriched diet for 4 or 6 weeks. At the end of the dietary treatments, acetylcholine (ACh) release was investigated by in vivo microdialysis in the right hippocampi. On completion of microdialysis studies, the rats were sacrificed, and the left hippocampi were obtained to determine the levels of choline, ACh, membrane phospholipids, synaptic proteins, and choline acetyltransferase. Our results revealed that supplementation with FC diet for 4 or 6 weeks, significantly enhanced basal and stimulated hippocampal ACh release and ACh tissue levels, along with levels of phospholipids. Feeding rats the FC diet for 6 weeks significantly increased the levels of choline acetyltransferase, the presynaptic marker Synapsin-1, and the postsynaptic marker PSD-95, but decreased levels of Nogo-A, a neurite outgrowth inhibitor. These data show that the FC diet enhances hippocampal cholinergic neurotransmission in aged rats and suggest that this effect is mediated by enhanced synaptic membrane formation. These data provide further insight into cellular and molecular mechanisms by which FC may support memory processes in Alzheimer's disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors.

PubMed

Schulz, Kalynn M; Pearson, Jennifer N; Gasparrini, Mary E; Brooks, Kayla F; Drake-Frazier, Chakeer; Zajkowski, Megan E; Kreisler, Alison D; Adams, Catherine E; Leonard, Sherry; Stevens, Karen E

2014-07-15

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress. Published by Elsevier B.V.

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors

PubMed Central

Schulz, Kalynn M.; Pearson, Jennifer N.; Gasparrini, Mary E.; Brooks, Kayla F.; Drake-Frazier, Chakeer; Zajkowski, Megan E.; Kreisler, Alison D.; Adams, Catherine E.; Leonard, Sherry; Stevens, Karen E.

2014-01-01

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress. PMID:24675162

THE EDINGER-WESTPHAL NUCLEUS: A HISTORICAL, STRUCTURAL AND FUNCTIONAL PERSPECTIVE ON A DICHOTOMOUS TERMINOLOGY

PubMed Central

Kozicz, Tamás; Bittencourt, Jackson C.; May, Paul J.; Reiner, Anton; Gamlin, Paul D. R.; Palkovits, Miklós; Horn, Anja K.E.; Toledo, Claudio A. B.; Ryabinin, Andrey E.

2013-01-01

The eponymous term nucleus of Edinger-Westphal (EW) has come to be used to describe two juxtaposed and somewhat intermingled cell groups of the midbrain that differ dramatically in their connectivity and neurochemistry. On one hand, the classically defined EW is the part of the oculomotor complex that is the source of the parasympathetic preganglionic motoneuron input to the ciliary ganglion (CG), through which it controls pupil constriction and lens accommodation. On the other hand, EW is applied to a population of centrally projecting neurons involved in sympathetic, consumptive and stress-related functions. This terminology problem arose because the name EW has historically been applied to the most prominent cell collection above or between the somatic oculomotor nuclei (III), an assumption based on the known location of the preganglionic motoneurons in monkeys. However, in many mammals, the nucleus designated as EW is not made up of cholinergic, preganglionic motoneurons supplying the CG, and instead contains neurons using peptides, such as urocortin 1, with diverse central projections. As a result, the literature has become increasingly confusing. To resolve this problem, we suggest that the term EW be supplemented with terminology based on connectivity. Specifically, we recommend that: 1. The cholinergic, preganglionic neurons supplying the CG be termed the Edinger-Westphal preganglionic (EWpg) population, and 2. The centrally projecting, peptidergic neurons be termed the Edinger-Westphal centrally projecting (EWcp) population. The history of this nomenclature problem and the rationale for our solutions are discussed in this review. PMID:21452224

Botulinum Neurotoxin Type A in Neurology: Update.

PubMed

Orsini, Marco; Leite, Marco Antonio Araujo; Chung, Tae Mo; Bocca, Wladimir; de Souza, Jano Alves; de Souza, Olivia Gameiro; Moreira, Rayele Priscila; Bastos, Victor Hugo; Teixeira, Silmar; Oliveira, Acary Bulle; Moraes, Bruno da Silva; Matta, André Palma; Jacinto, Luis Jorge

2015-09-24

This paper reviews the current and most neurological (central nervous system, CNS) uses of the botulinum neurotoxin type A. The effect of these toxins at neuromuscular junction lends themselves to neurological diseases of muscle overactivity, particularly abnormalities of muscle control. There are seven serotypes of the toxin, each with a specific activity at the molecular level. Currently, serotypes A (in two preparations) and B are available for clinical purpose, and they have proved to be safe and effective for the treatment of dystonia, spasticity, headache, and other CNS disorders in which muscle hyperactivity gives rise to symptoms. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neuro-transmitters involved in pain regulation. Its effects are transient and nondestructive, and largely limited to the area in which it is administered. These effects are also graded according to the dose, allowing individualized treatment of patients and disorders. It may also prove to be useful in the control of autonomic dysfunction and sialorrhea. In over 20 years of use in humans, botulinum toxin has accumulated a considerable safety record, and in many cases represents relief for thousands of patients unaided by other therapy.

Botulinum Neurotoxin Type A in Neurology: Update

PubMed Central

Orsini, Marco; Leite, Marco Antonio Araujo; Chung, Tae Mo; Bocca, Wladimir; de Souza, Jano Alves; de Souza, Olivia Gameiro; Moreira, Rayele Priscila; Bastos, Victor Hugo; Teixeira, Silmar; Oliveira, Acary Bulle; Moraes, Bruno da Silva; Matta, André Palma; Jacinto, Luis Jorge

2015-01-01

This paper reviews the current and most neurological (central nervous system, CNS) uses of the botulinum neurotoxin type A. The effect of these toxins at neuromuscular junction lends themselves to neurological diseases of muscle overactivity, particularly abnormalities of muscle control. There are seven serotypes of the toxin, each with a specific activity at the molecular level. Currently, serotypes A (in two preparations) and B are available for clinical purpose, and they have proved to be safe and effective for the treatment of dystonia, spasticity, headache, and other CNS disorders in which muscle hyperactivity gives rise to symptoms. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neuro-transmitters involved in pain regulation. Its effects are transient and nondestructive, and largely limited to the area in which it is administered. These effects are also graded according to the dose, allowing individualized treatment of patients and disorders. It may also prove to be useful in the control of autonomic dysfunction and sialorrhea. In over 20 years of use in humans, botulinum toxin has accumulated a considerable safety record, and in many cases represents relief for thousands of patients unaided by other therapy. PMID:26487928

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.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients.

PubMed

Di Bari, Maria; Reale, Marcella; Di Nicola, Marta; Orlando, Viviana; Galizia, Sabrina; Porfilio, Italo; Costantini, Erica; D'Angelo, Chiara; Ruggieri, Serena; Biagioni, Stefano; Gasperini, Claudio; Tata, Ada Maria

2016-11-30

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

PubMed Central

Di Bari, Maria; Reale, Marcella; Di Nicola, Marta; Orlando, Viviana; Galizia, Sabrina; Porfilio, Italo; Costantini, Erica; D’Angelo, Chiara; Ruggieri, Serena; Biagioni, Stefano; Gasperini, Claudio; Tata, Ada Maria

2016-01-01

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis. PMID:27916909

Central anticholinergic syndrome: a case report.

PubMed

Moos, Daniel D

2007-10-01

Postoperative central anticholinergic syndrome (CAS) is caused by anticholinergic medications that cross the blood-brain barrier. Medications with central anticholinergic effects block muscarinic cholinergic receptors, resulting in a wide array of symptoms. Symptoms may range from coma to a highly agitated state. CAS may be underdiagnosed because of its varying presentation and lack of awareness. Differential diagnosis for the patient presenting with abnormal neurological signs and symptoms should include CAS after the exclusion of other potential causes. This case report details the occurrence of CAS in a patient in her 20's. A review of CAS including causes, signs and symptoms, incidence, differential diagnosis, and treatment is discussed.

Noradrenergic innervation of the rat spinal cord caudal to a complete spinal cord transection: effects of olfactory ensheathing glia.

PubMed

Takeoka, Aya; Kubasak, Marc D; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R; Phelps, Patricia E

2010-03-01

Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG- than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now we report that NA axons are present throughout the caudal stump of both media- and OEG-injected spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This effect could be mediated through direct association with SMNs and/or indirectly via cholinergic interneurons. Copyright 2009 Elsevier Inc. All rights reserved.

STIMULATION OF NICOTINE REWARD AND CENTRAL CHOLINERGIC ACTIVITY IN SPRAGUE-DAWLEY RATS EXPOSED PERINATALLY TO A FAT-RICH DIET

PubMed Central

Morganstern, Irene; Lukatskaya, Olga; Moon, Sang-Ho; Guo, Wei-Ran; Shaji, Jane; Karatayev, Olga; Leibowitz, Sarah F.

2014-01-01

Rationale While clinical studies show maternal consumption of palatable fat-rich diets during pregnancy to negatively impact the children’s behaviors and increase their vulnerability to drug abuse, the precise behavioral and neurochemical mechanisms mediating these phenomena have yet to be examined. Objective The study examined in rats whether gestational exposure to a high-fat diet (HFD) can increase the offspring’s propensity to use nicotine and whether disturbances in central nicotinic cholinergic signaling accompany this behavioral effect. Methods Rat offspring exposed perinatally to a HFD or Chow diet were characterized in terms of their nicotine self-administration behavior in a series of operant response experiments and the activity of acetylcholinesterase (AChE) and density of nicotinic ACh receptors (nAChRs) in different brain areas. Result Perinatal HFD compared to Chow exposure increased nicotine-self administration behavior during fixed-ratio and dose-response testing and caused an increase in breakpoint using progressive ratio testing, while nicotine-seeking in response to nicotine prime-induced reinstatement was reduced. This behavioral change induced by the HFD was associated with a significant reduction in activity of AChE in the midbrain, hypothalamus and striatum and increased density of β2-nAChRs in the ventral tegmental area and substantia nigra and of α7-nAChRs in the lateral and ventromedial hypothalamus. Conclusions Perinatal exposure to a HFD increases the vulnerability of the offspring to excessive nicotine use by enhancing its reward potential, and these behavioral changes are accompanied by a stimulation of nicotinic cholinergic signaling in mesostriatal and hypothalamic brain areas important for reinforcement and consummatory behavior. PMID:23836027

Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage.

PubMed

He, Yifan; Zhu, Jihong; Huang, Fang; Qin, Liu; Fan, Wenguo; He, Hongwen

2014-11-15

The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory behaviors and structural changes in related brain regions, in a mouse model of Alzheimer's disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learning and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltransferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic fibers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no significant differences in histology or behavior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present findings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer's disease, and indicate that tooth extraction should be avoided in these populations.

A Subset of Cholinergic Mushroom Body Neurons Requires Go Signaling to Regulate Sleep in Drosophila

PubMed Central

Yi, Wei; Zhang, Yunpeng; Tian, Yinjun; Guo, Jing; Li, Yan; Guo, Aike

2013-01-01

Study Objectives: Identifying the neurochemistry and neural circuitry of sleep regulation is critical for understanding sleep and various sleep disorders. Fruit flies display sleep-like behavior, sharing essential features with sleep of vertebrate. In the fruit fly's central brain, the mushroom body (MB) has been highlighted as a sleep center; however, its neurochemical nature remains unclear, and whether it promotes sleep or wake is still a topic of controversy. Design: We used a video recording system to accurately monitor the locomotor activity and sleep status. Gene expression was temporally and regionally manipulated by heat induction and the Gal4/UAS system. Measurements and Results: We found that expressing pertussis toxin (PTX) in the MB by c309-Gal4 to block Go activity led to unique sleep defects as dramatic sleep increase in daytime and fragmented sleep in nighttime. We narrowed down the c309-Gal4 expressing brain regions to the MB α/β core neurons that are responsible for the Go-mediated sleep effects. Using genetic tools of neurotransmitter-specific Gal80 and RNA interference approach to suppress acetylcholine signal, we demonstrated that these MB α/β core neurons were cholinergic and sleep-promoting neurons, supporting that Go mediates an inhibitory signal. Interestingly, we found that adjacent MB α/β neurons were also cholinergic but wake-promoting neurons, in which Go signal was also required. Conclusion: Our findings in fruit flies characterized a group of sleep-promoting neurons surrounded by a group of wake-promoting neurons. The two groups of neurons are both cholinergic and use Go inhibitory signal to regulate sleep. Citation: Yi W; Zhang Y; Tian Y; Guo J; Li Y; Guo A. A subset of cholinergic mushroom body neurons requires go signaling to regulate sleep in Drosophila. SLEEP 2013;36(12):1809-1821. PMID:24293755

Deanol affects choline metabolism in peripheral tissues of mice.

PubMed

Haubrich, D R; Gerber, N H; Pflueger, A B

1981-08-01

Administration of 2-dimethylaminoethanol (deanol) to mice induced an increase in both the concentration and the rate of turnover of free choline in blood. Treatment with deanol also caused an increase in the concentration of choline in kidneys, and markedly inhibited the rates of oxidation and phosphorylation of intravenously administered [3H-methyl]choline. In the liver, deanol inhibited the rate of phosphorylation of [3H-methyl]choline, but did not inhibit its rate of oxidation or cause an increase in the level of free choline. These findings suggest that deanol increases the choline concentration in blood by inhibition of its metabolism in tissues. Deanol may ultimately produce its central cholinergic effects by inhibition of choline metabolism in peripheral tissues, causing free choline choline to accumulate in blood, enter the brain, and stimulate cholinergic receptors.

Scopolamine impairs memory recall in Octopus vulgaris.

PubMed

Fiorito, G; Agnisola, C; d'Addio, M; Valanzano, A; Calamandrei, G

1998-09-04

The involvement of the central cholinergic system in predatory performance, and on the recall of individual and observational memory in Octopus vulgaris was studied by treating the animals with the muscarinic antagonist scopolamine (2 mg/kg). The absence of the effects of the injection of scopolamine on blood circulation was also checked. Scopolamine did not affect the ability of octopuses to prey on live crabs. However, it interfered significantly with memory recall. In fact, the ability to solve the jar problem was impaired within the first hour after injection (short-term effects) and was only partially recovered after 24 h (long-term). Moreover, both individual and observational learning of a visual discrimination were significantly reduced at the short- and long-term testing. These results support a role of the cholinergic system in the processes of memory recall of O. vulgaris.

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.

Attentional control of associative learning--a possible role of the central cholinergic system.

PubMed

Pauli, Wolfgang M; O'Reilly, Randall C

2008-04-02

How does attention interact with learning? Kruschke [Kruschke, J.K. (2001). Toward a unified Model of Attention in Associative Learning. J. Math. Psychol. 45, 812-863.] proposed a model (EXIT) that captures Mackintosh's [Mackintosh, N.J. (1975). A theory of attention: Variations in the associability of stimuli with reinforcement. Psychological Review, 82(4), 276-298.] framework for attentional modulation of associative learning. We developed a computational model that showed analogous interactions between selective attention and associative learning, but is significantly simplified and, in contrast to EXIT, is motivated by neurophysiological findings. Competition among input representations in the internal representation layer, which increases the contrast between stimuli, is critical for simulating these interactions in human behavior. Furthermore, this competition is modulated in a way that might be consistent with the phasic activation of the central cholinergic system, which modulates activity in sensory cortices. Specifically, phasic increases in acetylcholine can cause increased excitability of both pyramidal excitatory neurons in cortical layers II/III and cortical GABAergic inhibitory interneurons targeting the same pyramidal neurons. These effects result in increased attentional contrast in our model. This model thus represents an initial attempt to link human attentional learning data with underlying neural substrates.

Attentional control of associative learning—A possible role of the central cholinergic system

PubMed Central

Pauli, Wolfgang M.; O'Reilly, Randall C.

2010-01-01

How does attention interact with learning? Kruschke [Kruschke, J.K. (2001). Toward a unified Model of Attention in Associative Learning. J. Math. Psychol. 45, 812–863.] proposed a model (EXIT) that captures Mackintosh's [Mackintosh, N.J. (1975). A theory of attention: Variations in the associability of stimuli with reinforcement. Psychological Review, 82(4), 276–298.] framework for attentional modulation of associative learning. We developed a computational model that showed analogous interactions between selective attention and associative learning, but is significantly simplified and, in contrast to EXIT, is motivated by neurophysiological findings. Competition among input representations in the internal representation layer, which increases the contrast between stimuli, is critical for simulating these interactions in human behavior. Furthermore, this competition is modulated in a way that might be consistent with the phasic activation of the central cholinergic system, which modulates activity in sensory cortices. Specifically, phasic increases in acetylcholine can cause increased excitability of both pyramidal excitatory neurons in cortical layers II/III and cortical GABAergic inhibitory interneurons targeting the same pyramidal neurons. These effects result in increased attentional contrast in our model. This model thus represents an initial attempt to link human attentional learning data with underlying neural substrates. PMID:17870060

Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging

PubMed Central

Bentley, Paul; Driver, Jon; Dolan, Raymond J.

2011-01-01

Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications. PMID:21708219

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

PubMed Central

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Kallás, Esper Georges; Irigoyen, Maria Cláudia

2016-01-01

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg−1·day−1) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups—denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups—were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3+ cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4+CD25+FOXP3+), and a less extreme decrease in conventional T cells (CD25+FOXP3−) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. PMID:26791829

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

PubMed

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

2016-04-15

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. Copyright © 2016 the American Physiological Society.

Cholinergic dysfunctions and enhanced oxidative stress in the neurobehavioral toxicity of lambda-cyhalothrin in developing rats.

PubMed

Ansari, Reyaz W; Shukla, Rajendra K; Yadav, Rajesh S; Seth, Kavita; Pant, Aditya B; Singh, Dhirendra; Agrawal, Ashok K; Islam, Fakhrul; Khanna, Vinay K

2012-11-01

This study is focused on understanding the mechanism of neurobehavioral toxicity of lambda-cyhalothrin, a new generation type II synthetic pyrethroid in developing rats following their exposure from post-lactational day (PLD)22 to PLD49 and investigate whether neurobehavioral alterations are transient or persistent. Post-lactational exposure to lambda-cyhalothrin (1.0 or 3.0 mg/kg body weight, p.o.) affected grip strength and learning activity in rats on PLD50 and the persistent impairment of grip strength and learning was observed at 15 days after withdrawal of exposure on PLD65. A decrease in the binding of muscarinic-cholinergic receptors in frontocortical, hippocampal, and cerebellar membranes associated with decreased expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in hippocampus was observed following exposure to lambda-cyhalothrin on PLD50 and PLD65. Exposure to lambda-cyhalothrin was also found to increase the expression of growth-associated protein-43 in hippocampus of rats on PLD50 and PLD65 as compared to controls. A significant increase in lipid peroxidation and protein carbonyl levels and decreased levels of reduced glutathione and activity of superoxide dismutase, catalase, and glutathione peroxidase in brain regions of lambda-cyhalothrin exposed rats were distinctly observed indicating increased oxidative stress. Inhibition of ChAT and AChE activity may cause down-regulation of muscarinic-cholinergic receptors consequently impairing learning activity in developing rats exposed to lambda-cyhalothrin. The data further indicate that long-term exposure to lambda-cyhalothrin at low doses may be detrimental and changes in selected behavioral and neurochemical end points may persist if exposure to lambda-cyhalothrin continues.

Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems.

PubMed

Le, Xoan Thi; Pham, Hang Thi Nguyet; Do, Phuong Thi; Fujiwara, Hironori; Tanaka, Ken; Li, Feng; Van Nguyen, Tai; Nguyen, Khoi Minh; Matsumoto, Kinzo

2013-10-01

This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.

Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia.

PubMed

Stryjer, Rafael; Strous, Rael D; Bar, Faina; Werber, Edith; Shaked, Ginette; Buhiri, Yosef; Kotler, Moshe; Weizman, Abraham; Rabey, Jose M

2003-01-01

Comorbid schizophrenia and dementia is a common clinical phenomenon; however, management of the coexisting illnesses remains incomplete. Donepezil, a cholinesterase inhibitor, may be beneficial for the management of symptoms of Alzheimer's disease, a disease in which cholinergic pathways in the cerebral cortex and basal forebrain are well known to be compromised. Furthermore, impaired cognition in elderly schizophrenic patients has been observed to be more than two thirds; however, there are no published controlled studies reporting the use of cholinesterase inhibitors in the management of schizophrenia in patients with associated dementia. In this study, six patients with chronic schizophrenia and comorbid dementia were administered donepezil, 5 mg, in single-blind fashion as augmentation to their standard antipsychotic medication for a 4-week period. Patients were evaluated with the Mini Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale, Cognitive subscale; Positive and Negative Symptom Scale (PANSS); and the Clinical Global Impression (CGI) scales. A significant improvement was noted in MMSE scores (P < 0.01) and for CGI scores (P < 0.01). In addition, three patients demonstrated improvement on the PANSS. Donepezil appears to be an effective treatment for the management of symptoms of dementia accompanying patients with comorbid schizophrenia and dementia. Since cholinergic dysfunction may be present in some patients with schizophrenia, the authors' findings further demonstrate the possibility that this disorder may be managed with cholinergic medications as augmenting agents, at least in this specific subpopulation of patients with comorbid dementia. To confirm the findings of this preliminary trial, further investigation is mandated with a larger sample of subjects in the context of a double-blind medication trial.

Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

PubMed

Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

2014-01-01

P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

PubMed

Sabri, Osama; Meyer, Philipp M; Gräf, Susanne; Hesse, Swen; Wilke, Stephan; Becker, Georg-Alexander; Rullmann, Michael; Patt, Marianne; Luthardt, Julia; Wagenknecht, Gudrun; Hoepping, Alexander; Smits, Rene; Franke, Annegret; Sattler, Bernhard; Tiepolt, Solveig; Fischer, Steffen; Deuther-Conrad, Winnie; Hegerl, Ulrich; Barthel, Henryk; Schönknecht, Peter; Brust, Peter

2018-06-01

In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.

Cholinergic agonists increase intracellular calcium concentration in frog vestibular hair cells.

PubMed

Ohtani, M; Devau, G; Lehouelleur, J; Sans, A

1994-11-01

Acetylcholine (ACh) is usually considered to be the neurotransmitter of the efferent vestibular system. The nature and the localization of cholinergic receptors have been investigated on frog isolated vestibular hair cells (VHCs), by measuring variations of intracellular calcium concentration ([Ca2+]i), using calcium sensitive dye fura-2. Focal iontophoretic ACh (1 M, 300 nA.40 ms) application induced a rapid increase in [Ca2+]i, reaching a peak in 20 s and representing about 5-fold the resting level (from 61 +/- 6 to 320 +/- 26 nM). Applications of muscarinic agonists as methacholine and carbachol induced weaker calcium responses (from 78 +/- 25 to 238 +/- 53 nM) than the one obtained with ACh applications. These muscarinic agonists were efficient only in precise zones. Desensitization of muscarinic receptors to successive stimulations was significant. Perfusion of nicotine or 1,1-dimethyl-4-phenyl-piperazinium (DMPP), a nicotinic agonist, induced an increase in [Ca2+]i only in some cells (4/28 with DMPP). These results indicated the presence of cholinergic receptors on frog VHCs: muscarinic receptors were more responsive than nicotinic receptors. Presence of muscarinic and nicotinic receptors in the membrane of VHCs could indicate different modulations of VHCs activity mediated by [Ca2+]i and involving an efferent control which represents a central regulation of the vestibular afferent message.

Stress, chemical defense agents, and cholinergic receptors. Midterm report, 1 November 1987-31 July 1989

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

Lane, J.D.

1989-11-30

This project is assessing the affects of exposure to a chemical defense agent on anxiety and stress, by using rat models of anxiety (conditioned emotional response (CER); conditioned suppression) and unconditioned non-specific stres (exposure to footshock). The specific experiments determined the plasticity of muscarinic cholinergic binding sites in the central nervous system. The neuroanatomical locus and neuropharmacological profile of changes in binding sites were assessed in brain areas enriched in cholinergic markers. Acetylcholine turnover was measured to determine if the receptor response is compensatory or independent. The effects of acute exposure to doses of a chemical defense agent (soman--XGD) onmore » lethality and behaviors were examined. The experiments involved training and conditioning adult rats to CER using standard operant/respondent techniques. The binding of radiolabelled ligand was studied in vitro using brain membranes and tissue sections (autoradiography). The major findings are that CER produces increases in acetylcholine turnover in brain areas involved in anxiety, and that primarily post-synaptic M1 receptors compensatorly decrease in response. These neurochemical phenomena are directly correlated with several behaviors, including onset and extinction of CER and non-specific stress. Followup experiments have been designed to test the interaction of CER, XGD and neurochemistry.« less

Tamoxifen enhances choline acetyltransferase mRNA expression in rat basal forebrain cholinergic neurons.

PubMed

McMillan, Pamela J; LeMaster, Ann M; Dorsa, Daniel M

2002-06-30

Novel estrogen-like molecules known as SERMs (selective estrogen receptor modulators) produce many of the beneficial estrogen-like actions without the detrimental side-effects. The SERM, tamoxifen, an estrogen-like molecule with both agonist and antagonist properties, is widely prescribed for the treatment of breast cancer. While the effects of tamoxifen are being evaluated in many peripheral tissues, its effects in the central nervous system (CNS) have been largely ignored. In the present study, we begin to evaluate the effects of tamoxifen in the rat basal forebrain, a region known to be highly responsive to estrogen. We compared the effects of short-term (24 h) tamoxifen treatment to that of estrogen on ChAT mRNA expression in cholinergic neurons. In addition, we examined the effect of tamoxifen in the presence and absence of estrogen. Our results indicate that tamoxifen enhances ChAT expression in a manner similar to that of estrogen in several basal forebrain regions. In contrast, tamoxifen exhibits antagonist properties with respect to estrogen-induction of progesterone receptor mRNA in the medial preoptic nucleus. These results indicate tamoxifen has estrogenic properties with respect to cholinergic neurons, suggesting a previously unidentified effect of this agent in the CNS. Copyright 2002 Elsevier Science B.V.

Neuronal sources of hedgehog modulate neurogenesis in the adult planarian brain.

PubMed

Currie, Ko W; Molinaro, Alyssa M; Pearson, Bret J

2016-11-19

The asexual freshwater planarian is a constitutive adult, whose central nervous system (CNS) is in a state of constant homeostatic neurogenesis. However, very little is known about the extrinsic signals that act on planarian stem cells to modulate rates of neurogenesis. We have identified two planarian homeobox transcription factors, Smed-nkx2.1 and Smed-arx , which are required for the maintenance of cholinergic, GABAergic, and octopaminergic neurons in the planarian CNS. These very same neurons also produce the planarian hedgehog ligand ( Smed-hh ), which appears to communicate with brain-adjacent stem cells to promote normal levels of neurogenesis. Planarian stem cells nearby the brain express core hh signal transduction genes, and consistent hh signaling levels are required to maintain normal production of neural progenitor cells and new mature cholinergic neurons, revealing an important mitogenic role for the planarian hh signaling molecule in the adult CNS.

[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.

[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.

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.

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.

An invertebrate model of the developmental neurotoxicity of insecticides: effects of chlorpyrifos and dieldrin in sea urchin embryos and larvae.

PubMed Central

Buznikov, G A; Nikitina, L A; Bezuglov, V V; Lauder, J M; Padilla, S; Slotkin, T A

2001-01-01

Chlorpyrifos targets mammalian brain development through a combination of effects directed at cholinergic receptors and intracellular signaling cascades that are involved in cell differentiation. We used sea urchin embryos as an invertebrate model system to explore the cellular mechanisms underlying the actions of chlorpyrifos and to delineate the critical period of developmental vulnerability. Sea urchin embryos and larvae were exposed to chlorpyrifos at different stages of development ranging from early cell cleavages through the prism stage. Although early cleavages were unaffected even at high chlorpyrifos concentrations, micromolar concentrations added at the mid-blastula stage evoked a prominent change in cell phenotype and overall larval structure, with appearance of pigmented cells followed by their accumulation in an extralarval cap that was extruded from the animal pole. At higher concentrations (20-40 microM), these abnormal cells constituted over 90% of the total cell number. Studies with cholinergic receptor blocking agents and protein kinase C inhibitors indicated two distinct types of effects, one mediated through stimulation of nicotinic cholinergic receptors and the other targeting intracellular signaling. The effects of chlorpyrifos were not mimicked by chlorpyrifos oxon, the active metabolite that inhibits cholinesterase, nor by nonorganophosphate cholinesterase inhibitors. Dieldrin, an organochlorine that targets GABA(A )receptors, was similarly ineffective. The effects of chlorpyrifos and its underlying cholinergic and signaling-related mechanisms parallel prior findings in mammalian embryonic central nervous system. Invertebrate test systems may thus provide both a screening procedure for potential neuroteratogenesis by organophosphate-related compounds, as well as a system with which to uncover novel mechanisms underlying developmental vulnerability. PMID:11485862

Myotropic Effects of Cholinergic Muscarinic Agonists and Antagonists in the Beetle Tenebrio molitor L.

PubMed

Chowanski, Szymon; Rosinski, Grzegorz

2017-01-01

In mammals, the cholinergic nervous system plays a crucial role in neuronal regulation of physiological processes. It acts on cells by two types of receptors - nicotinic and muscarinic receptors. Both signal transmission pathways also operate in the central and peripheral cholinergic nervous system of insects. In our pharmacological experiments, we studied the effects of two muscarinic agonists (carbachol, pilocarpine) and two muscarinic antagonists (atropine, scopolamine) on the muscle contractile activity of visceral organs in the beetle, Tenebrio molitor. Both antagonists, when injected to haemolymph at concentration 10-5 M, caused delayed and prolonged cardioinhibitory effects on heart contractility in ortho- and antidromic phases of heart activity in T. molitor pupa what was observed as negative chrono- and inotropic effects. Agonist of muscarinic receptors - carbachol evoked opposite effect and increased contraction rate but only in antidromic phase. Pilocarpine, the second agonist induced weak negative chronotropic effects in the antiand orthodromic phases of heart activity. However, neither agonists had an effect on semi-isolated beetle heart in vitro. Only atropine at the highest tested concentrations slightly decreased the frequency of myocardial contractions. These suggest the regulation of heart activity by muscarinic system indirectly. The tested compounds also affected the contractility of the oviduct and hindgut, but the responses of these organs were varied and depended on the concentration of the applied compounds. These pharmacological experiments suggest the possible modulation of insect visceral muscle contractility by the cholinergic nervous system and indirectly indicate the presence of muscarinic receptor(s) in the visceral organs of the beetle T. molitor. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

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.

Neural Mechanisms Underlying Lower Urinary Tract Dysfunction

PubMed Central

Ogawa, Teruyuki; Miyazato, Minoru; Kitta, Takeya; Furuta, Akira; Chancellor, Michael B.; Tyagi, Pradeep

2014-01-01

This article summarizes anatomical, neurophysiological, and pharmacological studies in humans and animals to provide insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract and alterations in these mechanisms in lower urinary tract dysfunction. The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Therefore, injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce lower urinary tract dysfunction, leading to lower urinary tract symptoms, including both storage and voiding symptoms, and pelvic pain. Neuroplasticity underlying pathological changes in lower urinary tract function is discussed. PMID:24578802

Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion.

PubMed

Qu, Jie; Zhou, Qiong; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Xi, Ye; Li, Zhuyi; Miao, Jianting

2014-08-01

Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer's disease. © 2014 The British Pharmacological Society.

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

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.

Effects of aniracetam on bladder overactivity in rats with cerebral infarction.

PubMed

Nakada, Y; Yokoyama, O; Komatsu, K; Kodama, K; Yotsuyanagi, S; Niikura, S; Nagasaka, Y; Namiki, M

2000-06-01

Aniracetam has been used to improve the mental condition of patients with cerebrovascular disease. Previous studies have demonstrated that aniracetam activates the residual functions of cholinergic neurons in damaged brain areas. In this study, the effects of aniracetam on bladder overactivity after left middle cerebral artery occlusion were assessed through oral or i.c.v. administration in sham-operated and cerebral infarcted rats. Oral administration of aniracetam (100 and 300 mg/kg) resulted in a significant and dose-dependent increase in bladder capacity in cerebral infarcted rats but had no effect on bladder capacity in sham-operated rats. Intracerebroventricular administration of aniracetam (0.25 and 2.5 microg/rat) resulted in a significant and dose-dependent increase in bladder capacity in cerebral infarcted rats but not in sham-operated rats. Aniracetam had no significant effect on bladder contraction pressure or micturition threshold pressure in either sham-operated or cerebral infarcted rats. Furthermore, i.c.v. administration of atropine (1 microg/rat), a muscarinic acetylcholine receptor antagonist, completely inhibited the enhancing effects of aniracetam on bladder capacity in cerebral infarcted rats. The effects of aniracetam on bladder overactivity are thought to be mediated in part by activation of cholinergic inhibitory mechanisms in the brain. These results indicate that aniracetam may improve the neurogenic voiding dysfunction observed in patients with cerebrovascular disease.

A Review of the Pedunculopontine Nucleus in Parkinson's Disease.

PubMed

French, Isobel T; Muthusamy, Kalai A

2018-01-01

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.

[Efferent innervation of the arteries of human leptomeninx in arterial hypertension].

PubMed

Chertok, V M; Kotsiuba, A E; Babich, E V

2009-01-01

Structure of the efferent nerve plexuses (adrenergic, acetylcholinestherase- and cholinacetyltranspherase-positive, NO-dependent), was studied in the arteries of human leptomeninx with different diameters. Material was obtained from the corpses of the healthy people and of the patients with initial stages of arterial hypertension (AH). It was shown that the concentrations of cholinergic and adrenergic nerve fibers and varicosities in axon terminal part, innervating the arteries with the diameters ranging from 450 till 100 microm, were not significantly different. In these arteries, NO-ergic plexuses were also detected. In patients with AH, regardless the arterial diameters, the significant increase (up to 15-20%) of adrenergic nerve fiber and varicosity concentrations was found. The changes in cholinergic nerve fiber concentration were found to depend on the vessel diameter: the significant decrease of these parameter was observed only in arteries with the diameter of 100-200 microm. No significant changes in nerve plexus concentration was noticed in the arteries with greater or smaller diameter. In NO-ergic neural conductors, the enzyme activity decreased only in the large arteries, and remained almost unchanged in the small vascular branches. The changes in the vasomotor innervation described in AH, are interpreted as a vasomotor innervation dysfunction of the leptomeninx arteries that may result in the hemodynamic disturbances.

A Review of the Pedunculopontine Nucleus in Parkinson's Disease

PubMed Central

French, Isobel T.; Muthusamy, Kalai A.

2018-01-01

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients. PMID:29755338

Olfaction in Parkinson's disease and related disorders

PubMed Central

Doty, Richard L.

2012-01-01

Olfactory dysfunction is an early ‘pre-clinical’ sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclein- and tau-related pathology,or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances. PMID:22192366

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.

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.

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.

Screening and Assessment of Young Children.

ERIC Educational Resources Information Center

Friedlander, Bernard Z.

Most language development hazards in infancy and early childhood fall into the categories of auditory impairment, central integrative dysfunction, inadequate environmental support, and peripheral expressive impairment. Existing knowledge and techniques are inadequate to meet the screening and assessment problems of central integrative dysfunction,…

Central Auditory Nervous System Dysfunction in Echolalic Autistic Individuals.

ERIC Educational Resources Information Center

Wetherby, Amy Miller; And Others

1981-01-01

The results showed that all the Ss had normal hearing on the monaural speech tests; however, there was indication of central auditory nervous system dysfunction in the language dominant hemisphere, inferred from the dichotic tests, for those Ss displaying echolalia. (Author)

Modulation of Cholinergic Pathways and Inflammatory Mediators in Blast-Induced Traumatic Brain Injury

DTIC Science & Technology

2013-01-01

matic brain injury (TBI). Centrally acting acetylcholinesterase (AChE) inhibitors are also being considered as potential therapeutic candidates...repeated blast exposures [12]. AChE inhibitors are possible therapeutic candidates against Alzheimer’s disease and TBI [13–15]. In this study, we...esterase inhibitor , as described earlier [12,17–19]. Brain AChE activity was expressed as milliunits/mg protein. 2.3. Microarray analysis Various

The Neuroprotective Benefits of Central Adenosine Receptor Stimulation in a Soman Nerve Agent Rat Model

DTIC Science & Technology

2014-04-01

irreversibly inhibit acetylcholinesterase (AChE), the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine (ACh) in the cholinergic... potential inhibitory compounds and drugs along these lines of neurotransmission perturbations have been investigated (McDonough and Shih 1997; Shih...effects, van Helden et al. (1998) recognized adenosine’s potential as a CWNA countermeasure. In their early study, the A1 adenosine agonist (6

Prolonged enhancement of REM sleep produced by carbachol microinjection into the amygdala.

PubMed

Calvo, J M; Simón-Arceo, K; Fernández-Mas, R

1996-01-31

The effect on sleep organization of carbachol microinjected into different amygdaloid nuclei was analysed in 12 cats. Single carbachol doses of 8 micrograms in 0.50 microliter saline were delivered unilaterally or bilaterally into the central, basal, lateral or basolateral amygdaloid nucleus. Carbachol administration into the central nucleus induced a prolonged (5 days) enhancement of both REM sleep and its preceeding slow wave sleep episodes with PGO waves (sommeil phasique a ondes lentes, SPHOL), which was more pronounced following bilateral than unilateral carbachol administration. However, neither SPHOL nor REM sleep changes were produced by administration of carbachol into the other amygdaloid nuclei. We conclude that cholinergic activation of the central amygdaloid nucleus produces a long-term facilitation of REM sleep occurrence.

Estrogen-Cholinergic Interactions: Implications for Cognitive Aging

PubMed Central

Newhouse, Paul; Dumas, Julie

2015-01-01

While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. PMID:26187712

Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain

PubMed Central

2012-01-01

Background Diabetes is one of the risk factors for cognitive deficits such as Alzheimer’s disease. To obtain a better understanding of the anti-dementia effect of chotosan (CTS), a Kampo formula, we investigated its effects on cognitive and emotional deficits of type 2 diabetic db/db mice and putative mechanism(s) underlying the effects. Methods Seven-week-old db/db mice received daily administration of CTS (375 – 750 mg/kg, p.o.) and the reference drug tacrine (THA: 2.5 mg/kg, i.p.) during an experimental period of 7 weeks. From the age of 9-week-old, the animals underwent the novel object recognition test, the modified Y-maze test, and the water maze test to elucidate cognitive performance and the elevated plus maze test to elucidate anxiety-related behavior. After completing behavioral studies, Western blotting and immunohistochemical studies were conducted. Results Compared with age-matched non-diabetic control strain (m/m) mice, db/db mice exhibited impaired cognitive performance and an increased level of anxiety. CTS ameliorated cognitive and emotional deficits of db/db mice, whereas THA improved only cognitive performance. The phosphorylated levels of Akt and PKCα in the hippocampus were significantly lower and higher, respectively, in db/db mice than in m/m mice. Expression levels of the hippocampal cholinergic marker proteins and the number of the septal cholinergic neurons were also reduced in db/db mice compared with those in m/m mice. Moreover, the db/db mice had significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF), VEGF receptor type 2, platelet-derived growth factor-B, and PDGF receptor β, in the hippocampus. CTS and THA treatment reversed these neurochemical and histological alterations caused by diabetes. Conclusion These results suggest that CTS ameliorates diabetes-induced cognitive deficits by protecting central cholinergic and VEGF/PDGF systems via Akt signaling pathway and that CTS exhibits the anxiolytic effect via neuronal mechanism(s) independent of cholinergic or VEGF/PDGF systems in db/db mice. PMID:23082896

Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain.

PubMed

Zhao, Qi; Niu, Yimin; Matsumoto, Kinzo; Tsuneyama, Koichi; Tanaka, Ken; Miyata, Takeshi; Yokozawa, Takako

2012-10-20

Diabetes is one of the risk factors for cognitive deficits such as Alzheimer's disease. To obtain a better understanding of the anti-dementia effect of chotosan (CTS), a Kampo formula, we investigated its effects on cognitive and emotional deficits of type 2 diabetic db/db mice and putative mechanism(s) underlying the effects. Seven-week-old db/db mice received daily administration of CTS (375 - 750 mg/kg, p.o.) and the reference drug tacrine (THA: 2.5 mg/kg, i.p.) during an experimental period of 7 weeks. From the age of 9-week-old, the animals underwent the novel object recognition test, the modified Y-maze test, and the water maze test to elucidate cognitive performance and the elevated plus maze test to elucidate anxiety-related behavior. After completing behavioral studies, Western blotting and immunohistochemical studies were conducted. Compared with age-matched non-diabetic control strain (m/m) mice, db/db mice exhibited impaired cognitive performance and an increased level of anxiety. CTS ameliorated cognitive and emotional deficits of db/db mice, whereas THA improved only cognitive performance. The phosphorylated levels of Akt and PKCα in the hippocampus were significantly lower and higher, respectively, in db/db mice than in m/m mice. Expression levels of the hippocampal cholinergic marker proteins and the number of the septal cholinergic neurons were also reduced in db/db mice compared with those in m/m mice. Moreover, the db/db mice had significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF), VEGF receptor type 2, platelet-derived growth factor-B, and PDGF receptor β, in the hippocampus. CTS and THA treatment reversed these neurochemical and histological alterations caused by diabetes. These results suggest that CTS ameliorates diabetes-induced cognitive deficits by protecting central cholinergic and VEGF/PDGF systems via Akt signaling pathway and that CTS exhibits the anxiolytic effect via neuronal mechanism(s) independent of cholinergic or VEGF/PDGF systems in db/db mice.

Current Concepts in Ejaculatory Dysfunction

PubMed Central

Wolters, Jeffrey P; Hellstrom, Wayne J. G

2006-01-01

Although erectile dysfunction has recently become the most well-known aspect of male sexual dysfunction, the most prevalent male sexual disorders are ejaculatory dysfunctions. Ejaculatory disorders are divided into 4 categories: premature ejaculation (PE), delayed ejaculation, retrograde ejaculation, and anejaculation/anorgasmia. Pharmacologic treatment for certain ejaculatory disorders exists, for example the off-label use of selective serotonin reuptake inhibitors for PE. Unfortunately, the other ejaculatory disorders are less studied and not as well understood. This review revisits the physiology of the normal ejaculatory response, specifically explores the mechanisms of anejaculation, and presents emerging data. The neurophysiology of the ejaculatory reflex is complex, making classification of the role of individual neurotransmitters extremely difficult. However, recent research has elucidated more about the role of serotonin and dopamine at the central level in the physiology of both arousal and orgasm. Other recent studies that look at differing pharmacokinetic profiles and binding affinities of the α1-antagonists serve as an indication of the centrally mediated role of ejaculation and orgasm. As our understanding of the interaction between central and peripheral modulations and regulation of the process of ejaculation increases, the probability of developing centrally acting pharmaceutical agents for the treatment of sexual dysfunction approaches reality. PMID:17215997

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

Cognitive Ameliorating Effect of Acanthopanax koreanum Against Scopolamine-Induced Memory Impairment in Mice.

PubMed

Lee, Sunhee; Park, Ho Jae; Jeon, Se Jin; Kim, Eunji; Lee, Hyung Eun; Kim, Haneul; Kwon, Yubeen; Zhang, Jiabao; Jung, In Ho; Ryu, Jong Hoon

2017-03-01

Acanthopanax koreanum Nakai (Araliaceae) is one of the most widely cultivated medicinal plants in Jeju Island, Korea, and the roots and stem bark of A. koreanum have been traditionally used as a tonic agent for general weakness. However, the use of A. koreanum for general weakness observed in the elderly, including those with declined cognitive function, has not been intensively investigated. This study was performed to investigate the effect of the ethanol extract of A. koreanum (EEAK) on cholinergic blockade-induced memory impairment in mice. To evaluate the ameliorating effects of EEAK against scopolamine-induced memory impairment, mice were orally administered EEAK (25, 50, 100, or 200 mg/kg), and several behavioral tasks, including a passive avoidance task, the Y-maze, and a novel object recognition task, were employed. Besides, western blot analysis was conducted to examine whether EEAK affected memory-associated signaling molecules, such as protein kinase B (Akt), Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), and cAMP response element-binding protein (CREB). The administration of EEAK (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in the passive avoidance task, the Y-maze, and the novel object recognition task. The phosphorylation levels of both Akt and CaMKII were significantly increased by approximately two-fold compared with the control group because of the administration of EEAK (100 or 200 mg/kg) (p < 0.05). Moreover, the phosphorylation level of CREB was also significantly increased compared with the control group by the administration of EEAK (200 mg/kg) (p < 0.05). The present study suggests that EEAK ameliorates the cognitive dysfunction induced by the cholinergic blockade, in part, via several memory-associated signaling molecules and may hold therapeutic potential against cognitive dysfunction, such as that presented in neurodegenerative diseases, for example, Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

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

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.

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.

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

PubMed

Zant, Janneke C; Kim, Tae; Prokai, Laszlo; Szarka, Szabolcs; McNally, James; McKenna, James T; Shukla, Charu; Yang, Chun; Kalinchuk, Anna V; McCarley, Robert W; Brown, Ritchie E; Basheer, Radhika

2016-02-10

Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that "selective" stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of "selective" optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons. Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior. Copyright © 2016 the authors 0270-6474/16/362058-11$15.00/0.

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study

PubMed Central

Zant, Janneke C.; Kim, Tae; Prokai, Laszlo; Szarka, Szabolcs; McNally, James; McKenna, James T.; Shukla, Charu; Yang, Chun; Kalinchuk, Anna V.; McCarley, Robert W.; Brown, Ritchie E.

2016-01-01

Understanding the control of sleep–wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep–wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that “selective” stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of “selective” optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons. SIGNIFICANCE STATEMENT Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel “opto-dialysis” probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of “opto-dialysis” for dissecting the complex brain circuitry underlying behavior. PMID:26865627

[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.

Reduced Vesicular Acetylcholine Transporter favors antidepressant behaviors and modulates serotonin and dopamine in female mouse brain.

PubMed

Pádua-Reis, Marina; Aquino, Nayara S; Oliveira, Vinícius E M; Szawka, Raphael E; Prado, Marco A M; Prado, Vânia F; Pereira, Grace S

2017-07-14

Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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

Estrogen-cholinergic interactions: Implications for cognitive aging.

PubMed

Newhouse, Paul; Dumas, Julie

2015-08-01

This article is part of a Special Issue "Estradiol and Cognition". While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. Published by Elsevier Inc.

Isolation of hydroxyoctaprenyl-1',4'-hydroquinone, a new octaprenylhydroquinone from the marine sponge Sarcotragus spinosulus and evaluation of its pharmacological activity on acetylcholine and glutamate release in the rat central nervous system.

PubMed

Bisio, Angela; Fedele, Ernesto; Pittaluga, Anna; Olivero, Guendalina; Grilli, Massimo; Chen, Jiayang; Mele, Giacomo; Malafronte, Nicola; De Tommasi, Nunziatina; Leddae, Fabio; Manconi, Renata; Pronzato, Roberto; Marchi, Mario

2014-11-01

Three polyprenyl-1',4'-hydroquinone derivatives, heptaprenyl-1',4'-hydroquinone (1), octaprenyl-1',4'-hydroquinone (2), and hydroxyoctaprenyl-1',4'- hydroquinone (3) were isolated from the marine sponge Sarcotragus spinosulus collected at Baia di Porto Conte, Alghero (Italy). Our findings indicate that the compounds isolated from S. spinosulus can significantly modulate the release of glutamate and acetylcholine in the rat hippocampus and cortex and might, therefore, represent the prototype of a new class of drugs regulating glutamatergic and cholinergic transmission in the mammalian central nervous system.

Augmentation of neurally evoked cholinergic bronchoconstrictor responses by prejunctional NK2 receptors in the guinea-pig.

PubMed

Hey, J A; Danko, G; del Prado, M; Chapman, R W

1996-02-01

1. We examined the effect of exogenously administered tachykinins, neurokinin A (NKA), substance P (SP) and neurokinin B (NKB) on neurally mediated cholinergic bronchoconstrictor responses in guinea-pigs. 2. Electrical stimulation of regions in the dorsal medulla oblongata produced a cholinergic bronchospasm that was not affected by depletion of endogenous tachykinins with capsaicin pretreatment (50 mg kg-1, s.c., 1 week earlier) or by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon (3 mg kg-1, i.v.). 3. Infusion of NKA (0.03-0.1 microgram kg-1 min-1), SP (1 microgram kg-1 min-1) or NKB (1 microgram kg-1 min-1) potentiated the bronchoconstrictor response to electrical stimulation of the dorsal medulla. The doses of tachykinins tested were subthreshold for direct activation of airway smooth muscle, because they were devoid of direct bronchoconstrictor effects. The relative rank order potency for augmentation of centrally induced bronchospasm was NKA > NKB approximately SP, suggesting activation of the NK2 receptor subtype. 4. Infusion of NKA, SP and NKB had no effect on bronchoconstrictor responses to i.v. methacholine (1 microgram kg-1) indicating that a prejunctional neural mechanism of action was responsible for the effects on CNS stimulation-induced bronchospasm. 5. Potentiation of the bronchoconstrictor response to dorsal medullary stimulation produced by infusion of NKA was blocked by pretreatment with the NK2 antagonist SR 48968 (1 mg kg-1, i.v.) but not by the NK1 antagoinst CP 96,345 (1 mg kg-1, i.v.). 6. The potentiation of CNS-induced bronchospasm produced by infusion of SP was partially inhibited by CP 96,345 (1 mg kg-1, i.v.) but not by SR 48968 (1 mg kg-1, i.v.). Treatment with combined SR 48968 (1 mg kg-1, i.v.) and CP 96,345 (1 mg kg-1, i.v.) completely blocked the SP-induced potentiation of CNS-stimulated bronchospasm. 7. These results identify an important modulatory role for NK2 receptors, located at prejunctional sites on parasympathetic nerves, on cholinergic bronchoconstrictor responses in guinea-pigs. 8. It is proposed that substances that release tachykinins from airway sensory nerves, e.g. inflammatory mediators or irritants, may induce hyperresponsiveness of cholinergic bronchomotor responses by activation of NK2-receptors on parasympathetic airway nerves. Furthermore, these studies indicate that endogenous tachykinins are not involved in the maintenance of basal cholinergic bronchomotor tone in the intact guinea-pig.

Molecular Targets for Organophosphates in the Central Nervous System

DTIC Science & Technology

2006-04-01

above and cholinesterase activity was measured in the supernatants after 0, 15, 30 and 60 min= exposure to PB (100 nM). Drugs and biological...a quaternary carbamate that does not cross the blood brain barrier (BBB) appreciably and inhibits reversibly AChE and BuChE with similar potencies... activity could be maintained by ACh released from cholinergic neurons in our culture. In the continuous presence of atropine, exposure of the neurons to

The Mechanism of Interaction of Oximes with the Muscarinic-Cholinergic Complex in the Central Nervous System

DTIC Science & Technology

1983-11-03

ACh binding to the remaining sites. However, the affinity of oxotremorine to the high affinity agonist binding sites was reduced. The relative...when examined in the remaining sites in the washed membranes, were similar to those in control membranes. The affinity of the agonist oxotremorine ... oxotremorine was substituted for atropine. All determinations were carriid out in quadruplicate, each one varying by < 15%. Centrifugation assays

Mechanisms of cholinergic dysfunction in rabbits following recurrent aspiration of cow's milk.

PubMed

Larsen, G L; Loader, J; Nguyen, D D; Colasurdo, G N

2001-12-01

Recurrent aspiration of cow's milk has been shown to alter neural control of airways in young rabbits (Gelfand et al., 1997). The purpose of this study was to define the mechanisms responsible for in vitro cholinergic hyperresponsiveness in this model. Beginning at 1 week of age, rabbits received either 0.5 mL/kg whole cow's milk or sterile saline intranasally while under light anesthesia. This was repeated each weekday for 2 weeks. At 8 weeks of age, rabbits were sacrificed. Portions of lungs underwent lavage with sterile saline. Tracheal smooth muscle (TSM) segments were also removed. Segments were assessed for acetylcholine (ACh) release by high-performance liquid chromatography ( HPLC) with electrochemical detection or acetylcholinesterase (AChE) kinetic activity by spectrophotometry. Substance P (SP), a neuropeptide that can increase ACh release from nerves, was also assessed using an enzyme immunoassay to define the content in lavage and TSM segments. Immunohistochemistry for SP within airways was also assessed. We found that recurrent aspiration of milk led to statistically significant alterations in many parameters. Acetylcholine release was significantly greater in segments of airways from rabbits that had aspirated cow's milk (27.5 +/- 1.7 vs. 20.1 +/- 1.6 pmol/min/g tissue) than saline. At the same time, AChE activity was less in the group that aspirated milk (8.7 +/- 0.4 vs. 10.2 +/- 0.5 nmol/min/mg protein) compared to saline. The amount of SP within both lavage as well as tissue homogenates was greater in the group that had aspirated the foreign protein (159.1 +/- 28.9 vs. 41.9 +/- 5.2 pmol/mg protein in lavage; 158.7 +/- 31.9 vs. 80.5 +/- 7.8 pmol/mg protein in tissues) than saline controls. While total cholinergic nerve density as assessed by choline acetyltransferase was not significantly different between groups, SP-positive immunoreactive nerves were easily identified in the group that aspirated cow's milk. This study suggests that cholinergic hyperresponsiveness caused by repeated aspiration of milk is due to several abnormalities, including prejunctional (increase in ACh release) as well as junctional (decrease in AChE) mechanisms within the airways. In addition, an upregulation of SP within airways is part of this process. Copyright 2001 Wiley-Liss, Inc.

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.

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.

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

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).

Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus

PubMed Central

The, FO; Cailotto, C; van der Vliet, J; de Jonge, WJ; Bennink, RJ; Buijs, RM; Boeckxstaens, GE

2011-01-01

BACKGROUND AND PURPOSE Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice. EXPERIMENTAL APPROACH Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg−1) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos. KEY RESULTS Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve. CONCLUSIONS AND IMPLICATIONS Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve. PMID:21371006

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.

Curcumin and Apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease

PubMed Central

Venigalla, Madhuri; Gyengesi, Erika; Münch, Gerald

2015-01-01

Alzheimer's disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer's disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer's disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer's disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer's disease or slow down its progression, and they should enter clinical trials as soon as possible. PMID:26487830

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.

Opioid receptor subtypes mediating the noise-induced decreases in high-affinity choline uptake in the rat brain.

PubMed

Lai, H; Carino, M A

1992-07-01

Acute (20 min) exposure to 100-dB white noise elicits a naltrexone-sensitive decrease in sodium-dependent high-affinity choline uptake in the frontal cortex and hippocampus of the rat. In the present study, the subtypes of opioid receptors involved were investigated by pretreating rats with microinjection of specific opioid-receptor antagonists into the lateral cerebroventricle before noise exposure. We found that the noise-induced decrease in high-affinity choline uptake in the hippocampus was blocked by pretreatment with either mu-, delta-, or kappa-opioid-receptor antagonists, whereas the effect of noise on frontal cortical high-affinity choline uptake was blocked by a mu- and delta- but not by a kappa-antagonist. These data further confirm the role of endogenous opioids in mediating the effects of noise on central cholinergic activity and indicate that different neural mechanisms are involved in the effects of noise on the frontal cortical and hippocampal cholinergic systems.

Experiment K-7-18: Effects of Spaceflight in the Muscle Adductor Longus of Rats Flown in the Soviet Biosatellite Cosmos 2044. Part 2; Quantitative Autoradiographic Analysis of Gaba (Benzodiazepine) and Muscarinic (Cholinergic) Receptors in the Forebrain of Rats Flown on Cosmos 2044

NASA Technical Reports Server (NTRS)

Wu, L.; Daunton, N. G.; Krasnov, I. B.; DAmelio, F.; Hyde, T. M.; Sigworth, S. K.

1994-01-01

Quantitative autoradiographic analysis of receptors for GABA and acetylcholine in the forebrain of rats flown on COSMOS 2044 was undertaken as part of a joint US-Soviet study to determine the effects of microgravity on the central nervous system, and in particular on the sensory and motor portions of the forebrain. Changes in binding of these receptors in tissue from animals exposed to microgravity would provide evidence for possible changes in neural processing as a result of exposure to microgravity. Tritium-labelled diazepam and Quinuclidinyl-benzilate (QNB) were used to visualize GABA (benzodiazepine) and muscarinic (cholinergic) receptors, respectively. The density of tritium-labelled radioligands bound to various regions in the forebrain of both flight and control animals were measured from autoradiograms. Data from rats flown in space and from ground-based control animals that were not exposed to microgravity were compared.

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

PubMed Central

Musicki, Biljana; Hannan, Johanna L.; Lagoda, Gwen; Bivalacqua, Trinity J.; Burnett, Arthur L.

2016-01-01

Men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED) have greater risk of cardiovascular events than T2DM men without ED, suggesting ED as a predictor of cardiovascular events in diabetic men. However, molecular mechanisms underlying endothelial dysfunction in the diabetic penis explaining these clinical observations are not known. We evaluated whether the temporal relationship between ED and endothelial dysfunction in the systemic vasculature in T2DM involves earlier redox imbalance and endothelial nitric oxidase synthase (eNOS) dysfunction in the penis than in the systemic vasculature, such as the carotid artery. Rats were rendered T2DM by high-fat diet for 2 weeks, followed by an injection with low-dose streptozotocin. After 3 weeks, erectile function (intracavernosal pressure) was measured and penes and carotid arteries were collected for molecular analyses of eNOS uncoupling, protein S-glutathionylation, oxidative stress (4-hydroxy-2-nonenal, 4-HNE), protein expression of NADPH oxidase subunit gp91phox, endothelium-dependent vasodilation in the carotid artery, and non-andrenergic, non-cholinergic (NANC) mediated cavernosal relaxation. Erectile response to electrical stimulation of the cavernous nerve and NANC mediated cavernosal relaxation were decreased (p<0.05), while relaxation of the carotid artery to acetylcholine was not impaired in T2DM rats. eNOS monomerization, protein expressions of 4-HNE and gp91phox, and protein S-glutathionylation, were increased (p<0.05) in the penis, but not in the carotid artery, of T2DM compared to nondiabetic rats. In conclusion, redox imbalance, increased oxidative stress by NADPH oxidase, and eNOS uncoupling, occur early in T2DM in the penis, but not in the carotid artery. These molecular changes contribute to T2DM ED, while vascular function in the systemic vasculature remains preserved. PMID:27153512

Conversion of elderly to Alzheimer's dementia: role of confluence of hypothermia and senescent stigmata--the plausible pathway.

PubMed

Daulatzai, Mak Adam

2010-01-01

Aging is a consequence of progressive decline in special and somatosensory functions and specific brain stem nuclei. Many senescent stigmata, including hypoxia, hypoxemia, depressed cerebral blood flow and glucose metabolism, diseases of senescence, and their medications all enhance hypothermia as do alcohol, cold environment, and malnutrition. Hypothermia is a critical factor having deleterious impact on brain stem and neocortical functions. Additionally, anesthesia in elderly also promotes hypothermia; anesthetics not only cause consciousness (sensory and motor) changes, but memory impairment as well. Anesthesia inhibits cholinergic pathways, reticular and thalamocortical systems, cortico-cortical connectivity, and causes post-operative delirium and cognitive dysfunction. Increasing evidence indicates that anesthetic exposures may contribute to dementia onset and Alzheimer's disease (AD) in hypothermic elderly. Inhaled anesthetics potentiate caspases, BACE, tau hyperphosphorylation, and apoptosis. This paper addresses the important question: "Why do only some elderly fall victim to AD"? Based on information on the pathogenesis of early stages of cognitive dysfunction in elderly (i.e., due to senescent stigmata), and the effects of anesthesia superimposed, a detailed plausible neuropathological substrate (mechanism/pathway) is delineated here that reveals the possible cause(s) of AD. Basically, it encompasses several risk factors for cognitive dysfunction during senescence plus several hypothermia-enhancing routes; they all converge and tip the balance towards dementia onset. This knowledge of the confluence of heterogeneous risk factors in perpetuating dementia relentlessly is of importance in order to: (a) avoid their convergence; (b) take measures to stop/reverse cognitive dysfunction; and (c) to develop therapeutic strategies to enhance cognitive function and attenuate AD.

Olfaction in Parkinson's disease and related disorders.

PubMed

Doty, Richard L

2012-06-01

Olfactory dysfunction is an early 'pre-clinical' sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclein- and tau-related pathology, or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances. Copyright © 2011 Elsevier Inc. All rights reserved.

Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET.

PubMed

Gjerløff, Trine; Fedorova, Tatyana; Knudsen, Karoline; Munk, Ole L; Nahimi, Adjmal; Jacobsen, Steen; Danielsen, Erik H; Terkelsen, Astrid J; Hansen, John; Pavese, Nicola; Brooks, David J; Borghammer, Per

2015-03-01

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Rescue of Amyloid-Beta-Induced Inhibition of Nicotinic Acetylcholine Receptors by a Peptide Homologous to the Nicotine Binding Domain of the Alpha 7 Subtype

PubMed Central

Trujillo, Cleber A.; Sathler, Luciana B.; Juliano, Maria A.; Juliano, Luiz; Ulrich, Henning; Ferreira, Sergio T.

2013-01-01

Alzheimer's disease (AD) is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ) and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs). Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD. PMID:23894286

Learning history and cholinergic modulation in the dorsal hippocampus are necessary for rats to infer the status of a hidden event.

PubMed

Fast, Cynthia D; Flesher, M Melissa; Nocera, Nathanial A; Fanselow, Michael S; Blaisdell, Aaron P

2016-06-01

Identifying statistical patterns between environmental stimuli enables organisms to respond adaptively when cues are later observed. However, stimuli are often obscured from detection, necessitating behavior under conditions of ambiguity. Considerable evidence indicates decisions under ambiguity rely on inference processes that draw on past experiences to generate predictions under novel conditions. Despite the high demand for this process and the observation that it deteriorates disproportionately with age, the underlying mechanisms remain unknown. We developed a rodent model of decision-making during ambiguity to examine features of experience that contribute to inference. Rats learned either a simple (positive patterning) or complex (negative patterning) instrumental discrimination between the illumination of one or two lights. During test, only one light was lit while the other relevant light was blocked from physical detection (covered by an opaque shield, rendering its status ambiguous). We found experience with the complex negative patterning discrimination was necessary for rats to behave sensitively to the ambiguous test situation. These rats behaved as if they inferred the presence of the hidden light, responding differently than when the light was explicitly absent (uncovered and unlit). Differential expression profiles of the immediate early gene cFos indicated hippocampal involvement in the inference process while localized microinfusions of the muscarinic antagonist, scopolamine, into the dorsal hippocampus caused rats to behave as if only one light was present. That is, blocking cholinergic modulation prevented the rat from inferring the presence of the hidden light. Collectively, these results suggest cholinergic modulation mediates recruitment of hippocampal processes related to past experiences and transfer of these processes to make decisions during ambiguous situations. Our results correspond with correlations observed between human brain function and inference abilities, suggesting our experiments may inform interventions to alleviate or prevent cognitive dysfunction. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

The Role Of Basal Forebrain Cholinergic Neurons In Fear and Extinction Memory

PubMed Central

Knox, Dayan

2016-01-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. PMID:27264248

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.

Cerebral protein kinase C and its mRNA level in apolipoprotein E-deficient mice.

PubMed

Hung, M C; Hayase, K; Yoshida, R; Sato, M; Imaizumi, K

2001-08-10

It is known that protein kinase C (PKC) activity may be one of the fundamental cellular changes associated with memory function. Apolipoprotein E (apoE) deficiency causes cholinergic deficits and memory impairment. ApoE-deficient mouse has been employed as a serviceable model for studying the relation between apoE and the memory deficit induced by cholinergic impairment. Brain-fatty acid binding protein (b-FABP) might be functional during development of the nervous system. Peroxisome proliferator-activated receptor (PPAR) is involved in the early change in lipid metabolism. We investigated the alterations not only in cerebral PKC activity, but also in the gene expressions of PKC-beta, brain-FABP and PPAR-alpha in apoE-deficient mice. The results showed that there was a lower cerebral membrane-bound PKC activity in the apoE-deficient mice than in its wild type strain (C57BL/6). But there were no significant differences in cytosolic PKC activity. PKC-beta, b-FABP and PPAR-alpha mRNA expressions in cerebrum were lowered in apoE-deficient mice. These findings may be involved in the dysfunction of the brain neurotransmission system in apoE-deficient mouse. Alternatively, these results also suggest that cerebral apoE plays an important role in brain PKC activation by maintaining an appropriate expression of b-FABP and PPAR-alpha mRNAs.

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

PubMed Central

Smith, Darrell R.; Frizzi, Katie; Sabbir, Mohammad Golam; Chowdhury, Subir K. Roy; Mixcoatl-Zecuatl, Teresa; Saleh, Ali; Muttalib, Nabeel; Van der Ploeg, Randy; Ochoa, Joseline; Gopaul, Allison; Tessler, Lori; Wess, Jürgen; Jolivalt, Corinne G.

2017-01-01

Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor–dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible. PMID:28094765

Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.

DTIC Science & Technology

1986-04-11

Leudee NWI 5th England 18. brain;striatum;hippocampus;cortex;brainstem;rat;hydrophilic drugs;hydrophobic drugs; oxotremorine ;physostigmine;choline...challenged with oxotremorine , marked cross-tolerance to the ACh-increasing action f the muscarinic receptor agonist was induced in both striatum and...responses except for slight tremor.A Fig. 2 shows the dose-response curves of the muscarinic agonists oxotremorine and the butynyl base, McN-A-343, a

Stimulation of Central A1 Adenosine Receptors Suppresses Seizure and Neuropathology in a Soman Nerve Agent Seizure Rat Model

DTIC Science & Technology

2014-05-22

acetylcholinesterase (AChE), the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine (ACh) in the cholinergic synapses and neuromuscular...1992; Fosbraey et al., 1990; Lallement et al., 1991; O’Donnell et al., 2010, 2011; Wade et al., 1987). Many potential inhibitory compounds and drugs...2005). Despite such cardiovascular effects, van Helden et al. (1998) recognized adenosine’s potential as a CWNA countermeas- ure. In their early

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

PubMed Central

Abou-Donia, Mohamed B.; Siracuse, Briana; Gupta, Natasha; Sokol, Ashly Sobel

2017-01-01

Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as “cholinergic crisis” (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam. PMID:27705071

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.

Hemodialysis Tunneled Catheter Noninfectious Complications

PubMed Central

Miller, Lisa M.; MacRae, Jennifer M.; Kiaii, Mercedeh; Clark, Edward; Dipchand, Christine; Kappel, Joanne; Lok, Charmaine; Luscombe, Rick; Moist, Louise; Oliver, Matthew; Pike, Pamela; Hiremath, Swapnil

2016-01-01

Noninfectious hemodialysis catheter complications include catheter dysfunction, catheter-related thrombus, and central vein stenosis. The definitions, causes, and treatment strategies for catheter dysfunction are reviewed below. Catheter-related thrombus is a less common but serious complication of catheters, requiring catheter removal and systemic anticoagulation. In addition, the risk factors, clinical manifestation, and treatment options for central vein stenosis are outlined. PMID:28270922

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.

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.

The role of basal forebrain cholinergic neurons in fear and extinction memory.

PubMed

Knox, Dayan

2016-09-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Biochemical factors modulating female genital sexual arousal physiology.

PubMed

Traish, Abdulmaged M; Botchevar, Ella; Kim, Noel N

2010-09-01

Female genital sexual arousal responses are complex neurophysiological processes consisting of central and peripheral components that occur following sexual stimulation. The peripheral responses in sexual arousal include genital vasocongestion, engorgement and lubrication resulting from a surge of vaginal and clitoral blood flow. These hemodynamic events are mediated by a host of neurotransmitters and vasoactive agents. To discuss the role of various biochemical factors modulating female genital sexual arousal responses. A comprehensive literature review was conducted using the PubMed database and citations were selected, based on topical relevance, and examined for study methodology and major findings. Data from peer-reviewed publications. Adrenergic as well as non-adrenergic non-cholinergic neurotransmitters play an important role in regulating genital physiological responses by mediating vascular and non-vascular smooth muscle contractility. Vasoactive peptides and neuropeptides also modulate genital sexual responses by regulating vascular and non-vascular smooth muscle cells and epithelial function. The endocrine milieu, particularly sex steroid hormones, is critical in the maintenance of tissue structure and function. Reduced levels of estrogens and androgen are associated with dramatic alterations in genital tissue structure, including the nerve network, as well as the response to physiological modulators. Furthermore, estrogen and androgen deficiency is associated with reduced expression of sex steroid receptors and most importantly with attenuated genital blood flow and lubrication in response to pelvic nerve stimulation. This article provides an integrated framework describing the physiological and molecular basis of various pathophysiological conditions associated with female genital sexual arousal dysfunction. © 2010 International Society for Sexual Medicine.

Potential clinical relevance of the 'little brain' on the mammalian heart.

PubMed

Armour, J A

2008-02-01

It is hypothesized that the heart possesses a nervous system intrinsic to it that represents the final relay station for the co-ordination of regional cardiac indices. This 'little brain' on the heart is comprised of spatially distributed sensory (afferent), interconnecting (local circuit) and motor (adrenergic and cholinergic efferent) neurones that communicate with others in intrathoracic extracardiac ganglia, all under the tonic influence of central neuronal command and circulating catecholamines. Neurones residing from the level of the heart to the insular cortex form temporally dependent reflexes that control overlapping, spatially determined cardiac indices. The emergent properties that most of its components display depend primarily on sensory transduction of the cardiovascular milieu. It is further hypothesized that the stochastic nature of such neuronal interactions represents a stabilizing feature that matches cardiac output to normal corporal blood flow demands. Thus, with regard to cardiac disease states, one must consider not only cardiac myocyte dysfunction but also the fact that components within this neuroaxis may interact abnormally to alter myocyte function. This review emphasizes the stochastic behaviour displayed by most peripheral cardiac neurones, which appears to be a consequence of their predominant cardiac chemosensory inputs, as well as their complex functional interconnectivity. Despite our limited understanding of the whole, current data indicate that the emergent properties displayed by most neurones comprising the cardiac neuroaxis will have to be taken into consideration when contemplating the targeting of its individual components if predictable, long-term therapeutic benefits are to accrue.

Central obesity is an independent predictor of erectile dysfunction in older men.

PubMed

Riedner, Charles Edison; Rhoden, Ernani Luis; Ribeiro, Eduardo Porto; Fuchs, Sandra Costa

2006-10-01

There is a growing body of evidence in the literature correlating erectile dysfunction to obesity. We investigated the correlation of different anthropometric indexes of central obesity to erectile dysfunction. A cross-sectional study was performed including 256 consecutive men 40 years old or older. All men completed the International Index of Erectile Function, and were evaluated routinely with a clinical history, physical examination and blood analysis for fasting serum glucose, lipid profile and serum testosterone. Anthropometric measures included body mass index, waist circumference, sagittal abdominal diameter, maximal abdominal circumference, and waist-hip, waist-thigh, waist-height, sagittal abdominal diameter-thigh and sagittal abdominal diameter-height indexes. In men 40 to 60 years old the different anthropometric indexes of central obesity were not correlated with the presence of erectile dysfunction (p > 0.05). Men older than 60 years (41%, range 61 to 81) demonstrated an association among erectile dysfunction and waist-hip index (p = 0.04), waist-thigh index (p = 0.02), sagittal abdominal diameter (p = 0.03), sagittal abdominal diameter-height index (p = 0.02) and maximal abdominal circumference (p = 0.04). After logistic regression analysis an independent effect on the presence of erectile dysfunction was observed for waist-hip index (OR 8.56, 95% CI 1.44-50.73), sagittal abdominal diameter (OR 7.87, 95% CI 1.24-49.75), sagittal abdominal diameter-height index (OR 14.21, 95% CI 1.11-182.32), maximum abdominal circumference (OR 11.72, 95% CI 1.73-79.18) and waist circumference (OR 19.37, 95% CI 1.15-326.55). This study suggests that central obesity, assessed by several anthropometric indicators, is associated to the presence of erectile dysfunction in men older than 60 years. Sagittal abdominal diameter, sagittal abdominal diameter-height index, maximum abdominal circumference, waist circumference and waist-hip index were useful indicators to predict the presence of erectile dysfunction.

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

Chagas disease: modulation of the inflammatory response by acetylcholinesterase in hematological cells and brain tissue.

PubMed

Silva, Aniélen D; Bottari, Nathieli B; do Carmo, Guilherme M; Baldissera, Matheus D; Souza, Carine F; Machado, Vanessa S; Morsch, Vera M; Schetinger, Maria Rosa C; Mendes, Ricardo E; Monteiro, Silvia G; Da Silva, Aleksandro S

2018-01-01

Chagas disease is an acute or chronic illness that causes severe inflammatory response, and consequently, it may activate the inflammatory cholinergic pathway, which is regulated by cholinesterases, including the acetylcholinesterase. This enzyme is responsible for the regulation of acetylcholine levels, an anti-inflammatory molecule linked to the inflammatory response during parasitic diseases. Thus, the aim of this study was to investigate whether Trypanosoma cruzi infection can alter the activity of acetylcholinesterase and acetylcholine levels in mice, and whether these alterations are linked to the inflammatory cholinergic signaling pathway. Twenty-four mice were divided into two groups: uninfected (control group, n = 12) and infected by T. cruzi, Y strain (n = 12). The animals developed acute disease with a peak of parasitemia on day 7 post-infection (PI). Blood, lymphocytes, and brain were analyzed on days 6 and 12 post-infection. In the brain, acetylcholine and nitric oxide levels, myeloperoxidase activity, and histopathology were analyzed. In total blood and brain, acetylcholinesterase activity decreased at both times. On the other hand, acetylcholinesterase activity in lymphocytes increased on day 6 PI compared with the control group. Infection by T. cruzi increased acetylcholine and nitric oxide levels and histopathological damage in the brain of mice associated to increased myeloperoxidase activity. Therefore, an intense inflammatory response in mice with acute Chagas disease in the central nervous system caused an anti-inflammatory response by the activation of the cholinergic inflammatory pathway.

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.

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.

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.

Peripheral Distribution of Thrombus Does Not Affect Outcomes After Surgical Pulmonary Embolectomy.

PubMed

Pasrija, Chetan; Shah, Aakash; George, Praveen; Mohammed, Isa; Brigante, Francis A; Ghoreishi, Mehrdad; Jeudy, Jean; Taylor, Bradley S; Gammie, James S; Griffith, Bartley P; Kon, Zachary N

2018-04-04

Thrombus located distal to the main or primary pulmonary arteries has been previously viewed as a relative contraindication to surgical pulmonary embolectomy. We compared outcomes for surgical pulmonary embolectomy for submassive and massive pulmonary embolism (PE) in patients with central versus peripheral thrombus burden. All consecutive patients (2011-2016) undergoing surgical pulmonary embolectomy at a single center were retrospectively reviewed. Based on computed tomographic angiography of each patient, central PE was defined as any thrombus originating within the lateral pericardial borders (main or right/left pulmonary arteries). Peripheral PE was defined as thrombus exclusively beyond the lateral pericardial borders, involving the lobar pulmonary arteries or distal. The primary outcome was in-hospital and 90-day survival. 70 patients were identified: 52 (74%) with central PE and 18 (26%) with peripheral PE. Preoperative vital signs and right ventricular dysfunction were similar between the two groups. Compared to the central PE cohort, operative time was significantly longer in the peripheral PE group (191 vs. 210 minutes, p<0.005)). Median right ventricular dysfunction decreased from moderate dysfunction preoperatively to no dysfunction at discharge in both groups. Overall 90-day survival was 94%, with 100% survival in patients with submassive PE in both cohorts. This single center experience demonstrates excellent overall outcomes for surgical pulmonary embolectomy with resolution of right ventricular dysfunction, and comparable morbidity and mortality for central and peripheral PE. In an experienced center and when physiologically warranted, surgical pulmonary embolectomy for peripheral distribution of thrombus is both technically feasible and effective. Copyright © 2018. Published by Elsevier Inc.

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.

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

Pharmacokinetic–pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects

PubMed Central

Liem-Moolenaar, Marieke; de Boer, Peter; Timmers, Maarten; Schoemaker, Rik C; van Hasselt, J G Coen; Schmidt, Stephan; van Gerven, Joop M A

2011-01-01

AIM(S) Although scopolamine is a frequently used memory impairment model, the relationships between exposure and corresponding central nervous system (CNS) effects are mostly unknown. The aim of our study was to characterize these using pharmacokinetic–pharmacodynamic (PK–PD) modelling. METHODS In two double-blind, placebo-controlled, four-way crossover studies, 0.5-mg scopolamine was administered i.v. to 90 healthy male subjects. PK and PD/safety measures were monitored pre-dose and up to 8.5 h after administration. PK–PD relationships were modelled using non-linear mixed-effect modelling. RESULTS Most PD responses following scopolamine administration in 85 subjects differed significantly from placebo. As PD measures lagged behind the plasma PK profile, PK–PD relationships were modelled using an effect compartment and arbitrarily categorized according to their equilibration half-lives (t1/2keo; hysteresis measure). t1/2keo for heart rate was 17 min, saccadic eye movements and adaptive tracking 1–1.5 h, body sway, smooth pursuit, visual analogue scales alertness and psychedelic 2.5–3.5 h, pupil size, finger tapping and visual analogue scales feeling high more than 8 h. CONCLUSIONS Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK–PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t1/2keo of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK–PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems. PMID:21306419

Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus.

PubMed

The, Fo; Cailotto, C; van der Vliet, J; de Jonge, W J; Bennink, R J; Buijs, R M; Boeckxstaens, G E

2011-07-01

Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice. Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg(-1) ) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos. Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve. Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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.

Conference on Dynamics of Cholinergic Function: Acetylcholine in Health, Disease and Aging Held at Oglebay Park, West Virginia on 31 October-4 November 1983.

DTIC Science & Technology

1984-04-01

aziridinium ion (ChM Az), was used as a probe as we have shown previously this compound can act as a selective and irreversible inhibitor of sodium...relatively selective antagonist of muscarinic receptors in the central nervous system (Dahlbom et.al., Life Sci. 5, 1625, 1966). We have used this compound...phosphoinositide response are distinguished by their sensitivity to agonists and responsiveness to oxotremor- ine. The use of these " selective

Cell-type Specific Optogenetic Mice for Dissecting Neural Circuitry Function

PubMed Central

Zhao, Shengli; Ting, Jonathan T.; Atallah, Hisham E.; Qiu, Li; Tan, Jie; Gloss, Bernd; Augustine, George J.; Deisseroth, Karl; Luo, Minmin; Graybiel, Ann M.; Feng, Guoping

2011-01-01

Optogenetic methods have emerged as powerful tools for dissecting neural circuit connectivity, function, and dysfunction. We used a Bacterial Artificial Chromosome (BAC) transgenic strategy to express Channelrhodopsin2 (ChR2) under the control of cell-type specific promoter elements. We provide a detailed functional characterization of the newly established VGAT-ChR2-EYFP, ChAT-ChR2-EYFP, TPH2-ChR2-EYFP and Pvalb-ChR2-EYFP BAC transgenic mouse lines and demonstrate the utility of these lines for precisely controlling action potential firing of GABAergic, cholinergic, serotonergic, and parvalbumin+ neuron subsets using blue light. This resource of cell type-specific ChR2 mouse lines will facilitate the precise mapping of neuronal connectivity and the dissection of the neural basis of behavior. PMID:21985008

Translational Rodent Models of Korsakoff Syndrome Reveal the Critical Neuroanatomical Substrates of Memory Dysfunction and Recovery

PubMed Central

Hall, Joseph M.; Resende, Leticia S.

2016-01-01

Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS. PMID:22528861

Translational rodent models of Korsakoff syndrome reveal the critical neuroanatomical substrates of memory dysfunction and recovery.

PubMed

Savage, Lisa M; Hall, Joseph M; Resende, Leticia S

2012-06-01

Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS.

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.

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

Prevalence and determinants of erectile dysfunction among diabetic patients attending in hospitals of central and northwestern zone of Tigray, northern Ethiopia: a cross-sectional study.

PubMed

Seid, Awole; Gerensea, Hadgu; Tarko, Shambel; Zenebe, Yosef; Mezemir, Rahel

2017-03-15

The prevalence of erectile dysfunction among diabetic men varies between 35-90%. Although erectile dysfunction is widespread among men with diabetes, the condition often remains undiagnosed and demands appropriate assessment and prompt treatment. Erectile dysfunction can affect all aspects of a patient's life including physical, emotional, social, sexual, and relationships. The main aim of this study is to determine the prevalence and determinants of erectile dysfunction among diabetic patients attending hospitals in the Central and Northwest zone of Tigray, Ethiopia. A hospital based cross-sectional study was conducted on 249 male diabetic patients attending five hospitals in the Central and Northwestern Zone of Tigray, Ethiopia using systematic random sampling. The data was collected from January 1 - February 30, 2016 and was entered and analyzed using SPSS version 20. Correlation and multivariate logistic regression was employed to test associations between independent and outcome variables. The mean age of study participants was 43.39 years and the mean duration of diabetes diagnosis was 6.22 years. The overall prevalence of erectile dysfunction was 69.9%, with 32.9% suffering from mild, 31.7% moderate, and 5.2% severe erectile dysfunction. Multivariate logistic regression revealed that erective dysfunction was significantly predicted by old age (Adjusted Odds Ratio [AOR] =15.013, CI:3.212-70.166), longer duration of diabetes (AOR = 3.77, CI:1.291-11.051), and lower monthly income (AOR = 0.285, CI:0.132-0.615). No association was found with body mass index, co-morbidity, glycemic control, and alcohol consumption. The prevalence of erective dysfunction in this study population was very high. Age, income, and duration of diabetes were the independent predictors of erectile dysfunction. Nearly all of the patients in the sample (97%) had not been screened or treated for erectile dysfunction. Assessment and management of erectile dysfunction in the diabetic clinic should be part of routine medical care during follow-up visits with diabetic patients. Healthcare providers should put an emphasis on screening and treating older patients and those who had a diabetes diagnosis for a longer duration.

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.

The Association between Central Adiposity and Autonomic Dysfunction in Obesity

PubMed Central

Fidan-Yaylali, Güzin; Yaylali, Yalin Tolga; Erdogan, Çağdaş; Can, Beray; Senol, Hande; Gedik-Topçu, Bengi; Topsakal, Senay

2016-01-01

Objective To determine the relationship between central adiposity parameters and autonomic nervous system (ANS) dysfunction. Subjects and Methods The study included 114 obese individuals without any cardiovascular risk factors. Weight (in kg), height (in m), and waist circumference (WC; in cm) were measured and body mass index was calculated. Echocardiographic examination was performed to measure left ventricular mass and epicardial fat thickness (EFT). All the participants underwent an exercise test and electrophysiological evaluation using electromyography. Heart rate recovery (HRR) at 1-5 min, R-R interval variation at rest and during hyperventilation, and sympathetic skin response were measured. Pearson's correlation analysis was used. Multiple linear regression analysis was used to identify the factors associated with autonomic dysfunction. Results The HRR at 1-5 min was negatively correlated with WC and age (WC-HRR1: r = −0.32; WC-HRR2: r = −0.31; WC-HRR3: r = −0.26; WC-HRR4: r = −0.23; WC-HRR5: r = −0.21; age-HRR2: r = −0.32; age-HRR3: r = −0.28; age-HRR4: r = −0.41; age-HRR5: r = −0.42). Age was the only independent predictor of reduced HRR at 1-5 min. In addition, WC predicted a reduced HRR at 3 min. There were no significant associations between central obesity and electrophysiological parameters. EFT was not associated with ANS dysfunction. Conclusion In this study, central adiposity and aging were associated with ANS dysfunction in obese individuals. The WC could be a marker of ANS dysfunction in obese individuals without any cardiovascular risk factors. The HRR assessment at a later decay phase could be more valuable for evaluating ANS function than during early recovery. PMID:27194294

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.

Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses involving combined peripheral and central vestibular dysfunction.

PubMed

Arshad, Q; Roberts, R E; Ahmad, H; Lobo, R; Patel, M; Ham, T; Sharp, D J; Seemungal, B M

2017-04-01

We hypothesised that chronic vestibular symptoms (CVS) of imbalance and dizziness post-traumatic head injury (THI) may relate to: (i) the occurrence of multiple simultaneous vestibular diagnoses including both peripheral and central vestibular dysfunction in individual patients increasing the chance of missed diagnoses and suboptimal treatment; (ii) an impaired response to vestibular rehabilitation since the central mechanisms that mediate rehabilitation related brain plasticity may themselves be disrupted. We report the results of a retrospective analysis of both the comprehensive clinical and vestibular laboratory testing of 20 consecutive THI patients with prominent and persisting vestibular symptoms still present at least 6months post THI. Individual THI patients typically had multiple vestibular diagnoses and unique to this group of vestibular patients, often displayed both peripheral and central vestibular dysfunction. Despite expert neuro-otological management, at two years 20% of patients still had persisting vestibular symptoms. In summary, chronic vestibular dysfunction in THI could relate to: (i) the presence of multiple vestibular diagnoses, increasing the risk of 'missed' vestibular diagnoses leading to persisting symptoms; (ii) the impact of brain trauma which may impair brain plasticity mediated repair mechanisms. Apart from alerting physicians to the potential for multiple vestibular diagnoses in THI, future work to identify the specific deficits in brain function mediating poor recovery from post-THI vestibular dysfunction could provide the rationale for developing new therapy for head injury patients whose vestibular symptoms are resistant to treatment. Copyright © 2017. Published by Elsevier B.V.

Isoflurane prevents neurocognitive dysfunction after cardiopulmonary bypass in rats.

PubMed

Li, Wen; Zheng, Beijie; Xu, Huan; Deng, Yuxiao; Wang, Shuyan; Wang, Xiangrui; Su, Diansan

2013-06-01

Postoperative cognitive dysfunction occurs frequently after cardiac surgeries with cardiopulmonary bypass (CPB). Available data from rat CPB models are conflicting. However, none of them was designed to investigate the role of isoflurane (the main anesthetic in all of these studies) in the neurocognitive dysfunction after CPB. Isoflurane has documented neuroprotective effects so the present authors hypothesized that isoflurane prevents the neurocognitive dysfunction in rats after CPB. A prospective, interventional study. A university research laboratory. Male Sprague-Dawley rats. Male Sprague-Dawley rats were divided into 5 groups: the isoflurane CPB group, the animals were anesthetized with isoflurane and underwent 60 minutes of normothermic CPB; the chloral hydrate CPB group, the animals were anesthetized with chloral hydrate and underwent 60 minutes of normothermic CPB; the isoflurane sham group, the animals were subjected only to cannulation and the same duration of anesthesia but no CPB; the chloral hydrate sham group, the animals received only cannulation and the same duration of anesthesia but no CPB; and the naive group, the animals received no treatment. The neurocognitive function of all rats was measured on days 4 to 6 (short-term) and 31 to 33 after CPB (long-term). After the behavior tests, the animals were sacrificed, and the brain was harvested for the measurement of acetylcholinesterase (AChE) and choline acetyltransferase protein levels. Short-term (days 4-6 after CPB) learning and memory were impaired after CPB when the animals were anesthetized with chloral hydrate. When isoflurane was used, the learning and memory did not change after CPB. No long-term (days 31-33 after CPB) neurocognitive changes were found after CPB. AChE decreased significantly after isoflurane anesthesia regardless of whether CPB was performed. Isoflurane prevented the neurocognitive dysfunction induced by CPB, which might involve the cerebral cholinergic system. Copyright © 2013 Elsevier Inc. All rights reserved.

Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study

PubMed Central

Koopman, F.A.; Tang, M.W.; Vermeij, J.; de Hair, M.J.; Choi, I.Y.; Vervoordeldonk, M.J.; Gerlag, D.M.; Karemaker, J.M.; Tak, P.P.

2016-01-01

Background Heart rate variability (HRV) is a validated method to establish autonomic nervous system (ANS) activity. Rheumatoid arthritis (RA) is accompanied by ANS imbalance. We hypothesized that ANS dysfunction may precede the development of RA, which would suggest that it plays a role in its etiopathogenesis. Methods First, we assessed HRV parameters in supine (resting) and upright (active) position in healthy subjects (HS, n = 20), individuals at risk of developing arthritis (AR subjects, n = 50) and RA patients (RA, n = 20). Next, we measured resting heart rate (RHR), a parasympathetic HRV parameter, in an independent prospective cohort of AR subjects (n = 45). We also evaluated expression levels of the parasympathetic nicotinic acetylcholine receptor type 7 (α7nAChR) on circulating monocytes. Findings Both AR subjects (68 beats per minute (bpm), interquartile range (IQR) 68–73) and RA patients (68 bpm, IQR 62–76) had a significantly higher RHR compared to HS (60 bpm, IQR 56–63). RHR was significantly higher at baseline in individuals who subsequently developed arthritis. Expression levels of α7nAChR were lower in AR subjects with RHR ≥ 70 bpm compared to those with RHR < 70 bpm, consistent with reduced activity of the parasympathetic cholinergic anti-inflammatory pathway. Interpretation These data support the notion that autonomic dysfunction precedes the development of RA. PMID:27211565

Dopaminergic neurotoxicity of S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, and S-methyl-N,N-diethylthiocarbamate (MeDETC) in Caenorhabditis elegans

PubMed Central

Caito, Samuel W.; Valentine, William M.; Aschner, Michael

2013-01-01

Epidemiological studies corroborate a correlation between pesticide use and Parkinson’s disease (PD). Thiocarbamate and dithiocarbamate pesticides are widely used and produce neurotoxicity in the peripheral nervous system. Recent evidence from rodent studies suggests that these compounds also cause dopaminergic (DAergic) dysfunction and altered protein processing, two hallmarks of PD. However, DAergic neurotoxicity has yet to be documented. We assessed DAergic dysfunction in Caenorhabditis elegans (C. elegans) to investigate the ability of thiocarbamate pesticides to induce DAergic neurodegeneration. Acute treatment with either S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, or a common reactive intermediate of dithiocarbamate and thiocarbamate metabolism, S-methyl-N,N-diethylthiocarbamate (MeDETC), to gradual loss of DAergic cell morphology and structure over the course of 6 days in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. HPLC analysis revealed decreased DA content in the worms immediately following exposure to MeDETC, EPTC, and molinate. Additionally, worms treated with the three test compounds showed a drastic loss of DAergic-dependent behavior over a time course similar to changes in DAergic cell morphology. Alterations in the DAergic system were specific, as loss of cell structure and neurotransmitter content was not observed in cholinergic, glutamatergic, or GABAergic systems. Overall, our data suggest that thiocarbamate pesticides promote neurodegeneration and DAergic cell dysfunction in C. elegans, and may be an environmental risk factor for PD. PMID:23786526

COGNITION AS A THERAPEUTIC TARGET IN LATE-LIFE DEPRESSION: POTENTIAL FOR NICOTINIC THERAPEUTICS

PubMed Central

Zurkovsky, Lilia; Taylor, Warren D.; Newhouse, Paul A.

2013-01-01

Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs and parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging. PMID:23933385

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.

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.

The Role of Gut Microflora and the Cholinergic Anti-inflammatory Neuroendocrine System in Diabetes Mellitus

PubMed Central

Parekh, Parth J.; Nayi, Vipul R.; Johnson, David A.; Vinik, Aaron I.

2016-01-01

The obesity epidemic has drastically impacted the state of health care in the United States. Paralleling this epidemic is the incidence of diabetes mellitus, with a notable shift toward a much younger age of onset. While central to the pathogenesis of diabetes associated with obesity is the role of inflammation attributed to “adiposopathy.” Emerging data suggest that changes in sympathetic/parasympathetic balance regulated by the brain precede changes in the inflammatory cascade. It has now been established that the gut microflora contributes significantly to the activation and inhibition of autonomic control and impact the set of the neuroinflammatory inhibitory reflex mediated by the cholinergic nervous system. There has been a paradigm shift toward further investigating commensal bacteria in the pathogenesis of obesity and diabetes mellitus and its complications, as dysbiosis is thought to play a pivotal role in diabetic-associated disorders. This paper is intended to evaluate the role of intestinal dysbiosis in the pathogenesis of diabetes mellitus and examine the potential for restoration of balance via use of probiotics. PMID:27375553

Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine.

PubMed

Spignoli, G; Pepeu, G

1987-07-01

The effect of cognition-enhancing agents oxiracetam and aniracetam on scopolamine-induced amnesia and brain acetylcholine decrease was investigated in the rat. Acetylcholine levels were measured by means of a gas-chromatographic method. Scopolamine (0.63 mg/kg IP 60 min before training) prevented the acquisition of a passive avoidance conditioned response ("step through": retest 30 min after training) and brought about a 64, 56 and 42% decrease in acetylcholine level in the cortex, hippocampus and striatum respectively. Oxiracetam (50 and 100 mg/kg IP) administered 30 min before scopolamine reduced the scopolamine-induced amnesic effect and decrease in acetylcholine level in the cortex and hippocampus, but not in the striatum. Lower and higher doses of oxiracetam were ineffective. Aniracetam (100 mg/kg PO) also prevented scopolamine-induced amnesia but attenuated acetylcholine decrease in the hippocampus only. Aniracetam (300 mg PO) reduced acetylcholine decrease in the hippocampus but did not prevent scopolamine-amnesia. In conclusion, oxiracetam and aniracetam exert a stimulatory effect on specific central cholinergic pathways. However, a direct relationship between cognition-enhancing properties and cholinergic activation needs further confirmation.

Effects of subcutaneous and intracerebroventricular injection of physostigmine on the acute corneal nociception in rats.

PubMed

Tamaddonfard, Esmaeal; Hamzeh-Gooshchi, Nasrin

2010-01-01

The present study investigated the effects of subcutaneous (sc) and intracerebroventricular (icv) injections of physostigmine (a cholinesterase inhibitor), atropine (an antagonist of muscarinic cholinergic receptors) and hexamethonium (an antagonist of nicotinic cholinergic receptors) on the acute corneal nociception in rats. Local application of 5 M NaCl solution on the corneal surface of the eye produced a significant nociceptive behavior, characterized by eye wiping. The number of eye wipes was counted during the first 30 s. The sc (0.25, 0.5 and 1 mg/kg) and icv (1.25, 2.5, 5 and 10 μg) injections of physostigmine significantly (p < 0.05) decreased the number of eye wipes. Atropine and hexamethonium at (2 mg/kg, sc and 20 μg, icv) had no effects when used alone, however, atropine, but not hexamethonium prevented the antinociception induced by physostigmine (sc and icv). The results of this study indicate that the central muscarinic, but not nicotinic receptors might be involved in the antinociceptive effect of physostigmine in the acute corneal model of pain in rats.

The Botulinum Toxin as a Therapeutic Agent: Molecular Structure and Mechanism of Action in Motor and Sensory Systems.

PubMed

Kumar, Raj; Dhaliwal, Harkiran Preet; Kukreja, Roshan Vijay; Singh, Bal Ram

2016-02-01

Botulinum neurotoxin (BoNT) produced by Clostridium botulinum is the most potent molecule known to mankind. Higher potency of BoNT is attributed to several factors, including structural and functional uniqueness, target specificity, and longevity. Although BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity. Weakening of muscles due to peripheral action of BoNT produces a therapeutic effect. Depending on the target tissue, BoNT can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. In recent observations of the analgesic properties of BoNT, the toxin modifies the sensory feedback loop to the central nervous system. Differential effects of BoNT in excitatory and inhibitory neurons provide a unique therapeutic tool. In this review the authors briefly summarize the structure and mechanism of actions of BoNT on motor and sensory neurons to explain its therapeutic effects and future potential. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Improvement in exercise performance by inhalation of methoxamine in patients with impaired left ventricular function.

PubMed

Cabanes, L; Costes, F; Weber, S; Regnard, J; Benvenuti, C; Castaigne, A; Guerin, F; Lockhart, A

1992-06-18

Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction. We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design. In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03). The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.

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

The phylogeny and ontogeny of autonomic control of the heart and cardiorespiratory interactions in vertebrates.

PubMed

Taylor, Edwin W; Leite, Cleo A C; Sartori, Marina R; Wang, Tobias; Abe, Augusto S; Crossley, Dane A

2014-03-01

Heart rate in vertebrates is controlled by activity in the autonomic nervous system. In spontaneously active or experimentally prepared animals, inhibitory parasympathetic control is predominant and is responsible for instantaneous changes in heart rate, such as occur at the first air breath following a period of apnoea in discontinuous breathers like inactive reptiles or species that surface to air breathe after a period of submersion. Parasympathetic control, exerted via fast-conducting, myelinated efferent fibres in the vagus nerve, is also responsible for beat-to-beat changes in heart rate such as the high frequency components observed in spectral analysis of heart rate variability. These include respiratory modulation of the heartbeat that can generate cardiorespiratory synchrony in fish and respiratory sinus arrhythmia in mammals. Both may increase the effectiveness of respiratory gas exchange. Although the central interactions generating respiratory modulation of the heartbeat seem to be highly conserved through vertebrate phylogeny, they are different in kind and location, and in most species are as yet little understood. The heart in vertebrate embryos possesses both muscarinic cholinergic and β-adrenergic receptors very early in development. Adrenergic control by circulating catecholamines seems important throughout development. However, innervation of the cardiac receptors is delayed and first evidence of a functional cholinergic tonus on the heart, exerted via the vagus nerve, is often seen shortly before or immediately after hatching or birth, suggesting that it may be coordinated with the onset of central respiratory rhythmicity and subsequent breathing.

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

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.

Hypothyroid-associated central vestibular disease in 10 dogs: 1999-2005.

PubMed

Higgins, Michael A; Rossmeisl, John H; Panciera, David L

2006-01-01

With the exception of myxedema coma, central nervous system signs are rare in hypothyroid dogs. Central vestibular dysfunction is a possible and reversible manifestation of hypothyroidism. Medical records of dogs with vestibular dysfunction and hypothyroidism were reviewed. Of 113 records identified, 10 dogs with at least 2 concurrent clinical neurologic abnormalities localizable to the central vestibular system were included. Retrospective, descriptive study. Median age at diagnosis was 7 years (range, 5-10 years). All dogs were referred for progressive neurologic disease. Lesions were localized to the myelencephalic region in 5 dogs and to the vestibulocerebellum in 5 dogs. Two dogs had evidence of multifocal intracranial disease. Non-neurologic physical abnormalities suggestive of hypothyroidism were absent in 7 of 10 dogs. Hypercholesterolemia was the only consistent clinicopathologic abnormality detected, and was present in 7 of 10 dogs. All dogs had total thyroxine (TT4) and free thyroxine (fT4) concentrations below reference ranges, and 9 of 10 had increased TSH concentrations. Intracranial imaging studies were normal in 5 of 8 dogs, and identified lesions consistent with infarctions in 3 of 8 dogs. Albuminocytologic dissociation was detected in 5 of 6 CSF analyses. Brainstem auditory-evoked responses disclosed prolonged wave V latencies in 3 of 4 dogs tested. No other causes of central vestibular dysfunction were identified during other diagnostic investigations. The median time from initiation of treatment to clinical improvement was 4 days. Vestibular signs resolved in 9 of 10 dogs within 4 weeks. Although the pathogenesis in dogs without evidence of infarction is unknown, central vestibular dysfunction appears to be a rare but reversible neurologic sequelae of hypothyroidism.

Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology.

PubMed

Sabbagh, Marwan; Cummings, Jeffrey

2011-02-07

Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.

Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion.

PubMed

Hannan, Johanna L; Matsui, Hotaka; Sopko, Nikolai A; Liu, Xiaopu; Weyne, Emmanuel; Albersen, Maarten; Watson, Joseph W; Hoke, Ahmet; Burnett, Arthur L; Bivalacqua, Trinity J

2016-07-08

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED.

Coexisting cholinergic and parahippocampal degeneration: a key to memory loss in dementia and a challenge for transgenic models?

PubMed

Cassel, Jean-Christophe; Mathis, Chantal; Majchrzak, Monique; Moreau, Pierre-Henri; Dalrymple-Alford, John C

2008-01-01

One century after Alzheimer's initial report, a variety of animal models of Alzheimer's disease (AD) are being used to mimic one or more pathological signs viewed as critical for the evolution of cognitive decline in dementia. Among the most common are, (a) traditional lesion models aimed at reproducing the degeneration of one of two key brain regions affected in AD, namely the cholinergic basal forebrain (CBF) and the transentorhinal region, and (b) transgenic mouse models aimed at reproducing AD histopathological hallmarks, namely amyloid plaques and neurofibrillary tangles. These models have provided valuable insights into the development and consequences of the pathology, but they have not consistently reproduced the severity of memory deficits exhibited in AD. The reasons for this lack of correspondence with the severity of expected deficits may include the limited replication of multiple neuropathology in potentially key brain regions. A recent lesion model in the rat found that severe memory impairment was obtained only when the two traditional lesions were combined together (i.e. conjoint CBF and entorhinal cortex lesions), indicative of a dramatic impact on cognitive function when there is coexisting, rather than isolated, damage in these two brain regions. It is proposed that combining AD transgenic mouse models with additional experimental damage to both the CBF and entorhinal regions might provide a unique opportunity to further understand the evolution of the disease and improve treatments of severe cognitive dysfunction in neurodegenerative dementias. (c) 2008 S. Karger AG, Basel

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

PubMed Central

Yu, Dou; Thakor, Devang K.; Han, Inbo; Ropper, Alexander E.; Haragopal, Hariprakash; Sidman, Richard L.; Zafonte, Ross; Schachter, Steven C.; Teng, Yang D.

2013-01-01

Diverse mechanisms including activation of NMDA receptors, microglial activation, reactive astrogliosis, loss of descending inhibition, and spasticity are responsible for ∼40% of cases of intractable neuropathic pain after spinal cord injury (SCI). Because conventional treatments blocking individual mechanisms elicit only short-term effectiveness, a multimodal approach with simultaneous actions against major pain-related pathways may have value for clinical management of chronic pain. We hypothesize that [-]-huperzine A (HUP-A), an alkaloid isolated from the club moss Huperzia serrata, that is a potent reversible inhibitor of acetylcholinesterase and NMDA receptors, could mitigate pain without invoking drug tolerance or dependence by stimulating cholinergic interneurons to impede pain signaling, inhibiting inflammation via microglial cholinergic activation, and blocking NMDA-mediated central hypersensitization. We tested our hypothesis by administering HUP-A i.p. or intrathecally to female Sprague–Dawley rats (200–235 g body weight) after moderate static compression (35 g for 5 min) of T10 spinal cord. Compared with controls, HUP-A treatment demonstrates significant analgesic effects in both regimens. SCI rats manifested no drug tolerance following repeated bolus i.p. or chronic intrathecal HUP-A dosing. The pain-ameliorating effect of HUP-A is cholinergic dependent. Relative to vehicle treatment, HUP-A administration also reduced neural inflammation, retained higher numbers of calcium-impermeable GluR2-containing AMPA receptors, and prevented Homer1a up-regulation in dorsal horn sensory neurons. Therefore, HUP-A may provide safe and effective management for chronic postneurotrauma pain by reestablishing homeostasis of sensory circuits. PMID:23386718

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A.

PubMed

Yu, Dou; Thakor, Devang K; Han, Inbo; Ropper, Alexander E; Haragopal, Hariprakash; Sidman, Richard L; Zafonte, Ross; Schachter, Steven C; Teng, Yang D

2013-02-19

Diverse mechanisms including activation of NMDA receptors, microglial activation, reactive astrogliosis, loss of descending inhibition, and spasticity are responsible for ∼40% of cases of intractable neuropathic pain after spinal cord injury (SCI). Because conventional treatments blocking individual mechanisms elicit only short-term effectiveness, a multimodal approach with simultaneous actions against major pain-related pathways may have value for clinical management of chronic pain. We hypothesize that [-]-huperzine A (HUP-A), an alkaloid isolated from the club moss Huperzia serrata, that is a potent reversible inhibitor of acetylcholinesterase and NMDA receptors, could mitigate pain without invoking drug tolerance or dependence by stimulating cholinergic interneurons to impede pain signaling, inhibiting inflammation via microglial cholinergic activation, and blocking NMDA-mediated central hypersensitization. We tested our hypothesis by administering HUP-A i.p. or intrathecally to female Sprague-Dawley rats (200-235 g body weight) after moderate static compression (35 g for 5 min) of T10 spinal cord. Compared with controls, HUP-A treatment demonstrates significant analgesic effects in both regimens. SCI rats manifested no drug tolerance following repeated bolus i.p. or chronic intrathecal HUP-A dosing. The pain-ameliorating effect of HUP-A is cholinergic dependent. Relative to vehicle treatment, HUP-A administration also reduced neural inflammation, retained higher numbers of calcium-impermeable GluR2-containing AMPA receptors, and prevented Homer1a up-regulation in dorsal horn sensory neurons. Therefore, HUP-A may provide safe and effective management for chronic postneurotrauma pain by reestablishing homeostasis of sensory circuits.

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 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.

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.

Autonomic dysfunction in pediatric patients with headache: migraine versus tension-type headache.

PubMed

Rabner, Jonathan; Caruso, Alessandra; Zurakowski, David; Lazdowsky, Lori; LeBel, Alyssa

2016-12-01

To examine symptoms indicating central nervous system (CNS) autonomic dysfunction in pediatric patients with migraine and tension-type headache. A retrospective chart review assessed six symptoms (i.e. constipation, insomnia, dizziness, blurry vision, abnormal blood pressure, and cold and clammy palms and soles) indicating central nervous system (CNS) autonomic dysfunction in 231 patients, ages 5-18 years, diagnosed with migraine, tension-type headache (TTH), or Idiopathic Scoliosis (IS). Higher frequencies of "insomnia," "dizziness," and "cold and clammy palms and soles" were found for both migraine and TTH patients compared to the IS control group (P < 0.001). Frequencies of all six symptoms were greater in TTH than migraine patients with "cold and clammy palms and soles" reaching significance (P < 0.001). The need for prospective research investigating autonomic dysfunction in pediatric headache patients is discussed.

Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report.

PubMed

Ohara, Nobumasa; Yoneoka, Yuichiro; Seki, Yasuhiro; Akiyama, Katsuhiko; Arita, Masataka; Ohashi, Kazumasa; Suzuki, Kazuo; Takada, Toshinori

2017-08-24

Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. An 83-year-old Japanese man developed acute anterior hypopituitarism; he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

Exercise training improves the defective centrally mediated erectile responses in rats with type I diabetes.

PubMed

Zheng, Hong; Mayhan, William G; Patel, Kaushik P

2011-11-01

Erectile dysfunction is a serious and common complication of diabetes mellitus. Apart from the peripheral actions, central mechanisms are also responsible for the penile erection. The goal of the present study was to determine the impact of exercise training (ExT) on the centrally mediated erectile dysfunction in streptozotocin (STZ)-induced type I diabetic (T1D) rats. Male Sprague-Dawley rats were injected with STZ to induce diabetes mellitus. Three weeks after STZ or vehicle injections, rats were assigned to either ExT (treadmill running for 3-4 weeks) or sedentary groups to produce four experimental groups: control + sedentary, T1D + sedentary, control + ExT, and T1D + ExT. After 3-4 weeks ExT, central N-methyl-D-aspartic acid (NMDA) or sodium nitroprusside (SNP)-induced penile erectile responses were measured. Neuronal nitric oxide synthase (nNOS) expression in the paraventricular nucleus (PVN) of the hypothalamus was measured by using histochemistry, real time polymerase chain reaction (PCR) and Western blot approaches. In rats with T1D, ExT significantly improved the blunted erectile response, and the intracavernous pressure changes to NMDA (50 ng) microinjection within the PVN (T1D + ExT: 3.0 ± 0.6 penile erection/rat; T1D + sedentary: 0.5 ± 0.3 penile erection/rat within 20 minutes, P < 0.05). ExT improved erectile dysfunction induced by central administration of exogenous nitric oxide (NO) donor, SNP in T1D rats. Other behavior responses including yawning and stretching, induced by central NMDA and SNP microinjection were also significantly increased in T1D rats after ExT. Furthermore, we found that ExT restored the nNOS mRNA and protein expression in the PVN in T1D rats. These results suggest that ExT may have beneficial effects on the erectile dysfunction in diabetes through improvement of NO bioavailability within the PVN. Thus, ExT may be used as therapeutic modality to up-regulate nNOS within the PVN and improve the central component of the erectile dysfunction in diabetes mellitus. © 2011 International Society for Sexual Medicine.

Vesicular glutamate transporter 1 and vesicular glutamate transporter 2 synapses on cholinergic neurons in the sublenticular gray of the rat basal forebrain: a double-label electron microscopic study.

PubMed

Hur, E E; Edwards, R H; Rommer, E; Zaborszky, L

2009-12-29

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 microm(2), 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.

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

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

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.

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…

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.

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.

Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.

PubMed

Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei; Hernandez-Franco, Pablo; Pappa, Aglaia; Panayiotidis, Mihalis I; Powers, Robert; Franco, Rodrigo

2017-07-01

The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

The Mechanism of Interaction of Oximes with the Muscarinic Cholinergic Complex in the Central Nervous System.

DTIC Science & Technology

1985-03-31

release (40-60%) and the time course of the inhibitory response were similar to those observed with the muscarinic agonist oxotremorine . It thus...to ’At i : ,-,- t he ri, arinik agonist oxotremorine . These results indicate f,~ ~ ~~k xi "/ ’ × (1- sati,iie~i here a1< t ;as T- l , n ,i :a ti t :r...acetylcholine from rat brainstem slices 19 Figure 6. Inhibition of K+-evoked [3H]-acetylcholine release by oxotremorine and its potentiation by

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.

Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer’s disease subjects: exploring the cholinergic anti-inflammatory pathway

PubMed Central

Reale, Marcella; Di Nicola, Marta; Velluto, Lucia; D’Angelo, Chiara; Costantini, Erica; Lahiri, Debomoy K.; Kamal, Mohammad A.; Yu, Qian-sheng; Greig, Nigel H.

2016-01-01

Increasing evidence suggests that the early pathogenesis of Alzheimer’s disease (AD) is driven by elevated production and/or reduced clearance of amyloid-β peptide (Aβ), which is derived from the larger Aβ precursor protein (APP). Aβ aggregates to form neurotoxic soluble oligomers that trigger a cascade of events leading to neuronal dysfunction, neurodegeneration and, ultimately, clinical dementia. Inflammation, both within the brain and systemically, together with a deficiency in the brain neurotransmitter acetylcholine, which underpinned the development of anticholinesterases for the symptomatic treatment of AD, are invariable hallmarks of the disease. The inter-relation between Aβ, inflammation and cholinergic signaling is complex, with each feeding back onto the others to drive disease progression. To elucidate these interactions plasma samples and peripheral blood mononuclear cells (PBMCs) were evaluated from healthy control (HC) subjects and AD patients. Plasma levels of acetyl- (AChE) and butyrylcholinesterase (BuChE) as well as Aβ were significantly elevated in AD vs. HC subjects, and acetylcholine showed a trend towards reduced levels. Aβ challenge of the AD and HC PBMCs resulted in greater release of inflammatory cytokines interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) from AD vs. HC subjects, with IL-10 expression being similarly affected. THP-1 monocytic cells, a cell culture counterpart of PBMCs and brain microglial cells, responded similarly to Aβ as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways that underpin Aβ-induced changes in cytokine expression. In light of prior studies demonstrating that APP expression was regulated by specific cytokines and anticholinesterase drugs, the latter were evaluated on Aβ- and PHA-induced chemo-cytokine expression. Co-incubation with selective inhibitors, such as the acetylcholinesterase (AChE)-inhibitor (−)-phenserine and the butyrylcholinesterase (BuChE)-inhibitor (−)-cymserine analogues mitigated the rise in cytokine levels, and suggest that augmentation of the cholinergic anti-inflammatory pathway may prove valuable in AD. PMID:24359497

Carbachol alleviates rat cytokine release and organ dysfunction induced by lipopolysaccharide.

PubMed

Zhou, Guoyong; Hu, Sen; Lv, Yi; Song, Qi; Zou, Xiaofang; Sheng, Zhiyong

2011-07-01

To observe the influence of carbachol on inflammatory cytokine release and its protective role on organ function in rat endotoxemia model, and, furthermore, to investigate its receptor mechanism in rat peritoneal macrophages in vitro. In the animal experiments, Wistar rats were subjected to lipopolysaccharide (LPS) injection (5 mg/kg body weight) to establish an endotoxemia animal model, and carbachol/nicotine was given 15 minutes after LPS injection. Serum contents of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were determined with enzyme-linked immunosorbent assay 4 hours after LPS injection. Plasma alanine aminotransferase, creatine kinase-MB, and diamine oxidase contents were detected 24 hours after LPS injection. In cell experiments, rat peritoneal macrophages were collected and initially pretreated with atropine (muscarinic cholinergic receptor antagonist) or α-Bungarotoxin (an antagonist that specifically binds α7 subunit of nicotinic cholinergic receptor), then with carbachol or nicotine, and finally stimulated with LPS. Contents of TNF-α, IL-6, and IL-10 in supernatant were assayed by enzyme-linked immunosorbent assay. Furthermore, macrophages were exposed to nicotine and carbachol of high concentration and then stained with fluorescein isothiocyanate-labeled α-bungarotoxin and observed with fluorescent confocal microscopy. Carbachol inhibited expression of TNF-α and IL-6 after LPS injection and had no significant effect on IL-10 in rat endotoxemia model. It also inhibited the increase of plasma alanine aminotransferase and creatine kinase-MB contents whereas restored the inhibited plasma diamine oxidase activity. Cell experiments also showed that increases of TNF-α and IL-6 after LPS stimulation could be significantly inhibited by carbachol or nicotine, whereas IL-10 was not apparently altered. Atropine did not downregulate the inhibitive effects of both carbachol and nicotine, whereas α-bungarotoxin significantly downregulated these effects. Fluorescent confocal microscopy showed that nicotine and carbachol pretreatment markedly reduced the intensity of binding between fluorescein isothiocyanate-labeled α-bungarotoxin and macrophages. The results suggested that both carbachol and nicotine play a role in the anti-inflammatory process and organ function protection through the α7 subunit of nicotinic cholinergic receptor.

Therapy against organophosphate poisoning: The importance of anticholinergic drugs with antiglutamatergic properties

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

Weissman, Ben Avi; Raveh, Lily

2008-10-15

Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of amore » stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.« less

R1 autonomic nervous system in acute kidney injury.

PubMed

Hering, Dagmara; Winklewski, Pawel J

2017-02-01

Acute kidney injury (AKI) is a rapid loss of kidney function resulting in accumulation of end metabolic products and associated abnormalities in fluid, electrolyte and acid-base homeostasis. The pathophysiology of AKI is complex and multifactorial involving numerous vascular, tubular and inflammatory pathways. Neurohumoral activation with heightened activity of the sympathetic nervous system and renin-angiotensin-aldosterone system play a critical role in this scenario. Inflammation and/or local renal ischaemia are underlying mechanisms triggering renal tissue hypoxia and resultant renal microcirculation dysfunction; a common feature of AKI occurring in numerous clinical conditions leading to a high morbidity and mortality rate. The contribution of renal nerves to the pathogenesis of AKI has been extensively demonstrated in a series of experimental models over the past decades. While this has led to better knowledge of the pathogenesis of human AKI, therapeutic approaches to improve patient outcomes are scarce. Restoration of autonomic regulatory function with vagal nerve stimulation resulting in anti-inflammatory effects and modulation of centrally-mediated mechanisms could be of clinical relevance. Evidence from experimental studies suggests that a therapeutic splenic ultrasound approach may prevent AKI via activation of the cholinergic anti-inflammatory pathway. This review briefly summarizes renal nerve anatomy, basic insights into neural control of renal function in the physiological state and the involvement of the autonomic nervous system in the pathophysiology of AKI chiefly due to sepsis, cardiopulmonary bypass and ischaemia/reperfusion experimental model. Finally, potentially preventive experimental pre-clinical approaches for the treatment of AKI aimed at sympathetic inhibition and/or parasympathetic stimulation are presented. © 2016 John Wiley & Sons Australia, Ltd.

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

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.

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

The Dysfunctions of Bureaucratic Structure.

ERIC Educational Resources Information Center

Duttweiler, Patricia Cloud

1988-01-01

Numerous dysfunctions result from bureaucratic school organization, including an overemphasis on specialized tasks, routine operating rules, and formal procedures for managing teaching and learning. Such schools are characterized by numerous regulations; formal communications; centralized decision making; and sharp distinctions among…

Pericyte function in the physiological central nervous system.

PubMed

Muramatsu, Rieko; Yamashita, Toshihide

2014-01-01

Damage to the central nervous system (CNS) leads to disruption of the vascular network, causing vascular dysfunction. Vascular dysfunction is the major event in the pathogenesis of CNS diseases and is closely associated with the severity of neuronal dysfunction. The suppression of vascular dysfunction has been considered a promising avenue to limit damage to the CNS, leading to efforts to clarify the cellular and molecular basis of vascular homeostasis maintenance. A reduction of trophic support and oxygen delivery due to circulatory insufficiency has long been regarded as a major cause of vascular damage. Moreover, recent studies provide a new perspective on the importance of the structural stability of blood vessels in CNS diseases. This updated article discusses emerging information on the key role of vascular integrity in CNS diseases, specially focusing on pericyte function. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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

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.

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.

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.

Efficiently Assessing Negative Cognition in Depression: An Item Response Theory Analysis of the Dysfunctional Attitude Scale

ERIC Educational Resources Information Center

Beevers, Christopher G.; Strong, David R.; Meyer, Bjorn; Pilkonis, Paul A.; Miller, Ivan R.

2007-01-01

Despite a central role for dysfunctional attitudes in cognitive theories of depression and the widespread use of the Dysfunctional Attitude Scale, form A (DAS-A; A. Weissman, 1979), the psychometric development of the DAS-A has been relatively limited. The authors used nonparametric item response theory methods to examine the DAS-A items and…

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

Need for tissue plasminogen activator for central venous catheter dysfunction is significantly associated with thrombosis in pediatric cancer patients.

PubMed

MacLean, Jessica; MacDonald, Tamara; Digout, Carol; Smith, Nadine; Rigby, Krista; Kulkarni, Ketan

2018-06-01

Central venous catheter (CVC) dysfunction is a common complication among pediatric cancer patients. Tissue plasminogen activator (tPA) is administered to resolve CVC dysfunction. The present study was designed to determine risk factors associated with requirement of tPA for CVC dysfunction and to assess the clinical impact of CVC dysfunction in terms of CVC loss and venous thrombotic events (VTE). Case records of all pediatric patients with cancer from the Maritimes, Canada were reviewed following ethics approval. Data regarding demographics, clinical diagnosis, CVC dysfunction, characteristics of CVCs, and VTE were pooled from multiple data sources. Seven hundred and forty-one patients required ≥1 CVC. 26.3% of patients required tPA for ≥1 episodes of CVC dysfunction. Requirement of one or more doses of tPA for episodes of CVC dysfunction increased the odds of VTE by two times (95% confidence interval, 1.1-3.6). Patients that required ≥1 doses of tPA required significantly more CVCs (2.05 ± 1.29 per individual patient, 55% of the patients needed >1 CVCs) as compared to the remainder (1.52 ± 0.95 per individual patient, 32% needed >1 CVCs) (P = 0.0001). Multivariate analysis revealed age > 10 years, diagnosis of sarcoma, and tunneled line were independently associated with tPA requirement. We determined independent risk factors associated with requirement of tPA for CVC dysfunction. Requirement of tPA for CVC dysfunction was associated with significantly increased risk of VTE and requirement of more CVCs. These observations can assist in identification of patients at increased risk of CVC dysfunction and inform approaches to reduce CVC loss and VTE. © 2018 Wiley Periodicals, Inc.

Learning Disability Assessed through Audiologic and Physiologic Measures: A Case Study.

ERIC Educational Resources Information Center

Greenblatt, Edward R.; And Others

1983-01-01

The report describes a child with central auditory dysfunction, the first reported case where brain-stem dysfunction on audiologic tests were associated with specific electrophysiologic changes in the brain-stem auditory-evoked responses. (Author/CL)

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.

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.

Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.

PubMed

Kulshreshtha, Akanksha; Piplani, Poonam

2016-10-21

The present study reports the effect of amide derivatives of 1,3,4-thiadizoles on scopolamine induced deficit cholinergic neurotransmission and oxidative stress serving as promising leads for the therapeutics of cognitive dysfunction. Fourteen compounds (2c-8d) have been synthesised and evaluated against behavioural alterations using step down passive avoidance protocol and morris water maze and at a dose of 0.5 mg/kg with reference to the standard, Rivastigmine. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, plasma nitrite, catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 5c, 6c and 8c displayed appreciable activity with an IC50 value of 3 μM, 3.033 μM and 2.743 μM, respectively towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably with the amino acids present in the active site of recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Repeated administration of almonds increases brain acetylcholine levels and enhances memory function in healthy rats while attenuates memory deficits in animal model of amnesia.

PubMed

Batool, Zehra; Sadir, Sadia; Liaquat, Laraib; Tabassum, Saiqa; Madiha, Syeda; Rafiq, Sahar; Tariq, Sumayya; Batool, Tuba Sharf; Saleem, Sadia; Naqvi, Fizza; Perveen, Tahira; Haider, Saida

2016-01-01

Dietary nutrients may play a vital role in protecting the brain from age-related memory dysfunction and neurodegenerative diseases. Tree nuts including almonds have shown potential to combat age-associated brain dysfunction. These nuts are an important source of essential nutrients, such as tocopherol, folate, mono- and poly-unsaturated fatty acids, and polyphenols. These components have shown promise as possible dietary supplements to prevent or delay the onset of age-associated cognitive dysfunction. This study investigated possible protective potential of almond against scopolamine induced amnesia in rats. The present study also investigated a role of acetylcholine in almond induced memory enhancement. Rats in test group were orally administrated with almond suspension (400 mg/kg/day) for four weeks. Both control and almond-treated rats were then divided into saline and scopolamine injected groups. Rats in the scopolamine group were injected with scopolamine (0.5 mg/kg) five minutes before the start of each memory test. Memory was assessed by elevated plus maze (EPM), Morris water maze (MWM) and novel object recognition (NOR) task. Cholinergic function was determined in terms of hippocampal and frontal cortical acetylcholine content and acetylcholinesterase activity. Results of the present study suggest that almond administration for 28 days significantly improved memory retention. This memory enhancing effect of almond was also observed in scopolamine induced amnesia model. Present study also suggests a role of acetylcholine in the attenuation of scopolamine induced amnesia by almond. Copyright © 2015 Elsevier Inc. All rights reserved.

Fascia: A missing link in our understanding of the pathology of fibromyalgia.

PubMed

Liptan, Ginevra L

2010-01-01

Significant evidence exists for central sensitization in fibromyalgia, however the cause of this process in fibromyalgia-and how it relates to other known abnormalities in fibromyalgia-remains unclear. Central sensitization occurs when persistent nociceptive input leads to increased excitability in the dorsal horn neurons of the spinal cord. In this hyperexcited state, spinal cord neurons produce an enhanced responsiveness to noxious stimulation, and even to formerly innocuous stimulation. No definite evidence of muscle pathology in fibromyalgia has been found. However, there is some evidence for dysfunction of the intramuscular connective tissue, or fascia, in fibromyalgia. This paper proposes that inflammation of the fascia is the source of peripheral nociceptive input that leads to central sensitization in fibromyalgia. The fascial dysfunction is proposed to be due to inadequate growth hormone production and HPA axis dysfunction in fibromyalgia. Fascia is richly innervated, and the major cell of the fascia, the fibroblast, has been shown to secrete pro-inflammatory cytokines, particularly IL-6, in response to strain. Recent biopsy studies using immuno-histochemical staining techniques have found increased levels of collagen and inflammatory mediators in the connective tissue surrounding the muscle cells in fibromyalgia patients. The inflammation of the fascia is similar to that described in conditions such as plantar fasciitis and lateral epicondylitis, and may be better described as a dysfunctional healing response. This may explain why NSAIDs and oral steroids have not been found effective in fibromyalgia. Inflammation and dysfunction of the fascia may lead to central sensitization in fibromyalgia. If this hypothesis is confirmed, it could significantly expand treatment options to include manual therapies directed at the fascia such as Rolfing and myofascial release, and direct further research on the peripheral pathology in fibromyalgia to the fascia.

Regulation of synaptic acetylcholine concentrations by acetylcholine transport in rat striatal cholinergic transmission.

PubMed

Muramatsu, Ikunobu; Uwada, Junsuke; Masuoka, Takayoshi; Yoshiki, Hatsumi; Sada, Kiyonao; Lee, Kung-Shing; Nishio, Matomo; Ishibashi, Takaharu; Taniguchi, Takanobu

2017-10-01

In addition to hydrolysis by acetylcholine esterase (AChE), acetylcholine (ACh) is also directly taken up into brain tissues. In this study, we examined whether the uptake of ACh is involved in the regulation of synaptic ACh concentrations. Superfusion experiments with rat striatal segments pre-incubated with [ 3 H]choline were performed using an ultra-mini superfusion vessel, which was developed to minimize superfusate retention within the vessel. Hemicholinium-3 (HC-3) at concentrations less than 1 μM, selectively inhibited the uptake of [ 3 H]choline by the high affinity-choline transporter 1 and had no effect on basal and electrically evoked [ 3 H]efflux in superfusion experiments. In contrast, HC-3 at higher concentrations, as well as tetraethylammonium (>10 μM), which inhibited the uptake of both [ 3 H]choline and [ 3 H]ACh, increased basal [ 3 H]overflow and potentiated electrically evoked [ 3 H]efflux. These effects of HC-3 and tetraethylammonium were also observed under conditions where tissue AChE was irreversibly inactivated by diisopropylfluorophosphate. Specifically, the potentiation of evoked [ 3 H]efflux was significantly higher in AChE-inactivated preparations and was attenuated by atropine. On the other hand, striatal segments pre-incubated with [ 3 H]ACh failed to increase [ 3 H]overflow in response to electrical stimulation. These results show that synaptic ACh concentrations are significantly regulated by the postsynaptic uptake of ACh, as well as by AChE hydrolysis and modulation of ACh release mediated through presynaptic muscarinic ACh receptors. In addition, these data suggest that the recycling of ACh-derived choline may be minor in cholinergic terminals. This study reveals a new mechanism of cholinergic transmission in the central nervous system. © 2017 International Society for Neurochemistry.

Effects of acute and repeated oral exposure to the organophosphate insecticide chlorpyrifos on open-field activity in chicks.

PubMed

Al-Badrany, Y M A; Mohammad, F K

2007-11-01

The effects of the organophosphate insecticide chlorpyrifos on 5min open-field activity were examined in a 7-15 days old chick model. Chlorpyrifos was acutely administered taking into account cholinesterase inhibition and determination of the acute (24h) median lethal dose (LD50). The oral LD50 value of chlorpyrifos in chicks was 18.14mg/kg, with cholinergic toxicosis observed on intoxicated chicks. Chlorpyrifos at the dose rates of 5,10 and 20mg/kg orally produced within 2h signs of cholinergic toxicosis in the chicks and significantly inhibited plasma (40-70%), whole brain (43-69%) and liver (31-46%) cholinesterase activities in a dose-dependent manner. Chlorpyrifos at 2 and 4mg/kg, orally did not produce overt signs of cholinergic toxicosis, but decreased (30, 60 and 90min after dosing) the general locomotor activity of the chicks as seen by a significant increase in the latency to move from the central square of the open-field arena, decreases in the numbers of lines crossed and vocalization score. Repeated daily chlorpyrifos treatments (2 and 4mg/kg, orally) for seven consecutive days also caused hypoactivity in chicks in the open-field behavioral paradigm. Only the high dose of chlorpyrifos (4mg/kg, orally) given repeatedly for 7 days caused significant cholinesterase inhibition in the whole brain (37%) and the liver (22%). In conclusion, chlorpyrifos at single or short-term repeated doses-induced behavioral changes in 7-15 days old chicks, in a model that could be used for further neurobehavioral studies involving subtle effects of organophosphates on chicks.

Short-latency afferent inhibition is a poor predictor of individual susceptibility to rTMS-induced plasticity in the motor cortex of young and older adults.

PubMed

Young-Bernier, Marielle; Tanguay, Annick N; Davidson, Patrick S R; Tremblay, François

2014-01-01

Cortical plasticity, including long-term potentiation (LTP)-like plasticity, can be assessed non-invasively with repetitive transcranial magnetic stimulation (rTMS) protocols. In this study, we examined age differences in responses to intermittent theta burst stimulation (iTBS) in a group of 20 young and 18 healthy older adults. Because the cholinergic system plays a role in the neural processes underlying learning and memory, including LTP, we also investigated whether short latency afferent inhibition (SAI), a neurophysiological marker of central cholinergic activity, would be associated with age-related differences in LTP-like plasticity induced by iTBS. SAI was first assessed by examining the modulation of motor evoked potentials (MEPs) in response to median nerve conditioning 20 ms prior to TMS. Participants then underwent iTBS (3 pulses at 50 Hz every 200 ms for 2 s with 8 s between trains, repeated 20 times). MEP responses (120% resting motor threshold (RMT)) were assessed immediately after iTBS and 5, 10, and 20 min post-application. Responses to iTBS were quite variable in both age groups, with only approximately 60% of the participants (n = 13 young and 10 older adults) showing the expected facilitation of MEP responses. There were no significant age group differences in MEP facilitation following iTBS. Although older adults exhibited reduced SAI, individual variations were not associated with susceptibility to express LTP-like induced plasticity after iTBS. Overall, these results are consistent with reports of high inter-individual variability in responses to iTBS. Although SAI was reduced in older adults, consistent with a deterioration of the cholinergic system with age, SAI levels were not associated with LTP-like plasticity as assessed with iTBS.

Short-latency afferent inhibition is a poor predictor of individual susceptibility to rTMS-induced plasticity in the motor cortex of young and older adults

PubMed Central

Young-Bernier, Marielle; Tanguay, Annick N.; Davidson, Patrick S. R.; Tremblay, François

2014-01-01

Cortical plasticity, including long-term potentiation (LTP)-like plasticity, can be assessed non-invasively with repetitive transcranial magnetic stimulation (rTMS) protocols. In this study, we examined age differences in responses to intermittent theta burst stimulation (iTBS) in a group of 20 young and 18 healthy older adults. Because the cholinergic system plays a role in the neural processes underlying learning and memory, including LTP, we also investigated whether short latency afferent inhibition (SAI), a neurophysiological marker of central cholinergic activity, would be associated with age-related differences in LTP-like plasticity induced by iTBS. Methods: SAI was first assessed by examining the modulation of motor evoked potentials (MEPs) in response to median nerve conditioning 20 ms prior to TMS. Participants then underwent iTBS (3 pulses at 50 Hz every 200 ms for 2 s with 8 s between trains, repeated 20 times). MEP responses (120% resting motor threshold (RMT)) were assessed immediately after iTBS and 5, 10, and 20 min post-application. Results: Responses to iTBS were quite variable in both age groups, with only approximately 60% of the participants (n = 13 young and 10 older adults) showing the expected facilitation of MEP responses. There were no significant age group differences in MEP facilitation following iTBS. Although older adults exhibited reduced SAI, individual variations were not associated with susceptibility to express LTP-like induced plasticity after iTBS. Conclusion: Overall, these results are consistent with reports of high inter-individual variability in responses to iTBS. Although SAI was reduced in older adults, consistent with a deterioration of the cholinergic system with age, SAI levels were not associated with LTP-like plasticity as assessed with iTBS. PMID:25147523

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.

Cholinergic regulation of the evoked quantal release at frog neuromuscular junction

PubMed Central

Nikolsky, Eugeny E; Vyskočil, František; Bukharaeva, Ella A; Samigullin, Dmitry; Magazanik, Lev G

2004-01-01

The effects of cholinergic drugs on the quantal contents of the nerve-evoked endplate currents (EPCs) and the parameters of the time course of quantal release (minimal synaptic latency, main modal value of latency histogram and variability of synaptic latencies) were studied at proximal, central and distal regions of the frog neuromuscular synapse. Acetylcholine (ACh, 5 × 10−4 m), carbachol (CCh, 1 × 10−5 m) or nicotine (5 × 10−6 m) increased the numbers of EPCs with long release latencies mainly in the distal region of the endplate (90–120 μm from the last node of Ranvier), where the synchronization of transmitter release was the most pronounced. The parameters of focally recorded motor nerve action potentials were not changed by either ACh or CCh. The effects of CCh and nicotine on quantal dispersion were reduced substantially by 5 × 10−7 m (+)tubocurarine (TC). The muscarinic agonists, oxotremorine and the propargyl ester of arecaidine, as well as antagonists such as pirenzepine, AF-DX 116 and methoctramine, alone or in combination, did not affect the dispersion of the release. Muscarinic antagonists did not block the dispersion action of CCh. Cholinergic drugs either decreased the quantal content mo (muscarinic agonist, oxotremorine M, and nicotinic antagonist, TC), or decreased mo and dispersed the release (ACh, CCh and nicotine). The effects on mo were not related either to the endplate region or to the initial level of release dispersion. It follows that the mechanisms regulating the amount and the time course of transmitter release are different and that, among other factors, they are altered by presynaptic nicotinic receptors. PMID:15254150

Can Salivary Acetylcholinesterase be a Diagnostic Biomarker for Alzheimer?

PubMed

Bakhtiari, Sedigheh; Moghadam, Nahid Beladi; Ehsani, Marjan; Mortazavi, Hamed; Sabour, Siamak; Bakhshi, Mahin

2017-01-01

The loss of brain cholinergic activity is a key phenomenon in the biochemistry of Alzheimer's Disease (AD). Due to the specific biosynthesis of Acetylcholinesterase (AChE) of cholinergic neurons, the enzyme has been proposed as a potential biochemical marker of cholinergic activity. AChE is expressed not only in the Central Nervous System (CNS), Peripheral Nervous System (PNS) and muscles, but also on the surface of blood cells and saliva. This study aimed to measure salivary AChE activity in AD and to determine the feasibility of creating a simple laboratory test for diagnosing such patients. In this cross-sectional study, the recorded data were obtained from 15 Alzheimer's patients on memantine therapy and 15 healthy subjects. Unstimulated whole saliva samples were collected from the participants and salivary levels of AChE activity were determined by using the Ellman colorimetric method. The Mann Whitney U test was used to compare the average (median) of AChE activity between AD and controls. In order to adjust for possible confounding factors, partial correlation coefficient and multivariate linear regressions were used. Although the average of AChE activity in the saliva of people with AD was lower compared to the control group, we found no statistically significant differences using Mann Whitney U test (138 in control group vs. 175 in Alzheimer's patients, p value=0.25). Additionally, no significant differences were observed in the activity of this enzyme in both sexes or with increased age or duration of the disease. After adjusting for age and gender, there was no association between AChE activity and AD (regression coefficient β=0.08; p value= 0.67). Saliva AChE activity was not significantly associated with AD. This study might help in introduce a new diagnostic aid for AD or monitor patients with AD.

Peptidergic contribution to posttetanic potentiation at a central synapse of aplysia.

PubMed

Koh, Hae-Young; Weiss, Klaudiusz R

2005-08-01

Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. Although neuropeptides are located in a large number of neurons and many neuropeptides, like PTP, can enhance synaptic transmission, there is a paucity of studies indicating that peptides may actually participate in PTP. Here, we utilize a single central synapse in the feeding circuit of Aplysia to investigate a possible peptidergic contribution to PTP in the CNS. The cholinergic command-like interneuron, cerebral-buccal interneuron 2 (CBI-2), contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that tetanic prestimulation or repeated stimulation of CBI-2, as well as perfusion of FCAP and CP2, increase the size of the cholinergic excitatory postsynaptic potentials (EPSPs) that CBI-2 evokes in the motoneurons B61/62 and shorten the latency to initiate B61/62 firing in response to CBI-2 stimulation. We used temperature-dependent suppression of peptide release and occlusion experiments to examine the possible contribution of FCAP and CP2 to PTP at the CBI-2 to B61/62 synapse. When peptide release was suppressed, perfusion of exogenous peptides increased the size of posttetanic EPSPs. In contrast, when peptide release was not suppressed, exogenous peptides did not enhance the size of posttetanic EPSPs, thus indicating occlusion. Temperature manipulation and occlusion experiments also indicated that peptides extend PTP duration. This peptide-dependent prolongation of PTP has functional consequences in that it extends the duration of time during which the latency to initiate B61/62 firing in response to CBI-2 stimulation is shortened.

Effect of high fat diets on the NTPDase, 5'-nucleotidase and acetylcholinesterase activities in the central nervous system.

PubMed

Kaizer, Rosilene Rodrigues; Spanevello, Rosélia Maria; Costa, Eduarda; Morsch, Vera Maria; Schetinger, Maria Rosa Chitolina

2018-02-01

High fat diets are associated with the promotion of neurological diseases, such as Alzheimer disease (AD). This study aim investigate the high fat diets role to promotion of AD using as biochemistry parameter of status of central nervous system through the NTPDase, 5'-nucleotidase and acetylcholinesterase (AChE) activities in brain of young rats. The intake of high fat diets promotes an inhibition of purinergic and cholinergic functions, mainly in the long-term exposure to saturated and saturated/unsaturated diets. The AChE activity was decreased to supernatant and synaptosomes tissues preparations obtained from cerebral cortex in average of 20%, to both groups exposed to saturated and saturated/unsaturated diets, when compared to the control group. Very similar results were found in hippocampus and cerebellum brain areas. At same time, the adenine nucleotides hydrolysis in synaptosomes of cerebral cortex were decreased to ATP, ADP and AMP after the long-term exposure to high fat diets, as saturated and saturated/unsaturated. The inhibition of ATP hydrolysis was of 26% and 39% to saturated and saturated/unsaturated diets, respectively. ADP hydrolysis was decreased in 20% to saturated diet, and AMP hydrolysis was decreased in 25% and 33% to saturated and saturated/unsaturated diets, respectively, all in comparison to the control. Thus, we can suggest that the effects of high diets on the purinergic and cholinergic nervous system may contribute to accelerate the progressive memory loss, to decline in language and other cognitive disruptions, such as AD patients presents. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

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

Hypothalamic disconnection caudal to paraventricular nucleus affects cardiovascular and drinking responses to central angiotensin II and carbachol.

PubMed

Urzedo-Rodrigues, Lilia Simone; Depieri, Tatiane; Cherobino, Anderson Julio; Lopes, Oswaldo U; Menani, José V; Colombari, Débora S A

2011-05-04

The paraventricular nucleus of the hypothalamus (PVN) is an important area of the brain involved in the control of cardiovascular system and fluid-electrolyte balance. In the present study we evaluated the effects of hypothalamic disconnection (HD) caudal to PVN in the pressor and dipsogenic responses induced by intracerebroventricular (icv) injections of angiotensin II (ANG II) or carbachol (cholinergic agonist). Male Holtzman rats (280-320 g) with a stainless steel cannula implanted into the lateral ventricle and submitted to sham or HD surgery were used. HD (2 or 15 days) reduced the pressor responses to ANG II (50 ng/1μl) icv (8±3 and 11±3 mm Hg, respectively, vs. sham: 23±3 and 21±2 mm Hg) or carbachol (4 nmol/1 μl) icv (8±2 and 21±3 mm Hg, respectively, vs. sham: 33±3 and 33±3 mm Hg), without changing baseline arterial pressure. Acutely (2-4 days), HD also reduced water intake to icv ANG II (3.3±2.2 vs. sham: 14.2±3.0 ml/60 min) or carbachol (4.4±1.8 vs. sham: 11.4±1.6 ml/60 min); however, chronically (15-17 days), HD produced no change on ANG II- and carbachol-induced water intake, in spite of the increased daily water intake and urinary volume. The results suggest that medial projections caudal to PVN are important for pressor and dipsogenic responses to central angiotensinergic and cholinergic activation. Copyright © 2011 Elsevier B.V. All rights reserved.

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

Central-Approach Surgical Repair of Coarctation of the Aorta with a Back-up Left Ventricular Assist Device for an Infant Presenting with Severe Left Ventricular Dysfunction.

PubMed

Kim, Tae Hoon; Shin, Yu Rim; Kim, Young Sam; Kim, Do Jung; Kim, Hyohyun; Shin, Hong Ju; Htut, Aung Thein; Park, Han Ki

2015-12-01

A two-month-old infant presented with coarctation of the aorta, severe left ventricular dysfunction, and moderate to severe mitral regurgitation. Through median sternotomy, the aortic arch was repaired under cardiopulmonary bypass and regional cerebral perfusion. The patient was postoperatively supported with a left ventricular assist device for five days. Left ventricular function gradually improved, eventually recovering with the concomitant regression of mitral regurgitation. Prompt surgical repair of coarctation of the aorta is indicated for patients with severe left ventricular dysfunction. A central approach for surgical repair with a back-up left ventricular assist device is a safe and effective treatment strategy for these patients.

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes.

PubMed

Deckmann, Klaus; Filipski, Katharina; Krasteva-Christ, Gabriela; Fronius, Martin; Althaus, Mike; Rafiq, Amir; Papadakis, Tamara; Renno, Liane; Jurastow, Innokentij; Wessels, Lars; Wolff, Miriam; Schütz, Burkhard; Weihe, Eberhard; Chubanov, Vladimir; Gudermann, Thomas; Klein, Jochen; Bschleipfer, Thomas; Kummer, Wolfgang

2014-06-03

Chemosensory cells in the mucosal surface of the respiratory tract ("brush cells") use the canonical taste transduction cascade to detect potentially hazardous content and trigger local protective and aversive respiratory reflexes on stimulation. So far, the urogenital tract has been considered to lack this cell type. Here we report the presence of a previously unidentified cholinergic, polymodal chemosensory cell in the mammalian urethra, the potential portal of entry for bacteria and harmful substances into the urogenital system, but not in further centrally located parts of the urinary tract, such as the bladder, ureter, and renal pelvis. Urethral brush cells express bitter and umami taste receptors and downstream components of the taste transduction cascade; respond to stimulation with bitter (denatonium), umami (monosodium glutamate), and uropathogenic Escherichia coli; and release acetylcholine to communicate with other cells. They are approached by sensory nerve fibers expressing nicotinic acetylcholine receptors, and intraurethral application of denatonium reflexively increases activity of the bladder detrusor muscle in anesthetized rats. We propose a concept of urinary bladder control involving a previously unidentified cholinergic chemosensory cell monitoring the chemical composition of the urethral luminal microenvironment for potential hazardous content.

Central cholinergic challenging of migraine by testing second-generation anticholinesterase drugs.

PubMed

Nicolodi, M; Galeotti, N; Ghelardini, C; Bartolini, A; Sicuteri, F

2002-01-01

The antinociceptive activity of donepezil, a novel cholinesterase inhibitor, was investigated in the mouse hot plate test. Donepezil (5 to 10 mg kg(-1) i.p.) induced a dose-dependent antinociception that reached its maximum effect 15 minutes after injection. Donepezil antinociception was prevented by the antimuscarinic drug scopolamine. At analgesic doses, donepezil did not alter gross animal behavior. These results indicate that donepezil is endowed by muscarinic antinociceptive properties, suggesting this compound as a potential therapeutic approach for the treatment of painful pathologies. Therefore, we investigated donepezil's effect in migraine. Donepezil (5 mg per os, evening assumption) was effective as a prophylatic agent in patients suffering from migraine with or without aura by reducing the number of hours with pain, the number of attacks, and the severity of the pain attack. The efficacy of donepezil was compared with that of the beta-blocker propranolol (40 mg bid per os), showing higher activity. Response rates of a large-sized open study devoid of entry criteria regarding migraine subtypes suggest the drug as an excellent prophylactic compound for migraine in general practice. Clinical results also indicate that the activation of the cholinergic system can represent a novel prophylactic approach to migraine.

Evidence of central cholinergic mechanisms in the appearance of affective aggressive behaviour: dissociation of aggression from autonomic and motor phenomena.

PubMed

Beleslin, D B; Samardzić, R

1979-04-11

Carbachol, muscarine, eserine and neostigmine injected into the cerebral ventricles of conscious cats evoked emotional behaviour with aggression, autonomic and motor phenomena as well as clonic-tonic convulsions. The main and the most impressive feature of the gross behavioural effects of intraventricular carbachol, muscarine, eserine and neostigmine in conscious cats was the affective type of aggression. However, neostigmine produced aggressive behaviour only in about one-quarter of the experiments. After intraventricular hemicholinium-3 and triethylcholine carbachol, muscarine, eserine and neostigmine elicited autonomic and motor phenomena. In these cats cholinomimetics and anticholinesterases evoked only slight hissing and snarling. Choline administered into the cerebral ventricles of hemicholinium-3 and triethylcholine-treated cats restored the emotional behaviour with aggression, autonomic and motor phenomena as well as clonic-tonic convulsions to intraventricular carbachol, muscarine, eserine and neostigmine. The restored gross behavioural changes to eserine were almost of the same intensity, while those to carbachol and muscarine were of lesser intensity than in control cats. From these experiments it is concluded that cholinergic neurones are involved in the appearance of the affective type of aggression resulting from intraventricular carbachol, muscarine, eserine and neostigmine.

Behavioral and biochemical effects of neonicotinoid thiamethoxam on the cholinergic system in rats.

PubMed

Rodrigues, K J A; Santana, M B; Do Nascimento, J L M; Picanço-Diniz, D L W; Maués, L A L; Santos, S N; Ferreira, V M M; Alfonso, M; Durán, R; Faro, L R F

2010-01-01

Thiamethoxam is a neonicotinoid insecticide, a group of pesticides that acts selectively on insect nicotinic acetylcholine receptors (nAChRs), with only a little action on mammalian nAChRs. Nevertheless, the selectivity of neonicotinoids for the insect nAChRs may change when these substances are metabolized. Therefore, we aimed to determine the potential effects of thiamethoxam on mammalian brain, testing the performance in the open field and elevated plus-maze of rats exposed to this insecticide and, in order to establish the neurochemical endpoints, we measured the acetylcholinesterase activity in different brain regions (hippocampus, striatum and cortex) and the high-affinity choline uptake (HACU) in synaptosomes from rat hippocampus. Treated animals received thiamethoxam (25, 50 or 100mg/kg) for 7 consecutive days. The results showed that treatment with thiamethoxam induced an increase in the anxiety behavior at two doses (50 or 100mg/kg). Moreover, there was a significant decrease in both HACU and acetylcholinesterase activity. Our hypothesis is that thiamethoxam (or its metabolites) could be acting on the central rats nAChRs. This would produce an alteration on the cholinergic transmission, modulating the anxiety behavior, acetylcholinesterase levels and HACU.

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

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β-amyloid in ageing and Alzheimer's disease.

PubMed

Weinreb, Orly; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H

2016-07-01

Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the Faculty of Medicine and Director of Eve Topf Center of Excellence in Technion-Israel Institute of Technology, and Chief Scientific Officer of ABITAL Pharma Pipeline Ltd., at the occasion of his 75th birthday. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. © 2015 The British Pharmacological Society.

Effect of dexmedetomidine on rats with convulsive status epilepticus and association with activation of cholinergic anti-inflammatory pathway.

PubMed

Xu, Kai-Liang; Liu, Xin-Qiu; Yao, Yu-Long; Ye, Ming-Rong; Han, Yao-Guo; Zhang, Tao; Chen, Gang; Lei, Ming

2018-01-01

Convulsive status epilepticus (CSE) is a neurological disease with contraction and extension of limbs, leading to damage of hippocampus and cognition. This study aimed to explore the effects of dexmedetomidine (DEX) on the cognitive function and neuroinflammation in CSE rats. All rats were divided into control group, CSE group and DEX group. Morris water maze test was used to measure cognitive function. Acute hippocampal slices were made to detect long-term potentiation (LTP). Immunohistochemistry was used to determine the expression of α7-nicotinic acetylcholine receptor (α7-nAChR) and interleukin-1β (IL-1β). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of IL-1β, tumor necrosis factor-α (TNF-α), S-100β and brain-derived neurotrophic factor (BDNF). Our results showed that DEX improved the memory damage caused by CSE. DEX reduced seizure severity and increased the amplitudes and sustainable time of LTP, and also inhibited the hippocampal expression of α7-nAChR and IL-1β in CSE rats. DEX treatment decreased serum IL-1β, TNF-α and S-100β levels and increased BDNF levels. The effects of DEX on seizure severity and LTP could be simulated by nicotine or attenuated by concurrent α-bungarotoxin (α-BGT) treatment. In conclusions, DEX significantly improved spatial cognitive dysfunction, reduced seizure severity and increased LTP in CSE rats. Improvements by DEX were closely related to enhancement of cholinergic anti-inflammatory pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress.

PubMed

Cattani, Daiane; Cesconetto, Patrícia Acordi; Tavares, Mauren Kruger; Parisotto, Eduardo Benedetti; De Oliveira, Paulo Alexandre; Rieg, Carla Elise Heinz; Leite, Marina Concli; Prediger, Rui Daniel Schröder; Wendt, Nestor Cubas; Razzera, Guilherme; Filho, Danilo Wilhelm; Zamoner, Ariane

2017-07-15

We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[ 14 C]-glutamate uptake and increased 45 Ca 2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice.

PubMed

Rajasekar, N; Dwivedi, Subhash; Tota, Santosh Kumar; Kamat, Pradeep Kumar; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

2013-09-05

Okadaic acid (OKA) has been observed to cause memory impairment in human subjects having seafood contaminated with dinoflagellate (Helicondria okadai). OKA induces tau hyperphosphorylation and oxidative stress leading to memory impairment as our previous study has shown. Curcumin a natural antioxidant has demonstrated neuroprotection in various models of neurodegeneration. However, the effect of curcumin has not been explored in OKA induced memory impairment. Therefore, present study evaluated the effect of curcumin on OKA (100ng, intracerebrally) induced memory impairment in male Swiss albino mice as evaluated in Morris water maze (MWM) and passive avoidance tests (PAT). OKA administration resulted in memory impairment with a decreased cerebral blood flow (CBF) (measured by laser doppler flowmetry), ATP level and increased mitochondrial (Ca(2+))i, neuroinflammation (increased TNF-α, IL-1β, COX-2 and GFAP), oxidative-nitrosative stress, increased Caspase-9 and cholinergic dysfunction (decreased AChE activity/expression and α7 nicotinic acetylcholine receptor expression) in cerebral cortex and hippocampus of mice brain. Oral administration of curcumin (50mg/kg) for 13 days significantly improved memory function in both MWM and PAT along with brain energy metabolism, CBF and cholinergic function. It decreased mitochondrial (Ca(2+))i, and ameliorated neuroinflammation and oxidative-nitrostative stress in different brain regions of OKA treated mice. Curcumin also inhibited astrocyte activation as evidenced by decreased GFAP expression. This neuroprotective effect of curcumin is due to its potent anti-oxidant action thus confirming previous studies. Therefore, use of curcumin should be encouraged in people consuming sea food (contaminated with dinoflagellates) to prevent cognitive impairment. © 2013 Elsevier B.V. All rights reserved.

Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats.

PubMed

Veena, J; Srikumar, B N; Mahati, K; Raju, T R; Shankaranarayana Rao, B S

2011-09-01

Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function. In the current study, we have looked into the possible involvement of adult neurogenesis in cognitive restoration by oxotremorine. Further, we have assessed the effect of oxotremorine treatment on depression-like behaviour and hippocampal volumes in stressed animals. Chronic restraint stressed rats were treated with either vehicle or oxotremorine. For neurogenesis studies, proliferation, survival and differentiation of the progenitor cells in the hippocampus were examined using 5'-bromo-2-deoxyuridine immunohistochemistry. Depression-like behaviour was evaluated using forced swim test (FST) and sucrose consumption test (SCT). Volumes were estimated using Cavalieri's estimator. Hippocampal neurogenesis was severely decreased in stressed rats. Ten days of oxotremorine treatment to stressed animals partially restored proliferation and survival, while it completely restored the differentiation of the newly formed cells. Stressed rats showed increased immobility and decreased sucrose preference in the FST and SCT, respectively, and oxotremorine ameliorated this depression-like behaviour. In addition, oxotremorine treatment recovered the stress-induced decrease in hippocampal volume. These results indicate that the restoration of impaired neurogenesis and hippocampal volume could be associated with the behavioural recovery by oxotremorine. Our results imply the muscarinic regulation of adult neurogenesis and incite the potential utility of cholinomimetics in ameliorating cognitive dysfunction in stress-related disorders.

Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice

PubMed Central

Ash, Jessica A.; Velazquez, Ramon; Kelley, Christy M.; Powers, Brian E.; Ginsberg, Stephen D.; Mufson, Elliott J.; Strupp, Barbara J.

2014-01-01

Down syndrome (DS) is marked by intellectual disability (ID) and early-onset of Alzheimer’s disease (AD) neuropathology, including basal forebrain cholinergic neuron (BFCN) degeneration. The present study tested the hypothesis that maternal choline supplementation (MCS) lessens hippocampal dysfunction and protects against BFCN degeneration in the Ts65Dn mouse model of DS and AD. During pregnancy and lactation, dams were assigned to either a choline sufficient (1.1 g/kg choline chloride) or choline supplemented (5.0 g/kg choline chloride) diet. Between 13 and 17 months of age, offspring were tested in the radial arm water maze (RAWM) to examine spatial learning and memory followed by unbiased quantitative morphometry of BFCNs. Spatial mapping was significantly impaired in unsupplemented Ts65Dn mice relative to normal disomic (2N) littermates. Additionally, a significantly lower number and density of medial septum (MS) hippocampal projection BFCNs was also found in unsupplemented Ts65Dn mice. Notably, MCS significantly improved spatial mapping and increased number, density, and size of MS BFCNs in Ts65Dn offspring. Moreover, the density and number of MS BFCNs correlated significantly with spatial memory proficiency, providing powerful support for a functional relationship between these behavioral and morphometric effects of MCS for the trisomic offspring. Thus, increasing maternal choline intake during pregnancy may represent a safe and effective treatment approach for expectant mothers carrying a DS fetus, as well as a possible means of BFCN neuroprotection during aging for the population at large. PMID:24932939

Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles.

PubMed

Kurakhmaeva, Kamila B; Djindjikhashvili, Irma A; Petrov, Valery E; Balabanyan, Vadim U; Voronina, Tatiana A; Trofimov, Sergey S; Kreuter, Jörg; Gelperina, Svetlana; Begley, David; Alyautdin, Renad N

2009-09-01

The nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons in the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant cause of dementia, and this observation may suggest a possible therapeutic benefit from treatment with NGF. In recent years, convincing data have been published involving neurotrophic factors for the modulation of dopaminergic transmission within the brain and concerning the ability of NGF to prevent the degeneration of dopaminergic neurons. In this connection, the administration of NGF may slow down the progression of Parkinson's disease. However, NGF, as well as other peptidic neurotrophic factors, does not significantly penetrate the blood-brain barrier (BBB) from the circulation. Therefore, any clinical usefulness of NGF as a potential CNS therapy will depend on the use of a suitable carrier system that enhances its transport through the BBB. The present study investigates brain delivery of NGF adsorbed on poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 and the pharmacological efficacy of this delivery system in the model of acute scopolamine-induced amnesia in rats as well as in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian syndrome. As shown by the passive avoidance reflex (PAR) test, the intravenous administration of the nanoparticle-bound NGF successfully reversed scopolamine-induced amnesia and improved recognition and memory. This formulation also demonstrated a significant reduction of the basic symptoms of Parkinsonism (oligokinesia, rigidity, tremor). In addition, the efficient transport of NGF across the BBB was confirmed by direct measurement of NGF concentrations in the murine brain. These results demonstrate that the PBCA nanoparticles coated with polysorbate 80 are an effective carrier system for the transport of NGF to the central nervous system across the BBB following intravenous injection. This approach may improve the NGF-based therapy of age-related neurodegenerative diseases.

Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system.

PubMed

Wine, Jeffrey J

2007-04-30

Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on non-cholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences of this for gland secretion and airway defense are poorly understood, but it is possible that interventions to modify submucosal gland secretion in transplanted lungs might have therapeutic consequences.

Gami-Chunghyuldan ameliorates memory impairment and neurodegeneration induced by intrahippocampal Aβ 1-42 oligomer injection.

PubMed

Choi, Jin Gyu; Moon, Minho; Kim, Hyo Geun; Mook-Jung, Inhee; Chung, Sun Yong; Kang, Tong Ho; Kim, Sun Yeou; Lee, Eunjoo H; Oh, Myung Sook

2011-09-01

Soluble oligomeric forms of amyloid beta (AβO) are regarded as a main cause of synaptic and cognitive dysfunction in Alzheimer's disease (AD) and have been a primary target in the development of drug treatments for AD. The present study utilized a mouse model of AD induced by intrahippocampal injection of AβO (10 μM) to investigate the effects of Gami-Chunghyuldan (GCD), a standardized multi-herbal medicinal formula, on the presentation of memory deficits and neurohistological pathogenesis. GCD (10 and 50mg/kg/day, 5 days, p.o.) improved AβO-induced memory impairment as well as reduced neuronal cell death, astrogliosis, and microgliosis in the hippocampus. In addition, GCD prevented AβO-triggered synaptic disruption and cholinergic fiber loss. These results suggest that GCD may be useful in the prevention and treatment of AD. Copyright © 2011 Elsevier Inc. All rights reserved.

The hippocampo-prefrontal pathway: a possible therapeutic target for negative and cognitive symptoms of schizophrenia

PubMed Central

Ghoshal, Ayan; Conn, P Jeffrey

2015-01-01

The hippocampo-prefrontal (H-PFC) pathway has been linked to cognitive and emotional disturbances in several psychiatric disorders including schizophrenia. Preclinical evidence from the NMDA receptor antagonism rodent model of schizophrenia shows severe pathology selective to the H-PFC pathway. It is speculated that there is an increased excitatory drive from the hippocampus to the prefrontal cortex due to dysfunctions in the H-PFC plasticity, which may serve as the basis for the behavioral consequences observed in this rodent model. Thus, the H-PFC pathway is currently emerging as a promising therapeutic target for the negative and cognitive symptom clusters of schizophrenia. Here, we have reviewed the physiological, pharmacological and functional characteristics of the H-PFC pathway and we propose that allosteric activation of glutamatergic and cholinergic neurotransmission can serve as a plausible therapeutic approach. PMID:25825588

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

PubMed Central

Govindpani, Karan; Calvo-Flores Guzmán, Beatriz; Vinnakota, Chitra; Waldvogel, Henry J.; Kwakowsky, Andrea

2017-01-01

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebrate brain. In the past, there has been a major research drive focused on the dysfunction of the glutamatergic and cholinergic neurotransmitter systems in Alzheimer’s disease (AD). However, there is now growing evidence in support of a GABAergic contribution to the pathogenesis of this neurodegenerative disease. Previous studies paint a complex, convoluted and often inconsistent picture of AD-associated GABAergic remodeling. Given the importance of the GABAergic system in neuronal function and homeostasis, in the maintenance of the excitatory/inhibitory balance, and in the processes of learning and memory, such changes in GABAergic function could be an important factor in both early and later stages of AD pathogenesis. Given the limited scope of currently available therapies in modifying the course of the disease, a better understanding of GABAergic remodeling in AD could open up innovative and novel therapeutic opportunities. PMID:28825683

Health Status and Performance of United States Air Force Airmen Following Mild Traumatic Brain Injury

DTIC Science & Technology

2010-09-01

adrenal insufficiency, hypopituitarism, hypothyroidism , growth- hormone deficiency and posterior pituitary dysfunction [53, 54, 56-60]. Growth...central hypothyroidism which can result in fatigue, apathy, decreased strength and cognitive dysfunction, symptoms commonly observed in PTSD [54

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.

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.

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

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.

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

Physical examination of dizziness in athletes after a concussion: A descriptive study.

PubMed

Reneker, Jennifer C; Cheruvu, Vinay K; Yang, Jingzhen; James, Mark A; Cook, Chad E

2018-04-01

Dizziness is commonly reported after concussion. With the forces experienced at the time of the injury, several anatomical locations may have been altered, causing dizziness. Describe an objective examination and the types of impairment/dysfunction implicated by the results of clinical examination tests in subjects with dizziness after a concussion. Cross-Sectional. Athletes between ages 10-23 were enrolled with a diagnosis of concussion. An examination was completed to identify areas potentially contributing to dizziness, including tests of oculomotor control, the vestibular system, neuromotor control, and musculoskeletal components of the cervical spine. Descriptive analyses were completed to define the anatomical areas/types of dysfunction identified by positive findings of the examination tests. All (n = 41; 100%) subjects had examination findings consistent with central dysfunction. Of these, 36 (97.8%) had oculomotor control deficits; 29 (70.7%) demonstrated motion sensitivity; and 6 (15%) had central vestibular deficits. Nineteen (46.3%) had peripheral dysfunction, including 18 (43.9%) with unilateral hypofunction, and 2 (4.9%) with Benign Paroxysmal Positional Vertigo. Thirty-four (82.9%) had cervical dysfunction, with 11 (26.8%) presenting with cervicogenic dizziness, and 31 (75.6%) with altered neuromotor control. Functional injury to centrally-mediated pathways, specifically oculomotor control, and afferent and efferent pathways in the cervical spine are commonly identified through clinical examination tests in individuals with a complaint of dizziness post-concussion. According to results presented here, a high majority (90%) of the participants demonstrated dizziness that appeared to be multifactorial in nature and was not attributable to one main type of dysfunction. The common pathways between the systems make it difficult to isolate only one anatomical area as a contributor to dizziness. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

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

Review of the pathophysiological aspects involved in urological disease associated with metabolic syndrome.

PubMed

Sáenz Medina, J; Carballido Rodríguez, J

2016-06-01

Metabolic syndrome is a constellation of disorders that includes insulin resistance, central obesity, arterial hypertension and hyperlipidaemia. These disorders can have implications for the genitourinary apparatus. To conduct a review on the pathophysiological aspects that explain the relationship between metabolic syndrome and sexual dysfunction, lower urinary tract syndrome, prostate cancer and stone disease. We performed a qualitative, narrative literature review through a literature search on PubMed of articles published between 1997 and 2015, using the terms pathophysiology, metabolic syndrome, endothelial dysfunction, lipotoxicity, mitochondrial dysfunction, kidney stones, hypogonadism, erectile dysfunction, lower urinary tract syndrome and prostate cancer. Metabolic syndrome constitutes an established complex of symptoms, defined as the presence of insulin resistance, central obesity, hypertension and hyperlipidaemia. Endothelial dysfunction secondary to lipotoxicity generates an inflammatory state, which involves renal cell metabolism, vascularisation of the pelvis and androgen production. These facts explain the relationship between metabolic syndrome, nephrolithiasis, lower urinary tract syndrome, hypogonadism and erectile dysfunction in men. Strategies such as proper diet, regular exercise, insulin treatment, testosterone-replacement therapy, therapy with antioxidants and free-radical inhibitors and urological treatments classically used for lower urinary tract syndrome have shown promising results in this syndrome. Copyright © 2015 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

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

Ineffectiveness of deanol in tardive dyskinesia: a placebo controlled study.

PubMed

de Montigny, C; Chouinard, G; Annable, L

1979-11-01

In a double-blind placebo-controlled study, deanol acetamidobenzoate, administered in doses up to 1.5 g q.d. for three weeks to chronic schizophrenic patients presenting moderate to severe tardive dyskinesia, failed to alleviate the dyskinetic movements. However, there was a tendency for a significant increase in the schizophrenic symptoms of the deanol-treated group relative to the control group. The ineffectiveness of deanol in alleviating tardive dyskinesia is consistent with its inability to enhance brain acetylcholine synthesis. The worsening of the schizophrenic symptoms may possibly result from an interference by deanol with central cholinergic function.

Hepatic dysfunction.

PubMed

McCord, Kelly W; Webb, Craig B

2011-07-01

This article reviews the common pathophysiology that constitutes hepatic dysfunction, regardless of the inciting cause. The systemic consequences of liver failure and the impact of this condition on other organ systems are highlighted. The diagnostic tests available for determining the cause and extent of liver dysfunction are outlined, treatment strategies aimed at supporting hepatic health and recovery are discussed, and prognosis is briefly covered. The article emphasizes the fact that because of the central role of the liver in maintaining normal systemic homeostasis, hepatic dysfunction cannot be effectively addressed as an isolated entity. Copyright © 2011 Elsevier Inc. All rights reserved.

Bridging Grafts and Transient Nerve Growth Factor Infusions Promote Long-Term Central Nervous System Neuronal Rescue and Partial Functional Recovery

NASA Astrophysics Data System (ADS)

Tuszynski, Mark H.; Gage, Fred H.

1995-05-01

Grafts of favorable axonal growth substrates were combined with transient nerve growth factor (NGF) infusions to promote morphological and functional recovery in the adult rat brain after lesions of the septohippocampal projection. Long-term septal cholinergic neuronal rescue and partial hippocampal reinnervation were achieved, resulting in partial functional recovery on a simple task assessing habituation but not on a more complex task assessing spatial reference memory. Control animals that received transient NGF infusions without axonal-growth-promoting grafts lacked behavioral recovery but also showed long-term septal neuronal rescue. These findings indicate that (i) partial recovery from central nervous system injury can be induced by both preventing host neuronal loss and promoting host axonal regrowth and (ii) long-term neuronal loss can be prevented with transient NGF infusions.

Auditory system dysfunction in Alzheimer disease and its prodromal states: A review.

PubMed

Swords, Gabriel M; Nguyen, Lydia T; Mudar, Raksha A; Llano, Daniel A

2018-07-01

Recent findings suggest that both peripheral and central auditory system dysfunction occur in the prodromal stages of Alzheimer Disease (AD), and therefore may represent early indicators of the disease. In addition, loss of auditory function itself leads to communication difficulties, social isolation and poor quality of life for both patients with AD and their caregivers. Developing a greater understanding of auditory dysfunction in early AD may shed light on the mechanisms of disease progression and carry diagnostic and therapeutic importance. Herein, we review the literature on hearing abilities in AD and its prodromal stages investigated through methods such as pure-tone audiometry, dichotic listening tasks, and evoked response potentials. We propose that screening for peripheral and central auditory dysfunction in at-risk populations is a low-cost and effective means to identify early AD pathology and provides an entry point for therapeutic interventions that enhance the quality of life of AD patients. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

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

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

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.

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).

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.

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease.

PubMed

Serrano, Mari Paz; Herrero-Labrador, Raquel; Futch, Hunter S; Serrano, Julia; Romero, Alejandro; Fernandez, Ana Patricia; Samadi, Abdelouahid; Unzeta, Mercedes; Marco-Contelles, Jose; Martínez-Murillo, Ricardo

2017-01-01

The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-β aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data. We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells. In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine. The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration. ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.

Nootropic activity of Crataeva nurvala Buch-Ham against scopolamine induced cognitive impairment

PubMed Central

Bhattacharjee, Atanu; Shashidhara, Shastry Chakrakodi; Saha, Santanu

2015-01-01

Loss of cognition is one of the age related mental problems and a characteristic symptom of neurodegenerative disorders like Alzheimer’s. Crataeva nurvala Buch-Ham, a well explored traditional Indian medicinal plant of Westernghats, is routinely used as folkloric medicine to treat various ailments in particular urolithiasis and neurological disorders associated with cognitive dysfunction. The objective of the study was to evaluate the nootropic activity of Crataeva nurvala Buch-Ham stem bark in different learning and memory paradigm viz. Elevated plus maze and Y-maze against scopolamine induced cognitive impairment. Moreover, to elucidate possible mechanism, we studied the influence of Crataeva nurvala ethanolic extract on central cholinergic activity via estimating the whole brain acetyl cholinesterase enzyme. Ethanolic extracts of Crataeva nurvala (100, 200 and 400 mg/kg body weight) were administered to adult Wistar rats for successive seven days and the acquisition, retention and retrieval of spatial recognition memory was determined against scopolamine (1 mg/kg, i.p.) induced amnesia through exteroceptive behavioral models viz. Elevated plus maze and Y-maze models. Further, whole brain acetyl cholinesterase enzyme was estimated through Ellman’s method. Pretreatment with Crataeva nurvala ethanolic extract significantly improved spatial learning and memory against scopolamine induced amnesia. Moreover, Crataeva nurvala extract decreased rat brain acetyl cholinesterase activity in a dose dependent manner and comparable to the standard drug Piracetam. The results indicate that ethanolic extract of Crataeva nurvala might be a useful as nootropic agent to delay the onset and reduce the severity of symptoms associated with dementia and Alzheimer’s disease. The underlying mechanism of action of its nootropic potentiality might be attributed to its anticholinesterase property. PMID:27065767