Science.gov

Sample records for acetylcholine enhances neural

  1. Bulbar acetylcholine enhances neural and perceptual odor discrimination.

    PubMed

    Chaudhury, Dipesh; Escanilla, Olga; Linster, Christiane

    2009-01-07

    Experimental and modeling data suggest that the circuitry of the main olfactory bulb (OB) plays a critical role in olfactory discrimination. Processing of such information arises from the interaction between OB output neurons local interneurons, as well as interactions between the OB network and centrifugal inputs. Cholinergic input to the OB in particular has been hypothesized to regulate mitral cell odorants receptive fields (ORFs) and behavioral discrimination of similar odorants. We recorded from individual mitral cells in the OB in anesthetized rats to determine the degree of overlap in ORFs of individual mitral cells after exposure to odorant stimuli. Increasing the efficacy of the cholinergic neurotransmission in the OB by addition of the anticholinesterase drug neostigmine (20 mM) sharpened the ORF responses of mitral cells. Furthermore, coaddition of either the nicotinic antagonist methyllycaconitine citrate hydrate (MLA) (20 mM) or muscarinic antagonist scopolamine (40 mM) together with neostigmine (20 mM) attenuated the neostigmine-dependent sharpening of ORFs. These electrophysiological findings are predictive of accompanying behavioral experiments in which cholinergic modulation was manipulated by direct infusion of neostigmine, MLA, and scopolamine into the OB during olfactory behavioral tasks. Increasing the efficacy of cholinergic action in the OB increased perceptual discrimination of odorants in these experiments, whereas blockade of nicotinic or muscarinic receptors decreased perceptual discrimination. These experiments show that behavioral discrimination is modulated in a manner predicted by the changes in mitral cell ORFs by cholinergic drugs. These results together present a first direct comparison between neural and perceptual effects of a bulbar neuromodulator.

  2. Acetylcholine mediates behavioral and neural post-error control.

    PubMed

    Danielmeier, Claudia; Allen, Elena A; Jocham, Gerhard; Onur, Oezguer A; Eichele, Tom; Ullsperger, Markus

    2015-06-01

    Humans often commit errors when they are distracted by irrelevant information and no longer focus on what is relevant to the task at hand. Adjustments following errors are essential for optimizing goal achievement. The posterior medial frontal cortex (pMFC), a key area for monitoring errors, has been shown to trigger such post-error adjustments by modulating activity in visual cortical areas. However, the mechanisms by which pMFC controls sensory cortices are unknown. We provide evidence for a mechanism based on pMFC-induced recruitment of cholinergic projections to task-relevant sensory areas. Using fMRI in healthy volunteers, we found that error-related pMFC activity predicted subsequent adjustments in task-relevant visual brain areas. In particular, following an error, activity increased in those visual cortical areas involved in processing task-relevant stimulus features, whereas activity decreased in areas representing irrelevant, distracting features. Following treatment with the muscarinic acetylcholine receptor antagonist biperiden, activity in visual areas was no longer under control of error-related pMFC activity. This was paralleled by abolished post-error behavioral adjustments under biperiden. Our results reveal a prominent role of acetylcholine in cognitive control that has not been recognized thus far. Regaining optimal performance after errors critically depends on top-down control of perception driven by the pMFC and mediated by acetylcholine. This may explain the lack of adaptivity in conditions with reduced availability of cortical acetylcholine, such as Alzheimer's disease.

  3. Neural Systems Governed by Nicotinic Acetylcholine Receptors: Emerging Hypotheses

    PubMed Central

    Miwa, Julie M.; Freedman, Robert; Lester, Henry A.

    2015-01-01

    Cholinergic neurons and nicotinic acetylcholine receptors (nAChRs) in the brain participate in diverse functions: reward, learning and memory, mood, sensory processing, pain, and neuroprotection. Nicotinic systems also have well-known roles in drug abuse. Here, we review recent insights into nicotinic function, linking exogenous and endogenous manipulations of nAChRs to alterations in synapses, circuits, and behavior. We also discuss how these contemporary advances can motivate attempts to exploit nicotinic systems therapeutically in Parkinson’s disease, cognitive decline, epilepsy, and schizophrenia. PMID:21482353

  4. Caffeine potentiates the enhancement by choline of striatal acetylcholine release

    NASA Technical Reports Server (NTRS)

    Johnson, D. A.; Ulus, I. H.; Wurtman, R. J.

    1992-01-01

    We investigated the effect of peripherally administered caffeine (50 mg/kg), choline (30, 60, or 120 mg/kg) or combinations of both drugs on the spontaneous release of acetylcholine (ACh) from the corpus striatum of anesthetized rats using in vivo microdialysis. Caffeine alone or choline in the 30 or 60 mg/kg dose failed to increase ACh in microdialysis samples; the 120 mg/kg choline dose significantly enhanced ACh during the 80 min following drug administration. Coadministration of caffeine with choline significantly increased ACh release after each of the choline doses tested. Peak microdialysate levels with the 120 mg/kg dose were increased 112% when caffeine was additionally administered, as compared with 54% without caffeine. These results indicate that choline administration can enhance spontaneous ACh release from neurons, and that caffeine, a drug known to block adenosine receptors on these neurons, can amplify the choline effect.

  5. Neural regulation of muscle acetylcholine receptor epsilon- and alpha- subunit gene promoters in transgenic mice

    PubMed Central

    1993-01-01

    The effects of denervation were investigated in mice with transgenes containing promoter elements from the muscle acetylcholine receptor epsilon- and alpha-subunit genes. The promoter sequences were coupled to a nuclear localization signal-beta-galactosidase fusion gene (nlacZ) as a reporter. While many postsynaptic specializations form in the embryo, expression of the epsilon subunit is induced during the first two postnatal weeks. When muscles were denervated at birth, before the onset of epsilon expression, epsilon nlacZ still appeared at the former synaptic sites on schedule. This result suggests that the nerve leaves a localized "trace" in the muscle that can continue to regulate transcription. An additional finding was that epsilon nlacZ expression was much stronger in denervated than in intact muscles. This suggests that the epsilon promoter is similar to the other subunits in containing elements that are activated on cessation of neural activity. However, even after denervation, epsilon nlacZ expression was always confined to the synaptic region whereas alpha nlacZ expression increased in nuclei along the entire length of the fiber. This suggests that while the epsilon gene is similar in its activity dependence to other subunit genes, it is unique in that local nerve-derived signals are essential for its expression. Consequently, inactivity enhances epsilon expression only in synaptic nuclei where such signals are present, but enhances expression throughout the muscle fiber. Truncations and an internal deletion of the epsilon promoter indicate that cis-elements essential for the response to synaptic signals are contained within 280 bp of the transcription start site. In contrast to these results in young animals, denervation in older animals leads to an unexpected reduction in nlacZ activity. However, mRNA measurements indicated that transgene expression was increased in these animals. This discordance between nlacZ mRNA and enzyme activity, demonstrates a

  6. Dynamical State Transition by Neuromodulation Due to Acetylcholine in Neural Network Model for Oscillatory Phenomena in Thalamus

    NASA Astrophysics Data System (ADS)

    Omori, Toshiaki; Horiguchi, Tsuyoshi

    2004-12-01

    We propose a two-layered neural network model for oscillatory phenomena in the thalamic system and investigate an effect of neuromodulation due to the acetylcholine on the oscillatory phenomena by numerical simulations. The proposed model consists of a layer of the thalamic reticular neurons and that of the cholinergic neurons. We introduce a dynamics of concentration of the acetylcholine which depends on a state of the cholinergic neurons, and assume that the conductance of the thalamic reticular neurons is dynamically regulated by the acetylcholine. From the results obtained by numerical simulations, we find that a dynamical transition between a bursting state and a resting state occurs successively in the layer of the thalamic reticular neurons due to the acetylcholine. Therefore it turns out that the neuromodulation due to the acetylcholine is important for the dynamical state transition in the thalamic system.

  7. Clitoria ternatea root extract enhances acetylcholine content in rat hippocampus.

    PubMed

    Rai, K S; Murthy, K D; Karanth, K S; Nalini, K; Rao, M S; Srinivasan, K K

    2002-12-01

    Treatment with 100 mg/kg of Clitoria ternatea aqueous root extract (CTR), for 30 days in neonatal and young adult age groups of rat, significantly increased acetylcholine (ACh) content in their hippocampi as compared to age matched controls. Increase in ACh content in their hippocampus may be the neurochemical basis for their improved learning and memory.

  8. Spintronic characteristics of self-assembled neurotransmitter acetylcholine molecular complexes enable quantum information processing in neural networks and brain

    NASA Astrophysics Data System (ADS)

    Tamulis, Arvydas; Majauskaite, Kristina; Kairys, Visvaldas; Zborowski, Krzysztof; Adhikari, Kapil; Krisciukaitis, Sarunas

    2016-09-01

    Implementation of liquid state quantum information processing based on spatially localized electronic spin in the neurotransmitter stable acetylcholine (ACh) neutral molecular radical is discussed. Using DFT quantum calculations we proved that this molecule possesses stable localized electron spin, which may represent a qubit in quantum information processing. The necessary operating conditions for ACh molecule are formulated in self-assembled dimer and more complex systems. The main quantum mechanical research result of this paper is that the neurotransmitter ACh systems, which were proposed, include the use of quantum molecular spintronics arrays to control the neurotransmission in neural networks.

  9. NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas.

    PubMed

    Osborne, Jihan K; Guerra, Marcy L; Gonzales, Joshua X; McMillan, Elizabeth A; Minna, John D; Cobb, Melanie H

    2014-06-01

    Cigarette smoking is a major risk factor for acquisition of small cell lung cancer (SCLC). A role has been demonstrated for the basic helix-loop-helix transcription factor NeuroD1 in the pathogenesis of neural and neuroendocrine lung cancer, including SCLC. In the present study we investigate the possible function of NeuroD1 in established tumors, as well as actions early on in pathogenesis, in response to nicotine. We demonstrate that nicotine up-regulates NeuroD1 in immortalized normal bronchial epithelial cells and a subset of undifferentiated carcinomas. Increased expression of NeuroD1 subsequently leads to regulation of expression and function of the nicotinic acetylcholine receptor subunit cluster of α3, α5, and β4. In addition, we find that coordinated expression of these subunits by NeuroD1 leads to enhanced nicotine-induced migration and invasion, likely through changes in intracellular calcium. These findings suggest that aspects of the pathogenesis of neural and neuroendocrine lung cancers may be affected by a nicotine- and NeuroD1-induced positive feedback loop.

  10. Acetylcholine Facilitates a Depolarization-Induced Enhancement of Inhibition in Rat CA1 Pyramidal Neurons.

    PubMed

    Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

    2017-01-01

    Cholinergic mechanisms in the hippocampus regulate forms of synaptic plasticity linked with cognition and spatial navigation, but the underlying mechanisms remain largely unknown. Here, in rat hippocampal CA1 pyramidal cells under blockade of ionotropic glutamate receptors, we report that a single acetylcholine pulse and repeated depolarization activated a robust and enduring postsynaptic depolarization-induced enhancement of inhibition (DEI) that masked a presynaptic depolarization-induced suppression of inhibition (DSI). Increased cytosolic Ca2+ and M1-muscarinic receptor activation caused the rise in voltage-sensitive α5βγ2-containing γ-aminobutyric acid type-A receptors that generated DEI. In summary, this muscarinic-mediated activity-dependent plasticity rapidly transfers depolarization effects on inhibition from presynaptic suppression or DSI to postsynaptic enhancement or DEI, a change potentially relevant in behavior.

  11. Nicotine enhances alcohol intake and dopaminergic responses through β2* and β4* nicotinic acetylcholine receptors

    PubMed Central

    Tolu, Stefania; Marti, Fabio; Morel, Carole; Perrier, Carole; Torquet, Nicolas; Pons, Stephanie; de Beaurepaire, Renaud; Faure, Philippe

    2017-01-01

    Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of β4 * nAChRs, but not β2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (β2−/− and β4−/− mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in β2−/− and β4−/− mice, suggesting that nicotine triggers β2* and β4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs. PMID:28332590

  12. Subtype-selective nicotinic acetylcholine receptor agonists enhance the responsiveness to citalopram and reboxetine in the mouse forced swim test.

    PubMed

    Andreasen, Jesper T; Nielsen, Elsebet Ø; Christensen, Jeppe K; Olsen, Gunnar M; Peters, Dan; Mirza, Naheed R; Redrobe, John P

    2011-10-01

    Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. Accordingly, nicotine enhances antidepressant-like actions of reuptake inhibitors selective for serotonin or noradrenaline in the mouse forced swim test and the mouse tail suspension test. Both high-affinity α4β2 and low-affinity α7 nicotinic acetylcholine receptor subtypes are implicated in nicotine-mediated release of serotonin and noradrenaline. The present study therefore investigated whether selective agonism of α4β2 or α7 nicotinic acetylcholine receptors would affect the mouse forced swim test activity of two antidepressants with distinct mechanisms of action, namely the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine. Subthreshold and threshold doses of citalopram (3 and 10 mg/kg) or reboxetine (10 and 20 mg/kg) were tested alone and in combination with the novel α4β2-selective partial nicotinic acetylcholine receptor agonist, NS3956 (0.3 and 1.0 mg/kg) or the α7-selective nicotinic acetylcholine receptor agonist, PNU-282987 (10 and 30 mg/kg). Alone, NS3956 and PNU-282987 were devoid of activity in the mouse forced swim test, but both 1.0 mg/kg NS3956 and 30 mg/kg PNU-282987 enhanced the effect of citalopram and also reboxetine. The data suggest that the activity of citalopram and reboxetine in the mouse forced swim test can be enhanced by agonists at either α4β2 or α7 nicotinic acetylcholine receptors, suggesting that both nicotinic acetylcholine receptor subtypes may be involved in the nicotine-enhanced action of antidepressants.

  13. α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia.

    PubMed

    Freedman, Robert

    2014-01-01

    α7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of α7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia. Further development of this therapeutic strategy requires assessment of interactions with patients' heavy cigarette smoking and the relationship of this mechanism to the therapeutic effects of clozapine and olanzapine, both highly effective therapeutics with significant side effects.

  14. Enhancement of excitatory postsynaptic potentials by preceding application of acetylcholine in mesencephalic dopamine neurons.

    PubMed

    Yamashita, Tetsuji; Isa, Tadashi

    2004-05-01

    Previously, we reported that Ca(2+) influx through nicotinic acetylcholine (ACh) receptors (nAChRs) activates a fulfenamic acid (FFA)-sensitive inward current, presumably a Ca(2+)-activated nonselective cation current (I(CAN)), in mesencephalic dopamine (DA) neurons. This current exhibited a negative slope conductance in the voltage range between -80 and -40mV and its activation led to a dramatic change in the responses to a transient application of glutamate, from single spikes to burst discharges. In this study, to examine the effect of activation of the FFA-sensitive current on EPSPs, we applied ACh (1mM) by transient air pressure shortly before electrical stimulation to evoke EPSPs in DA neurons. Application of ACh enhanced the amplitude of EPSPs when it preceded the electrical stimulation by less than 2 s, but not when the interval was longer than 3 s. In addition, this enhancement was critically dependent on intracellular Ca(2+) and the membrane potentials of the postsynaptic cell. Furthermore, the enhancing effect of ACh on EPSPs was sensitive to FFA and phenytoin. These results suggest that Ca(2+) influx caused by cholinergic inputs enhances EPSPs via activation of the FFA- and phenytoin-sensitive current.

  15. Enhancing neural-network performance via assortativity

    SciTech Connect

    Franciscis, Sebastiano de; Johnson, Samuel; Torres, Joaquin J.

    2011-03-15

    The performance of attractor neural networks has been shown to depend crucially on the heterogeneity of the underlying topology. We take this analysis a step further by examining the effect of degree-degree correlations - assortativity - on neural-network behavior. We make use of a method recently put forward for studying correlated networks and dynamics thereon, both analytically and computationally, which is independent of how the topology may have evolved. We show how the robustness to noise is greatly enhanced in assortative (positively correlated) neural networks, especially if it is the hub neurons that store the information.

  16. Enhancing neural-network performance via assortativity.

    PubMed

    de Franciscis, Sebastiano; Johnson, Samuel; Torres, Joaquín J

    2011-03-01

    The performance of attractor neural networks has been shown to depend crucially on the heterogeneity of the underlying topology. We take this analysis a step further by examining the effect of degree-degree correlations--assortativity--on neural-network behavior. We make use of a method recently put forward for studying correlated networks and dynamics thereon, both analytically and computationally, which is independent of how the topology may have evolved. We show how the robustness to noise is greatly enhanced in assortative (positively correlated) neural networks, especially if it is the hub neurons that store the information.

  17. Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine.

    PubMed

    Hikida, Takatoshi; Kitabatake, Yasuji; Pastan, Ira; Nakanishi, Shigetada

    2003-05-13

    Drug addiction poses serious social, medical, and economic problems, but effective treatments for drug addiction are still limited. Cocaine and morphine elevate dopamine levels in the nucleus accumbens (NAc), and the overwhelming actions of dopamine are implicated in reinforcement and addiction of abusive drugs. In our previous studies, we reported the regulatory role of acetylcholine (ACh) in the NAc function by selectively ablating the NAc cholinergic neurons with use of immunotoxin-mediated cell targeting. These studies indicated that ACh and dopamine acted convergently but oppositely on the NAc circuit and that cholinergic cell ablation enhanced long-lasting behavioral changes of cocaine addiction. In this investigation, we showed that immunotoxin-mediated ablation of the NAc cholinergic neurons enhanced not only the sensitivity to morphine in conditioned place preference but also negative reinforcement of morphine withdrawal in conditioned place aversion. Remarkably, acetylcholinesterase (AChE) inhibitors that act on the brain AChE suppressed both cocaine- and morphine-induced conditioned place preference and blocked the induction and persistence of cocaine-evoked hyperlocomotion. Importantly, this inhibition was abolished by ablation of the NAc cholinergic neurons. These results demonstrate that centrally active AChE inhibitors prevent long-lasting behavioral abnormalities associated with cocaine and morphine addictions by potentiating the actions of ACh released from the NAc cholinergic neurons. Centrally active AChE inhibitors could thus be approached as novel and potential therapeutic agents for drug addiction.

  18. Conservation of neural nicotinic acetylcholine receptors from Drosophila to vertebrate central nervous systems.

    PubMed Central

    Bossy, B; Ballivet, M; Spierer, P

    1988-01-01

    Nicotinic acetylcholine receptors (nAChR) are found both in vertebrate and insect central nervous systems. We have isolated a Drosophila gene by crosshybridization with a vertebrate probe. Structural conservation of domains of the deduced protein and of intron/exon boundaries indicate that the Drosophila gene encodes an nAChR alpha-like subunit (ALS). That the Drosophila gene product most resembles the neuronal set of vertebrate nAChRs alpha-subunits is also indicated by the failure of an ALS-beta-galactosidase fusion protein to bind alpha-bungarotoxin on blots in contrast to vertebrate endplate alpha-subunit constructions. The ALS encoding gene exceeds 54 kb in length and the transcript has a very long and unusual 5' leader. As we found previously for a gene whose product is also involved in cholinergic synapses, acetylcholinesterase, the leader encodes short open reading frames, which might be involved in translation control. We also note the presence of opa repeats in the gene, as has been found for various Drosophila genes expressed in the nervous system. Images PMID:2840281

  19. Presynaptic α7 Nicotinic Acetylcholine Receptors Enhance Hippocampal Mossy Fiber Glutamatergic Transmission via PKA Activation

    PubMed Central

    Cheng, Qing

    2014-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an α7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an α7 nAChR agonist), and was absent in α7 nAChR knock-out mice. These data indicate that activation of α7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the α7 nAChRs. We also observed α7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional α7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of α7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission. PMID:24381273

  20. Increasing Hippocampal Acetylcholine Levels Enhances Behavioral Performance in an Animal Model of Diencephalic Amnesia

    PubMed Central

    Roland, Jessica J.; Mark, Katherine; Vetreno, Ryan P.; Savage, Lisa M.

    2008-01-01

    Pyrithiamine-induced thiamine deficiency (PTD) was used to produce a rodent model of Wernicke-Korsakoff syndrome that results in acute neurological disturbances, thalamic lesions, and learning and memory impairments. There is also cholinergic septo-hippocampal dysfunction in the PTD model. Systemic (Experiment 1) and intrahippocampal (Experiment 2) injections of the acetylcholinesterase inhibitor physostigmine were administered to determine if increasing acetylcholine levels would eliminate the behavioral impairment produced by PTD. Prior to spontaneous alternation testing, rats received injections of either physostigmine (systemic = 0.075 mg/kg; intrahippocampal = 20, 40 ng/µl) or saline. In Experiment 2, intrahippocampal injections of physostigmine significantly enhanced alternation rates in the PTD-treated rats. In addition, although intrahippocampal infusions of 40 ng of physostigmine increased the available amount of ACh in both Pair-fed (PF) and PTD rats, it did so to a greater extent in PF rats. The increase in ACh levels induced by the direct hippocampal application of physostigmine in the PTD model likely increased activation of the extended limbic system, which was dysfunctional, and therefore led to recovery of function on the spontaneous alternation task. In contrast, the lack of behavioral improvement by intrahippocampal physostigmine infusion in the PF rats, despite a greater rise in hippocampal ACh levels, supports the theory that there is a optimal range of cholinergic tone for optimal behavioral and hippocampal function. PMID:18706897

  1. alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

    PubMed

    de Fiebre, Nancyellen C; de Fiebre, Christopher M

    2005-01-03

    The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

  2. Number of junctional acetylcholine receptors: control by neural and muscular influences in the rat.

    PubMed Central

    Andreose, J S; Fumagalli, G; Lømo, T

    1995-01-01

    1. The number of acetylcholine receptors (AChRs) per neuromuscular junction in soleus muscles of adult rats was estimated from counts of 125I-alpha-bungarotoxin binding sites. The muscles were either denervated, denervated and electrically stimulated, paralysed by botulinum toxin (BoTX), or paralysed by tetrodotoxin (TTX). 2. After denervation, the number of junctional AChRs was normal after 18 days and then fell to 54 and 35% of normal after 33 and 57 days, respectively. 3. Direct high frequency muscle stimulation (100 Hz) maintained a normal number of junctional AChRs for at least 2 months when the stimulation started on the day of denervation. When the stimulation was started progressively later, the effect of the stimulation on AChR number disappeared within about a week. The disappearance was gradual and appeared to affect all the muscle fibres equally. 4. Stimulation at 100 Hz, starting on the day of denervation and stopping after 18 days, did not prevent the endplates from losing AChRs during the subsequent 15 days without stimulation. Thus 100 Hz stimulation and innervation are not equivalent in their effects on junctional AChR number. 5. Direct low frequency muscle stimulation from the day of denervation did not maintain a normal number of junctional AChRs, as the number of AChRs fell to 70 and 62% of normal after 33 days of stimulation at 20 and 10 Hz, respectively. 6. Endplates paralysed by BoTX or TTX for 33 days lost about as many junctional AChRs (54 and 55%) as endplates denervated for 33 days (46%). Direct stimulation at 100 Hz during the last 15 days of BoTX treatment reduced but did not prevent this AChR loss (36% loss at 33 days). 7. The results show that when motor nerve terminals in rat soleus muscles are removed by axotomy, they leave a 'trace' which, in conjunction with appropriate muscle stimulation, can maintain a normal number of AChRs in the postsynaptic region. In non-stimulated muscles the trace responsible for this maintenance

  3. Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade.

    PubMed

    Hellsten, Ylva; Krustrup, Peter; Iaia, F Marcello; Secher, Niels H; Bangsbo, Jens

    2009-04-01

    This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one-legged knee-extensor exercise (18 W) during control conditions and with cisatracurium blockade, as well as with cisatracurium blockade with prior glycopyrrone infusion. Thigh blood flow and vascular conductance in control and with cisatracurium infusion were similar at rest and during passive movement of the leg, but higher (P < 0.05) during exercise with cisatracurium than in control (3.83 +/- 0.42 vs. 2.78 +/- 0.21 l/min and 26.9 +/- 3.4 vs. 21.8 +/- 2.0 ml.min(-1).mmHg(-1) at the end of exercise). Thigh oxygen uptake was similar in control and with cisatracurium infusion both at rest and during exercise, being 354 +/- 33 and 406 +/- 34 ml/min, at the end of exercise. Combined infusion of cisatracurium and glycopyrrone caused a similar increase in blood flow as cisatracurium infusion alone. The current results demonstrate that neuromuscular blockade leads to enhanced thigh blood flow and vascular conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperemia or for the enhanced blood flow during neuromuscular blockade. The enhanced exercise hyperemia during partial neuromuscular blockade may be related to a greater recruitment of fast-twitch muscle fibers.

  4. Burst Firing Enhances Neural Output Correlation

    PubMed Central

    Chan, Ho Ka; Yang, Dong-Ping; Zhou, Changsong; Nowotny, Thomas

    2016-01-01

    Neurons communicate and transmit information predominantly through spikes. Given that experimentally observed neural spike trains in a variety of brain areas can be highly correlated, it is important to investigate how neurons process correlated inputs. Most previous work in this area studied the problem of correlation transfer analytically by making significant simplifications on neural dynamics. Temporal correlation between inputs that arises from synaptic filtering, for instance, is often ignored when assuming that an input spike can at most generate one output spike. Through numerical simulations of a pair of leaky integrate-and-fire (LIF) neurons receiving correlated inputs, we demonstrate that neurons in the presence of synaptic filtering by slow synapses exhibit strong output correlations. We then show that burst firing plays a central role in enhancing output correlations, which can explain the above-mentioned observation because synaptic filtering induces bursting. The observed changes of correlations are mostly on a long time scale. Our results suggest that other features affecting the prevalence of neural burst firing in biological neurons, e.g., adaptive spiking mechanisms, may play an important role in modulating the overall level of correlations in neural networks. PMID:27242499

  5. Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

    PubMed

    Ondrejcak, Tomas; Wang, Qinwen; Kew, James N C; Virley, David J; Upton, Neil; Anwyl, Roger; Rowan, Michael J

    2012-02-29

    Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.

  6. Nanoparticle-enhanced infrared neural stimulation

    NASA Astrophysics Data System (ADS)

    Paviolo, Chiara; Thompson, Alexander C.; Yong, Jiawey; Brown, William G. A.; Stoddart, Paul R.

    2014-12-01

    Objective. Recent research has demonstrated that nerves can be stimulated by transient heating associated with the absorption of infrared light by water in the tissue. There is a great deal of interest in using this technique in neural prostheses, due to the potential for increased localization of the stimulus and minimization of contact with the tissue. However, thermal modelling suggests that the full benefits of increased localization may be reduced by cumulative heating effects when multiple stimulus sites and/or high repetition rates are used. Approach. Here we review recent in vitro and in vivo results suggesting that the transient heating associated with plasmon absorption in gold nanorods can also be used to stimulate nerves. Main results. Patch clamp experiments on cultured spiral ganglion neurons exhibited action potentials when exposed to 780 nm light at the plasmon absorption peak, while the amplitude of compound action potentials in the rat sciatic nerve were increased by laser irradiation of gold nanorods in the vicinity of the plasma membrane. Similarly, calcium imaging studies of NG108-15 neuronal cells incubated with Au nanorods revealed an increased level of intracellular calcium activity synchronized with laser exposure. Significance. Given that the plasmon absorption peak of gold nanorods can be matched with the transparency window of biological tissues, these results demonstrate that nanorod absorbers hold great promise to enhance the process of infrared neural stimulation for future applications in neural prostheses and fundamental studies in neuroscience.

  7. Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

    SciTech Connect

    Newsom-Davis, J.; Willcox, N.; Calder, L.

    1981-11-26

    We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.

  8. An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.

    PubMed

    Timmermann, Daniel B; Grønlien, Jens Halvard; Kohlhaas, Kathy L; Nielsen, Elsebet Ø; Dam, Eva; Jørgensen, Tino D; Ahring, Philip K; Peters, Dan; Holst, Dorte; Christensen, Jeppe K; Chrsitensen, Jeppe K; Malysz, John; Briggs, Clark A; Gopalakrishnan, Murali; Olsen, Gunnar M

    2007-10-01

    Augmentation of nicotinic alpha7 receptor function is considered to be a potential therapeutic strategy aimed at ameliorating cognitive and mnemonic dysfunction in relation to debilitating pathological conditions, such as Alzheimer's disease and schizophrenia. In the present report, a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (nAChR), 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea (NS1738), is described. NS1738 was unable to displace or affect radioligand binding to the agonist binding site of nicotinic receptors, and it was devoid of effect when applied alone in electrophysiological paradigms. However, when applied in the presence of acetylcholine (ACh), NS1738 produced a marked increase in the current flowing through alpha7 nAChRs, as determined in both oocyte electrophysiology and patch-clamp recordings from mammalian cells. NS1738 acted by increasing the peak amplitude of ACh-evoked currents at all concentrations; thus, it increased the maximal efficacy of ACh. Oocyte experiments indicated an increase in ACh potency as well. NS1738 had only marginal effects on the desensitization kinetics of alpha7 nAChRs, as determined from patch-clamp studies of both transfected cells and cultured hippocampal neurons. NS1738 was modestly brain-penetrant, and it was demonstrated to counteract a (-)-scopolamine-induced deficit in acquisition of a water-maze learning task in rats. Moreover, NS1738 improved performance in the rat social recognition test to the same extent as (-)-nicotine, demonstrating that NS1738 is capable of producing cognitive enhancement in vivo. These data support the notion that alpha7 nAChR allosteric modulation may constitute a novel pharmacological principle for the treatment of cognitive dysfunction.

  9. Adiponectin at Physiologically Relevant Concentrations Enhances the Vasorelaxative Effect of Acetylcholine via Cav-1/AdipoR-1 Signaling

    PubMed Central

    Du, Yunhui; Li, Rui; Lau, Wayne Bigond; Zhao, Jianli; Lopez, Bernard; Christopher, Theodore A.; Ma, Xin-Liang; Wang, Yajing

    2016-01-01

    Clinical studies have identified hypoadiponectinemia as an independent hypertension risk factor. It is known that adiponectin (APN) can directly cause vasodilation, but the doses required exceed physiologic levels several fold. In the current study, we determine the effect of physiologically relevant APN concentrations upon vascular tone, and investigate the mechanism(s) responsible. Physiologic APN concentrations alone induced no significant vasorelaxation. Interestingly, pretreatment of wild type mouse aortae with physiologic APN levels significantly enhanced acetylcholine (ACh)-induced vasorelaxation (P<0.01), an endothelium-dependent and nitric oxide (NO)-mediated process. Knockout of adiponectin receptor 1 (AdipoR1) or caveolin-1 (Cav-1, a cell signaling facilitating molecule), but not adiponectin receptor 2 (AdipoR2) abolished APN-enhanced ACh-induced vasorelaxation. Immunoblot assay revealed APN promoted the AdipoR1/Cav1 signaling complex in human endothelial cells. Treatment of HUVECs with physiologic APN concentrations caused significant eNOS phosphorylation and nitric oxide (NO) production (P<0.01), an effect abolished in knockdown of either AdipoR1 or Cav-1. Taken together, these data demonstrate for the first time physiologic APN levels enhance the vasorelaxative response to ACh by inducing NO production through AdipoR1/Cav-1 mediated signaling. In physiologic conditions, APN plays an important function of maintaining vascular tone. PMID:27023866

  10. Chronic Exposure to Nicotine Enhances Insulin Sensitivity through α7 Nicotinic Acetylcholine Receptor-STAT3 Pathway

    PubMed Central

    Wang, Pei; Song, Jie; Le, Ying-Ying; Viollet, Benoit; Miao, Chao-Yu

    2012-01-01

    This study was to investigate the effect of nicotine on insulin sensitivity and explore the underlying mechanisms. Treatment of Sprague-Dawley rats with nicotine (3 mg/kg/day) for 6 weeks reduced 43% body weight gain and 65% blood insulin level, but had no effect on blood glucose level. Both insulin tolerance test and glucose tolerance test demonstrated that nicotine treatment enhanced insulin sensitivity. Pretreatment of rats with hexamethonium (20 mg/kg/day) to antagonize peripheral nicotinic receptors except for α7 nicotinic acetylcholine receptor (α7-nAChR) had no effect on the insulin sensitizing effect of nicotine. However, the insulin sensitizing effect but not the bodyweight reducing effect of nicotine was abrogated in α7-nAChR knockout mice. Further, chronic treatment with PNU-282987 (0.53 mg/kg/day), a selective α7-nAChR agonist, significantly enhanced insulin sensitivity without apparently modifying bodyweight not only in normal mice but also in AMP-activated kinase-α2 knockout mice, an animal model of insulin resistance with no sign of inflammation. Moreover, PNU-282987 treatment enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in skeletal muscle, adipose tissue and liver in normal mice. PNU-282987 treatment also increased glucose uptake by 25% in C2C12 myotubes and this effect was total abrogated by STAT3 inhibitor, S3I-201. All together, these findings demonstrated that nicotine enhanced insulin sensitivity in animals with or without insulin resistance, at least in part via stimulating α7-nAChR-STAT3 pathway independent of inflammation. Our results contribute not only to the understanding of the pharmacological effects of nicotine, but also to the identifying of new therapeutic targets against insulin resistance. PMID:23251458

  11. High school music classes enhance the neural processing of speech.

    PubMed

    Tierney, Adam; Krizman, Jennifer; Skoe, Erika; Johnston, Kathleen; Kraus, Nina

    2013-01-01

    Should music be a priority in public education? One argument for teaching music in school is that private music instruction relates to enhanced language abilities and neural function. However, the directionality of this relationship is unclear and it is unknown whether school-based music training can produce these enhancements. Here we show that 2 years of group music classes in high school enhance the neural encoding of speech. To tease apart the relationships between music and neural function, we tested high school students participating in either music or fitness-based training. These groups were matched at the onset of training on neural timing, reading ability, and IQ. Auditory brainstem responses were collected to a synthesized speech sound presented in background noise. After 2 years of training, the neural responses of the music training group were earlier than at pre-training, while the neural timing of students in the fitness training group was unchanged. These results represent the strongest evidence to date that in-school music education can cause enhanced speech encoding. The neural benefits of musical training are, therefore, not limited to expensive private instruction early in childhood but can be elicited by cost-effective group instruction during adolescence.

  12. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents.

    PubMed

    Bubser, Michael; Bridges, Thomas M; Dencker, Ditte; Gould, Robert W; Grannan, Michael; Noetzel, Meredith J; Lamsal, Atin; Niswender, Colleen M; Daniels, J Scott; Poslusney, Michael S; Melancon, Bruce J; Tarr, James C; Byers, Frank W; Wess, Jürgen; Duggan, Mark E; Dunlop, John; Wood, Michael W; Brandon, Nicholas J; Wood, Michael R; Lindsley, Craig W; Conn, P Jeffrey; Jones, Carrie K

    2014-10-15

    Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.

  13. Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents

    PubMed Central

    2015-01-01

    Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders. PMID:25137629

  14. Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats.

    PubMed

    Nikiforuk, Agnieszka; Kos, Tomasz; Potasiewicz, Agnieszka; Popik, Piotr

    2015-08-01

    A wide body of preclinical and clinical data suggests that alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) may represent useful targets for cognitive improvement in schizophrenia and Alzheimer׳s disease. A promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs due to their several advantages over the direct agonists. Nevertheless, the behavioural effects of this class of compounds, particularly with regard to higher-order cognitive functions, have not been broadly characterised. The aim of the present study was to evaluate the procognitive efficacies of type I and type II α7-nAChRs PAMs, N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) in the novel object recognition task (NORT), attentional set-shifting task (ASST) and five-choice serial reaction time task (5-CSRTT) in rats. Additionally, the effects of galantamine, an acetylcholinesterase inhibitor that also allosterically modulates nAChRs, were assessed. We report that CCMI (0.3-3mg/kg), PNU-120596 (0.3-3mg/kg) and galantamine (1-3mg/kg) attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. Methyllycaconitine (3mg/kg) blocked the actions of CCMI, PNU-120596 and galantamine in the NORT and ASST, suggesting that the procognitive effects of these compounds are α7-nAChRs-dependent. However, none of the compounds tested affected the rats' attentional performance in the 5-CSRTT. The present findings confirm and extend the observations indicating that the positive allosteric modulation of α7-nAChRs enhances recognition memory and cognitive flexibility in preclinical tasks. Therefore, the present study supports the utility of α7-nAChRs PAMs as a potential cognitive enhancing therapy.

  15. The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine.

    PubMed

    Palmatier, Matthew I; Liu, Xiu; Caggiula, Anthony R; Donny, Eric C; Sved, Alan F

    2007-05-01

    The primary reinforcing effects of nicotine are mediated by the drugs action at central nervous system nicotinic acetylcholine receptors (nAChRs). Although previous studies have demonstrated that nicotine potently enhances responding for non-pharmacological stimuli, the role of nAChRs in this reinforcement-enhancing effect is not known. The two reinforcement-related effects of nicotine can be dissociated in a paradigm that provides concurrent access to drug infusions and a non-pharmacological visual stimulus (VS). The present study characterized the role of nAChRs in the primary reinforcing effect of nicotine and the reinforcement-enhancing effect of nicotine. For rats with access to VS (VS-Only), nicotine (NIC-Only), both reinforcers contingent upon one response (NIC+VS) or both reinforcers contingent upon separate responses (2-Lever), unit dose-response relationships (0, 30, 60, or 90 microg/kg/infusion, free base) were determined over a 22-day acquisition period. Expression of the two reinforcement-related effects of nicotine was manipulated by pharmacological antagonism of nAChRs (1 mg/kg mecamylamine, subcutaneous, 5-min before the session) or by substituting saline for nicotine infusions (ie extinction) over a series of seven test sessions. Unit dose manipulations yielded an inverse dose-response relationship for active lever responding in the NIC+VS group. The dose-response relationships for rats with independent access to each reinforcer (2-Lever group) were relatively flat. For the 2-Lever group, acute mecamylamine challenge blocked the reinforcement-enhancing effects of nicotine, VS-lever responding decreased to basal levels on the first day of mecamylamine treatment or saline substitution (to the level of the VS-Only group). In contrast, nicotine-lever responding decreased gradually over the 7-day testing period (similar to saline extinction). The two reinforcement-related effects of nicotine are mediated by nAChRs but can be dissociated by acute and

  16. Long-lasting enhancement of corticostriatal transmission by taurine: role of dopamine and acetylcholine.

    PubMed

    Chepkova, A N; Sergeeva, O A; Haas, H L

    2005-06-01

    1. Taurine applied to mouse brain slices evokes a long-lasting enhancement (LLE) of corticostriatal synaptic transmission, LLE(TAU). 2. The occurrence of LLE(TAU) was significantly decreased in the presence of the specific antagonists at either D1 (SCH23390) or D2 (raclopride) dopamine (DA) receptors. 3. LLE(TAU) was prevented by scopolamine, a muscarinic antagonist, and significantly suppressed by the nicotinic antagonist mecamylamine. 4. Thus, dopaminergic and cholinergic mechanisms, in concert with the taurine transporter and glycine receptors, contribute critically to the induction of corticostriatal LLE(TAU).

  17. Loop 2 of Ophiophagus hannah toxin b binds with neuronal nicotinic acetylcholine receptors and enhances intracranial drug delivery.

    PubMed

    Zhan, Changyou; Yan, Zhiqiang; Xie, Cao; Lu, Weiyue

    2010-12-06

    Three-finger snake neurotoxins have been widely investigated for their high binding affinities with nicotinic acetylcholine receptors (nAChRs), which are widely expressed in the central nervous system including the blood-brain barrier and thus mediate intracranial drug delivery. The loop 2 segments of three-finger snake neurotoxins are considered as the binding domain with nAChRs, and thus, they may have the potential to enhance drug or drug delivery system intracranial transport. In the present work, binding of the synthetic peptides to the neuronal nAChRs was assessed by measuring their ability to inhibit the binding of (125)I-α-bungarotoxin to the receptor. The loop 2 segment of Ophiophagus hannah toxin b (KC2S) showed high binding affinity, and the competitive binding IC(50) value was 32.51 nM. Furthermore, the brain targeting efficiency of KC2S had been investigated in vitro and in vivo. The specific uptake by brain capillary endothelial cells (BCECs) demonstrated that KC2S could be endocytosized after binding with nAChRs. In vivo, the qualitative and quantitative biodistribution results of fluorescent dyes (DiR or coumarin-6) indicated that KC2S modified poly(ethylene glycol)-poly(lactic acid) micelles (KC2S-PEG-PLA micelles) could enhance intracranial drug delivery. Furthermore, intravenous treatment with paclitaxel-encapsulated KC2S-PEG-PLA micelles (KC2S-PEG-PLA-PTX micelles) afforded robust inhibition of intracranial glioblastoma. The median survival time of KC2S-PEG-PLA-PTX-micelle-treated mice (47.5 days) was significantly longer than that of mice treated by mPEG-PLA-PTX micelles (41.5 days), Taxol (38.5 days), or saline (34 days). Compared with the short peptide derived from rabies virus glycoprotein (RVG29) that has been previously reported as an excellent brain targeting ligand, KC2S has a similar binding affinity with neuronal nAChRs but fewer amino acid residues. Thus, we concluded that the loop 2 segment of Ophiophagus hannah toxin b could bind

  18. Gamma oscillations of spiking neural populations enhance signal discrimination.

    PubMed

    Masuda, Naoki; Doiron, Brent

    2007-11-01

    Selective attention is an important filter for complex environments where distractions compete with signals. Attention increases both the gamma-band power of cortical local field potentials and the spike-field coherence within the receptive field of an attended object. However, the mechanisms by which gamma-band activity enhances, if at all, the encoding of input signals are not well understood. We propose that gamma oscillations induce binomial-like spike-count statistics across noisy neural populations. Using simplified models of spiking neurons, we show how the discrimination of static signals based on the population spike-count response is improved with gamma induced binomial statistics. These results give an important mechanistic link between the neural correlates of attention and the discrimination tasks where attention is known to enhance performance. Further, they show how a rhythmicity of spike responses can enhance coding schemes that are not temporally sensitive.

  19. Cholinergic enhancement differentially modulates neural response to encoding during face identity and face location working memory tasks.

    PubMed

    Handjaras, Giacomo; Ricciardi, Emiliano; Szczepanik, Joanna; Pietrini, Pietro; Furey, Maura L

    2013-09-01

    Potentiation of cholinergic transmission influences stimulus processing by enhancing signal detection through suppression and/or filtering out of irrelevant information (bottom-up modulation) and with top-down task-oriented executive mechanisms based on the recruitment of prefrontal and parietal attentional systems. The cholinergic system also plays a critical role in working memory (WM) processes and preferentially modulates WM encoding, likely through stimulus-processing mechanisms. Previous research reported increased brain responses in visual extrastriate cortical regions during cholinergic enhancement in the encoding phase of WM, independently addressing object and spatial encoding. The current study used functional magnetic resonance imaging to determine the effects of cholinergic enhancement on encoding of key visual processing features. Subjects participated in two scanning sessions, one during an intravenous (i.v.) infusion of saline and the other during an infusion of the acetylcholinesterase inhibitor physostigmine. In each scan session, subjects alternated between a face identity recognition and a spatial location WM. Enhanced cholinergic function increased neural activity in the ventral stream during encoding of face identity and in the dorsal stream during encoding of face location. Conversely, a reduction in brain response was found for scrambled sensorimotor control images. The cholinergic effects on neural activity in the ventral stream during encoding of face identity were stronger than those observed in the dorsal stream during encoding of face location, likely as a consequence of the role of acetylcholine in establishing the inherently relevant nature of face identity. Despite the limited sample-size, the results suggest the stimulus-dependent role of cholinergic system in signal detection, as they show that cholinergic potentiation enhances neural activity in regions associated with early perceptual processing in a selective manner depending on

  20. The potential transformation of our species by neural enhancement.

    PubMed

    Zehr, E Paul

    2015-01-01

    Neural enhancement represents recovery of function that has been lost due to injury or disease pathology. Restoration of functional ability is the objective. For example, a neuroprosthetic to replace a forearm and hand lost to the ravages of war or industrial accident. However, the same basic constructs used for neural enhancement after injury could amplify abilities that are already in the natural normal range. That is, neural enhancement technologies to restore function and improve daily abilities for independent living could be used to improve so-called normal function to ultimate function. Approaching that functional level by use and integration of technology takes us toward the concept of a new species. This new subspecies--homo sapiens technologicus--is one that uses technology not just to assist but to change its own inherent biological function. The author uses examples from prosthetics and neuroprosthetics to address the issue of the limitations of constructs on the accepted range of human performance ability and aims to provide a cautionary view toward reflection on where our science may take the entire species.

  1. The Potential Transformation of Our Species by Neural Enhancement

    PubMed Central

    Zehr, E. Paul

    2015-01-01

    ABSTRACT. Neural enhancement represents recovery of function that has been lost due to injury or disease pathology. Restoration of functional ability is the objective. For example, a neuroprosthetic to replace a forearm and hand lost to the ravages of war or industrial accident. However, the same basic constructs used for neural enhancement after injury could amplify abilities that are already in the natural normal range. That is, neural enhancement technologies to restore function and improve daily abilities for independent living could be used to improve so-called normal function to ultimate function. Approaching that functional level by use and integration of technology takes us toward the concept of a new species. This new subspecies—homo sapiens technologicus—is one that uses technology not just to assist but to change its own inherent biological function. The author uses examples from prosthetics and neuroprosthetics to address the issue of the limitations of constructs on the accepted range of human performance ability and aims to provide a cautionary view toward reflection on where our science may take the entire species. PMID:25575224

  2. Enhanced memory performance thanks to neural network assortativity

    SciTech Connect

    Franciscis, S. de; Johnson, S.; Torres, J. J.

    2011-03-24

    The behaviour of many complex dynamical systems has been found to depend crucially on the structure of the underlying networks of interactions. An intriguing feature of empirical networks is their assortativity--i.e., the extent to which the degrees of neighbouring nodes are correlated. However, until very recently it was difficult to take this property into account analytically, most work being exclusively numerical. We get round this problem by considering ensembles of equally correlated graphs and apply this novel technique to the case of attractor neural networks. Assortativity turns out to be a key feature for memory performance in these systems - so much so that for sufficiently correlated topologies the critical temperature diverges. We predict that artificial and biological neural systems could significantly enhance their robustness to noise by developing positive correlations.

  3. Activation of nicotinic acetylcholine receptors enhances a slow calcium-dependent potassium conductance and reduces the firing of stratum oriens interneurons.

    PubMed

    Griguoli, Marilena; Scuri, Rossana; Ragozzino, Davide; Cherubini, Enrico

    2009-09-01

    A large variety of distinct locally connected GABAergic cells are present in the hippocampus. By releasing GABA into principal cells and interneurons, they exert a powerful control on neuronal excitability and are responsible for network oscillations crucial for information processing in the brain. Here, whole-cell patch clamp recordings in current and voltage clamp mode were used to study the functional role of nicotinic acetylcholine receptors (nAChRs) on the firing properties of stratum oriens interneurons in hippocampal slices from transgenic mice expressing enhanced green fluorescent protein in a subpopulation of GABAergic cells containing somatostatin (GIN mice). Unexpectedly, activation of nAChRs by nicotine or endogenously released acetylcholine strongly enhanced spike frequency adaptation. This effect was blocked by apamin, suggesting the involvement of small calcium-dependent potassium channels (SK channels). Nicotine-induced reduction in firing frequency was dependent on intracellular calcium rise through calcium-permeable nAChRs and voltage-dependent calcium channels activated by the depolarizing action of nicotine. Calcium imaging experiments directly showed that nicotine effects on firing rate were correlated with large increases in intracellular calcium. Furthermore, blocking ryanodine receptors with ryanodine or sarcoplasmic-endoplasmic reticulum calcium ATPase with thapsygargin or cyclopiazonic acid fully prevented the effects of nicotine, suggesting that mobilization of calcium from the internal stores contributed to the observed effects. By regulating cell firing, cholinergic signalling through nAChRs would be instrumental for fine-tuning the output of stratum oriens interneurons and correlated activity at the network level.

  4. Musical training enhances neural processing of binaural sounds.

    PubMed

    Parbery-Clark, Alexandra; Strait, Dana L; Hittner, Emily; Kraus, Nina

    2013-10-16

    While hearing in noise is a complex task, even in high levels of noise humans demonstrate remarkable hearing ability. Binaural hearing, which involves the integration and analysis of incoming sounds from both ears, is an important mechanism that promotes hearing in complex listening environments. Analyzing inter-ear differences helps differentiate between sound sources--a key mechanism that facilitates hearing in noise. Even when both ears receive the same input, known as diotic hearing, speech intelligibility in noise is improved. Although musicians have better speech-in-noise perception compared with non-musicians, we do not know to what extent binaural processing contributes to this advantage. Musicians often demonstrate enhanced neural responses to sound, however, which may undergird their speech-in-noise perceptual enhancements. Here, we recorded auditory brainstem responses in young adult musicians and non-musicians to a speech stimulus for which there was no musician advantage when presented monaurally. When presented diotically, musicians demonstrated faster neural timing and greater intertrial response consistency relative to non-musicians. Furthermore, musicians' enhancements to the diotically presented stimulus correlated with speech-in-noise perception. These data provide evidence for musical training's impact on biological processes and suggest binaural processing as a possible contributor to more proficient hearing in noise.

  5. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain.

    PubMed

    Ryu, Sun; Lee, Seung-Hoon; Kim, Seung U; Yoon, Byung-Woo

    2016-02-01

    Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2'-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen NeuN, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2'-deoxyuridine-positive ⁄ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke.

  6. Neural activity associated with enhanced facial attractiveness by cosmetics use.

    PubMed

    Ueno, Aya; Ito, Ayahito; Kawasaki, Iori; Kawachi, Yousuke; Yoshida, Kazuki; Murakami, Yui; Sakai, Shinya; Iijima, Toshio; Matsue, Yoshihiko; Fujii, Toshikatsu

    2014-04-30

    Previous psychological studies have shown that make-up enhances facial attractiveness. Although neuroimaging evidence indicates that the orbitofrontal cortex (OFC) shows greater activity for faces of attractive people than for those of unattractive people, there is no direct evidence that the OFC also shows greater activity for the face of an individual wearing make-up than for the same face without make-up. Using functional magnetic resonance imaging (fMRI), we investigated neural activity while subjects viewed 144 photographs of the same faces with and without make-up (48 with make-up, 48 without make-up, and 48 scrambled photographs) and assigned these faces an attractiveness rating. The behavioral data showed that the faces with make-up were rated as more attractive than those without make-up. The imaging data revealed that the left OFC and the right hippocampus showed greater activity for faces with make-up than for those without make-up. Furthermore, the activities of the right anterior cingulate cortex, left hippocampus, and left OFC increased with increasing facial attractiveness resulting from cosmetics use. These results provide direct evidence of the neural underpinnings of cosmetically enhanced facial attractiveness.

  7. A role for protein kinase A and protein kinase M zeta in muscarinic acetylcholine receptor-initiated persistent synaptic enhancement in rat hippocampus in vivo.

    PubMed

    Hayes, J; Li, S; Anwyl, R; Rowan, M J

    2008-01-24

    Antagonists at presynaptic muscarinic autoreceptors increase endogenous acetylcholine (ACh) release and enhance cognition but little is known regarding their actions on plasticity at glutamatergic synapses. Here the mechanisms of the persistent enhancement of hippocampal excitatory transmission induced by the M2/M4 muscarinic ACh receptor antagonist methoctramine were investigated in vivo. The persistent facilitatory effect of i.c.v. methoctramine in the CA1 region of urethane-anesthetized rats was mimicked by gallamine, an M2 receptor antagonist, supporting a role for this receptor subtype. Neither the N-methyl-D-aspartate (NMDA) receptor antagonists D-(-)-2-amino phosphonopentanoic acid (d-AP5) and memantine, nor the metabotropic glutamate receptor subtype 1a antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) significantly affected the methoctramine-induced persistent synaptic enhancement, indicating a lack of requirement for these glutamate receptors. The selective kinase inhibitors Rp-adenosine-3', 5'-cyclic monophosphorothioate (Rp-cAMPS) and the myrostylated pseudosubstrate peptide, Myr-Ser-Ile-Tyr-Arg-Arg-Gly-Ala-Arg-Arg-Trp-Arg-Lys-Leu-OH (ZIP), were used to investigate the roles of protein kinase A (PKA) and the atypical protein kinase C, protein kinase Mzeta (PKM zeta), respectively. Remarkably, pretreatment with either agent prevented the induction of the persistent synaptic enhancement by methoctramine and post-methoctramine treatment with Rp-cAMPS transiently reversed the enhancement. These findings are strong evidence that antagonism of M2 muscarinic ACh receptors in vivo induces an NMDA receptor-independent persistent synaptic enhancement that requires activation of both PKA and PKM zeta.

  8. Neural regulation of MRNA for the alpha-subunit of acetylcholine receptors: Role of neuromuscular transmission. (Reannouncement with new availability information)

    SciTech Connect

    Lipsky, N.G.; Drachman, D.B.; Pestronk, A.; Shih, P.J.

    1989-12-31

    Levels of mRNA for acetylcholine receptor (AChR) subunits are relatively low in innervated skeletal muscles. Following denervation they rise rapidly, leading to increased AChR synthesis. The mechanism by which motor nerves normally regulate these mRNA levels is not yet known. In order to determine the possible role of synaptic transmission in this process, the authors have compared the effect of blockade of cholinergic ACh transmission with that of surgical denervation. Blockade of quantal ACh transmission was produced by injection of type A botulinum toxin into the soleus muscles of rats.

  9. Hypocretin (orexin) receptor subtypes differentially enhance acetylcholine release and activate g protein subtypes in rat pontine reticular formation.

    PubMed

    Bernard, René; Lydic, Ralph; Baghdoyan, Helen A

    2006-04-01

    The hypothalamic peptides hypocretin-1 (orexin A) and -2 (orexin B) promote wakefulness by mechanisms that are not well understood. Defects in hypocretinergic neurotransmission underlie the human sleep disorder narcolepsy. Hypocretins alter cell excitability via two receptor subtypes, hypocretin receptor subtype 1 (hcrt-r1) and hypocretin receptor subtype 2 (hcrt-r2). This study aimed to identify G protein subtypes activated by hypocretin in rat pontine reticular nucleus oral part (PnO) and the hypocretin receptor subtype modulating acetylcholine (ACh) release in the PnO. G protein activation was quantified using in vitro [(35)S]guanylyl-5'-O-(gamma-thio)triphosphate autoradiography. ACh release was measured using in vivo microdialysis and high-performance liquid chromatography. Hypocretin-1-stimulated G protein activation was significantly decreased by pertussis toxin, demonstrating that some hypocretin receptors in rat PnO activate inhibitory G proteins. Hypocretin-1-stimulated ACh release was not blocked by pertussis toxin, supporting the conclusion that the hypocretin receptors modulating ACh release in rat PnO activate stimulatory G proteins. Hypocretin-1 and -2 each caused a concentration-dependent increase in ACh release with similar potencies, indicating that hcrt-r2 modulates ACh release in PnO. Hypocretin-1 caused a significantly greater increase in ACh release than hypocretin-2, suggesting a role for hcrt-r1 in the modulation of PnO ACh release. Taken together, these data provide the first evidence that hypocretin receptors in rat PnO signal via inhibitory and stimulatory G proteins and that ACh release in rat PnO is modulated by hcrt-r2 and hcrt-r1. One mechanism by which hypocretin promotes arousal may be to increase ACh release in the pontine reticular formation.

  10. Thujone inhibits the function of α7-nicotinic acetylcholine receptors and impairs nicotine-induced memory enhancement in one-trial passive avoidance paradigm.

    PubMed

    Sultan, Ahmed; Yang, Keun-Hang Susan; Isaev, Dmitro; Nebrisi, Eslam El; Syed, Nurulain; Khan, Nadia; Howarth, Christopher F; Sadek, Bassem; Oz, Murat

    2017-04-07

    Effects of thujone, a major ingredient of absinthe, wormwood oil and some herbal medicines, were tested on the function of α7 subunit of the human nicotinic acetylcholine (α7 nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Thujone reversibly inhibited ACh (100μM)-induced currents with an IC50 value of 24.7μM. The effect of thujone was not dependent on the membrane potential and did not involve Ca(2+)-dependent Cl(-) channels expressed endogenously in oocytes. Inhibition by thujone was not reversed by increasing ACh concentrations. Moreover, specific binding of [(125)I] α-bungarotoxin was not altered by thujone. Further experiments in SH-EP1 cells expressing human α7 nACh receptor indicated that thujone suppressed choline induced Ca(2+) transients in a concentration-dependent manner. In rat hippocampal CA3-dentate gyrus synapses, nicotine-induced enhancement of long-term potentiation was also inhibited by thujone. Furthermore, the results observed in in-vivo one-trial passive avoidance paradigm show that thujone (1.25mg/kg, i.p.) significantly impaired nicotine-induced enhancement of learning and memory in Wistar rats. Collectively, our results indicate that thujone inhibits the function of the α7-nACh receptor and impairs cellular and behavioral correlates of cholinergic modulation of learning and memory.

  11. Enhanced expression of FNDC5 in human embryonic stem cell-derived neural cells along with relevant embryonic neural tissues.

    PubMed

    Ghahrizjani, Fatemeh Ahmadi; Ghaedi, Kamran; Salamian, Ahmad; Tanhaei, Somayeh; Nejati, Alireza Shoaraye; Salehi, Hossein; Nabiuni, Mohammad; Baharvand, Hossein; Nasr-Esfahani, Mohammad Hossein

    2015-02-25

    Availability of human embryonic stem cells (hESCs) has enhanced the capability of basic and clinical research in the context of human neural differentiation. Derivation of neural progenitor (NP) cells from hESCs facilitates the process of human embryonic development through the generation of neuronal subtypes. We have recently indicated that fibronectin type III domain containing 5 protein (FNDC5) expression is required for appropriate neural differentiation of mouse embryonic stem cells (mESCs). Bioinformatics analyses have shown the presence of three isoforms for human FNDC5 mRNA. To differentiate which isoform of FNDC5 is involved in the process of human neural differentiation, we have used hESCs as an in vitro model for neural differentiation by retinoic acid (RA) induction. The hESC line, Royan H5, was differentiated into a neural lineage in defined adherent culture treated by RA and basic fibroblast growth factor (bFGF). We collected all cell types that included hESCs, rosette structures, and neural cells in an attempt to assess the expression of FNDC5 isoforms. There was a contiguous increase in all three FNDC5 isoforms during the neural differentiation process. Furthermore, the highest level of expression of the isoforms was significantly observed in neural cells compared to hESCs and the rosette structures known as neural precursor cells (NPCs). High expression levels of FNDC5 in human fetal brain and spinal cord tissues have suggested the involvement of this gene in neural tube development. Additional research is necessary to determine the major function of FDNC5 in this process.

  12. Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice.

    PubMed

    Wakai, Takuma; Narasimhan, Purnima; Sakata, Hiroyuki; Wang, Eric; Yoshioka, Hideyuki; Kinouchi, Hiroyuki; Chan, Pak H

    2016-12-01

    Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.

  13. Attention enhances contrast appearance via increased input baseline of neural responses

    PubMed Central

    Cutrone, Elizabeth K.; Heeger, David J.; Carrasco, Marisa

    2014-01-01

    Covert spatial attention increases the perceived contrast of stimuli at attended locations, presumably via enhancement of visual neural responses. However, the relation between perceived contrast and the underlying neural responses has not been characterized. In this study, we systematically varied stimulus contrast, using a two-alternative, forced-choice comparison task to probe the effect of attention on appearance across the contrast range. We modeled performance in the task as a function of underlying neural contrast-response functions. Fitting this model to the observed data revealed that an increased input baseline in the neural responses accounted for the enhancement of apparent contrast with spatial attention. PMID:25549920

  14. Conducting polymers with immobilised fibrillar collagen for enhanced neural interfacing.

    PubMed

    Liu, Xiao; Yue, Zhilian; Higgins, Michael J; Wallace, Gordon G

    2011-10-01

    Conducting polymers with pendant functionality are advantageous in various bionic and organic bioelectronic applications, as they allow facile incorporation of bio-regulative cues to provide bio-mimicry and conductive environments for cell growth, differentiation and function. In this work, polypyrrole substrates doped with chondroitin sulfate (CS), an extracellular matrix molecule bearing carboxylic acid moieties, were electrochemically synthesized and conjugated with type I collagen. During the coupling process, the conjugated collagen formed a 3-dimensional fibrillar matrix in situ at the conducting polymer interface, as evidenced by atomic force microscopy (AFM) and fluorescence microscopy under aqueous physiological conditions. Cyclic voltammetry (CV) and impedance measurement confirmed no significant reduction in the electroactivity of the fibrillar collagen-modified conducting polymer substrates. Rat pheochromocytoma (nerve) cells showed increased differentiation and neurite outgrowth on the fibrillar collagen, which was further enhanced through electrical stimulation of the underlying conducting polymer substrate. Our study demonstrates that the direct coupling of ECM components such as collagen, followed by their further self-assembly into 3-dimensional matrices, has the potential to improve the neural-electrode interface of implant electrodes by encouraging nerve cell attachment and differentiation.

  15. MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice.

    PubMed

    Murai, S; Saito, H; Abe, E; Masuda, Y; Odashima, J; Itoh, T

    1994-01-01

    The effects of acute and chronic administration of MKC-231, a new choline uptake enhancer, and two other nootropic agents, linopiridine (Dup 996) and tetrahydroaminoacridine (THA) on working memory deficits and decreased hippocampal acetylcholine (ACh) content were studied in a delayed non-matching to sample task, using a T-maze, in ethylcholine aziridinium ion (AF64A)-treated mice. Treatment with AF64A (3.5 nmol, i.c.v.) produced memory deficits and decreased hippocampal ACh content. In acute behavioral experiments, MKC-231 and THA had no significant effect on AF64A-induced memory deficits at any doses tested (0.3, 1.0 and 3.0 mg/kg), whereas Dup 996, at a dose of 1.0 mg/kg, significantly improved memory deficits. In chronic experiments, MKC-231 improved memory deficit at all doses tested (0.3, 1.0, or 3.0 mg/kg p.o., once daily for 11 days) and Dup 996 did so only at a dose of 3.0 mg/kg, whereas THA did not improve memory deficit at any doses tested. In acute neurochemical experiments, MKC-231 and THA did not reverse the AF64A-induced hippocampal ACh depletion. Dup 996, however, further decreased hippocampal ACh content compared to that in the AF64A-treated group. In chronic experiments, MKC-231 significantly reversed hippocampal ACh depletion at doses of 0.3 and 1.0 mg/kg, whereas neither Dup 996 nor THA reversed hippocampal ACh depletion at any doses tested. These results indicate that MKC-231 improved the AF64A-induced working memory deficit and hippocampal ACh depletion, probably by recovering reduced high-affinity choline uptake and ACh release.

  16. Low-dimensional recurrent neural network-based Kalman filter for speech enhancement.

    PubMed

    Xia, Youshen; Wang, Jun

    2015-07-01

    This paper proposes a new recurrent neural network-based Kalman filter for speech enhancement, based on a noise-constrained least squares estimate. The parameters of speech signal modeled as autoregressive process are first estimated by using the proposed recurrent neural network and the speech signal is then recovered from Kalman filtering. The proposed recurrent neural network is globally asymptomatically stable to the noise-constrained estimate. Because the noise-constrained estimate has a robust performance against non-Gaussian noise, the proposed recurrent neural network-based speech enhancement algorithm can minimize the estimation error of Kalman filter parameters in non-Gaussian noise. Furthermore, having a low-dimensional model feature, the proposed neural network-based speech enhancement algorithm has a much faster speed than two existing recurrent neural networks-based speech enhancement algorithms. Simulation results show that the proposed recurrent neural network-based speech enhancement algorithm can produce a good performance with fast computation and noise reduction.

  17. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): blocking 5HT3 receptors enhances release of serotonin, norepinephrine, and acetylcholine.

    PubMed

    Stahl, Stephen M

    2015-10-01

    Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. 5HT3 receptor antagonism is one of these actions, and this leads to increased release of norepinephrine (NE), acetylcholine (ACh), and serotonin (5HT) within various brain circuits.

  18. YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

    SciTech Connect

    Han, Dasol; Byun, Sung-Hyun; Park, Soojeong; Kim, Juwan; Kim, Inhee; Ha, Soobong; Kwon, Mookwang; Yoon, Keejung

    2015-02-27

    Mammalian brain development is regulated by multiple signaling pathways controlling cell proliferation, migration and differentiation. Here we show that YAP/TAZ enhance embryonic neural stem cell characteristics in a cell autonomous fashion using diverse experimental approaches. Introduction of retroviral vectors expressing YAP or TAZ into the mouse embryonic brain induced cell localization in the ventricular zone (VZ), which is the embryonic neural stem cell niche. This change in cell distribution in the cortical layer is due to the increased stemness of infected cells; YAP-expressing cells were colabeled with Sox2, a neural stem cell marker, and YAP/TAZ increased the frequency and size of neurospheres, indicating enhanced self-renewal- and proliferative ability of neural stem cells. These effects appear to be TEA domain family transcription factor (Tead)–dependent; a Tead binding-defective YAP mutant lost the ability to promote neural stem cell characteristics. Consistently, in utero gene transfer of a constitutively active form of Tead2 (Tead2-VP16) recapitulated all the features of YAP/TAZ overexpression, and dominant negative Tead2-EnR resulted in marked cell exit from the VZ toward outer cortical layers. Taken together, these results indicate that the Tead-dependent YAP/TAZ signaling pathway plays important roles in neural stem cell maintenance by enhancing stemness of neural stem cells during mammalian brain development. - Highlights: • Roles of YAP and Tead in vivo during mammalian brain development are clarified. • Expression of YAP promotes embryonic neural stem cell characteristics in vivo in a cell autonomous fashion. • Enhancement of neural stem cell characteristics by YAP depends on Tead. • Transcriptionally active form of Tead alone can recapitulate the effects of YAP. • Transcriptionally repressive form of Tead severely reduces stem cell characteristics.

  19. Novel flexible Parylene neural probe with 3D sheath structure for enhancing tissue integration.

    PubMed

    Kuo, Jonathan T W; Kim, Brian J; Hara, Seth A; Lee, Curtis D; Gutierrez, Christian A; Hoang, Tuan Q; Meng, Ellis

    2013-02-21

    A Parylene C neural probe with a three dimensional sheath structure was designed, fabricated, and characterized. Multiple platinum (Pt) electrodes for recording neural signals were fabricated on both inner and outer surfaces of the sheath structure. Thermoforming of Parylene was used to create the three dimensional sheath structures from flat surface micromachined microchannels using solid microwires as molds. Benchtop electrochemical characterization was performed on the thin film Pt electrodes using cyclic voltammetry and electrochemical impedance spectroscopy and showed that electrodes possessed low impedances suitable for neuronal recordings. A procedure for implantation of the neural probe was developed and successfully demonstrated in vitro into an agarose brain tissue model. The electrode-lined sheath will be decorated with eluting neurotrophic factors to promote in vivo neural tissue ingrowth post-implantation. These features will enhance tissue integration and improve recording quality towards realizing reliable chronic neural interfaces.

  20. Neural Networks Based Approach to Enhance Space Hardware Reliability

    NASA Technical Reports Server (NTRS)

    Zebulum, Ricardo S.; Thakoor, Anilkumar; Lu, Thomas; Franco, Lauro; Lin, Tsung Han; McClure, S. S.

    2011-01-01

    This paper demonstrates the use of Neural Networks as a device modeling tool to increase the reliability analysis accuracy of circuits targeted for space applications. The paper tackles a number of case studies of relevance to the design of Flight hardware. The results show that the proposed technique generates more accurate models than the ones regularly used to model circuits.

  1. Heterogeneity of neural progenitor cells revealed by enhancers in the nestin gene

    PubMed Central

    Yaworsky, Paul J.; Kappen, Claudia

    2014-01-01

    Using transgenic embryos, we have identified two distinct CNS progenitor cell-specific enhancers, each requiring the cooperation of at least two independent regulatory sites, within the second intron of the rat nestin gene. One enhancer is active throughout the developing CNS while the other is specifically active in the ventral midbrain. These experiments demonstrate that neural progenitor cells in the midbrain constitute a unique subpopulation based upon their ability to activate the midbrain regulatory elements. Our finding of differential enhancer activity from a gene encoding a structural protein reveals a previously unrecognized diversity in neural progenitor cell populations. PMID:9917366

  2. Enhanced neural cell adhesion and neurite outgrowth on graphene-based biomimetic substrates.

    PubMed

    Hong, Suck Won; Lee, Jong Ho; Kang, Seok Hee; Hwang, Eun Young; Hwang, Yu-Shik; Lee, Mi Hee; Han, Dong-Wook; Park, Jong-Chul

    2014-01-01

    Neural cell adhesion and neurite outgrowth were examined on graphene-based biomimetic substrates. The biocompatibility of carbon nanomaterials such as graphene and carbon nanotubes (CNTs), that is, single-walled and multiwalled CNTs, against pheochromocytoma-derived PC-12 neural cells was also evaluated by quantifying metabolic activity (with WST-8 assay), intracellular oxidative stress (with ROS assay), and membrane integrity (with LDH assay). Graphene films were grown by using chemical vapor deposition and were then coated onto glass coverslips by using the scooping method. Graphene sheets were patterned on SiO2/Si substrates by using photolithography and were then covered with serum for a neural cell culture. Both types of CNTs induced significant dose-dependent decreases in the viability of PC-12 cells, whereas graphene exerted adverse effects on the neural cells just at over 62.5 ppm. This result implies that graphene and CNTs, even though they were the same carbon-based nanomaterials, show differential influences on neural cells. Furthermore, graphene-coated or graphene-patterned substrates were shown to substantially enhance the adhesion and neurite outgrowth of PC-12 cells. These results suggest that graphene-based substrates as biomimetic cues have good biocompatibility as well as a unique surface property that can enhance the neural cells, which would open up enormous opportunities in neural regeneration and nanomedicine.

  3. Inhibition of GSK-3β enhances neural differentiation in unrestricted somatic stem cells.

    PubMed

    Dastjerdi, Fatemeh Vahid; Zeynali, Bahman; Tafreshi, Azita Parvaneh; Shahraz, Anahita; Chavoshi, Mahin Sadat; Najafabadi, Irandokht Khaki; Vardanjani, Marzieh Mowlavi; Atashi, Amir; Soleimani, Masoud

    2012-11-01

    GSK-3β is a key molecule in several signalling pathways, including the Wnt/β-catenin signalling pathway. There is increasing evidence suggesting Wnt/β-catenin signalling is involved in the neural differentiation of embryonic, somatic and neural stem cells. However, a large body of evidence indicates that this pathway maintains stem cells in a proliferative state. To address this controversy, we have investigated whether the Wnt/β-catenin pathway is present and involved in the neural differentiation of newly introduced USSCs (unrestricted somatic stem cells). Our results indicate that the components of Wnt/β-catenin signalling are present in undifferentiated USSCs. We also show that the treatment of neurally induced USSCs with BIO (6-bromoindirubin-3'-oxime), a specific GSK-3β inhibitor and Wnt activator, for 5 and 10 days results in increased expression of a general neuronal marker (β-tubulin III). Moreover, the expression of pGSK-3β and stabilized β-catenin increased by BIO in neurally induced USSCs, indicates that the Wnt pathway is activated and functional in these cells. Thus, inhibition of GSK-3β in USSCs enhances their neural differentiation, which suggests a positive role of the Wnt/β-catenin signalling pathway towards neural fate.

  4. Diminished neural responses predict enhanced intrinsic motivation and sensitivity to external incentive.

    PubMed

    Marsden, Karen E; Ma, Wei Ji; Deci, Edward L; Ryan, Richard M; Chiu, Pearl H

    2015-06-01

    The duration and quality of human performance depend on both intrinsic motivation and external incentives. However, little is known about the neuroscientific basis of this interplay between internal and external motivators. Here, we used functional magnetic resonance imaging to examine the neural substrates of intrinsic motivation, operationalized as the free-choice time spent on a task when this was not required, and tested the neural and behavioral effects of external reward on intrinsic motivation. We found that increased duration of free-choice time was predicted by generally diminished neural responses in regions associated with cognitive and affective regulation. By comparison, the possibility of additional reward improved task accuracy, and specifically increased neural and behavioral responses following errors. Those individuals with the smallest neural responses associated with intrinsic motivation exhibited the greatest error-related neural enhancement under the external contingency of possible reward. Together, these data suggest that human performance is guided by a "tonic" and "phasic" relationship between the neural substrates of intrinsic motivation (tonic) and the impact of external incentives (phasic).

  5. Neuronal Nicotinic Acetylcholine Receptors and Epilepsy

    PubMed Central

    Bertrand, Daniel

    2002-01-01

    The identification of a genetically transmissible form of epilepsy that is associated with a mutation in CHRNA4, the gene that encodes the α4 subunit of the high-affinity nicotinic acetylcholine receptor, was the first demonstration that an alteration in a ligand-gated ion channel can cause seizures. Since then, nine mutations have been found, and analysis of their physiologic properties has revealed that all of them enhance receptor function. PMID:15309115

  6. Integrated Eye Tracking and Neural Monitoring for Enhanced Assessment of Mild TBI

    DTIC Science & Technology

    2016-04-01

    DATES COVERED 8 Mar 2015 - 7 Mar 2016 4. TITLE AND SUBTITLE Integrated Eye Tracking and Neural Monitoring for Enhanced Assessment of Mild TBI 5a...SUPPLEMENTARY NOTES 14. ABSTRACT During the Year 3 POP (08 MAR 2015 – 07 MAR 2016), data collection for the pilot study (n=30) was completed. HRPO approval

  7. Musical Training during Early Childhood Enhances the Neural Encoding of Speech in Noise

    ERIC Educational Resources Information Center

    Strait, Dana L.; Parbery-Clark, Alexandra; Hittner, Emily; Kraus, Nina

    2012-01-01

    For children, learning often occurs in the presence of background noise. As such, there is growing desire to improve a child's access to a target signal in noise. Given adult musicians' perceptual and neural speech-in-noise enhancements, we asked whether similar effects are present in musically-trained children. We assessed the perception and…

  8. Axonal alignment and enhanced neuronal differentiation of neural stem cells on graphene-nanoparticle hybrid structures.

    PubMed

    Solanki, Aniruddh; Chueng, Sy-Tsong Dean; Yin, Perry T; Kappera, Rajesh; Chhowalla, Manish; Lee, Ki-Bum

    2013-10-11

    Human neural stem cells (hNSCs) cultured on graphene-nanoparticle hybrid structures show a unique behavior wherein the axons from the differentiating hNSCs show enhanced growth and alignment. We show that the axonal alignment is primarily due to the presence of graphene and the underlying nanoparticle monolayer causes enhanced neuronal differentiation of the hNSCs, thus having great implications of these hybrid-nanostructures for neuro-regenerative medicine.

  9. Comparison enhances size sensitivity: neural correlates of outcome magnitude processing.

    PubMed

    Luo, Qiuling; Qu, Chen

    2013-01-01

    Magnitude is a critical feature of outcomes. In the present study, two event-related potential (ERP) experiments were implemented to explore the neural substrates of outcome magnitude processing. In Experiment 1, we used an adapted gambling paradigm where physical area symbols were set to represent potential relative outcome magnitudes in order to exclude the possibility that the participants would be ignorant of the magnitudes. The context was manipulated as total monetary amount: ¥4 and ¥40. In these two contexts, the relative outcome magnitudes were ¥1 versus ¥3, and ¥10 versus ¥30, respectively. Experiment 2, which provided two area symbols with similar outcome magnitudes, was conducted to exclude the possible interpretation of physical area symbol for magnitude effect of feedback-related negativity (FRN) in Experiment 1. Our results showed that FRN responded to the relative outcome magnitude but not to the context or area symbol, with larger amplitudes for relatively small outcomes. A larger FRN effect (the difference between losses and wins) was found for relatively large outcomes than relatively small outcomes. Relatively large outcomes evoked greater positive ERP waves (P300) than relatively small outcomes. Furthermore, relatively large outcomes in a high amount context elicited a larger P300 than those in a low amount context. The current study indicated that FRN is sensitive to variations in magnitude. Moreover, relative magnitude was integrated in both the early and late stages of feedback processing, while the monetary amount context was processed only in the late stage of feedback processing.

  10. Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells

    PubMed Central

    Zhang, Lei; Laaniste, Liisi; Jiang, Yiwen; Alafuzoff, Irina; Uhrbom, Lene; Dimberg, Anna

    2016-01-01

    Pleiotrophin (PTN) augments tumor growth by increasing proliferation of tumor cells and promoting vascular abnormalization, but its role in early gliomagenesis has not been evaluated. Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development. To elucidate the role of PTN in tumor initiation we employed the RCAS/tv-a model that allows glioma induction by RCAS-virus mediated expression of oncogenes in neural progenitor cells. Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF)B-induced gliomagenesis. PTN co-treatment augmented PDGFB-induced Akt activation in neural progenitor cells in vitro, and enhanced neural sphere size associated with increased proliferation. Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells. PMID:27806344

  11. Pleiotrophin enhances PDGFB-induced gliomagenesis through increased proliferation of neural progenitor cells.

    PubMed

    Zhang, Lei; Laaniste, Liisi; Jiang, Yiwen; Alafuzoff, Irina; Uhrbom, Lene; Dimberg, Anna

    2016-12-06

    Pleiotrophin (PTN) augments tumor growth by increasing proliferation of tumor cells and promoting vascular abnormalization, but its role in early gliomagenesis has not been evaluated. Through analysis of publically available datasets, we demonstrate that increased PTN mRNA expression is associated with amplification of chromosome 7, identified as one of the earliest steps in glioblastoma development. To elucidate the role of PTN in tumor initiation we employed the RCAS/tv-a model that allows glioma induction by RCAS-virus mediated expression of oncogenes in neural progenitor cells. Intracranial injection of RCAS-PTN did not induce glioma formation when administrated alone, but significantly enhanced RCAS-platelet derived growth factor (PDGF)B-induced gliomagenesis. PTN co-treatment augmented PDGFB-induced Akt activation in neural progenitor cells in vitro, and enhanced neural sphere size associated with increased proliferation. Our data indicates that PTN expression is associated with chromosome 7 gain, and that PTN enhances PDGFB-induced gliomagenesis by stimulating proliferation of neural progenitor cells.

  12. Neural correlates of context-dependent perceptual enhancement in the inferior colliculus

    PubMed Central

    Nelson, Paul C.; Young, Eric D.

    2010-01-01

    In certain situations, preceding auditory stimulation can actually result in heightened sensitivity to subsequent sounds. Many of these phenomena appear to be generated in the brain as reflections of central computations. One example is the robust perceptual enhancement (or “pop out”) of a probe signal within a broad-band sound whose onset time is delayed relative to the remainder of a mixture of tones. Here we show that the neural representation of such stimuli undergoes a dramatic transformation as the pathway is ascended, from an implicit and distributed peripheral code to explicitly facilitated single-neuron responses at the level of the inferior colliculus (IC) of two awake and passively listening female marmoset monkeys (callithrix jacchus). Many key features of the IC responses directly parallel psychophysical measures of enhancement, including the dependence on the width of a spectral notch surrounding the probe, the overall level of the complex, and the duration of the preceding sound (referred to as the conditioner). Neural detection thresholds for the probe with and without the conditioner were also in qualitative agreement with analogous psychoacoustic measures. Response characteristics during the conditioners were predictive of the enhancement or suppression of the ensuing probe response: build-up responses were associated with enhancement while adapting conditioner responses were more likely to result in suppression. These data can be largely explained by a phenomenological computational model using dynamic (adapting) inhibition as a necessary ingredient in the generation of neural enhancement. PMID:20463220

  13. Morphogenetic roles of acetylcholine.

    PubMed Central

    Lauder, J M; Schambra, U B

    1999-01-01

    In the adult nervous system, neurotransmitters mediate cellular communication within neuronal circuits. In developing tissues and primitive organisms, neurotransmitters subserve growth regulatory and morphogenetic functions. Accumulated evidence suggests that acetylcholine, (ACh), released from growing axons, regulates growth, differentiation, and plasticity of developing central nervous system neurons. In addition to intrinsic cholinergic neurons, the cerebral cortex and hippocampus receive extensive innervation from cholinergic neurons in the basal forebrain, beginning prenatally and continuing throughout the period of active growth and synaptogenesis. Acute exposure to ethanol in early gestation (which prevents formation of basal forebrain cholinergic neurons) or neonatal lesioning of basal forebrain cholinergic neurons, significantly compromises cortical development and produces persistent impairment of cognitive functions. Neonatal visual deprivation alters developmental expression of muscarinic acetylcholine receptors (mAChR) in visual cortex, whereas local infusion of mAChR antagonists impairs plasticity of visual cortical neurons. These findings raise the possibility that exposure to environmental neurotoxins that affect cholinergic systems may seriously compromise brain development and have long-lasting morphologic, neurochemical, and functional consequences. PMID:10229708

  14. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain.

    PubMed

    Ben-Shaanan, T L; Ben-Hur, T; Yanai, J

    2008-02-01

    Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg(-1) heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P<0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P<0.006) and reversed the behavioral defects (P<0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

  15. Enhancement of neural and thermal vasoconstriction by prostaglandin B1.

    PubMed

    Engelbrecht, J A; Greenberg, S; Wilson, W R

    1975-03-01

    The vascular effects of prostaglandin B1 (PGB1) were studied during constant-flow perfusion of the canine hindpaw. The effects of PGB1 (50-200 ng/kg/min ia) on systemic and hindpaw perfusion pressures and on responses to local cooling (4 degrees C for 90 sec) and local heating (45 degrees C for 60 sec) were measured in 15 dogs. PGB1 (50-100 ng/kg/min) decreased perfusion pressure without any significant effect on systemic arterial pressure. Higher concentrations of PGB1 (200 ng/kg/min) elevated perfusion pressure to control values. The pressor responses to local cooling were increased from 11 to 32 mmHg while the dilator responses to local heating and nitroglycerin were reduced during infusions of PGB1. PGB1 also enhanced the pressor responses to norepinephrine or tyramine. These findings support the conclusions that (1) low concentrations of prostaglandin B1 enhance neurotransmitter release with minimal effects on vascular smooth muscle cells and (2) these effects are not secondary to increased perfusion pressures or vascular wall stresses since infusions of PGB1 resulted in vasodilation.

  16. Identification of a retinoic acid-responsive neural enhancer in the Ciona intestinalis Hox1 gene.

    PubMed

    Kanda, Miyuki; Ikeda, Taku; Fujiwara, Shigeki

    2013-02-01

    The Hox1 gene in the urochordate ascidian Ciona intestinalis (Ci-Hox1) is expressed in the nerve cord and epidermis. We identified a nerve cord enhancer in the second intron of Ci-Hox1, and demonstrated that retinoic acid (RA) plays a major role in activating this enhancer. The enhancer contained a putative retinoic acid-response element (RARE). Mutation of the RARE in the Ci-Hox1 nerve cord enhancer only partially abolished the enhancer activity. Genes encoding RA synthase and the RA receptor were knocked down using specific antisense morpholino oligos (MOs), and injection of embryos with these MOs resulted in the complete disappearance of epidermal expression of Ci-Hox1 and reduction of neural expression. However, nerve cord expression was not completely repressed. These results suggest that the nerve cord enhancer is activated by two partially redundant pathways; one RA-dependent and one RA-independent.

  17. Canonical Wnt signaling transiently stimulates proliferation and enhances neurogenesis in neonatal neural progenitor cultures

    SciTech Connect

    Hirsch, Cordula; Campano, Louise M.; Woehrle, Simon; Hecht, Andreas . E-mail: andreas.hecht@mol-med.uni-freiburg.de

    2007-02-01

    Canonical Wnt signaling triggers the formation of heterodimeric transcription factor complexes consisting of {beta}-catenin and T cell factors, and thereby controls the execution of specific genetic programs. During the expansion and neurogenic phases of embryonic neural development canonical Wnt signaling initially controls proliferation of neural progenitor cells, and later neuronal differentiation. Whether Wnt growth factors affect neural progenitor cells postnatally is not known. Therefore, we have analyzed the impact of Wnt signaling on neural progenitors isolated from cerebral cortices of newborn mice. Expression profiling of pathway components revealed that these cells are fully equipped to respond to Wnt signals. However, Wnt pathway activation affected only a subset of neonatal progenitors and elicited a limited increase in proliferation and neuronal differentiation in distinct subsets of cells. Moreover, Wnt pathway activation only transiently stimulated S-phase entry but did not support long-term proliferation of progenitor cultures. The dampened nature of the Wnt response correlates with the predominant expression of inhibitory pathway components and the rapid actuation of negative feedback mechanisms. Interestingly, in differentiating cell cultures activation of canonical Wnt signaling reduced Hes1 and Hes5 expression suggesting that during postnatal neural development, Wnt/{beta}-catenin signaling enhances neurogenesis from progenitor cells by interfering with Notch pathway activity.

  18. Overexpression of human CD38/ADP-ribosyl cyclase enhances acetylcholine-induced Ca2+ signalling in rodent NG108-15 neuroblastoma cells.

    PubMed

    Higashida, Haruhiro; Bowden, Sarah E H; Yokoyama, Shigeru; Salmina, Alla; Hashii, Minako; Hoshi, Naoto; Zhang, Jia-Sheng; Knijnik, Rimma; Noda, Mami; Zhong, Zen-Guo; Jin, Duo; Higashida, Kazuhiro; Takeda, Hisashi; Akita, Tenpei; Kuba, Kenji; Yamagishi, Sayaka; Shimizu, Noriaki; Takasawa, Shin; Okamoto, Hiroshi; Robbins, Jon

    2007-03-01

    The role of cyclic ADP-ribose (cADPR) and its synthetic enzyme, CD38, as a downstream signal of muscarinic acetylcholine receptors (mAChRs) was examined in neuroblastoma cells expressing M1 mAChRs (NGM1). NGM1 cells were further transformed with both wild-type and mutant (C119K/C201E) human CD38. The dual transformed cells exhibited higher cADPR formation than ADPR production and elevated intracellular free Ca(2+) concentrations ([Ca(2+)](i)) in response to ACh. These phenotypes were analyzed in detail in a representative CD38 clone. The intracellular cADPR concentration by ACh application was significantly increased by CD38 overexpression. Digital image analysis by a confocal microscopy revealed that topographical distribution of the sites of Ca(2+) release was unchanged between control and overexpressed cells. These results indicate that cADPR is an intracellular messenger of Ca(2+) signalling, suggesting that CD38 can contribute to mAChR-cADPR signalling.

  19. Dimethyloxalylglycine may be enhance the capacity of neural-like cells in treatment of Alzheimer disease.

    PubMed

    Ghasemi Moravej, Fahimeh; Vahabian, Mehrangiz; Soleimani Asl, Sara

    2016-06-01

    Although using differentiated stem cells is the best proposed option for the treatment of Alzheimer disease (AD), an efficient differentiation and cell therapy require enhanced cell survival and homing and decreased apoptosis. It seems that hypoxia preconditioning via Dimethyloxalylglycine (DMOG) may increase the capacity of MSC to induce neural like stem cells (NSCs). Furthermore, it can likely improve the viability of NSCs when transplanted into the brain of AD rats.

  20. Continuous infusion of the α7 nicotinic acetylcholine receptor agonist EVP-6124 produces no signs of tolerance at memory-enhancing doses in rats: a pharmacokinetic and behavioral study.

    PubMed

    van Goethem, Nick P; Prickaerts, Jos; Welty, Devin; Flood, Dorothy G; Koenig, Gerhard

    2015-06-01

    We investigated whether the effects of acutely administered EVP-6124, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, on cognition were maintained after 6-day continuous minipump administration. Performance in a delay-dependent forgetting test was measured in the object recognition task after single-oral doses of 0.3 or 1 mg/kg, or at plasma steady-state concentrations (Css) of 0.6 or 2 ng/ml, which were similar to the efficacious plasma concentrations after single-oral dosing. The 0.3 mg/kg acute dose enhanced memory at a total plasma concentration of ∼0.3 ng/ml at 1-4 h after dosing. Continuous treatment produced total plasma Css values of 0.48 and 1.93 ng/ml on day 6 and enhanced memory. At EVP-6124 plasma concentrations that optimally enhance memory in the object recognition task, tolerance did not develop after 6 days of continuous treatment.

  1. ROCK inhibition enhances neurite outgrowth in neural stem cells by upregulating YAP expression in vitro

    PubMed Central

    Jia, Xu-feng; Ye, Fei; Wang, Yan-bo; Feng, Da-xiong

    2016-01-01

    Spontaneous axonal regeneration of neurons does not occur after spinal cord injury because of inhibition by myelin and other inhibitory factors. Studies have demonstrated that blocking the Rho/Rho-kinase (ROCK) pathway can promote neurite outgrowth in spinal cord injury models. In the present study, we investigated neurite outgrowth and neuronal differentiation in neural stem cells from the mouse subventricular zone after inhibition of ROCK in vitro. Inhibition of ROCK with Y-27632 increased neurite length, enhanced neuronal differentiation, and upregulated the expression of two major signaling pathway effectors, phospho-Akt and phospho-mitogen-activated protein kinase, and the Hippo pathway effector YAP. These results suggest that inhibition of ROCK mediates neurite outgrowth in neural stem cells by activating the Hippo signaling pathway. PMID:27482229

  2. Histamine H3 receptors regulate acetylcholine release from the guinea pig ileum myenteric plexus

    SciTech Connect

    Poli, E.; Coruzzi, G.; Bertaccini, G. )

    1991-01-01

    The effect of selective histamine H3-receptor agonists and antagonists on the acetylcholine release from peripheral nerves was evaluated in the guinea pig longitudinal muscle-myenteric plexus preparations, preloaded with ({sup 3}H)choline. In the presence of H1 and H2 blockade, histamine and (R)-{alpha}-methylhistamine inhibited the electrically-evoked acetylcholine release, being (R)-{alpha}-methylhistamine more active than histamine, but behaving as a partial agonist. The effect of histamine was completely reversed by selective H3-blocking drugs, thioperamide and impromidine, while only submaximal doses of (R)-{alpha}-methylhistamine were antagonized. Furthermore, thioperamide and impromidine enhanced the electrically-evoked acetylcholine release. On the contrary, the new H3-blocker, HST-7, was found substantially ineffective, both as histamine antagonist and as acetylcholine overflow enhancer. These data suggest that histamine exerts an inhibitory control on the acetylcholine release from intestinal cholinergic nerves through the activation of H3 receptors.

  3. Identification and dissection of a key enhancer mediating cranial neural crest specific expression of transcription factor, Ets-1.

    PubMed

    Barembaum, Meyer; Bronner, Marianne E

    2013-10-15

    Neural crest cells form diverse derivatives that vary according to their level of origin along the body axis, with only cranial neural crest cells contributing to facial skeleton. Interestingly, the transcription factor Ets-1 is uniquely expressed in cranial but not trunk neural crest, where it functions as a direct input into neural crest specifier genes, Sox10 and FoxD3. We have isolated and interrogated a cis-regulatory element, conserved between birds and mammals, that drives reporter expression in a manner that recapitulates that of endogenous Ets-1 expression in the neural crest. Within a minimal Ets-1 enhancer region, mutation of putative binding sites for SoxE, homeobox, Ets, TFAP2 or Fox proteins results in loss or reduction of neural crest enhancer activity. Morpholino-mediated loss-of-function experiments show that Sox9, Pax7, Msx1/2, Ets-1, TFAP2A and FoxD3, all are required for enhancer activity. In contrast, mutation of a putative cMyc/E-box sequence augments reporter expression, consistent with this being a repressor binding site. Taken together, these results uncover new inputs into Ets-1, revealing critical links in the cranial neural crest gene regulatory network.

  4. Training of goal-directed attention regulation enhances control over neural processing for individuals with brain injury.

    PubMed

    Chen, Anthony J-W; Novakovic-Agopian, Tatjana; Nycum, Terrence J; Song, Shawn; Turner, Gary R; Hills, Nancy K; Rome, Scott; Abrams, Gary M; D'Esposito, Mark

    2011-05-01

    Deficits in attention and executive control are some of the most common, debilitating and persistent consequences of brain injuries. Understanding neural mechanisms that support clinically significant improvements, when they do occur, may help advance treatment development. Intervening via rehabilitation provides an opportunity to probe such mechanisms. Our objective was to identify neural mechanisms that underlie improvements in attention and executive control with rehabilitation training. We tested the hypothesis that intensive training enhances modulatory control of neural processing of perceptual information in patients with acquired brain injuries. Patients (n=12) participated either in standardized training designed to target goal-directed attention regulation, or a comparison condition (brief education). Training resulted in significant improvements on behavioural measures of attention and executive control. Functional magnetic resonance imaging methods adapted for testing the effects of intervention for patients with varied injury pathology were used to index modulatory control of neural processing. Pattern classification was utilized to decode individual functional magnetic resonance imaging data acquired during a visual selective attention task. Results showed that modulation of neural processing in extrastriate cortex was significantly enhanced by attention regulation training. Neural changes in prefrontal cortex, a candidate mediator for attention regulation, appeared to depend on individual baseline state. These behavioural and neural effects did not occur with the comparison condition. These results suggest that enhanced modulatory control over visual processing and a rebalancing of prefrontal functioning may underlie improvements in attention and executive control.

  5. EP-DNN: A Deep Neural Network-Based Global Enhancer Prediction Algorithm

    NASA Astrophysics Data System (ADS)

    Kim, Seong Gon; Harwani, Mrudul; Grama, Ananth; Chaterji, Somali

    2016-12-01

    We present EP-DNN, a protocol for predicting enhancers based on chromatin features, in different cell types. Specifically, we use a deep neural network (DNN)-based architecture to extract enhancer signatures in a representative human embryonic stem cell type (H1) and a differentiated lung cell type (IMR90). We train EP-DNN using p300 binding sites, as enhancers, and TSS and random non-DHS sites, as non-enhancers. We perform same-cell and cross-cell predictions to quantify the validation rate and compare against two state-of-the-art methods, DEEP-ENCODE and RFECS. We find that EP-DNN has superior accuracy with a validation rate of 91.6%, relative to 85.3% for DEEP-ENCODE and 85.5% for RFECS, for a given number of enhancer predictions and also scales better for a larger number of enhancer predictions. Moreover, our H1 → IMR90 predictions turn out to be more accurate than IMR90 → IMR90, potentially because H1 exhibits a richer signature set and our EP-DNN model is expressive enough to extract these subtleties. Our work shows how to leverage the full expressivity of deep learning models, using multiple hidden layers, while avoiding overfitting on the training data. We also lay the foundation for exploration of cross-cell enhancer predictions, potentially reducing the need for expensive experimentation.

  6. EP-DNN: A Deep Neural Network-Based Global Enhancer Prediction Algorithm

    PubMed Central

    Kim, Seong Gon; Harwani, Mrudul; Grama, Ananth; Chaterji, Somali

    2016-01-01

    We present EP-DNN, a protocol for predicting enhancers based on chromatin features, in different cell types. Specifically, we use a deep neural network (DNN)-based architecture to extract enhancer signatures in a representative human embryonic stem cell type (H1) and a differentiated lung cell type (IMR90). We train EP-DNN using p300 binding sites, as enhancers, and TSS and random non-DHS sites, as non-enhancers. We perform same-cell and cross-cell predictions to quantify the validation rate and compare against two state-of-the-art methods, DEEP-ENCODE and RFECS. We find that EP-DNN has superior accuracy with a validation rate of 91.6%, relative to 85.3% for DEEP-ENCODE and 85.5% for RFECS, for a given number of enhancer predictions and also scales better for a larger number of enhancer predictions. Moreover, our H1 → IMR90 predictions turn out to be more accurate than IMR90 → IMR90, potentially because H1 exhibits a richer signature set and our EP-DNN model is expressive enough to extract these subtleties. Our work shows how to leverage the full expressivity of deep learning models, using multiple hidden layers, while avoiding overfitting on the training data. We also lay the foundation for exploration of cross-cell enhancer predictions, potentially reducing the need for expensive experimentation. PMID:27929098

  7. Enzyme-linked DNA dendrimer nanosensors for acetylcholine

    NASA Astrophysics Data System (ADS)

    Walsh, Ryan; Morales, Jennifer M.; Skipwith, Christopher G.; Ruckh, Timothy T.; Clark, Heather A.

    2015-10-01

    It is currently difficult to measure small dynamics of molecules in the brain with high spatial and temporal resolution while connecting them to the bigger picture of brain function. A step towards understanding the underlying neural networks of the brain is the ability to sense discrete changes of acetylcholine within a synapse. Here we show an efficient method for generating acetylcholine-detecting nanosensors based on DNA dendrimer scaffolds that incorporate butyrylcholinesterase and fluorescein in a nanoscale arrangement. These nanosensors are selective for acetylcholine and reversibly respond to levels of acetylcholine in the neurophysiological range. This DNA dendrimer architecture has the potential to overcome current obstacles to sensing in the synaptic environment, including the nanoscale size constraints of the synapse and the ability to quantify the spatio-temporal fluctuations of neurotransmitter release. By combining the control of nanosensor architecture with the strategic placement of fluorescent reporters and enzymes, this novel nanosensor platform can facilitate the development of new selective imaging tools for neuroscience.

  8. Prior perceptual processing enhances the effect of emotional arousal on the neural correlates of memory retrieval.

    PubMed

    Dew, Ilana T Z; Ritchey, Maureen; LaBar, Kevin S; Cabeza, Roberto

    2014-07-01

    A fundamental idea in memory research is that items are more likely to be remembered if encoded with a semantic, rather than perceptual, processing strategy. Interestingly, this effect has been shown to reverse for emotionally arousing materials, such that perceptual processing enhances memory for emotional information or events. The current fMRI study investigated the neural mechanisms of this effect by testing how neural activations during emotional memory retrieval are influenced by the prior encoding strategy. Participants incidentally encoded emotional and neutral pictures under instructions to attend to either semantic or perceptual properties of each picture. Recognition memory was tested 2 days later. fMRI analyses yielded three main findings. First, right amygdalar activity associated with emotional memory strength was enhanced by prior perceptual processing. Second, prior perceptual processing of emotional pictures produced a stronger effect on recollection- than familiarity-related activations in the right amygdala and left hippocampus. Finally, prior perceptual processing enhanced amygdalar connectivity with regions strongly associated with retrieval success, including hippocampal/parahippocampal regions, visual cortex, and ventral parietal cortex. Taken together, the results specify how encoding orientations yield alterations in brain systems that retrieve emotional memories.

  9. Structurally enhanced incremental neural learning for image classification with subgraph extraction.

    PubMed

    Yang, Yu-Bin; Li, Ya-Nan; Gao, Yang; Yin, Hujun; Tang, Ye

    2014-11-01

    In this paper, a structurally enhanced incremental neural learning technique is proposed to learn a discriminative codebook representation of images for effective image classification applications. In order to accommodate the relationships such as structures and distributions among visual words into the codebook learning process, we develop an online codebook graph learning method based on a novel structurally enhanced incremental learning technique, called as "visualization-induced self-organized incremental neural network (ViSOINN)". The hidden structural information in the images is embedded into the graph representation evolving dynamically with the adaptive and competitive learning mechanism. Afterwards, image features can be coded using a sub-graph extraction process based on the learned codebook graph, and a classifier is subsequently used to complete the image classification task. Compared with other codebook learning algorithms originated from the classical Bag-of-Features (BoF) model, ViSOINN holds the following advantages: (1) it learns codebook efficiently and effectively from a small training set; (2) it models the relationships among visual words in metric scaling fashion, so preserving high discriminative power; (3) it automatically learns the codebook without a fixed pre-defined size; and (4) it enhances and preserves better the structure of the data. These characteristics help to improve image classification performance and make it more suitable for handling large-scale image classification tasks. Experimental results on the widely used Caltech-101 and Caltech-256 benchmark datasets demonstrate that ViSOINN achieves markedly improved performance and reduces the computational cost considerably.

  10. Using Artificial Neural Networks Approach for the Color Enhance of High Power LEDs

    NASA Astrophysics Data System (ADS)

    Chen, Hsi-Chao; Wu, Guo-Yang; Yang, Chi-Hao; Chen, Peng-Ying; Lai, Mei-Jyun; Huang, Kuo-Ting

    2012-10-01

    High power light-emitting diodes (HP-LEDs) always are applied for energy-saving to replace the traditional light sources. HP-LEDs lighting has been regarded in the next generation lighting. In this study, the RGY colors enhance of whit LED lighting was researched and modulated by artificial neural network (ANN). An ANN model was used to investigate the correlated color temperature (CCT) and luminous flux (Lux) for the white LED enhanced with different power of single RYG LEDs. The starting color temperature of the white LED will be set at 7500K (D75 white light standard), then changed the voltage of the single LED of the red, green or yellow, respectively, to find the best tuning function for the color temperature and luminous efficiency. These results exhibited that changing the voltage of red LED had the broader color temperature from 7500 K to 1500 K than the range of green and yellow LEDs from 7500K to 8200K and 7500K to 4700K, respectively. Then, these experimental results were used as input data for the training model. After the learning model was completed, an analysis was used to obtain the internal representation of the color information by the responses of the individual chips of the three hidden units in the middle layer. Identification rate of data would be achieved to 100% by the neural network pattern-recognition tool. Anyway, the correlation coefficient could reach to 99% by the ANN fitting tool for the color enhancement.

  11. Musical intervention enhances infants’ neural processing of temporal structure in music and speech

    PubMed Central

    Zhao, T. Christina; Kuhl, Patricia K.

    2016-01-01

    Individuals with music training in early childhood show enhanced processing of musical sounds, an effect that generalizes to speech processing. However, the conclusions drawn from previous studies are limited due to the possible confounds of predisposition and other factors affecting musicians and nonmusicians. We used a randomized design to test the effects of a laboratory-controlled music intervention on young infants’ neural processing of music and speech. Nine-month-old infants were randomly assigned to music (intervention) or play (control) activities for 12 sessions. The intervention targeted temporal structure learning using triple meter in music (e.g., waltz), which is difficult for infants, and it incorporated key characteristics of typical infant music classes to maximize learning (e.g., multimodal, social, and repetitive experiences). Controls had similar multimodal, social, repetitive play, but without music. Upon completion, infants’ neural processing of temporal structure was tested in both music (tones in triple meter) and speech (foreign syllable structure). Infants’ neural processing was quantified by the mismatch response (MMR) measured with a traditional oddball paradigm using magnetoencephalography (MEG). The intervention group exhibited significantly larger MMRs in response to music temporal structure violations in both auditory and prefrontal cortical regions. Identical results were obtained for temporal structure changes in speech. The intervention thus enhanced temporal structure processing not only in music, but also in speech, at 9 mo of age. We argue that the intervention enhanced infants’ ability to extract temporal structure information and to predict future events in time, a skill affecting both music and speech processing. PMID:27114512

  12. Musical intervention enhances infants' neural processing of temporal structure in music and speech.

    PubMed

    Zhao, T Christina; Kuhl, Patricia K

    2016-05-10

    Individuals with music training in early childhood show enhanced processing of musical sounds, an effect that generalizes to speech processing. However, the conclusions drawn from previous studies are limited due to the possible confounds of predisposition and other factors affecting musicians and nonmusicians. We used a randomized design to test the effects of a laboratory-controlled music intervention on young infants' neural processing of music and speech. Nine-month-old infants were randomly assigned to music (intervention) or play (control) activities for 12 sessions. The intervention targeted temporal structure learning using triple meter in music (e.g., waltz), which is difficult for infants, and it incorporated key characteristics of typical infant music classes to maximize learning (e.g., multimodal, social, and repetitive experiences). Controls had similar multimodal, social, repetitive play, but without music. Upon completion, infants' neural processing of temporal structure was tested in both music (tones in triple meter) and speech (foreign syllable structure). Infants' neural processing was quantified by the mismatch response (MMR) measured with a traditional oddball paradigm using magnetoencephalography (MEG). The intervention group exhibited significantly larger MMRs in response to music temporal structure violations in both auditory and prefrontal cortical regions. Identical results were obtained for temporal structure changes in speech. The intervention thus enhanced temporal structure processing not only in music, but also in speech, at 9 mo of age. We argue that the intervention enhanced infants' ability to extract temporal structure information and to predict future events in time, a skill affecting both music and speech processing.

  13. Sea clutter reduction and target enhancement by neural networks in a marine radar system.

    PubMed

    Vicen-Bueno, Raúl; Carrasco-Álvarez, Rubén; Rosa-Zurera, Manuel; Nieto-Borge, José Carlos

    2009-01-01

    The presence of sea clutter in marine radar signals is sometimes not desired. So, efficient radar signal processing techniques are needed to reduce it. In this way, nonlinear signal processing techniques based on neural networks (NNs) are used in the proposed clutter reduction system. The developed experiments show promising results characterized by different subjective (visual analysis of the processed radar images) and objective (clutter reduction, target enhancement and signal-to-clutter ratio improvement) criteria. Moreover, a deep study of the NN structure is done, where the low computational cost and the high processing speed of the proposed NN structure are emphasized.

  14. Transient Stability Enhancement of Power Systems by Lyapunov-Based Recurrent Neural Networks UPFC Controllers

    NASA Astrophysics Data System (ADS)

    Chu, Chia-Chi; Tsai, Hung-Chi; Chang, Wei-Neng

    A Lyapunov-based recurrent neural networks unified power flow controller (UPFC) is developed for improving transient stability of power systems. First, a simple UPFC dynamical model, composed of a controllable shunt susceptance on the shunt side and an ideal complex transformer on the series side, is utilized to analyze UPFC dynamical characteristics. Secondly, we study the control configuration of the UPFC with two major blocks: the primary control, and the supplementary control. The primary control is implemented by standard PI techniques when the power system is operated in a normal condition. The supplementary control will be effective only when the power system is subjected by large disturbances. We propose a new Lyapunov-based UPFC controller of the classical single-machine-infinite-bus system for damping enhancement. In order to consider more complicated detailed generator models, we also propose a Lyapunov-based adaptive recurrent neural network controller to deal with such model uncertainties. This controller can be treated as neural network approximations of Lyapunov control actions. In addition, this controller also provides online learning ability to adjust the corresponding weights with the back propagation algorithm built in the hidden layer. The proposed control scheme has been tested on two simple power systems. Simulation results demonstrate that the proposed control strategy is very effective for suppressing power swing even under severe system conditions.

  15. Acetylcholine Mediates a Slow Synaptic Potential in Hippocampal Pyramidal Cells

    NASA Astrophysics Data System (ADS)

    Cole, A. E.; Nicoll, R. A.

    1983-09-01

    The hippocampal slice preparation was used to study the role of acetylcholine as a synaptic transmitter. Bath-applied acetylcholine had three actions on pyramidal cells: (i) depolarization associated with increased input resistance, (ii) blockade of calcium-activated potassium responses, and (iii) blockade of accommodation of cell discharge. All these actions were reversed by the muscarinic antagonist atropine. Stimulation of sites in the slice known to contain cholinergic fibers mimicked all the actions. Furthermore, these evoked synaptic responses were enhanced by the cholinesterase inhibitor eserine and were blocked by atropine. These findings provide electrophysiological support for the role of acetylcholine as a synaptic transmitter in the brain and demonstrate that nonclassical synaptic responses involving the blockade of membrane conductances exist in the brain.

  16. Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation

    PubMed Central

    Krucoff, Max O.; Rahimpour, Shervin; Slutzky, Marc W.; Edgerton, V. Reggie; Turner, Dennis A.

    2016-01-01

    After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain-machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required—a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural

  17. Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation.

    PubMed

    Krucoff, Max O; Rahimpour, Shervin; Slutzky, Marc W; Edgerton, V Reggie; Turner, Dennis A

    2016-01-01

    After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain-machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required-a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural interfacing

  18. Stemness enhancement of human neural stem cells following bone marrow MSC coculture.

    PubMed

    Haragopal, Hariprakash; Yu, Dou; Zeng, Xiang; Kim, Soo-Woo; Han, In-Bo; Ropper, Alexander E; Anderson, Jamie E; Teng, Yang D

    2015-01-01

    Rapid loss of stemness capacity in purified prototype neural stem cells (NSCs) remains a serious challenge to basic and clinical studies aiming to repair the central nervous system. Based on the essential role of mesodermal guidance in the process of neurulation, we hypothesized that coculture of human NSCs (hNSCs) with human bone marrow-derived mesenchymal stromal stem cells (hMSCs) could enhance the stemness of hNSCs through Notch-1 signaling. We have now tested the hypothesis by assessing behaviors of hNSCs and hMSCs under systematically designed coculture conditions relative to monocultures, with or without Notch-1 manipulation in vitro. Our data demonstrate that expression levels of Notch-1 and Hes-1 as determined by immunocytochemistry are significantly higher in hNSCs cocultured with hMSCs than those of controls. Furthermore, coculturing significantly increases immunoreactivity of CD15, a neural stemness marker, but decreases CD24, a marker of neural/neuronal commitment in hNSCs. The effect is independent from the physical status of cell growth since coculture and notch signaling actually promotes hNSC adhesion. Importantly, coculture with hMSCs markedly augments hNSC proliferation rate (e.g., higher yield in G2/M phase subpopulation in a notch-dependent manner detected by flow cytometry) without diminishing their lineage differentiation capabilities. The results suggest that coculture of hNSCs with hMSCs enhances stemness biology of hNSCs partially via activation of Notch-1 signal transduction. Our finding sheds new light on mesoderm-ectoderm cell fate determination via contact-based hMSC-hNSC interactions and provides mechanistic leads for devising effective regimens to sustain and augment stemness of in vitro established hNSC and hMSC lines for basic science, translational and clinical applications.

  19. Stochastic resonance enhancement of small-world neural networks by hybrid synapses and time delay

    NASA Astrophysics Data System (ADS)

    Yu, Haitao; Guo, Xinmeng; Wang, Jiang

    2017-01-01

    The synergistic effect of hybrid electrical-chemical synapses and information transmission delay on the stochastic response behavior in small-world neuronal networks is investigated. Numerical results show that, the stochastic response behavior can be regulated by moderate noise intensity to track the rhythm of subthreshold pacemaker, indicating the occurrence of stochastic resonance (SR) in the considered neural system. Inheriting the characteristics of two types of synapses-electrical and chemical ones, neural networks with hybrid electrical-chemical synapses are of great improvement in neuron communication. Particularly, chemical synapses are conducive to increase the network detectability by lowering the resonance noise intensity, while the information is better transmitted through the networks via electrical coupling. Moreover, time delay is able to enhance or destroy the periodic stochastic response behavior intermittently. In the time-delayed small-world neuronal networks, the introduction of electrical synapses can significantly improve the signal detection capability by widening the range of optimal noise intensity for the subthreshold signal, and the efficiency of SR is largely amplified in the case of pure chemical couplings. In addition, the stochastic response behavior is also profoundly influenced by the network topology. Increasing the rewiring probability in pure chemically coupled networks can always enhance the effect of SR, which is slightly influenced by information transmission delay. On the other hand, the capacity of information communication is robust to the network topology within the time-delayed neuronal systems including electrical couplings.

  20. Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest.

    PubMed

    Prescott, Sara L; Srinivasan, Rajini; Marchetto, Maria Carolina; Grishina, Irina; Narvaiza, Iñigo; Selleri, Licia; Gage, Fred H; Swigut, Tomek; Wysocka, Joanna

    2015-09-24

    cis-regulatory changes play a central role in morphological divergence, yet the regulatory principles underlying emergence of human traits remain poorly understood. Here, we use epigenomic profiling from human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate divergence of craniofacial cis-regulatory landscapes. Epigenomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We explore properties of this cis-regulatory change, revealing the role of particular retroelements, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differences of crucial neural crest regulators. Our work provides a wealth of candidates for future evolutionary studies and demonstrates the value of "cellular anthropology," a strategy of using in-vitro-derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates.

  1. Neural substrates underlying stimulation-enhanced motor skill learning after stroke.

    PubMed

    Lefebvre, Stéphanie; Dricot, Laurence; Laloux, Patrice; Gradkowski, Wojciech; Desfontaines, Philippe; Evrard, Frédéric; Peeters, André; Jamart, Jacques; Vandermeeren, Yves

    2015-01-01

    Motor skill learning is one of the key components of motor function recovery after stroke, especially recovery driven by neurorehabilitation. Transcranial direct current stimulation can enhance neurorehabilitation and motor skill learning in stroke patients. However, the neural mechanisms underlying the retention of stimulation-enhanced motor skill learning involving a paretic upper limb have not been resolved. These neural substrates were explored by means of functional magnetic resonance imaging. Nineteen chronic hemiparetic stroke patients participated in a double-blind, cross-over randomized, sham-controlled experiment with two series. Each series consisted of two sessions: (i) an intervention session during which dual transcranial direct current stimulation or sham was applied during motor skill learning with the paretic upper limb; and (ii) an imaging session 1 week later, during which the patients performed the learned motor skill. The motor skill learning task, called the 'circuit game', involves a speed/accuracy trade-off and consists of moving a pointer controlled by a computer mouse along a complex circuit as quickly and accurately as possible. Relative to the sham series, dual transcranial direct current stimulation applied bilaterally over the primary motor cortex during motor skill learning with the paretic upper limb resulted in (i) enhanced online motor skill learning; (ii) enhanced 1-week retention; and (iii) superior transfer of performance improvement to an untrained task. The 1-week retention's enhancement driven by the intervention was associated with a trend towards normalization of the brain activation pattern during performance of the learned motor skill relative to the sham series. A similar trend towards normalization relative to sham was observed during performance of a simple, untrained task without a speed/accuracy constraint, despite a lack of behavioural difference between the dual transcranial direct current stimulation and sham

  2. Neural coordination can be enhanced by occasional interruption of normal firing patterns: a self-optimizing spiking neural network model.

    PubMed

    Woodward, Alexander; Froese, Tom; Ikegami, Takashi

    2015-02-01

    The state space of a conventional Hopfield network typically exhibits many different attractors of which only a small subset satisfies constraints between neurons in a globally optimal fashion. It has recently been demonstrated that combining Hebbian learning with occasional alterations of normal neural states avoids this problem by means of self-organized enlargement of the best basins of attraction. However, so far it is not clear to what extent this process of self-optimization is also operative in real brains. Here we demonstrate that it can be transferred to more biologically plausible neural networks by implementing a self-optimizing spiking neural network model. In addition, by using this spiking neural network to emulate a Hopfield network with Hebbian learning, we attempt to make a connection between rate-based and temporal coding based neural systems. Although further work is required to make this model more realistic, it already suggests that the efficacy of the self-optimizing process is independent from the simplifying assumptions of a conventional Hopfield network. We also discuss natural and cultural processes that could be responsible for occasional alteration of neural firing patterns in actual brains.

  3. Polyester with Pendent Acetylcholine-Mimicking Functionalities Promotes Neurite Growth.

    PubMed

    Wang, Shaofei; Jeffries, Eric; Gao, Jin; Sun, Lijie; You, Zhengwei; Wang, Yadong

    2016-04-20

    Successful regeneration of nerves can benefit from biomaterials that provide a supportive biochemical and mechanical environment while also degrading with controlled inflammation and minimal scar formation. Herein, we report a neuroactive polymer functionalized by covalent attachment of the neurotransmitter acetylcholine (Ach). The polymer was readily synthesized in two steps from poly(sebacoyl diglyceride) (PSeD), which previously demonstrated biocompatibility and biodegradation in vivo. Distinct from prior acetylcholine-biomimetic polymers, PSeD-Ach contains both quaternary ammonium and free acetyl moieties, closely resembling native acetylcholine structure. The polymer structure was confirmed via (1)H nuclear magnetic resonance and Fourier-transform infrared spectroscopy. Hydrophilicity, charge, and thermal properties of PSeD-Ach were determined by tensiometer, zetasizer, differential scanning calorimetry, and thermal gravimetric analysis, respectively. PC12 cells exhibited the greatest proliferation and neurite outgrowth on PSeD-Ach and laminin substrates, with no significant difference between these groups. PSeD-Ach yielded much longer neurite outgrowth than the control polymer containing ammonium but no the acetyl group, confirming the importance of the entire acetylcholine-like moiety. Furthermore, PSeD-Ach supports adhesion of primary rat dorsal root ganglions and subsequent neurite sprouting and extension. The sprouting rate is comparable to the best conditions from previous report. Our findings are significant in that they were obtained with acetylcholine-like functionalities in 100% repeating units, a condition shown to yield significant toxicity in prior publications. Moreover, PSeD-Ach exhibited favorable mechanical and degradation properties for nerve tissue engineering application. Humidified PSeD-Ach had an elastic modulus of 76.9 kPa, close to native neural tissue, and could well recover from cyclic dynamic compression. PSeD-Ach showed a gradual in

  4. Nonopioid effect of morphine on electrically evoked acetylcholine release from Torpedo electromotor neurons.

    PubMed

    Oron, L; Sarne, Y; Michaelson, D M

    1992-02-01

    The release of acetylcholine from Torpedo electric organ slices following their electrical stimulation was modulated by morphine, by the muscarinic antagonist atropine, and by the nicotinic antagonist tubocurarine. Addition of either atropine or tubocurarine in the presence of the acetylcholinesterase inhibitor phospholine iodide enhanced acetylcholine release. The effects of the two antagonists were additive, a result suggesting that the secreted acetylcholine regulates its own release by activating both muscarinic and nicotinic cholinergic receptors and that these receptors inhibit acetylcholine release by different mechanisms. The effects of opiates on acetylcholine release were examined under conditions in which the cholinergic modulation of release is blocked, i.e., in the presence of atropine and tubocurarine. These experiments revealed that electrically evoked release of acetylcholine is blocked by the opiate agonists morphine and levorphanol. However, the inhibitory effect of morphine on acetylcholine release was not reversed by the opioid antagonist naloxone. Furthermore, dextrorphan, the nonopioid stereoisomer of levorphanol, had the same inhibitory effect as its opioid counterpart. These findings suggest that the effects of opiates on electrically evoked release of acetylcholine are not mediated by opioid receptors. The possible mechanisms underlying these nonopioid effects of morphine and levorphanol are discussed.

  5. Neurally released pituitary adenylate cyclase-activating polypeptide enhances guinea pig intrinsic cardiac neurone excitability.

    PubMed

    Tompkins, John D; Ardell, Jeffrey L; Hoover, Donald B; Parsons, Rodney L

    2007-07-01

    Intracellular recordings were made in vitro from guinea-pig cardiac ganglia to determine whether endogenous neuropeptides such as pituitary adenylate cyclase-activating polypeptide (PACAP) or substance P released during tetanic neural stimulation modulate cardiac neurone excitability and/or contribute to slow excitatory postsynaptic potentials (sEPSPs). When nicotinic and muscarinic receptors were blocked by hexamethonium and atropine, 20 Hz stimulation for 10 s initiated a sEPSP in all innervated neurones. In 40% of the cells, excitability was enhanced after termination of the sEPSP. This suggested that non-cholinergic receptor-mediated mechanisms contributed to the sEPSP and modulated neuronal excitability. Exogenous PACAP and substance P initiated a slow depolarization in the neurones whereas neuronal excitability was only increased by PACAP. When ganglia were treated with the PAC1 antagonist PACAP6-38 (500 nM), the sEPSP evoked by 20 Hz stimulation was reduced by approximately 50% and an enhanced excitability occurred in only 10% of the cells. These observations suggested that PACAP released from preganglionic nerve terminals during tetanic stimulation enhanced neuronal excitability and evoked sEPSPs. After addition of 1 nM PACAP to the bath, 7 of 9 neurones exhibited a tonic firing pattern whereas in untreated preparations, the neurons had a phasic firing pattern. PACAP6-38 (500 nM) diminished the increase in excitability caused by 1 nM PACAP so that only 4 of 13 neurones exhibited a tonic firing pattern and the other 9 cells retained a phasic firing pattern. These findings indicate that PACAP can be released by tetanic neural stimulation in vitro and increase the excitability of intrinsic cardiac neurones. We hypothesize that in vivo PACAP released during preganglionic firing may modulate neurotransmission within the intrinsic cardiac ganglia.

  6. A neural network for enhancing boundaries and surfaces in synthetic aperture radar images.

    PubMed

    Mingolla, Ennio; Ross, William; Grossberg, Stephen

    1999-04-01

    A neural network system for boundary segmentation and surface representation, inspired by a new local-circuit model of visual processing in the cerebral cortex, is used to enhance images of range data gathered by a synthetic aperture radar (SAR) sensor. Boundary segmentation is accomplished by an improved Boundary Contour System (BCS) model which completes coherent boundaries that retain their sensitivity to image contrasts and locations. A Feature Contour System (FCS) model compensates for local contrast variations and uses the compensated signals to diffusively fill-in surface regions within the BCS boundaries. Image noise pixels that are not supported by BCS boundaries are hereby eliminated. More generally, BCS/FCS processing normalizes input dynamic range, reduces noise, and enhances contrasts between surface regions. BCS/FCS processing hereby makes structures such as motor vehicles, roads, and buildings more salient to human observers than in original imagery. The new BCS model improves image enhancement with significant reductions in processing time and complexity over previous BCS applications. The new system also outperforms several established techniques for image enhancement.

  7. Speech enhancement based on neural networks improves speech intelligibility in noise for cochlear implant users.

    PubMed

    Goehring, Tobias; Bolner, Federico; Monaghan, Jessica J M; van Dijk, Bas; Zarowski, Andrzej; Bleeck, Stefan

    2017-02-01

    Speech understanding in noisy environments is still one of the major challenges for cochlear implant (CI) users in everyday life. We evaluated a speech enhancement algorithm based on neural networks (NNSE) for improving speech intelligibility in noise for CI users. The algorithm decomposes the noisy speech signal into time-frequency units, extracts a set of auditory-inspired features and feeds them to the neural network to produce an estimation of which frequency channels contain more perceptually important information (higher signal-to-noise ratio, SNR). This estimate is used to attenuate noise-dominated and retain speech-dominated CI channels for electrical stimulation, as in traditional n-of-m CI coding strategies. The proposed algorithm was evaluated by measuring the speech-in-noise performance of 14 CI users using three types of background noise. Two NNSE algorithms were compared: a speaker-dependent algorithm, that was trained on the target speaker used for testing, and a speaker-independent algorithm, that was trained on different speakers. Significant improvements in the intelligibility of speech in stationary and fluctuating noises were found relative to the unprocessed condition for the speaker-dependent algorithm in all noise types and for the speaker-independent algorithm in 2 out of 3 noise types. The NNSE algorithms used noise-specific neural networks that generalized to novel segments of the same noise type and worked over a range of SNRs. The proposed algorithm has the potential to improve the intelligibility of speech in noise for CI users while meeting the requirements of low computational complexity and processing delay for application in CI devices.

  8. Winning territorial disputes selectively enhances androgen sensitivity in neural pathways related to motivation and social aggression.

    PubMed

    Fuxjager, Matthew J; Forbes-Lorman, Robin M; Coss, Dylan J; Auger, Catherine J; Auger, Anthony P; Marler, Catherine A

    2010-07-06

    Winning aggressive disputes can enhance future fighting ability and the desire to seek out additional contests. In some instances, these effects are long lasting and vary in response to the physical location of a fight. Thus, in principle, winning aggressive encounters may cause long-term and context-dependent changes to brain areas that control the output of antagonistic behavior or the motivation to fight (or both). We examined this issue in the territorial California mouse (Peromyscus californicus) because males of this species are more likely to win fights after accruing victories in their home territory but not after accruing victories in unfamiliar locations. Using immunocytochemistry and real-time quantitative PCR, we found that winning fights either at home or away increases the expression of androgen receptors (AR) in the medial anterior bed nucleus of the stria terminalis, a key brain area that controls social aggression. We also found that AR expression in brain regions that mediate motivation and reward, nucleus accumbens (NAcc) and ventral tegmental area (VTA), increases only in response to fights in the home territory. These effects of winning were likely exclusive to the neural androgenic system because they have no detectible impact on the expression of progestin receptors. Finally, we demonstrated that the observed changes in androgen sensitivity in the NAcc and VTA are positively associated with the ability to win aggressive contests. Thus, winning fights can change brain phenotype in a manner that likely promotes future victory and possibly primes neural circuits that motivate individuals to fight.

  9. Computer-Aided Diagnosis of Parkinson's Disease Using Enhanced Probabilistic Neural Network.

    PubMed

    Hirschauer, Thomas J; Adeli, Hojjat; Buford, John A

    2015-11-01

    Early and accurate diagnosis of Parkinson's disease (PD) remains challenging. Neuropathological studies using brain bank specimens have estimated that a large percentages of clinical diagnoses of PD may be incorrect especially in the early stages. In this paper, a comprehensive computer model is presented for the diagnosis of PD based on motor, non-motor, and neuroimaging features using the recently-developed enhanced probabilistic neural network (EPNN). The model is tested for differentiating PD patients from those with scans without evidence of dopaminergic deficit (SWEDDs) using the Parkinson's Progression Markers Initiative (PPMI) database, an observational, multi-center study designed to identify PD biomarkers for diagnosis and disease progression. The results are compared to four other commonly-used machine learning algorithms: the probabilistic neural network (PNN), support vector machine (SVM), k-nearest neighbors (k-NN) algorithm, and classification tree (CT). The EPNN had the highest classification accuracy at 92.5% followed by the PNN (91.6%), k-NN (90.8%) and CT (90.2%). The EPNN exhibited an accuracy of 98.6% when classifying healthy control (HC) versus PD, higher than any previous studies.

  10. Immersive audiomotor game play enhances neural and perceptual salience of weak signals in noise.

    PubMed

    Whitton, Jonathon P; Hancock, Kenneth E; Polley, Daniel B

    2014-06-24

    All sensory systems face the fundamental challenge of encoding weak signals in noisy backgrounds. Although discrimination abilities can improve with practice, these benefits rarely generalize to untrained stimulus dimensions. Inspired by recent findings that action video game training can impart a broader spectrum of benefits than traditional perceptual learning paradigms, we trained adult humans and mice in an immersive audio game that challenged them to forage for hidden auditory targets in a 2D soundscape. Both species learned to modulate their angular search vectors and target approach velocities based on real-time changes in the level of a weak tone embedded in broadband noise. In humans, mastery of this tone in noise task generalized to an improved ability to comprehend spoken sentences in speech babble noise. Neural plasticity in the auditory cortex of trained mice supported improved decoding of low-intensity sounds at the training frequency and an enhanced resistance to interference from background masking noise. These findings highlight the potential to improve the neural and perceptual salience of degraded sensory stimuli through immersive computerized games.

  11. Self-organization of a neural network with heterogeneous neurons enhances coherence and stochastic resonance

    NASA Astrophysics Data System (ADS)

    Li, Xiumin; Zhang, Jie; Small, Michael

    2009-03-01

    Most network models for neural behavior assume a predefined network topology and consist of almost identical elements exhibiting little heterogeneity. In this paper, we propose a self-organized network consisting of heterogeneous neurons with different behaviors or degrees of excitability. The synaptic connections evolve according to the spike-timing dependent plasticity mechanism and finally a sparse and active-neuron-dominant structure is observed. That is, strong connections are mainly distributed to the synapses from active neurons to inactive ones. We argue that this self-emergent topology essentially reflects the competition of different neurons and encodes the heterogeneity. This structure is shown to significantly enhance the coherence resonance and stochastic resonance of the entire network, indicating its high efficiency in information processing.

  12. Comparation of enhanced green fluorescent protein gene transfected and wild-type porcine neural stem cells.

    PubMed

    Zheng, Yue-Mao; An, Zhi-Xing; Zhao, Xiao-E; Quan, Fu-Sheng; Zhao, Hui-Ying; Zhang, Ya-Rong; Liu, Jun; He, Xiao-Ying; He, Xiao-Ning

    2010-02-01

    The aim of this study was to transfect and express the enhanced green fluorescence protein (EGFP) gene into porcine neural stem cells (NSCs) to determine whether EGFP can be used as a marker to monitor NSCs. NSCs were isolated from embryonic day 30 fetal pig brain and transfected with EGFP gene using lipofection. Transfected and wild-type NSCs were induced to differentiate into cells of neuronal and myogenic lineages. Markers of passage three NSCs and their differentiated cells were tested by reverse transcription polymerase chain reaction. The results showed that EGFP could be expressed in NSCs and the differentiated cells. NSCs expressed Nestin, NogoA, DCX, Hes1, Oct4, CD-90 and Sox2. NSCs could differentiated into astrocyte (GFAP(+)), oligodendrocyte (GalC(+)), neuron (NF(+), NSE(+) and MAP2(+)) and myocyte (myf-6(+) and myoD(+)). We concluded that EGFP can be used as a marker in monitoring NSCs.

  13. 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.

  14. Enhancing neural stem cell response to SDF-1α gradients through hyaluronic acid-laminin hydrogels.

    PubMed

    Addington, C P; Heffernan, J M; Millar-Haskell, C S; Tucker, E W; Sirianni, R W; Stabenfeldt, S E

    2015-12-01

    Traumatic brain injury (TBI) initiates an expansive biochemical insult that is largely responsible for the long-term dysfunction associated with TBI; however, current clinical treatments fall short of addressing these underlying sequelae. Pre-clinical investigations have used stem cell transplantation with moderate success, but are plagued by staggeringly low survival and engraftment rates (2-4%). As such, providing cell transplants with the means to better dynamically respond to injury-related signals within the transplant microenvironment may afford improved transplantation survival and engraftment rates. The chemokine stromal cell-derived factor-1α (SDF-1α) is a potent chemotactic signal that is readily present after TBI. In this study, we sought to develop a transplantation vehicle to ultimately enhance the responsiveness of neural transplants to injury-induced SDF-1α. Specifically, we hypothesize that a hyaluronic acid (HA) and laminin (Lm) hydrogel would promote 1. upregulated expression of the SDF-1α receptor CXCR4 in neural progenitor/stem cells (NPSCs) and 2. enhanced NPSC migration in response to SDF-1α gradients. We demonstrated successful development of a HA-Lm hydrogel and utilized standard protein and cellular assays to probe NPSC CXCR4 expression and NPSC chemotactic migration. The findings demonstrated that NPSCs significantly increased CXCR4 expression after 48 h of culture on the HA-Lm gel in a manner critically dependent on both HA and laminin. Moreover, the HA-Lm hydrogel significantly increased NPSC chemotactic migration in response to SDF-1α at 48 h, an effect that was critically dependent on HA, laminin and the SDF-1α gradient. Therefore, this hydrogel serves to 1. prime NPSCs for the injury microenvironment and 2. provide the appropriate infrastructure to support migration into the surrounding tissue, equipping cells with the tools to more effectively respond to the injury microenvironment.

  15. Depression Risk Predicts Blunted Neural Responses to Gains and Enhanced Responses to Losses in Healthy Children

    PubMed Central

    Luking, Katherine R.; Pagliaccio, David; Luby, Joan L.; Barch, Deanna M.

    2016-01-01

    Objective Maternal major depressive disorder (MDD) increases risk for MDD and predicts reduced reward responding in adolescent offspring. However, it is unclear whether alterations in neural response to reward can be detected in school-aged children at high risk prior to the typical increase in reward response observed in adolescence. Method To assess relationships between neural response to gain/loss feedback, MDD risk, and child depressive symptoms, forty-seven psychiatrically healthy 7–10-year-old children (16 at high-risk given maternal MDD) completed questionnaires and a functional magnetic resonance imaging (fMRI) card-guessing game where candy was gained and lost. Results High-risk children showed both blunted response to gain and greater deactivation/reduced activation to loss within the ventral striatum and anterior insula. Within the striatum, risk-group differences in response to loss feedback were significantly larger than for gain, with greater deactivation to loss predicting risk-group status above and beyond blunted gain activation. Anhedonia was related to reduced deactivation to loss (i.e. reduced sensitivity to loss), while negative mood was related to enhanced deactivation to loss (i.e. enhanced sensitivity to loss) in the ventral striatum. Conclusion High-risk children showed blunted ventral striatal activation to gain feedback, but ventral striatal deactivation to loss was a stronger predictor of MDD risk. Further, relationships between response to loss and elevated depressive symptoms within the ventral striatum and cingulate differed depending on the type of depressive symptom. Together these results highlight the potentially important role of response to loss of reward in childhood risk for depression. PMID:27015724

  16. Acetylcholine stimulates cortical precursor cell proliferation in vitro via muscarinic receptor activation and MAP kinase phosphorylation.

    PubMed

    Ma, W; Maric, D; Li, B S; Hu, Q; Andreadis, J D; Grant, G M; Liu, Q Y; Shaffer, K M; Chang, Y H; Zhang, L; Pancrazio, J J; Pant, H C; Stenger, D A; Barker, J L

    2000-04-01

    Increasing evidence has shown that some neurotransmitters act as growth-regulatory signals during brain development. Here we report a role for the classical neurotransmitter acetylcholine (ACh) to stimulate proliferation of neural stem cells and stem cell-derived progenitor cells during neural cell lineage progression in vitro. Neuroepithelial cells in the ventricular zone of the embryonic rat cortex were found to express the m2 subtype of the muscarinic receptor. Neural precursor cells dissociated from the embryonic rat cortical neuroepithelium were expanded in culture with basic fibroblast growth factor (bFGF). reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the presence of m2, m3 and m4 muscarinic receptor subtype transcripts, while immunocytochemistry demonstrated m2 protein. ACh and carbachol induced an increase in cytosolic Ca2+ and membrane currents in proliferating (BrdU+) cells, both of which were abolished by atropine. Exposure of bFGF-deprived precursor cells to muscarinic agonists not only increased both cell number and DNA synthesis, but also enhanced differentiation of neurons. These effects were blocked by atropine, indicating the involvement of muscarinic ACh receptors. The growth-stimulating effects were also antagonized by a panel of inhibitors of second messengers, including 1,2-bis-(O-aminophenoxy)-ethane-N,N,N', N'-tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, EGTA to complex extracellular Ca2+, pertussis toxin, which uncouples certain G-proteins, the protein kinase C inhibitor H7 and the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Muscarinic agonists activated MAPK, which was significantly inhibited by atropine and the same panel of inhibitors. Thus, muscarinic receptors expressed by neural precursors transduce a growth-regulatory signal during neurogenesis via pathways involving pertussis toxin-sensitive G-proteins, Ca2+ signalling, protein kinase C activation, MAPK phosphorylation and DNA synthesis.

  17. Alcohol's actions on neuronal nicotinic acetylcholine receptors.

    PubMed

    Davis, Tiffany J; de Fiebre, Christopher M

    2006-01-01

    Although it has been known for many years that alcoholism and tobacco addiction often co-occur, relatively little information is available on the biological factors that regulate the co-use and abuse of nicotine and alcohol. In the brain, nicotine acts at several different types of receptors collectively known as nicotinic acetylcholine receptors (nAChRs). Alcohol also acts on at least some of these receptors, enhancing the function of some nAChR subtypes and inhibiting the activity of others. Chronic alcohol and nicotine administration also lead to changes in the numbers of nAChRs. Natural variations (i.e., polymorphisms) in the genes encoding different nAChR subunits may be associated with individual differences in the sensitivity to some of alcohol's and nicotine's effects. Finally, at least one subtype of nAChR may help protect cells against alcohol-induced neurotoxicity.

  18. Enhancement of Interface Characteristics of Neural Probe Based on Graphene, ZnO Nanowires, and Conducting Polymer PEDOT.

    PubMed

    Ryu, Mingyu; Yang, Jae Hoon; Ahn, Yumi; Sim, Minkyung; Lee, Kyung Hwa; Kim, Kyungsoo; Lee, Taeju; Yoo, Seung-Jun; Kim, So Yeun; Moon, Cheil; Je, Minkyu; Choi, Ji-Woong; Lee, Youngu; Jang, Jae Eun

    2017-03-29

    In the growing field of brain-machine interface (BMI), the interface between electrodes and neural tissues plays an important role in the recording and stimulation of neural signals. To minimize tissue damage while retaining high sensitivity, a flexible and a smaller electrode with low impedance is required. However, it is a major challenge to reduce electrode size while retaining the conductive characteristics of the electrode. In addition, the mechanical mismatch between stiff electrodes and soft tissues creates damaging reactive tissue responses. Here, we demonstrate a neural probe structure based on graphene, ZnO nanowires, and conducting polymer that provides flexibility and low impedance performance. A hybrid Au and graphene structure was utilized to achieve both flexibility and good conductivity. Using ZnO nanowires to increase the effective surface area drastically decreased the impedance value and enhanced the signal-to-noise ratio (SNR). A poly[3,4-ethylenedioxythiophene] (PEDOT) coating on the neural probe improved the electrical characteristics of the electrode while providing better biocompatibility. In vivo neural signal recordings showed that our neural probe can detect clearer signals.

  19. Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors.

    PubMed

    Xue, Bing; Mao, Li-Min; Jin, Dao-Zhong; Wang, John Q

    2015-10-01

    Dopamine and acetylcholine are two principal transmitters in the striatum and are usually balanced to modulate local neural activity and to maintain striatal homeostasis. This study investigates the role of dopamine and muscarinic acetylcholine receptors in the regulation of a central signaling protein, i.e., the mitogen-activated protein kinase (MAPK). We focus on the synaptic pool of MAPKs because of the fact that these kinases reside in peripheral synaptic structures in addition to their somatic locations. We show that a systemic injection of dopamine D1 receptor (D1R) agonist SKF81297 enhances phosphorylation of extracellular signal-regulated kinases (ERKs), a prototypic subclass of MAPKs, in the adult rat striatum. Similar results were observed in another dopamine-responsive region, the medial prefrontal cortex (mPFC). The dopamine D2 receptor agonist quinpirole had no such effects. Pretreatment with a positive allosteric modulator (PAM) of muscarinic acetylcholine M4 receptors (M4Rs), VU0152100, attenuated the D1R agonist-stimulated ERK phosphorylation in the two regions, whereas the PAM itself did not alter basal ERK phosphorylation. All drug treatments had no effect on phosphorylation of c-Jun N-terminal kinases (JNKs), another MAPK subclass, in the striatum and mPFC. These results demonstrate that dopamine and acetylcholine are integrated to control synaptic ERK but not JNK activation in striatal and mPFC neurons in vivo. Activation of M4Rs exerts an inhibitory effect on the D1R-mediated upregulation of synaptic ERK phosphorylation.

  20. Acetylcholine Protects against Candida albicans Infection by Inhibiting Biofilm Formation and Promoting Hemocyte Function in a Galleria mellonella Infection Model

    PubMed Central

    Rajendran, Ranjith; Borghi, Elisa; Falleni, Monica; Perdoni, Federica; Tosi, Delfina; Lappin, David F.; O'Donnell, Lindsay; Greetham, Darren; Ramage, Gordon

    2015-01-01

    Both neuronal acetylcholine and nonneuronal acetylcholine have been demonstrated to modulate inflammatory responses. Studies investigating the role of acetylcholine in the pathogenesis of bacterial infections have revealed contradictory findings with regard to disease outcome. At present, the role of acetylcholine in the pathogenesis of fungal infections is unknown. Therefore, the aim of this study was to determine whether acetylcholine plays a role in fungal biofilm formation and the pathogenesis of Candida albicans infection. The effect of acetylcholine on C. albicans biofilm formation and metabolism in vitro was assessed using a crystal violet assay and phenotypic microarray analysis. Its effect on the outcome of a C. albicans infection, fungal burden, and biofilm formation were investigated in vivo using a Galleria mellonella infection model. In addition, its effect on modulation of host immunity to C. albicans infection was also determined in vivo using hemocyte counts, cytospin analysis, larval histology, lysozyme assays, hemolytic assays, and real-time PCR. Acetylcholine was shown to have the ability to inhibit C. albicans biofilm formation in vitro and in vivo. In addition, acetylcholine protected G. mellonella larvae from C. albicans infection mortality. The in vivo protection occurred through acetylcholine enhancing the function of hemocytes while at the same time inhibiting C. albicans biofilm formation. Furthermore, acetylcholine also inhibited inflammation-induced damage to internal organs. This is the first demonstration of a role for acetylcholine in protection against fungal infections, in addition to being the first report that this molecule can inhibit C. albicans biofilm formation. Therefore, acetylcholine has the capacity to modulate complex host-fungal interactions and plays a role in dictating the pathogenesis of fungal infections. PMID:26092919

  1. A new paradigm of electrical stimulation to enhance sensory neural function.

    PubMed

    Breen, Paul P; ÓLaighin, Gearóid; McIntosh, Caroline; Dinneen, Sean F; Quinlan, Leo R; Serrador, Jorge M

    2014-08-01

    The ability to improve peripheral neural transmission would have significant therapeutic potential in medicine. A technology of this kind could be used to restore and/or enhance sensory function in individuals with depressed sensory function, such as older adults or patients with peripheral neuropathies. The goal of this study was to investigate if a new paradigm of subsensory electrical noise stimulation enhances somatosensory function. Vibration (50Hz) was applied with a Neurothesiometer to the plantar aspect of the foot in the presence or absence of subsensory electrical noise (1/f type). The noise was applied at a proximal site, on a defined region of the tibial nerve path above the ankle. Vibration perception thresholds (VPT) of younger adults were measured in control and experimental conditions, in the absence or presence of noise respectively. An improvement of ∼16% in VPT was found in the presence of noise. These are the first data to demonstrate that modulation of axonal transmission with externally applied electrical noise improves perception of tactile stimuli in humans.

  2. An enhanced fuzzy min-max neural network for pattern classification.

    PubMed

    Mohammed, Mohammed Falah; Lim, Chee Peng

    2015-03-01

    An enhanced fuzzy min-max (EFMM) network is proposed for pattern classification in this paper. The aim is to overcome a number of limitations of the original fuzzy min-max (FMM) network and improve its classification performance. The key contributions are three heuristic rules to enhance the learning algorithm of FMM. First, a new hyperbox expansion rule to eliminate the overlapping problem during the hyperbox expansion process is suggested. Second, the existing hyperbox overlap test rule is extended to discover other possible overlapping cases. Third, a new hyperbox contraction rule to resolve possible overlapping cases is provided. Efficacy of EFMM is evaluated using benchmark data sets and a real medical diagnosis task. The results are better than those from various FMM-based models, support vector machine-based, Bayesian-based, decision tree-based, fuzzy-based, and neural-based classifiers. The empirical findings show that the newly introduced rules are able to realize EFMM as a useful model for undertaking pattern classification problems.

  3. Musicians' Enhanced Neural Differentiation of Speech Sounds Arises Early in Life: Developmental Evidence from Ages 3 to 30

    PubMed Central

    Strait, Dana L.; O'Connell, Samantha; Parbery-Clark, Alexandra; Kraus, Nina

    2014-01-01

    The perception and neural representation of acoustically similar speech sounds underlie language development. Music training hones the perception of minute acoustic differences that distinguish sounds; this training may generalize to speech processing given that adult musicians have enhanced neural differentiation of similar speech syllables compared with nonmusicians. Here, we asked whether this neural advantage in musicians is present early in life by assessing musically trained and untrained children as young as age 3. We assessed auditory brainstem responses to the speech syllables /ba/ and /ga/ as well as auditory and visual cognitive abilities in musicians and nonmusicians across 3 developmental time-points: preschoolers, school-aged children, and adults. Cross-phase analyses objectively measured the degree to which subcortical responses differed to these speech syllables in musicians and nonmusicians for each age group. Results reveal that musicians exhibit enhanced neural differentiation of stop consonants early in life and with as little as a few years of training. Furthermore, the extent of subcortical stop consonant distinction correlates with auditory-specific cognitive abilities (i.e., auditory working memory and attention). Results are interpreted according to a corticofugal framework for auditory learning in which subcortical processing enhancements are engendered by strengthened cognitive control over auditory function in musicians. PMID:23599166

  4. Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine.

    PubMed

    Ren, Zuo Jun; Mummalaneni, Shobha; Qian, Jie; Baumgarten, Clive M; DeSimone, John A; Lyall, Vijay

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol.

  5. Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine

    PubMed Central

    Ren, Zuo Jun; Mummalaneni, Shobha; Qian, Jie; Baumgarten, Clive M.; DeSimone, John A.; Lyall, Vijay

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol. PMID:26039516

  6. The Hippo pathway member YAP enhances human neural crest cell fate and migration.

    PubMed

    Hindley, Christopher J; Condurat, Alexandra Larisa; Menon, Vishal; Thomas, Ria; Azmitia, Luis M; Davis, Jason A; Pruszak, Jan

    2016-03-16

    The Hippo/YAP pathway serves as a major integrator of cell surface-mediated signals and regulates key processes during development and tumorigenesis. The neural crest is an embryonic tissue known to respond to multiple environmental cues in order to acquire appropriate cell fate and migration properties. Using multiple in vitro models of human neural development (pluripotent stem cell-derived neural stem cells; LUHMES, NTERA2 and SH-SY5Y cell lines), we investigated the role of Hippo/YAP signaling in neural differentiation and neural crest development. We report that the activity of YAP promotes an early neural crest phenotype and migration, and provide the first evidence for an interaction between Hippo/YAP and retinoic acid signaling in this system.

  7. Effect of opioid peptides on electrically evoked acetylcholine release from Torpedo electromotor neurons.

    PubMed

    Oron, L; Sarne, Y; Michaelson, D M

    1991-04-29

    The opioid peptide dynorphin A(1-8) (1 micron) increased acetylcholine release from the Torpedo electric organ by approximately twofold. This effect was reversed by the opiate antagonist naloxone. The effect of Dyn A(1-8) on acetylcholine release was found to vary in magnitude with the seasons of the year, with maximal enhancement being observed in the summer and none in winter. Dynorphin B, methionine-enkephalin and leucine-enkephalin also increased acetylcholine release and showed similar seasonal variations. These findings suggest that acetylcholine release from Torpedo electromotor neurons is regulated by opiate receptors. The physiological significance of these observations is discussed in view of the previous findings that the Torpedo neurons contain an endogenous enkephalin-like peptide.

  8. Enhanced biocompatibility of neural probes by integrating microstructures and delivering anti-inflammatory agents via microfluidic channels

    NASA Astrophysics Data System (ADS)

    Liu, Bin; Kim, Eric; Meggo, Anika; Gandhi, Sachin; Luo, Hao; Kallakuri, Srinivas; Xu, Yong; Zhang, Jinsheng

    2017-04-01

    Objective. Biocompatibility is a major issue for chronic neural implants, involving inflammatory and wound healing responses of neurons and glial cells. To enhance biocompatibility, we developed silicon-parylene hybrid neural probes with open architecture electrodes, microfluidic channels and a reservoir for drug delivery to suppress tissue responses. Approach. We chronically implanted our neural probes in the rat auditory cortex and investigated (1) whether open architecture electrode reduces inflammatory reaction by measuring glial responses; and (2) whether delivery of antibiotic minocycline reduces inflammatory and tissue reaction. Four weeks after implantation, immunostaining for glial fibrillary acid protein (astrocyte marker) and ionizing calcium-binding adaptor molecule 1 (macrophages/microglia cell marker) were conducted to identify immunoreactive astrocyte and microglial cells, and to determine the extent of astrocytes and microglial cell reaction/activation. A comparison was made between using traditional solid-surface electrodes and newly-designed electrodes with open architecture, as well as between deliveries of minocycline and artificial cerebral-spinal fluid diffused through microfluidic channels. Main results. The new probes with integrated micro-structures induced minimal tissue reaction compared to traditional electrodes at 4 weeks after implantation. Microcycline delivered through integrated microfluidic channels reduced tissue response as indicated by decreased microglial reaction around the neural probes implanted. Significance. The new design will help enhance the long-term stability of the implantable devices.

  9. Transit Clairvoyance: Enhancing TESS follow-up using artificial neural networks

    NASA Astrophysics Data System (ADS)

    Lam, Christopher; Kipping, David M.

    2017-01-01

    The upcoming TESS mission is expected to find thousands of transiting planets around bright stars, yet for three-quarters of the fields observed, the temporal coverage will limit discoveries to planets with guaranteed measured orbital periods below 13.7 days. From the Kepler catalog, the mean probability of these short-period transiting planets having additional longer period transiters, which would be missed by TESS, is 18%, a value ten times higher than that of the average star. It is perhaps not surprising that this probability is not uniform but functionally dependent upon the properties of the observed short-period transiters, ranging from less than 1% up to ~50%. Using artificial neural networks (ANNs) trained on the Kepler catalog and careful feature selection accounting for the differing sensitivity of TESS, we are able to predict the most likely short-period transiters to be accompanied by additional transiters. Through cross-validation, we predict that a targeted, optimized TESS transit follow-up survey using our trained ANN would have a discovery yield improved by a factor of two. Our work should enhance the efficiency of surveys following TESS targets for additional planets, improving the science yield derived from TESS and particularly benefiting the search for habitable-zone transiting worlds.

  10. Long-term enhancement (LTE) of postsynaptic potentials following neural conditioning, in mammalian sympathetic ganglia.

    PubMed

    Libet, B; Mochida, S

    1988-11-15

    Orthodromic, preganglionic conditioning stimulation can consistently induce long-term enhancement (LTE) (greater than 3 h) of the muscarinically mediated slow excitatory postsynaptic potential and the slow inhibitory postsynaptic potential. This was shown for superior cervical ganglia of rabbit and rat. Effective conditioning stimuli are in a physiologically observed range (3/s for 7 min, 5/s for 4 min, 10/s for 2 min, 20/s for 1 min). LTE was producible both homosynaptically and heterosynaptically. LTE can thus be associative, with conditioning synaptic input in one line inducing long-term changes in postsynaptic responses to another (heterosynaptic) input. The dopamine antagonist butaclamol depressed LTE, particularly that following the initial postconditioning period of 30 min. Adrenergic antagonists had no effect. This pharmacological evidence, coupled with the heterosynaptic induction of LTE, supports the view that neurally induced LTE may be at least partly mediated by endogenous dopamine. Another non-cholinergic but non-adrenergic transmitter (possibly a peptide) might contribute to the LTE seen in the initial 30 min postconditioning. The present, orthodromically induced LTE is clearly different from the long-term potentiation widely studied in hippocampus, etc., in the modes of induction and synaptic mediation.

  11. Linagliptin enhances neural stem cell proliferation after stroke in type 2 diabetic mice.

    PubMed

    Darsalia, Vladimer; Olverling, Anna; Larsson, Martin; Mansouri, Shiva; Nathanson, David; Nyström, Thomas; Klein, Thomas; Sjöholm, Åke; Patrone, Cesare

    2014-05-01

    Dipeptidyl peptidase 4 (DPP-4) inhibitors are current drugs for the treatment of type 2 diabetes (T2D) based on their main property to enhance endogenous glucagon-like peptide-1 (GLP-1) levels, thus increasing insulin secretion. However, the mechanism of action of DPP-4 inhibition in extra pancreatic tissues has been poorly investigated and it might occur differently from that induced by GLP-1R agonists. Increased adult neurogenesis by GLP-1R agonists has been suggested to play a role in functional recovery in animal models of brain disorders. We recently showed that the DPP-4 inhibitor linagliptin reduces brain damage after stroke in normal and type 2 diabetic (T2D) mice. The aim of this study was to determine whether linagliptin impacts stroke-induced neurogenesis. T2D was induced by 25 weeks of high-fat diet. Linagliptin treatment was carried out for 7 weeks. Standard diet fed-mice were used as controls. Stroke was induced by middle cerebral artery occlusion 4 weeks into the linagliptin treatment. Neural stem cell (NSC) proliferation/neuroblast formation and striatal neurogenesis/gliogenesis were assessed 3 weeks after stroke. The effect of linagliptin on NSC viability was also determined in vitro. The results show that linagliptin enhances NSC proliferation in T2D mice but not in normal mice. Linagliptin did not increase NSC number in vitro indicating that the effect of linagliptin on NSC proliferation in T2D is indirect. Neurogenesis and gliogenesis were not affected. In conclusion, we found no correlation between acute neuroprotection (occurring in both T2D and normal mice) and increased NSC proliferation (occurring only in T2D mice). However, our results show that linagliptin evokes a differential response on NSC proliferation after stroke in normal and T2D mice suggesting that DPP-4 inhibition effect in the CNS might go beyond the well known increase of GLP-1.

  12. Enhanced proliferation of PC12 neural cells on untreated, nanotextured glass coverslips

    NASA Astrophysics Data System (ADS)

    Islam, Muhymin; Atmaramani, Rahul; Mukherjee, Siddhartha; Ghosh, Santaneel; Iqbal, Samir M.

    2016-10-01

    Traumatic injury to the central nervous system is a significant health problem. There is no effective treatment available partly because of the complexity of the system. Implementation of multifunctional micro- and nano-device based combinatorial therapeutics can provide biocompatible and tunable approaches to perform on-demand release of specific drugs. This can help the damaged cells to improve neuronal survival, regeneration of axons, and their reconnection to appropriate targets. Nano-topological features induced rapid cell growth is especially important towards the design of effective platforms to facilitate damaged neural circuit reconstruction. In this study, for the first time, feasibility of neuron-like PC12 cell growth on untreated and easy to prepare nanotextured surfaces has been carried out. The PC12 neuron-like cells were cultured on micro reactive ion etched nanotextured glass coverslips. The effect of nanotextured topology as physical cue for the growth of PC12 cells was observed exclusively, eliminating the possible influence(s) of the enhanced concentration of coated materials on the surface. The cell density was observed to increase by almost 200% on nanotextured coverslips compared to plain coverslips. The morphology study indicated that PC12 cell attachment and growth on the nanotextured substrates did not launch any apoptotic machinery of the cell. Less than 5% cells deformed and depicted condensed nuclei with apoptotic bodies on nanotextured surfaces which is typical for the normal cell handling and culture. Enhanced PC12 cell proliferation by such novel and easy to prepare substrates is not only attractive for neurite outgrowth and guidance, but may be used to increase the affinity of similar cancerous cells (ex: B35 neuroblastoma) and rapid proliferation thereafter—towards the development of combinatorial theranostics to diagnose and treat aggressive cancers like neuroblastoma.

  13. Enhanced proliferation of PC12 neural cells on untreated, nanotextured glass coverslips.

    PubMed

    Islam, Muhymin; Atmaramani, Rahul; Mukherjee, Siddhartha; Ghosh, Santaneel; Iqbal, Samir M

    2016-10-14

    Traumatic injury to the central nervous system is a significant health problem. There is no effective treatment available partly because of the complexity of the system. Implementation of multifunctional micro- and nano-device based combinatorial therapeutics can provide biocompatible and tunable approaches to perform on-demand release of specific drugs. This can help the damaged cells to improve neuronal survival, regeneration of axons, and their reconnection to appropriate targets. Nano-topological features induced rapid cell growth is especially important towards the design of effective platforms to facilitate damaged neural circuit reconstruction. In this study, for the first time, feasibility of neuron-like PC12 cell growth on untreated and easy to prepare nanotextured surfaces has been carried out. The PC12 neuron-like cells were cultured on micro reactive ion etched  nanotextured glass coverslips. The effect of nanotextured topology as physical cue for the growth of PC12 cells was observed exclusively, eliminating the possible influence(s) of the enhanced concentration of coated materials on the surface. The cell density was observed to increase by almost 200% on nanotextured coverslips compared to plain coverslips. The morphology study indicated that PC12 cell attachment and growth on the nanotextured substrates did not launch any apoptotic machinery of the cell. Less than 5% cells deformed and depicted condensed nuclei with apoptotic bodies on nanotextured surfaces which is typical for the normal cell handling and culture. Enhanced PC12 cell proliferation by such novel and easy to prepare substrates is not only attractive for neurite outgrowth and guidance, but may be used to increase the affinity of similar cancerous cells (ex: B35 neuroblastoma) and rapid proliferation thereafter-towards the development of combinatorial theranostics to diagnose and treat aggressive cancers like neuroblastoma.

  14. Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats.

    PubMed

    Sakata, Hiroyuki; Niizuma, Kuniyasu; Yoshioka, Hideyuki; Kim, Gab Seok; Jung, Joo Eun; Katsu, Masataka; Narasimhan, Purnima; Maier, Carolina M; Nishiyama, Yasuhiro; Chan, Pak H

    2012-03-07

    Transplantation of neural stem cells (NSCs) offers a novel therapeutic strategy for stroke; however, massive grafted cell death following transplantation, possibly due to a hostile host brain environment, lessens the effectiveness of this approach. Here, we have investigated whether reprogramming NSCs with minocycline, a broadly used antibiotic also known to possess cytoprotective properties, enhances survival of grafted cells and promotes neuroprotection in ischemic stroke. NSCs harvested from the subventricular zone of fetal rats were preconditioned with minocycline in vitro and transplanted into rat brains 6 h after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from days 0-28 after stroke. For in vitro experiments, NSCs were subjected to oxygen-glucose deprivation and reoxygenation. Cell viability and antioxidant gene expression were analyzed. Minocycline preconditioning protected the grafted NSCs from ischemic reperfusion injury via upregulation of Nrf2 and Nrf2-regulated antioxidant genes. Additionally, preconditioning with minocycline induced the NSCs to release paracrine factors, including brain-derived neurotrophic factor, nerve growth factor, glial cell-derived neurotrophic factor, and vascular endothelial growth factor. Moreover, transplantation of the minocycline-preconditioned NSCs significantly attenuated infarct size and improved neurological performance, compared with non-preconditioned NSCs. Minocycline-induced neuroprotection was abolished by transfecting the NSCs with Nrf2-small interfering RNA before transplantation. Thus, preconditioning with minocycline, which reprograms NSCs to tolerate oxidative stress after ischemic reperfusion injury and express higher levels of paracrine factors through Nrf2 up-regulation, is a simple and safe approach to enhance the effectiveness of transplantation therapy in ischemic stroke.

  15. Enhanced Neural Responses to Imagined Primary Rewards Predict Reduced Monetary Temporal Discounting.

    PubMed

    Hakimi, Shabnam; Hare, Todd A

    2015-09-23

    The pervasive tendency to discount the value of future rewards varies considerably across individuals and has important implications for health and well-being. Here, we used fMRI with human participants to examine whether an individual's neural representation of an imagined primary reward predicts the degree to which the value of delayed monetary payments is discounted. Because future rewards can never be experienced at the time of choice, imagining or simulating the benefits of a future reward may play a critical role in decisions between alternatives with either immediate or delayed benefits. We found that enhanced ventromedial prefrontal cortex response during imagined primary reward receipt was correlated with reduced discounting in a separate monetary intertemporal choice task. Furthermore, activity in enhanced ventromedial prefrontal cortex during reward imagination predicted temporal discounting behavior both between- and within-individual decision makers with 62% and 73% mean balanced accuracy, respectively. These results suggest that the quality of reward imagination may impact the degree to which future outcomes are discounted. Significance statement: We report a novel test of the hypothesis that an important factor influencing the discount rate for future rewards is the quality with which they are imagined or estimated in the present. Previous work has shown that temporal discounting is linked to individual characteristics ranging from general intelligence to the propensity for addiction. We demonstrate that individual differences in a neurobiological measure of primary reward imagination are significantly correlated with discounting rates for future monetary payments. Moreover, our neurobiological measure of imagination can be used to accurately predict choice behavior both between and within individuals. These results suggest that improving reward imagination may be a useful therapeutic target for individuals whose high discount rates promote

  16. Nicotinic Acetylcholine Receptors in Sensory Cortex

    ERIC Educational Resources Information Center

    Metherate, Raju

    2004-01-01

    Acetylcholine release in sensory neocortex contributes to higher-order sensory function, in part by activating nicotinic acetylcholine receptors (nAChRs). Molecular studies have revealed a bewildering array of nAChR subtypes and cellular actions; however, there is some consensus emerging about the major nAChR subtypes and their functions in…

  17. Spaced Learning Enhances Subsequent Recognition Memory by Reducing Neural Repetition Suppression

    ERIC Educational Resources Information Center

    Xue, Gui; Mei, Leilei; Chen, Chuansheng; Lu, Zhong-Lin; Poldrack, Russell; Dong, Qi

    2011-01-01

    Spaced learning usually leads to better recognition memory as compared with massed learning, yet the underlying neural mechanisms remain elusive. One open question is whether the spacing effect is achieved by reducing neural repetition suppression. In this fMRI study, participants were scanned while intentionally memorizing 120 novel faces, half…

  18. Specificity of CNS and PNS regulatory subelements comprising pan-neural enhancers of the deadpan and scratch genes is achieved by repression.

    PubMed

    Emery, J F; Bier, E

    1995-11-01

    The Drosophila pan-neural genes deadpan (dpn) and scratch (scrt) are expressed in most or all developing neural precursor cells of the central nervous system (CNS) and peripheral nervous system (PNS). We have identified a cis-acting enhancer element driving full pan-neural expression of the dpn gene which is composed of independent CNS- and PNS-specific subelements. We have also identified CNS- and PNS-specific subelements of the scrt enhancer. Deletion analysis of the dpn and scrt PNS-specific subelements reveals that PNS specificity of these two evolutionarily unrelated enhancers is achieved in part by repression of CNS expression. We discuss the implications of the striking organizational similarities of the dpn, scrt, and sna pan-neural enhancers.

  19. Prediction of municipal solid waste generation using artificial neural network approach enhanced by structural break analysis.

    PubMed

    Adamović, Vladimir M; Antanasijević, Davor Z; Ristić, Mirjana Đ; Perić-Grujić, Aleksandra A; Pocajt, Viktor V

    2017-01-01

    This paper presents the development of a general regression neural network (GRNN) model for the prediction of annual municipal solid waste (MSW) generation at the national level for 44 countries of different size, population and economic development level. Proper modelling of MSW generation is essential for the planning of MSW management system as well as for the simulation of various environmental impact scenarios. The main objective of this work was to examine the potential influence of economy crisis (global or local) on the forecast of MSW generation obtained by the GRNN model. The existence of the so-called structural breaks that occur because of the economic crisis in the studied period (2000-2012) for each country was determined and confirmed using the Chow test and Quandt-Andrews test. Two GRNN models, one which did not take into account the influence of the economic crisis (GRNN) and another one which did (SB-GRNN), were developed. The novelty of the applied method is that it uses broadly available social, economic and demographic indicators and indicators of sustainability, together with GRNN and structural break testing for the prediction of MSW generation at the national level. The obtained results demonstrate that the SB-GRNN model provide more accurate predictions than the model which neglected structural breaks, with a mean absolute percentage error (MAPE) of 4.0 % compared to 6.7 % generated by the GRNN model. The proposed model enhanced with structural breaks can be a viable alternative for a more accurate prediction of MSW generation at the national level, especially for developing countries for which a lack of MSW data is notable.

  20. Overexpression of MCT8 enhances the differentiation of ES cells into neural progenitors.

    PubMed

    Sugiura, Mika; Nagaoka, Masato; Yabuuchi, Hikaru; Akaike, Toshihiro

    2007-09-07

    Embryonic stem (ES) cell differentiation is regulated by cytokines and growth factors, as well as small-compound chemicals incorporated into cells by transporter proteins. Little is known regarding the effect of transporters on ES cell differentiation. This study focused on the effect of transporters during the neural-lineage differentiation of ES cells. Among the 27 types of SLC family transporters, MCT8 expression was coincident with that of neural stem cell markers, and the overexpression of MCT8 accelerated the differentiation into neural cells. These results suggested that the transporters and their substrates also play a crucial role in the regulation of ES cell differentiation.

  1. Locomotion Enhances Neural Encoding of Visual Stimuli in Mouse V1.

    PubMed

    Dadarlat, Maria C; Stryker, Michael P

    2017-04-05

    Neurons in mouse primary visual cortex (V1) are selective for particular properties of visual stimuli. Locomotion causes a change in cortical state that leaves their selectivity unchanged but strengthens their responses. Both locomotion and the change in cortical state are thought to be initiated by projections from the mesencephalic locomotor region, the latter through a disinhibitory circuit in V1. By recording simultaneously from a large number of single neurons in alert mice viewing moving gratings, we investigated the relationship between locomotion and the information contained within the neural population. We found that locomotion improved encoding of visual stimuli in V1 by two mechanisms. First, locomotion-induced increases in firing rates enhanced the mutual information between visual stimuli and single neuron responses over a fixed window of time. Second, stimulus discriminability was improved, even for fixed population firing rates, because of a decrease in noise correlations across the population. These two mechanisms contributed differently to improvements in discriminability across cortical layers, with changes in firing rates most important in the upper layers and changes in noise correlations most important in layer V. Together, these changes resulted in a threefold to fivefold reduction in the time needed to precisely encode grating direction and orientation. These results support the hypothesis that cortical state shifts during locomotion to accommodate an increased load on the visual system when mice are moving.SIGNIFICANCE STATEMENT This paper contains three novel findings about the representation of information in neurons within the primary visual cortex of the mouse. First, we show that locomotion reduces by at least a factor of 3 the time needed for information to accumulate in the visual cortex that allows the distinction of different visual stimuli. Second, we show that the effect of locomotion is to increase information in cells of all

  2. Synergistic combination of near-infrared irradiation and targeted gold nanoheaters for enhanced photothermal neural stimulation

    PubMed Central

    Eom, Kyungsik; Im, Changkyun; Hwang, Seoyoung; Eom, Seyoung; Kim, Tae-Seong; Jeong, Hae Sun; Kim, Kyung Hwan; Byun, Kyung Min; Jun, Sang Beom; Kim, Sung June

    2016-01-01

    Despite a potential of infrared neural stimulation (INS) for modulating neural activities, INS suffers from limited light confinement and bulk tissue heating. Here, a novel methodology for an advanced optical stimulation is proposed by combining near-infrared (NIR) stimulation with gold nanorods (GNRs) targeted to neuronal cell membrane. We confirmed experimentally that in vitro and in vivo neural activation is associated with a local heat generation based on NIR stimulation and GNRs. Compared with the case of NIR stimulation without an aid of GNRs, combination with cell-targeted GNRs allows photothermal stimulation with faster neural response, lower delivered energy, higher stimulation efficiency and stronger behavior change. Since the suggested method can reduce a requisite radiant exposure level and alleviate a concern of tissue damage, it is expected to open up new possibilities for applications to optical neuromodulations for diverse excitable tissues and treatments of neurological disorders. PMID:27446678

  3. Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

    PubMed Central

    Singh, Sandeep; Pillai, Smitha; Chellappan, Srikumar

    2011-01-01

    Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer. PMID:21541211

  4. Principal component analysis-enhanced cosine radial basis function neural network for robust epilepsy and seizure detection.

    PubMed

    Ghosh-Dastidar, Samanwoy; Adeli, Hojjat; Dadmehr, Nahid

    2008-02-01

    A novel principal component analysis (PCA)-enhanced cosine radial basis function neural network classifier is presented. The two-stage classifier is integrated with the mixed-band wavelet-chaos methodology, developed earlier by the authors, for accurate and robust classification of electroencephalogram (EEGs) into healthy, ictal, and interictal EEGs. A nine-parameter mixed-band feature space discovered in previous research for effective EEG representation is used as input to the two-stage classifier. In the first stage, PCA is employed for feature enhancement. The rearrangement of the input space along the principal components of the data improves the classification accuracy of the cosine radial basis function neural network (RBFNN) employed in the second stage significantly. The classification accuracy and robustness of the classifier are validated by extensive parametric and sensitivity analysis. The new wavelet-chaos-neural network methodology yields high EEG classification accuracy (96.6%) and is quite robust to changes in training data with a low standard deviation of 1.4%. For epilepsy diagnosis, when only normal and interictal EEGs are considered, the classification accuracy of the proposed model is 99.3%. This statistic is especially remarkable because even the most highly trained neurologists do not appear to be able to detect interictal EEGs more than 80% of the times.

  5. SBE6: a novel long-range enhancer involved in driving sonic hedgehog expression in neural progenitor cells

    PubMed Central

    Benabdallah, Nezha S.; Gautier, Philippe; Hekimoglu-Balkan, Betul; Lettice, Laura A.; Bhatia, Shipra

    2016-01-01

    The expression of genes with key roles in development is under very tight spatial and temporal control, mediated by enhancers. A classic example of this is the sonic hedgehog gene (Shh), which plays a pivotal role in the proliferation, differentiation and survival of neural progenitor cells both in vivo and in vitro. Shh expression in the brain is tightly controlled by several known enhancers that have been identified through genetic, genomic and functional assays. Using chromatin profiling during the differentiation of embryonic stem cells to neural progenitor cells, here we report the identification of a novel long-range enhancer for Shh—Shh-brain-enhancer-6 (SBE6)—that is located 100 kb upstream of Shh and that is required for the proper induction of Shh expression during this differentiation programme. This element is capable of driving expression in the vertebrate brain. Our study illustrates how a chromatin-focused approach, coupled to in vivo testing, can be used to identify new cell-type specific cis-regulatory elements, and points to yet further complexity in the control of Shh expression during embryonic brain development. PMID:27852806

  6. SBE6: a novel long-range enhancer involved in driving sonic hedgehog expression in neural progenitor cells.

    PubMed

    Benabdallah, Nezha S; Gautier, Philippe; Hekimoglu-Balkan, Betul; Lettice, Laura A; Bhatia, Shipra; Bickmore, Wendy A

    2016-11-01

    The expression of genes with key roles in development is under very tight spatial and temporal control, mediated by enhancers. A classic example of this is the sonic hedgehog gene (Shh), which plays a pivotal role in the proliferation, differentiation and survival of neural progenitor cells both in vivo and in vitro. Shh expression in the brain is tightly controlled by several known enhancers that have been identified through genetic, genomic and functional assays. Using chromatin profiling during the differentiation of embryonic stem cells to neural progenitor cells, here we report the identification of a novel long-range enhancer for Shh-Shh-brain-enhancer-6 (SBE6)-that is located 100 kb upstream of Shh and that is required for the proper induction of Shh expression during this differentiation programme. This element is capable of driving expression in the vertebrate brain. Our study illustrates how a chromatin-focused approach, coupled to in vivo testing, can be used to identify new cell-type specific cis-regulatory elements, and points to yet further complexity in the control of Shh expression during embryonic brain development.

  7. Formation and reverberation of sequential neural activity patterns evoked by sensory stimulation are enhanced during cortical desynchronization.

    PubMed

    Bermudez Contreras, Edgar J; Schjetnan, Andrea Gomez Palacio; Muhammad, Arif; Bartho, Peter; McNaughton, Bruce L; Kolb, Bryan; Gruber, Aaron J; Luczak, Artur

    2013-08-07

    Memory formation is hypothesized to involve the generation of event-specific neural activity patterns during learning and the subsequent spontaneous reactivation of these patterns. Here, we present evidence that these processes can also be observed in urethane-anesthetized rats and are enhanced by desynchronized brain state evoked by tail pinch, subcortical carbachol infusion, or systemic amphetamine administration. During desynchronization, we found that repeated tactile or auditory stimulation evoked unique sequential patterns of neural firing in somatosensory and auditory cortex and that these patterns then reoccurred during subsequent spontaneous activity, similar to what we have observed in awake animals. Furthermore, the formation of these patterns was blocked by an NMDA receptor antagonist, suggesting that the phenomenon depends on synaptic plasticity. These results suggest that anesthetized animals with a desynchronized brain state could serve as a convenient model for studying stimulus-induced plasticity to improve our understanding of memory formation and replay in the brain.

  8. The conformation of acetylcholine at its target site in the membrane-embedded nicotinic acetylcholine receptor

    PubMed Central

    Williamson, P. T. F.; Verhoeven, A.; Miller, K. W.; Meier, B. H.; Watts, A.

    2007-01-01

    The conformation of the neurotransmitter acetylcholine bound to the fully functional nicotinic acetylcholine receptor embedded in its native membrane environment has been characterized by using frequency-selective recoupling solid-state NMR. Six dipolar couplings among five resolved 13C-labeled atoms of acetylcholine were measured. Bound acetylcholine adopts a bent conformation characterized with a quaternary ammonium-to-carbonyl distance of 5.1 Å. In this conformation, and with its orientation constrained to that previously determined by us, the acetylcholine could be docked satisfactorily in the agonist pocket of the agonist-bound, but not the agonist-free, crystal structure of a soluble acetylcholine-binding protein from Lymnaea stagnali. The quaternary ammonium group of the acetylcholine was determined to be within 3.9 Å of five aromatic residues and its acetyl group close to residues C187/188 of the principle and residue L112 of the complementary subunit. The observed >CO chemical shift is consistent with H bonding to the nicotinic acetylcholine receptor residues γY116 and δT119 that are homologous to L112 in the soluble acetylcholine-binding protein. PMID:17989232

  9. (R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties.

    PubMed

    Tatsumi, Ryo; Fujio, Masakazu; Takanashi, Shin-ichi; Numata, Atsushi; Katayama, Jiro; Satoh, Hiroyuki; Shiigi, Yasuyuki; Maeda, Jun-ichi; Kuriyama, Makoto; Horikawa, Takashi; Murozono, Takahiro; Hashimoto, Kenji; Tanaka, Hiroshi

    2006-07-13

    Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

  10. Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.

    PubMed

    Chan-Il, Choi; Young-Don, Lee; Heejaung, Kim; Kim, Seung Hyun; Suh-Kim, Haeyoung; Kim, Sung-Soo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.

  11. A new source difference artificial neural network for enhanced positioning accuracy

    NASA Astrophysics Data System (ADS)

    Bhatt, Deepak; Aggarwal, Priyanka; Devabhaktuni, Vijay; Bhattacharya, Prabir

    2012-10-01

    Integrated inertial navigation system (INS) and global positioning system (GPS) units provide reliable navigation solution compared to standalone INS or GPS. Traditional Kalman filter-based INS/GPS integration schemes have several inadequacies related to sensor error model and immunity to noise. Alternatively, multi-layer perceptron (MLP) neural networks with three layers have been implemented to improve the position accuracy of the integrated system. However, MLP neural networks show poor accuracy for low-cost INS because of the large inherent sensor errors. For the first time the paper demonstrates the use of knowledge-based source difference artificial neural network (SDANN) to improve navigation performance of low-cost sensor, with or without external aiding sources. Unlike the conventional MLP or artificial neural networks (ANN), the structure of SDANN consists of two MLP neural networks called the coarse model and the difference model. The coarse model learns the input-output data relationship whereas the difference model adds knowledge to the system and fine-tunes the coarse model output by learning the associated training or estimation error. Our proposed SDANN model illustrated a significant improvement in navigation accuracy of up to 81% over conventional MLP. The results demonstrate that the proposed SDANN method is effective for GPS/INS integration schemes using low-cost inertial sensors, with and without GPS.

  12. Fuzzy wavelet plus a quantum neural network as a design base for power system stability enhancement.

    PubMed

    Ganjefar, Soheil; Tofighi, Morteza; Karami, Hamidreza

    2015-11-01

    In this study, we introduce an indirect adaptive fuzzy wavelet neural controller (IAFWNC) as a power system stabilizer to damp inter-area modes of oscillations in a multi-machine power system. Quantum computing is an efficient method for improving the computational efficiency of neural networks, so we developed an identifier based on a quantum neural network (QNN) to train the IAFWNC in the proposed scheme. All of the controller parameters are tuned online based on the Lyapunov stability theory to guarantee the closed-loop stability. A two-machine, two-area power system equipped with a static synchronous series compensator as a series flexible ac transmission system was used to demonstrate the effectiveness of the proposed controller. The simulation and experimental results demonstrated that the proposed IAFWNC scheme can achieve favorable control performance.

  13. Gestational naltrexone ameliorates fetal ethanol exposures enhancing effect on the postnatal behavioral and neural response to ethanol

    PubMed Central

    Youngentob, Steven L; Kent, Paul F; Youngentob, Lisa M

    2012-01-01

    The association between gestational exposure to ethanol and adolescent ethanol abuse is well established. Recent animal studies support the role of fetal ethanol experience-induced chemosensory plasticity as contributing to this observation. Previously, we established that fetal ethanol exposure, delivered through a dam’s diet throughout gestation, tuned the neural response of the peripheral olfactory system of early postnatal rats to the odor of ethanol. This occurred in conjunction with a loss of responsiveness to other odorants. The instinctive behavioral response to the odor of ethanol was also enhanced. Importantly, there was a significant contributory link between the altered response to the odor of ethanol and increased ethanol avidity when assessed in the same animals. Here, we tested whether the neural and behavioral olfactory plasticity, and their relationship to enhanced ethanol intake, is a result of the mere exposure to ethanol or whether it requires the animal to associate ethanol’s reinforcing properties with its odor attributes. In this later respect, the opioid system is important in the mediation (or modulation) of the reinforcing aspects of ethanol. To block endogenous opiates during prenatal life, pregnant rats received daily intraperitoneal administration of the opiate antagonist naltrexone from gestational day 6–21 jointly with ethanol delivered via diet. Relative to control progeny, we found that gestational exposure to naltrexone ameliorated the enhanced postnatal behavioral response to the odor of ethanol and postnatal drug avidity. Our findings support the proposition that in utero ethanol-induced olfactory plasticity (and its relationship to postnatal intake) requires, at least in part, the associative pairing between ethanol’s odor quality and its reinforcing aspects. We also found suggestive evidence that fetal naltrexone ameliorated the untoward effects of gestational ethanol exposure on the neural response to non

  14. Insect-machine interface: a carbon nanotube-enhanced flexible neural probe.

    PubMed

    Tsang, W M; Stone, Alice L; Otten, David; Aldworth, Zane N; Daniel, Tom L; Hildebrand, John G; Levine, Richard B; Voldman, Joel

    2012-03-15

    We developed microfabricated flexible neural probes (FNPs) to provide a bi-directional electrical link to the moth Manduca sexta. These FNPs can deliver electrical stimuli to, and capture neural activity from, the insect's central nervous system. They are comprised of two layers of polyimide with gold sandwiched in between in a split-ring geometry that incorporates the bi-cylindrical anatomical structure of the insect's ventral nerve cord. The FNPs provide consistent left and right abdominal stimulation both across animals and within an individual animal. The features of the stimulation (direction, threshold charge) are aligned with anatomical features of the moth. We also have used these FNPs to record neuronal activity in the ventral nerve cord of the moth. Finally, by integrating carbon nanotube (CNT)-Au nanocomposites into the FNPs we have reduced the interfacial impedance between the probe and the neural tissue, thus reducing the magnitude of stimulation voltage. This in turn allows use of the FNPs with a wireless stimulator, enabling stimulation and flight biasing of freely flying moths. Together, these FNPs present a potent new platform for manipulating and measuring the neural circuitry of insects, and for other nerves in humans and other animals with similar dimensions as the ventral nerve cord of the moth.

  15. Neural Basis of Repetition Priming during Mathematical Cognition: Repetition Suppression or Repetition Enhancement?

    ERIC Educational Resources Information Center

    Salimpoor, Valorie N.; Chang, Catie; Menon, Vinod

    2010-01-01

    We investigated the neural basis of repetition priming (RP) during mathematical cognition. Previous studies of RP have focused on repetition suppression as the basis of behavioral facilitation, primarily using word and object identification and classification tasks. More recently, researchers have suggested associative stimulus-response learning…

  16. Evidence for Neural Computations of Temporal Coherence in an Auditory Scene and Their Enhancement during Active Listening.

    PubMed

    O'Sullivan, James A; Shamma, Shihab A; Lalor, Edmund C

    2015-05-06

    The human brain has evolved to operate effectively in highly complex acoustic environments, segregating multiple sound sources into perceptually distinct auditory objects. A recent theory seeks to explain this ability by arguing that stream segregation occurs primarily due to the temporal coherence of the neural populations that encode the various features of an individual acoustic source. This theory has received support from both psychoacoustic and functional magnetic resonance imaging (fMRI) studies that use stimuli which model complex acoustic environments. Termed stochastic figure-ground (SFG) stimuli, they are composed of a "figure" and background that overlap in spectrotemporal space, such that the only way to segregate the figure is by computing the coherence of its frequency components over time. Here, we extend these psychoacoustic and fMRI findings by using the greater temporal resolution of electroencephalography to investigate the neural computation of temporal coherence. We present subjects with modified SFG stimuli wherein the temporal coherence of the figure is modulated stochastically over time, which allows us to use linear regression methods to extract a signature of the neural processing of this temporal coherence. We do this under both active and passive listening conditions. Our findings show an early effect of coherence during passive listening, lasting from ∼115 to 185 ms post-stimulus. When subjects are actively listening to the stimuli, these responses are larger and last longer, up to ∼265 ms. These findings provide evidence for early and preattentive neural computations of temporal coherence that are enhanced by active analysis of an auditory scene.

  17. Neural responses to target features outside a search array are enhanced during conjunction but not unique-feature search.

    PubMed

    Painter, David R; Dux, Paul E; Travis, Susan L; Mattingley, Jason B

    2014-02-26

    The visual world is typically too complex to permit full apprehension of its content from a single fixation. Humans therefore use visual search to direct attention and eye movements to locations or objects of interest in cluttered scenes. Psychophysical investigations have revealed that observers can select target elements from within an array of distractors on the basis of their spatial location or simple features, such as color. It remains unclear, however, how stimuli that lie outside the current search array are represented in the visual system. To investigate this, we recorded continuous neural activity using EEG while participants searched a foveal array of colored targets and distractors, and ignored irrelevant objects in the periphery. Search targets were defined either by a unique feature within the array or by a conjunction of features. Objects outside the array could match the target or distractor color within the array, or otherwise possessed a baseline (neutral) color present only in the periphery. The search array and irrelevant peripheral objects flickered at unique rates and thus evoked distinct frequency-tagged neural oscillations. During conjunction but not unique-feature search, target-colored objects outside the array evoked enhanced activity relative to distractor-colored and neutral objects. The results suggest that feature-based selection applies to stimuli at ignored peripheral locations, but only when central targets compete with distractors within the array. Distractor-colored and neutral objects evoked equivalent oscillatory responses, suggesting that feature-based selection at ignored locations during visual search arises exclusively from enhancement rather than suppression of neural activity.

  18. Extremely low-frequency electromagnetic fields enhance the proliferation and differentiation of neural progenitor cells cultured from ischemic brains.

    PubMed

    Cheng, Yannan; Dai, Yiqin; Zhu, Ximin; Xu, Haochen; Cai, Ping; Xia, Ruohong; Mao, Lizhen; Zhao, Bing-Qiao; Fan, Wenying

    2015-10-21

    In the mammalian brain, neurogenesis persists throughout the embryonic period and adulthood in the subventricular zone of the lateral ventricle and the granular zone (dentate gyrus) of the hippocampus. Newborn neural progenitor cells (NPCs) in the two regions play a critical role in structural and functional plasticity and neural regeneration after brain injury. Previous studies have reported that extremely low-frequency electromagnetic fields (ELF-EMF) could promote osteogenesis, angiogenesis, and cardiac stem cells' differentiation, which indicates that ELF-EMF might be an effective tool for regenerative therapy. The present studies were carried out to examine the effects of ELF-EMF on hippocampal NPCs cultured from embryonic and adult ischemic brains. We found that exposure to ELF-EMF (50 Hz, 0.4 mT) significantly enhanced the proliferation capability both in embryonic NPCs and in ischemic NPCs. Neuronal differentiation was also enhanced after 7 days of cumulative ELF-EMF exposure, whereas glial differentiation was not influenced markedly. The expression of phosphorylated Akt increased during the proliferation process when ischemic NPCs were exposed to ELF-EMF. However, blockage of the Akt pathway abolished the ELF-EMF-induced proliferation of ischemic NPCs. These data show that ELF-EMF promotes neurogenesis of ischemic NPCs and suggest that this effect may occur through the Akt pathway.Video abstract, Supplemental Digital Content 1, http://links.lww.com/WNR/A347.

  19. Language Learning Enhanced by Massive Multiple Online Role-Playing Games (MMORPGs) and the Underlying Behavioral and Neural Mechanisms

    PubMed Central

    Zhang, Yongjun; Song, Hongwen; Liu, Xiaoming; Tang, Dinghong; Chen, Yue-e; Zhang, Xiaochu

    2017-01-01

    Massive Multiple Online Role-Playing Games (MMORPGs) have increased in popularity among children, juveniles, and adults since MMORPGs’ appearance in this digital age. MMORPGs can be applied to enhancing language learning, which is drawing researchers’ attention from different fields and many studies have validated MMORPGs’ positive effect on language learning. However, there are few studies on the underlying behavioral or neural mechanism of such effect. This paper reviews the educational application of the MMORPGs based on relevant macroscopic and microscopic studies, showing that gamers’ overall language proficiency or some specific language skills can be enhanced by real-time online interaction with peers and game narratives or instructions embedded in the MMORPGs. Mechanisms underlying the educational assistant role of MMORPGs in second language learning are discussed from both behavioral and neural perspectives. We suggest that attentional bias makes gamers/learners allocate more cognitive resources toward task-related stimuli in a controlled or an automatic way. Moreover, with a moderating role played by activation of reward circuit, playing the MMORPGs may strengthen or increase functional connectivity from seed regions such as left anterior insular/frontal operculum (AI/FO) and visual word form area to other language-related brain areas. PMID:28303097

  20. Language Learning Enhanced by Massive Multiple Online Role-Playing Games (MMORPGs) and the Underlying Behavioral and Neural Mechanisms.

    PubMed

    Zhang, Yongjun; Song, Hongwen; Liu, Xiaoming; Tang, Dinghong; Chen, Yue-E; Zhang, Xiaochu

    2017-01-01

    Massive Multiple Online Role-Playing Games (MMORPGs) have increased in popularity among children, juveniles, and adults since MMORPGs' appearance in this digital age. MMORPGs can be applied to enhancing language learning, which is drawing researchers' attention from different fields and many studies have validated MMORPGs' positive effect on language learning. However, there are few studies on the underlying behavioral or neural mechanism of such effect. This paper reviews the educational application of the MMORPGs based on relevant macroscopic and microscopic studies, showing that gamers' overall language proficiency or some specific language skills can be enhanced by real-time online interaction with peers and game narratives or instructions embedded in the MMORPGs. Mechanisms underlying the educational assistant role of MMORPGs in second language learning are discussed from both behavioral and neural perspectives. We suggest that attentional bias makes gamers/learners allocate more cognitive resources toward task-related stimuli in a controlled or an automatic way. Moreover, with a moderating role played by activation of reward circuit, playing the MMORPGs may strengthen or increase functional connectivity from seed regions such as left anterior insular/frontal operculum (AI/FO) and visual word form area to other language-related brain areas.

  1. Enhancement of drilling safety and quality using online sensors and artificial neural networks.

    PubMed

    Liu, Tien-I; Kumagai, Akihiko; Lee, Chongchan

    2003-01-01

    Cutting force sensors and neural networks have been used for the occupational safety of the drilling process. The drill conditions have been online classified into 3 categories: safe, caution, and danger. This approach can change the drill just before its failure. The inputs to neural networks include drill size, feed rate, spindle speed, and features that were extracted from drilling force measurements. The outputs indicate the safety states. This detection system can reach a success rate of over 95%. Furthermore, the one misclassification during online tests was a one-step ahead pre-alarm that is acceptable from the safety and quality viewpoint. The developed online detection system is very robust and can be used in very complex manufacturing environments.

  2. A neural network approach for enhancing information extraction from multispectral image data

    USGS Publications Warehouse

    Liu, J.; Shao, G.; Zhu, H.; Liu, S.

    2005-01-01

    A back-propagation artificial neural network (ANN) was applied to classify multispectral remote sensing imagery data. The classification procedure included four steps: (i) noisy training that adds minor random variations to the sampling data to make the data more representative and to reduce the training sample size; (ii) iterative or multi-tier classification that reclassifies the unclassified pixels by making a subset of training samples from the original training set, which means the neural model can focus on fewer classes; (iii) spectral channel selection based on neural network weights that can distinguish the relative importance of each channel in the classification process to simplify the ANN model; and (iv) voting rules that adjust the accuracy of classification and produce outputs of different confidence levels. The Purdue Forest, located west of Purdue University, West Lafayette, Indiana, was chosen as the test site. The 1992 Landsat thematic mapper imagery was used as the input data. High-quality airborne photographs of the same Lime period were used for the ground truth. A total of 11 land use and land cover classes were defined, including water, broadleaved forest, coniferous forest, young forest, urban and road, and six types of cropland-grassland. The experiment, indicated that the back-propagation neural network application was satisfactory in distinguishing different land cover types at US Geological Survey levels II-III. The single-tier classification reached an overall accuracy of 85%. and the multi-tier classification an overall accuracy of 95%. For the whole test, region, the final output of this study reached an overall accuracy of 87%. ?? 2005 CASI.

  3. Enhanced growth of neural networks on conductive cellulose-derived nanofibrous scaffolds.

    PubMed

    Kuzmenko, Volodymyr; Kalogeropoulos, Theodoros; Thunberg, Johannes; Johannesson, Sara; Hägg, Daniel; Enoksson, Peter; Gatenholm, Paul

    2016-01-01

    The problem of recovery from neurodegeneration needs new effective solutions. Tissue engineering is viewed as a prospective approach for solving this problem since it can help to develop healthy neural tissue using supportive scaffolds. This study presents effective and sustainable tissue engineering methods for creating biomaterials from cellulose that can be used either as scaffolds for the growth of neural tissue in vitro or as drug screening models. To reach this goal, nanofibrous electrospun cellulose mats were made conductive via two different procedures: carbonization and addition of multi-walled carbon nanotubes. The resulting scaffolds were much more conductive than untreated cellulose material and were used to support growth and differentiation of SH-SY5Y neuroblastoma cells. The cells were evaluated by scanning electron microscopy and confocal microscopy methods over a period of 15 days at different time points. The results showed that the cellulose-derived conductive scaffolds can provide support for good cell attachment, growth and differentiation. The formation of a neural network occurred within 10 days of differentiation, which is a promising length of time for SH-SY5Y neuroblastoma cells.

  4. Allosteric modulation of alpha4beta2 nicotinic acetylcholine receptors by HEPES.

    PubMed

    Weltzin, Maegan M; Huang, Yanzhou; Schulte, Marvin K

    2014-06-05

    A number of new positive allosteric modulators (PAMs) have been reported that enhance responses of neuronal alpha7 and alpha4beta2 nicotinic acetylcholine receptor subtypes to orthosteric ligands. PAMs represent promising new leads for the development of therapeutic agents for disorders involving alterations in nicotinic neurotransmission including Autism, Alzheimer's and Parkinson's disease. During our recent studies of alpha4beta2 PAMs, we identified a novel effect of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). The effects of HEPES were evaluated in a phosphate buffered recording solution using two-electrode voltage clamp techniques and alpha4beta2 and alpha7 nicotinic acetylcholine receptor subtypes expressed in Xenopus laevis oocytes. Acetylcholine induced responses of high-sensitivity alpha4beta2 receptors were potentiated 190% by co-exposure to HEPES. Responses were inhibited at higher concentrations (bell-shaped concentration/response curve). Coincidentally, at concentrations of HEPES typically used in oocyte recording (5-10mM), the potentiating effects of HEPES are matched by its inhibitory effects, thus producing no net effect. Mutagenesis results suggest HEPES potentiates the high-sensitivity stoichiometry of the alpha4beta2 receptors through action at the beta2+/beta2- interface and is dependent on residue beta2D218. HEPES did not potentiate low-sensitivity alpha4beta2 receptors and did not produce any observable effect on acetylcholine induced responses on alpha7 nicotinic acetylcholine receptors.

  5. Progesterone Modulates a Neuronal Nicotinic Acetylcholine Receptor

    NASA Astrophysics Data System (ADS)

    Valera, S.; Ballivet, M.; Bertrand, D.

    1992-10-01

    The major brain nicotinic acetylcholine receptor is assembled from two subunits termed α 4 and nα 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor.

  6. Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain

    PubMed Central

    Urban, Kimberly R.; Gao, Wen-Jun

    2014-01-01

    Cognitive enhancement is perhaps one of the most intriguing and controversial topics in neuroscience today. Currently, the main classes of drugs used as potential cognitive enhancers include psychostimulants (methylphenidate (MPH), amphetamine), but wakefulness-promoting agents (modafinil) and glutamate activators (ampakine) are also frequently used. Pharmacologically, substances that enhance the components of the memory/learning circuits—dopamine, glutamate (neuronal excitation), and/or norepinephrine—stand to improve brain function in healthy individuals beyond their baseline functioning. In particular, non-medical use of prescription stimulants such as MPH and illicit use of psychostimulants for cognitive enhancement have seen a recent rise among teens and young adults in schools and college campuses. However, this enhancement likely comes with a neuronal, as well as ethical, cost. Altering glutamate function via the use of psychostimulants may impair behavioral flexibility, leading to the development and/or potentiation of addictive behaviors. Furthermore, dopamine and norepinephrine do not display linear effects; instead, their modulation of cognitive and neuronal function maps on an inverted-U curve. Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, thus vitiating the very behaviors they are striving to improve. Finally, recent studies have begun to highlight potential damaging effects of stimulant exposure in healthy juveniles. This review explains how the main classes of cognitive enhancing drugs affect the learning and memory circuits, and highlights the potential risks and concerns in healthy individuals, particularly juveniles and adolescents. We emphasize the performance enhancement at the potential cost of brain plasticity that is associated with the neural ramifications of nootropic drugs in the healthy developing brain. PMID:24860437

  7. Effects of acetylcholine on neuronal properties in entorhinal cortex

    PubMed Central

    Heys, James G.; Schultheiss, Nathan W.; Shay, Christopher F.; Tsuno, Yusuke; Hasselmo, Michael E.

    2012-01-01

    The entorhinal cortex (EC) receives prominent cholinergic innervation from the medial septum and the vertical limb of the diagonal band of Broca (MSDB). To understand how cholinergic neurotransmission can modulate behavior, research has been directed toward identification of the specific cellular mechanisms in EC that can be modulated through cholinergic activity. This review focuses on intrinsic cellular properties of neurons in EC that may underlie functions such as working memory, spatial processing, and episodic memory. In particular, the study of stellate cells (SCs) in medial entorhinal has resulted in discovery of correlations between physiological properties of these neurons and properties of the unique spatial representation that is demonstrated through unit recordings of neurons in medial entorhinal cortex (mEC) from awake-behaving animals. A separate line of investigation has demonstrated persistent firing behavior among neurons in EC that is enhanced by cholinergic activity and could underlie working memory. There is also evidence that acetylcholine plays a role in modulation of synaptic transmission that could also enhance mnemonic function in EC. Finally, the local circuits of EC demonstrate a variety of interneuron physiology, which is also subject to cholinergic modulation. Together these effects alter the dynamics of EC to underlie the functional role of acetylcholine in memory. PMID:22837741

  8. Metabolism of acetylcholine in human erythrocytes

    SciTech Connect

    Chapman, E.S.

    1990-01-01

    In order to examine the possible role of erythrocyte acetylcholinesterase in the maintenance of membrane phospholipid content and membrane fluidity, experiments were performed to monitor the activity of the enzyme and follow the fate of one of its hydrolytic products, choline. Intact human erythrocytes were incubated with acetylcholine (choline methyl-{sup 14}C). The incubation resulted in the hydrolysis of acetylcholine to acetate and choline; the reaction was catalyzed by membrane acetylcholinesterase. The studies demonstrate the further metabolism of choline. Experiments were carried out to determine rate of hydrolysis of acetylcholine, uptake of choline, identification of intracellular metabolites of choline, and identification of radiolabeled membrane components. Erythrocytes at a 25% hematocrit were incubated in an isoosmotic bicarbonate buffer pH 7.4, containing glucose, adenosine, streptomycin and penicillin with 0.3 {mu}Ci of acetylcholine (choline methyl-{sup 14}C), for 24 hours. Aliquots of the erythrocyte suspension were taken throughout for analysis. Erythrocytes were washed free of excess substrate, lysed, and the hemolysate was extracted for choline and its metabolites. Blank samples containing incubation buffer and radiolabeled acetylcholine only, and erythrocyte hemolysate extracts were analyzed for choline content, the difference between blank samples and hemolysate extracts was the amount of choline originating from acetylcholine and attributable to acetylcholinesterase activity. The conversion of choline to {sup 14}C-betaine is noted after several minutes of incubation; at 30 minutes, more than 80% of {sup 14}C-choline is taken up and after several hours, detectable levels of radiolabeled S-adenosylmethionine were present in the hemolysate extract.

  9. Enhanced neural function in highly aberrated eyes following perceptual learning with adaptive optics.

    PubMed

    Sabesan, Ramkumar; Barbot, Antoine; Yoon, Geunyoung

    2017-03-01

    Highly aberrated keratoconic (KC) eyes do not elicit the expected visual advantage from customized optical corrections. This is attributed to the neural insensitivity arising from chronic visual experience with poor retinal image quality, dominated by low spatial frequencies. The goal of this study was to investigate if targeted perceptual learning with adaptive optics (AO) can stimulate neural plasticity in these highly aberrated eyes. The worse eye of 2 KC subjects was trained in a contrast threshold test under AO correction. Prior to training, tumbling 'E' visual acuity and contrast sensitivity at 4, 8, 12, 16, 20, 24 and 28 c/deg were measured in both the trained and untrained eyes of each subject with their routine prescription and with AO correction for a 6mm pupil. The high spatial frequency requiring 50% contrast for detection with AO correction was picked as the training frequency. Subjects were required to train on a contrast detection test with AO correction for 1h for 5 consecutive days. During each training session, threshold contrast measurement at the training frequency with AO was conducted. Pre-training measures were repeated after the 5 training sessions in both eyes (i.e., post-training). After training, contrast sensitivity under AO correction improved on average across spatial frequency by a factor of 1.91 (range: 1.77-2.04) and 1.75 (1.22-2.34) for the two subjects. This improvement in contrast sensitivity transferred to visual acuity with the two subjects improving by 1.5 and 1.3 lines respectively with AO following training. One of the two subjects denoted an interocular transfer of training and an improvement in performance with their routine prescription post-training. This training-induced visual benefit demonstrates the potential of AO as a tool for neural rehabilitation in patients with abnormal corneas. Moreover, it reveals a sufficient degree of neural plasticity in normally developed adults who have a long history of abnormal visual

  10. Short-term Music Training Enhances Complex, Distributed Neural Communication during Music and Linguistic Tasks

    PubMed Central

    Carpentier, Sarah M.; Moreno, Sylvain; McIntosh, Anthony R.

    2016-01-01

    Musical training is frequently associated with benefits to linguistic abilities, and recent focus has been placed on possible benefits of bilingualism to lifelong executive functions; however, the neural mechanisms for such effects are unclear. The aim of this study was to gain better understanding of the whole-brain functional effects of music and second-language training that could support such previously observed cognitive transfer effects. We conducted a 28-day longitudinal study of monolingual English-speaking 4- to 6-year-old children randomly selected to receive daily music or French language training, excluding weekends. Children completed passive EEG music note and French vowel auditory oddball detection tasks before and after training. Brain signal complexity was measured on source waveforms at multiple temporal scales as an index of neural information processing and network communication load. Comparing pretraining with posttraining, musical training was associated with increased EEG complexity at coarse temporal scales during the music and French vowel tasks in widely distributed cortical regions. Conversely, very minimal decreases in complexity at fine scales and trends toward coarse-scale increases were displayed after French training during the tasks. Spectral analysis failed to distinguish between training types and found overall theta (3.5–7.5 Hz) power increases after all training forms, with spatially fewer decreases in power at higher frequencies (>10 Hz). These findings demonstrate that musical training increased diversity of brain network states to support domain-specific music skill acquisition and music-to-language transfer effects. PMID:27243611

  11. The Synapse Project: Engagement in mentally challenging activities enhances neural efficiency

    PubMed Central

    McDonough, Ian M.; Haber, Sara; Bischof, Gérard N.; Park, Denise C.

    2015-01-01

    Purpose: Correlational and limited experimental evidence suggests that an engaged lifestyle is associated with the maintenance of cognitive vitality in old age. However, the mechanisms underlying these engagement effects are poorly understood. We hypothesized that mental effort underlies engagement effects and used fMRI to examine the impact of high-challenge activities (digital photography and quilting) compared with low-challenge activities (socializing or performing low-challenge cognitive tasks) on neural function at pretest, posttest, and one year after the engagement program. Methods: In the scanner, participants performed a semantic-classification task with two levels of difficulty to assess the modulation of brain activity in response to task demands. Results: The High-Challenge group, but not the Low-Challenge group, showed increased modulation of brain activity in medial frontal, lateral temporal, and parietal cortex—regions associated with attention and semantic processing—some of which were maintained a year later. This increased modulation stemmed from decreases in brain activity during the easy condition for the High-Challenge group and was associated with time committed to the program, age, and cognition. Conclusions: Sustained engagement in cognitively demanding activities facilitated cognition by increasing neural efficiency. Mentally-challenging activities may be neuroprotective and an important element to maintaining a healthy brain into late adulthood. PMID:26484698

  12. Short-term Music Training Enhances Complex, Distributed Neural Communication during Music and Linguistic Tasks.

    PubMed

    Carpentier, Sarah M; Moreno, Sylvain; McIntosh, Anthony R

    2016-10-01

    Musical training is frequently associated with benefits to linguistic abilities, and recent focus has been placed on possible benefits of bilingualism to lifelong executive functions; however, the neural mechanisms for such effects are unclear. The aim of this study was to gain better understanding of the whole-brain functional effects of music and second-language training that could support such previously observed cognitive transfer effects. We conducted a 28-day longitudinal study of monolingual English-speaking 4- to 6-year-old children randomly selected to receive daily music or French language training, excluding weekends. Children completed passive EEG music note and French vowel auditory oddball detection tasks before and after training. Brain signal complexity was measured on source waveforms at multiple temporal scales as an index of neural information processing and network communication load. Comparing pretraining with posttraining, musical training was associated with increased EEG complexity at coarse temporal scales during the music and French vowel tasks in widely distributed cortical regions. Conversely, very minimal decreases in complexity at fine scales and trends toward coarse-scale increases were displayed after French training during the tasks. Spectral analysis failed to distinguish between training types and found overall theta (3.5-7.5 Hz) power increases after all training forms, with spatially fewer decreases in power at higher frequencies (>10 Hz). These findings demonstrate that musical training increased diversity of brain network states to support domain-specific music skill acquisition and music-to-language transfer effects.

  13. Neural Basis of Working Memory Enhancement after Acute Aerobic Exercise: fMRI Study of Preadolescent Children

    PubMed Central

    Chen, Ai-Guo; Zhu, Li-Na; Yan, Jun; Yin, Heng-Chan

    2016-01-01

    Working memory lies at the core of cognitive function and plays a crucial role in children’s learning, reasoning, problem solving, and intellectual activity. Behavioral findings have suggested that acute aerobic exercise improves children’s working memory; however, there is still very little knowledge about whether a single session of aerobic exercise can alter working memory’s brain activation patterns, as assessed by functional magnetic resonance imaging (fMRI). Therefore, we investigated the effect of acute moderate-intensity aerobic exercise on working memory and its brain activation patterns in preadolescent children, and further explored the neural basis of acute aerobic exercise on working memory in these children. We used a within-subjects design with a counterbalanced order. Nine healthy, right-handed children were scanned with a Siemens MAGNETOM Trio 3.0 Tesla magnetic resonance imaging scanner while they performed a working memory task (N-back task), following a baseline session and a 30-min, moderate-intensity exercise session. Compared with the baseline session, acute moderate-intensity aerobic exercise benefitted performance in the N-back task, increasing brain activities of bilateral parietal cortices, left hippocampus, and the bilateral cerebellum. These data extend the current knowledge by indicating that acute aerobic exercise enhances children’s working memory, and the neural basis may be related to changes in the working memory’s brain activation patterns elicited by acute aerobic exercise. PMID:27917141

  14. Neural Basis of Working Memory Enhancement after Acute Aerobic Exercise: fMRI Study of Preadolescent Children.

    PubMed

    Chen, Ai-Guo; Zhu, Li-Na; Yan, Jun; Yin, Heng-Chan

    2016-01-01

    Working memory lies at the core of cognitive function and plays a crucial role in children's learning, reasoning, problem solving, and intellectual activity. Behavioral findings have suggested that acute aerobic exercise improves children's working memory; however, there is still very little knowledge about whether a single session of aerobic exercise can alter working memory's brain activation patterns, as assessed by functional magnetic resonance imaging (fMRI). Therefore, we investigated the effect of acute moderate-intensity aerobic exercise on working memory and its brain activation patterns in preadolescent children, and further explored the neural basis of acute aerobic exercise on working memory in these children. We used a within-subjects design with a counterbalanced order. Nine healthy, right-handed children were scanned with a Siemens MAGNETOM Trio 3.0 Tesla magnetic resonance imaging scanner while they performed a working memory task (N-back task), following a baseline session and a 30-min, moderate-intensity exercise session. Compared with the baseline session, acute moderate-intensity aerobic exercise benefitted performance in the N-back task, increasing brain activities of bilateral parietal cortices, left hippocampus, and the bilateral cerebellum. These data extend the current knowledge by indicating that acute aerobic exercise enhances children's working memory, and the neural basis may be related to changes in the working memory's brain activation patterns elicited by acute aerobic exercise.

  15. The neural transfer effect of working memory training to enhance hedonic processing in individuals with social anhedonia

    PubMed Central

    Li, Xu; Li, Zhi; Li, Ke; Zeng, Ya-wei; Shi, Hai-song; Xie, Wen-lan; Yang, Zhuo-ya; Lui, Simon S. Y.; Cheung, Eric F. C.; Leung, Ada W. S.; Chan, Raymond C. K.

    2016-01-01

    Anhedonia, the diminished ability to experience pleasure, is a challenging negative symptom in patients with schizophrenia and can be observed in at-risk individuals with schizotypy. Deficits in hedonic processing have been postulated to be related to decreased motivation to engage in potentially rewarding events. It remains unclear whether non-pharmacological interventions, such as cognitive training, could improve anhedonia. The present study aimed to examine the neural mechanism for alleviating hedonic deficits with working memory (WM) training in individuals with social anhedonia. Fifteen individuals with social anhedonia were recruited and received 20 sessions of training on a dual n-back task, five sessions a week. Functional imaging paradigms of the Monetary Incentive Delay (MID) and the Affective Incentive Delay (AID) tasks were administered both before and after the training to evaluate the neural transfer effects on hedonic processing ability. Enhanced brain activations related to anticipation were observed at the anterior cingulate cortex, the left dorsal striatum and the left precuneus with the AID task, and at the dorsolateral prefrontal cortex and the supramarginal gyrus with the MID task. The present findings support that WM training may improve monetary-based and affective-based hedonic processing in individuals with social anhedonia. PMID:27752140

  16. A new hyperbox selection rule and a pruning strategy for the enhanced fuzzy min-max neural network.

    PubMed

    Mohammed, Mohammed Falah; Lim, Chee Peng

    2017-02-01

    In this paper, we extend our previous work on the Enhanced Fuzzy Min-Max (EFMM) neural network by introducing a new hyperbox selection rule and a pruning strategy to reduce network complexity and improve classification performance. Specifically, a new k-nearest hyperbox expansion rule (for selection of a new winning hyperbox) is first introduced to reduce the network complexity by avoiding the creation of too many small hyperboxes within the vicinity of the winning hyperbox. A pruning strategy is then deployed to further reduce the network complexity in the presence of noisy data. The effectiveness of the proposed network is evaluated using a number of benchmark data sets. The results compare favorably with those from other related models. The findings indicate that the newly introduced hyperbox winner selection rule coupled with the pruning strategy are useful for undertaking pattern classification problems.

  17. Neural Network based Control of SG based Standalone Generating System with Energy Storage for Power Quality Enhancement

    NASA Astrophysics Data System (ADS)

    Nayar, Priya; Singh, Bhim; Mishra, Sukumar

    2016-09-01

    An artificial intelligence based control algorithm is used in solving power quality problems of a diesel engine driven synchronous generator with automatic voltage regulator and governor based standalone system. A voltage source converter integrated with a battery energy storage system is employed to mitigate the power quality problems. An adaptive neural network based signed regressor control algorithm is used for the estimation of the fundamental component of load currents for control of a standalone system with load leveling as an integral feature. The developed model of the system performs accurately under varying load conditions and provides good dynamic response to the step changes in loads. The real time performance is achieved using MATLAB along with simulink/simpower system toolboxes and results adhere to an IEEE-519 standard for power quality enhancement.

  18. Increased extracellular dopamine and 5-hydroxytryptamine levels contribute to enhanced subthalamic nucleus neural activity during exhausting exercise

    PubMed Central

    Hu, Y; Liu, X

    2015-01-01

    The purpose of the study was to explore the mechanism underlying the enhanced subthalamic nucleus (STN) neural activity during exhausting exercise from the perspective of monoamine neurotransmitters and changes of their corresponding receptors. Rats were randomly divided into microdialysis and immunohistochemistry study groups. For microdialysis study, extracellular fluid of the STN was continuously collected with a microdialysis probe before, during and 90 min after one bout of exhausting exercise. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were subsequently detected with high-performance liquid chromatography (HPLC). For immunohistochemistry study, the expression of DRD2 and HT2C receptors in the STN, before, immediately after and 90 min after exhaustion was detected through immunohistochemistry technique. Microdialysis study results showed that the extracellular DA and 5-HT neurotransmitters increased significantly throughout the procedure of exhausting exercise and the recovery period (P<0.05 or P<0.01). Immunohistochemistry study results showed that the expression levels of DRD2 and HT2C in the rat STN immediately after exhausting exercise and at the time point of 90 min after exhaustion were both higher than those of the rest condition, but the difference was not significant (P>0.05). Our results suggest that the increased extracellular DA and 5-HT in the STN might be one important factor leading to the enhanced STN neural activity and the development of fatigue during exhausting exercise. This study may essentially offer useful evidence for better understanding of the mechanism of the central type of exercise-induced fatigue. PMID:26424920

  19. Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence.

    PubMed

    Murphy, Anna; Nestor, Liam J; McGonigle, John; Paterson, Louise; Boyapati, Venkataramana; Ersche, Karen D; Flechais, Remy; Kuchibatla, Shankar; Metastasio, Antonio; Orban, Csaba; Passetti, Filippo; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor; Robbins, Trevor W; Lingford-Hughes, Anne; Nutt, David J; Deakin, John Fw; Elliott, Rebecca

    2017-04-01

    Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.

  20. Nicotinic acetylcholine receptor from chick optic lobe.

    PubMed Central

    Norman, R I; Mehraban, F; Barnard, E A; Dolly, J O

    1982-01-01

    An alpha-bungarotoxin-sensitive nicotinic cholinergic receptor from chick optic lobe has been completely purified. Its standard sedimentation coefficient is 9.1 S. The value near 12 S reported for the related component from other brain regions can be reproduced when the initial extraction is by Triton X-100 (rather than Lubrol PX), but other protein is then complexed with it. A single subunit of apparent molecular weight 54,000 is detected, and this subunit is specifically labeled by bromo-[3H]acetylcholine, but only after disulfide reduction. The same size subunit likewise is labeled in the protein (purified similarly) from the rest of the chick brain which can also bind alpha-bungarotoxin and nicotinic ligands. Immunological crossreactivity is demonstrated between both of these proteins with an antiserum to pure acetylcholine receptor from skeletal muscle. The acetylcholine receptor from chick optic lobe and the alpha-bungarotoxin-binding protein from the rest of the brain appear similar or identical by a series of criteria and are related to (but with differences from) peripheral acetylcholine receptors. Images PMID:6175967

  1. Primary Structure of Nicotinic Acetylcholine Receptor

    DTIC Science & Technology

    1986-08-01

    quantities of starting material (for reviews of receptor, see Popot and Changeux, 1984; Stroud and Finer-Moore, 1985). This work led to the...Cloning of the Acetylcholine Receptor. Cold Spring Harbor Symp. on Quant. Biol. XLVIH: 71-78. 15. Popot , J-L. and Changeux, J-P. (1984) The

  2. Turnover of Acetylcholine Receptors: Mechanisms of Regulation

    DTIC Science & Technology

    1988-12-01

    ME, Whittingham S, and Duane DD (1976) Antibody to acetylcholine receptor in myasthenia gravis : prevalance, clinical correlates and diagnostic value...transferred to nitorcellulose. Proc Natl Acad Sci 77:5201-5205. Weinberg CB and Hall ZW (1979) Antibodies from patients with myasthenia gravis recognize

  3. Endogenous Repair Signaling after Brain Injury and Complementary Bioengineering Approaches to Enhance Neural Regeneration

    PubMed Central

    Addington, Caroline P; Roussas, Adam; Dutta, Dipankar; Stabenfeldt, Sarah E

    2015-01-01

    Traumatic brain injury (TBI) affects 5.3 million Americans annually. Despite the many long-term deficits associated with TBI, there currently are no clinically available therapies that directly address the underlying pathologies contributing to these deficits. Preclinical studies have investigated various therapeutic approaches for TBI: two such approaches are stem cell transplantation and delivery of bioactive factors to mitigate the biochemical insult affiliated with TBI. However, success with either of these approaches has been limited largely due to the complexity of the injury microenvironment. As such, this review outlines the many factors of the injury microenvironment that mediate endogenous neural regeneration after TBI and the corresponding bioengineering approaches that harness these inherent signaling mechanisms to further amplify regenerative efforts. PMID:25983552

  4. Modification by ouabain of the electrical and mechanical effects of acetylcholine in isolated rabbit atria

    PubMed Central

    Kajimoto, N.; Toda, N.

    1970-01-01

    1. Left atrial preparations isolated from rabbits were stimulated electrically at frequencies between 6 and 240/min. Tension-frequency curves were obtained from control preparations and preparations treated with ouabain and acetylcholine. Transmembrane potentials were recorded from single cells of the left atrium stimulated at different frequencies. 2. The tension-frequency curve was moved downwards by acetylcholine (10-6 g/ml). Ouabain (10-6 g/ml) caused characteristic alterations in the tension-frequency relationship, enhancing the contractile tension at low but not high frequencies. The negative inotropic effect of acetylcholine was reduced by treatment with ouabain. 3. Action potential durations were significantly influenced by alterations in frequency of contraction. The 10% duration increased with frequency within the range between 6 and 60/min but decreased at frequencies higher than 120/min. The 50% duration increased with frequency between 6 and 120/min but decreased at frequencies higher than 180/min. The dependence of the 50% duration upon frequency paralleled that of contractile tension. The 90% duration, the overshoot and the resting potential were not affected by frequency of contraction. 4. Acetylcholine (10-6 g/ml) shifted the 10%, 50% and 90% duration-frequency curves downwards, but did not significantly alter the overshoot and the resting potential. Ouabain (10-6 g/ml) shifted the duration-frequency curves downwards and also reduced the size of the overshoot and the resting potential. Treatment of atrial preparations with 10-6 g/ml ouabain potentiated the membrane effects of acetylcholine. 5. The inhibition by ouabain of the negative inotropic effect of acetylcholine did not appear to be due to antagonism at the receptor level, but to interference with the mechanisms responsible for the mechanical events. PMID:5425273

  5. Effects of nicotine, methamphetamine and cocaine on extracellular levels of acetylcholine in the interpeduncular nucleus of rats.

    PubMed

    Hussain, Rifat J; Taraschenko, Olga D; Glick, Stanley D

    2008-08-08

    There is increasing evidence that the cholinergic habenulo-interpeduncular pathway and the dopaminergic mesolimbic pathway may jointly mediate the reinforcing properties of addictive drugs. However, the effects of addictive drug on the functioning of the habenulo-interpeduncular pathway have not been well-characterized. Thus, several drugs of abuse (i.e., nicotine, cocaine, amphetamine) have been shown to alter the morphology of the habenulo-interpeduncular pathway, causing selective degeneration of the cholinergic neurons in this area. On the other hand, morphine was shown to alter the neurochemistry of the habenulo-interpeduncular pathway, inducing biphasic changes in acetylcholine release in the interpeduncular nucleus. In order to determine the effects of cocaine, amphetamine and nicotine on cholinergic neurotransmission in the habenulo-interpeduncular pathway, levels of acetylcholine were assessed during microdialysis in freely moving rats. Nicotine (0.1 and 0.4 mg/kg s.c.) produced a dose-dependent decrease in extracellular levels of acetylcholine, while methamphetamine (1 and 4 mg/kg i.p.) produced an increase in acetylcholine release in the interpeduncular nucleus. Cocaine (5 and 20 mg/kg i.p.) produced a biphasic effect on extracellular acetylcholine release, i.e., a low dose enhanced the release of acetylcholine and a high dose decreased its release. These results suggest that the habenulo-intepeduncular pathway may be a common target for drugs of abuse and, by modulating the mesolimbic pathway, may mediate unique aspects of the rewarding effects of different drugs.

  6. Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability.

    PubMed

    Gresser, Amy L; Gutzwiller, Lisa M; Gauck, Mackenzie K; Hartenstein, Volker; Cook, Tiffany A; Gebelein, Brian

    2015-01-01

    Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin-targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety-like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability.

  7. Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability

    PubMed Central

    Gresser, Amy L.; Gutzwiller, Lisa M.; Gauck, Mackenzie K.; Hartenstein, Volker; Cook, Tiffany A.; Gebelein, Brian

    2015-01-01

    Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin-targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety-like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability. PMID

  8. Enhancement of cognitive and neural functions through complex reasoning training: evidence from normal and clinical populations

    PubMed Central

    Chapman, Sandra B.; Mudar, Raksha A.

    2014-01-01

    Public awareness of cognitive health is fairly recent compared to physical health. Growing evidence suggests that cognitive training offers promise in augmenting cognitive brain performance in normal and clinical populations. Targeting higher-order cognitive functions, such as reasoning in particular, may promote generalized cognitive changes necessary for supporting the complexities of daily life. This data-driven perspective highlights cognitive and brain changes measured in randomized clinical trials that trained gist reasoning strategies in populations ranging from teenagers to healthy older adults, individuals with brain injury to those at-risk for Alzheimer's disease. The evidence presented across studies support the potential for Gist reasoning training to strengthen cognitive performance in trained and untrained domains and to engage more efficient communication across widespread neural networks that support higher-order cognition. The meaningful benefits of Gist training provide compelling motivation to examine optimal dose for sustained benefits as well as to explore additive benefits of meditation, physical exercise, and/or improved sleep in future studies. PMID:24808834

  9. Transit clairvoyance: enhancing TESS follow-up using artificial neural networks

    NASA Astrophysics Data System (ADS)

    Kipping, David M.; Lam, Christopher

    2017-03-01

    The upcoming Transiting Exoplanet Survey Satellite (TESS) mission is expected to find thousands of transiting planets around bright stars, yet for three-quarters of the fields observed the temporal coverage will limit discoveries to planets with orbital periods below 13.7 d. From the Kepler catalogue, the mean probability of these short-period transiting planets having additional longer period transiters (which would be missed by TESS) is 18 per cent, a value 10 times higher than the average star. In this work, we show how this probability is not uniform but functionally dependent upon the properties of the observed short-period transiters, ranging from less than 1 per cent up to over 50 per cent. Using artificial neural networks (ANNs) trained on the Kepler catalogue and making careful feature selection to account for the differing sensitivity of TESS, we are able to predict the most likely short-period transiters to be accompanied by additional transiters. Through cross-validation, we predict that a targeted, optimized TESS transit and/or radial velocity follow-up programme using our trained ANN would have a discovery yield improved by a factor of 2. Our work enables a near-optimal follow-up strategy for surveys following TESS targets for additional planets, improving the science yield derived from TESS and particularly beneficial in the search for habitable-zone transiting worlds.

  10. Broadband neural encoding in the cricket cereal sensory system enhanced by stochastic resonance

    NASA Astrophysics Data System (ADS)

    Levin, Jacob E.; Miller, John P.

    1996-03-01

    SENSORY systems are often required to detect a small amplitude signal embedded in broadband background noise. Traditionally, ambient noise is regarded as detrimental to encoding accuracy. Recently, however, a phenomenon known as stochastic resonance has been described in which, for systems with a nonlinear threshold, increasing the input noise level can actually improve the output signal-to-noise ratio over a limited range of signal and noise strengths. Previous theoretical and experimental studies of stochastic resonance in physical1-7and biological6-10 systems have dealt exclusively with single-frequency sine stimuli embedded in a broadband noise background. In the past year it has been shown in a theoretical and modelling study that stochastic resonance can be observed with broadband signals11,12. Here we demonstrate that broadband stochastic resonance is manifest in the peripheral layers of neural processing in a simple sensory system, and that it plays a role over a wide range of biologically relevant stimulus parameters. Further, we quantify the functional significance of the phenomenon within the context of signal processing, using information theory.

  11. Protoplasmic Astrocytes Enhance the Ability of Neural Stem Cells to Differentiate into Neurons In Vitro

    PubMed Central

    Liu, Yuan; Wang, Li; Long, Zaiyun; Zeng, Lin; Wu, Yamin

    2012-01-01

    Protoplasmic astrocytes have been reported to exhibit neuroprotective effects on neurons, but there has been no direct evidence for a functional relationship between protoplasmic astrocytes and neural stem cells (NSCs). In this study, we examined neuronal differentiation of NSCs induced by protoplasmic astrocytes in a co-culture model. Protoplasmic astrocytes were isolated from new-born and NSCs from the E13-15 cortex of rats respectively. The differentiated cells labeled with neuron-specific marker β-tubulin III, were dramatically increased at 7 days in the co-culture condition. Blocking the effects of brain-derived neurotrophic factor (BDNF) with an anti-BDNF antibody reduced the number of neurons differentiated from NSCs when co-cultured with protoplasmic astrocytes. In fact, the content of BDNF in the supernatant obtained from protoplasmic astrocytes and NSCs co-culture media was significantly greater than that from control media conditions. These results indicate that protoplasmic astrocytes promote neuronal differentiation of NSCs, which is driven, at least in part, by BDNF. PMID:22693605

  12. Second-hand stress: inhalation of stress sweat enhances neural response to neutral faces

    PubMed Central

    Rubin, Denis; Botanov, Yevgeny; Hajcak, Greg

    2012-01-01

    This study investigated whether human chemosensory-stress cues affect neural activity related to the evaluation of emotional stimuli. Chemosensory stimuli were obtained from the sweat of 64 male donors during both stress (first-time skydive) and control (exercise) conditions, indistinguishable by odor. We then recorded event-related potentials (ERPs) from an unrelated group of 14 participants while they viewed faces morphed with neutral-to-angry expressions and inhaled nebulized stress and exercise sweat in counter-balanced blocks, blind to condition. Results for the control condition ERPs were consistent with previous findings: the late positive potential (LPP; 400–600 ms post stimulus) in response to faces was larger for threatening than both neutral and ambiguous faces. In contrast, the stress condition was associated with a heightened LPP across all facial expressions; relative to control, the LPP was increased for both ambiguous and neutral faces in the stress condition. These results suggest that stress sweat may impact electrocortical activity associated with attention to salient environmental cues, potentially increasing attentiveness to otherwise inconspicuous stimuli. PMID:21208988

  13. Centered Kernel Alignment Enhancing Neural Network Pretraining for MRI-Based Dementia Diagnosis

    PubMed Central

    Cárdenas-Peña, David; Collazos-Huertas, Diego; Castellanos-Dominguez, German

    2016-01-01

    Dementia is a growing problem that affects elderly people worldwide. More accurate evaluation of dementia diagnosis can help during the medical examination. Several methods for computer-aided dementia diagnosis have been proposed using resonance imaging scans to discriminate between patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) and healthy controls (NC). Nonetheless, the computer-aided diagnosis is especially challenging because of the heterogeneous and intermediate nature of MCI. We address the automated dementia diagnosis by introducing a novel supervised pretraining approach that takes advantage of the artificial neural network (ANN) for complex classification tasks. The proposal initializes an ANN based on linear projections to achieve more discriminating spaces. Such projections are estimated by maximizing the centered kernel alignment criterion that assesses the affinity between the resonance imaging data kernel matrix and the label target matrix. As a result, the performed linear embedding allows accounting for features that contribute the most to the MCI class discrimination. We compare the supervised pretraining approach to two unsupervised initialization methods (autoencoders and Principal Component Analysis) and against the best four performing classification methods of the 2014 CADDementia challenge. As a result, our proposal outperforms all the baselines (7% of classification accuracy and area under the receiver-operating-characteristic curve) at the time it reduces the class biasing. PMID:27148392

  14. Muscarinic Acetylcholine Receptor Localization and Activation Effects on Ganglion Response Properties

    PubMed Central

    Renna, Jordan M.; Amthor, Franklin R.; Keyser, Kent T.

    2010-01-01

    Purpose. The activation and blockade of muscarinic acetylcholine receptors (mAChRs) affects retinal ganglion cell light responses and firing rates. This study was undertaken to identify the full complement of mAChRs expressed in the rabbit retina and to assess mAChR distribution and the functional effects of mAChR activation and blockade on retinal response properties. Methods. RT-PCR, Western blot analysis, and immunohistochemistry were used to identify the complement and distribution of mAChRs in the rabbit retina. Extracellular electrophysiology was used to determine the effects of the activation or blockade of mAChRs on ganglion cell response properties. Results. RT-PCR of whole neural retina resulted in the amplification of mRNA transcripts for the m1 to m5 mAChR subtypes. Western blot and immunohistochemical analyses confirmed that all five mAChR subtypes were expressed by subpopulations of bipolar, amacrine, and ganglion cells in the rabbit retina, including subsets of cells in cholinergic and glycinergic circuits. Nonspecific muscarinic activation and blockade resulted in the class-specific modulation of maintained ganglion cell firing rates and light responses. Conclusions. The expression of mAChR subtypes on subsets of bipolar, amacrine, and ganglion cells provides a substrate for both enhancement and suppression of retinal responses via activation by cholinergic agents. Thus, the muscarinic cholinergic system in the retina may contribute to the modulation of complex stimuli. Understanding the distribution and function of mAChRs in the retina has the potential to provide important insights into the visual changes that are caused by decreased ACh in the retinas of Alzheimer's patients and the potential visual effects of anticholinergic treatments for ocular diseases. PMID:20042645

  15. Hypoxic-preconditioning enhances the regenerative capacity of neural stem/progenitors in subventricular zone of newborn piglet brain.

    PubMed

    Ara, Jahan; De Montpellier, Sybille

    2013-09-01

    Perinatal hypoxia-ischemia (HI) results in brain injury, whereas mild hypoxic episodes result in preconditioning, which can significantly reduce the vulnerability of the brain to subsequent severe hypoxia-ischemia. Hypoxic-preconditioning (PC) has been shown to enhance cell survival and differentiation of progenitor cells in the central nervous system (CNS). The purpose of this study was to determine whether pretreatment with PC prior to HI stimulates subventricular zone (SVZ) proliferation and neurogenesis in newborn piglets. One-day-old piglets were subjected to PC (8% O2/92% N2) for 3h and 24h later were exposed to HI produced by combination of hypoxia (5% FiO2) for a pre-defined period of 30min and ischemia induced by a period of 10min of hypotension. Here we demonstrate that SVZ derived neural stem/progenitor cells (NSPs) from PC, HI and PC+HI piglets proliferated as neurospheres, expressed neural progenitor and neurodevelopmental markers, and that greater proportion of the spheres generated are multipotential. Neurosphere assay revealed that preconditioning pretreatment increased the number of NSP-derived neurospheres in SVZ following HI compared to normoxic and HI controls. NSPs from preconditioned SVZ generated twice as many neurons and astrocytes in vitro. Injections with 5-Bromo-2-deoxyuridine (BrdU) after PC revealed a robust proliferative response within the SVZ that continued for one week. PC also increased neurogenesis in vivo, doublecortin positive cells with migratory profiles were observed streaming from the SVZ to striatum and neocortex. These findings show that the induction of proliferation and neurogenesis by PC might be a positive adaptation for an efficient repair and plasticity in the event of a hypoxic-ischemic insult.

  16. Dual function of Slit2 in repulsion and enhanced migration of trunk, but not vagal, neural crest cells.

    PubMed

    De Bellard, Maria Elena; Rao, Yi; Bronner-Fraser, Marianne

    2003-07-21

    Neural crest precursors to the autonomic nervous system form different derivatives depending upon their axial level of origin; for example, vagal, but not trunk, neural crest cells form the enteric ganglia of the gut. Here, we show that Slit2 is expressed at the entrance of the gut, which is selectively invaded by vagal, but not trunk, neural crest. Accordingly, only trunk neural crest cells express Robo receptors. In vivo and in vitro experiments demonstrate that trunk, not vagal, crest cells avoid cells or cell membranes expressing Slit2, thereby contributing to the differential ability of neural crest populations to invade and innervate the gut. Conversely, exposure to soluble Slit2 significantly increases the distance traversed by trunk neural crest cells. These results suggest that Slit2 can act bifunctionally, both repulsing and stimulating the motility of trunk neural crest cells.

  17. Attention enhances synaptic efficacy and the signal-to-noise ratio in neural circuits.

    PubMed

    Briggs, Farran; Mangun, George R; Usrey, W Martin

    2013-07-25

    Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behaviour are poorly understood. To elucidate the synaptic mechanisms of attention, we developed a sensitive assay of attentional modulation of neuronal communication. In alert monkeys performing a visual spatial attention task, we probed thalamocortical communication by electrically stimulating neurons in the lateral geniculate nucleus of the thalamus while simultaneously recording shock-evoked responses from monosynaptically connected neurons in primary visual cortex. We found that attention enhances neuronal communication by increasing the efficacy of presynaptic input in driving postsynaptic responses, by increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and by decreasing redundant signals between postsynaptic neurons receiving common input. The results demonstrate that attention finely tunes neuronal communication at the synaptic level by selectively altering synaptic weights, enabling enhanced detection of salient events in the noisy sensory environment.

  18. Poly-L-ornithine enhances migration of neural stem/progenitor cells via promoting α-Actinin 4 binding to actin filaments

    PubMed Central

    Ge, Hongfei; Yu, Anyong; Chen, Jingyu; Yuan, Jichao; Yin, Yi; Duanmu, Wangsheng; Tan, Liang; Yang, Yang; Lan, Chuan; Chen, Weixiang; Feng, Hua; Hu, Rong

    2016-01-01

    The recruitment of neural stem/progenitor cells (NSPCs) for brain restoration after injury is a promising regenerative therapeutic strategy. This strategy involves enhancing proliferation, migration and neuronal differentation of NSPCs. To date, the lack of biomaterials, which facilitate these processes to enhance neural regeneration, is an obstacle for the cell replacement therapies. Our previous study has shown that NSPCs grown on poly-L-ornithine (PO) could proliferate more vigorously and differentiate into more neurons than that on Poly-L-Lysine (PLL) and Fibronectin (FN). Here, we demonstrate that PO could promote migration of NSPCs in vitro, and the underlying mechanism is PO activates α-Actinins 4 (ACTN4), which is firstly certified to be expessed in NSPCs, to promote filopodia formation and therefore enhances NSPCs migration. Taken together, PO might serve as a better candidate for transplanted biomaterials in the regenerative therapeutic strategy, compared with PLL and FN. PMID:27874083

  19. Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

    NASA Astrophysics Data System (ADS)

    Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

    2016-04-01

    Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

  20. Elastin-like polypeptide matrices for enhancing adeno-associated virus-mediated gene delivery to human neural stem cells.

    PubMed

    Kim, J-S; Chu, H S; Park, K I; Won, J-I; Jang, J-H

    2012-03-01

    The successful development of efficient and safe gene delivery vectors continues to be a major obstacle to gene delivery in stem cells. In this study, we have developed an elastin-like polypeptide (ELP)-mediated adeno-associated virus (AAV) delivery system for transducing fibroblasts and human neural stem cells (hNSCs). AAVs have significant promise as therapeutic vectors because of their safety and potential for use in gene targeting in stem cell research. ELP has been recently employed as a biologically inspired 'smart' biomaterial that exhibits an inverse temperature phase transition, thereby demonstrating promise as a novel drug carrier. The ELP that was investigated in this study was composed of a repetitive penta-peptide with [Val-Pro-Gly-Val-Gly]. A novel AAV variant, AAV r3.45, which was previously engineered by directed evolution to enhance transduction in rat NSCs, was nonspecifically immobilized onto ELPs that were adsorbed beforehand on a tissue culture polystyrene surface (TCPS). The presence of different ELP quantities on the TCPS led to variations in surface morphology, roughness and wettability, which were ultimately key factors in the modulation of cellular transduction. Importantly, with substantially reduced viral quantities compared with bolus delivery, ELP-mediated AAV delivery significantly enhanced delivery efficiency in fibroblasts and hNSCs, which have great potential for use in tissue engineering applications and neurodegenerative disorder treatments, respectively. The enhancement of cellular transduction in stem cells, as well as the feasibility of ELPs for utilization in three-dimensional scaffolds, will contribute to the advancement of gene therapy for stem cell research and tissue regenerative medicine.

  1. Agonists block currents through acetylcholine receptor channels.

    PubMed Central

    Sine, S M; Steinbach, J H

    1984-01-01

    We have examined the effects of high concentrations of cholinergic agonists on currents through single acetylcholine receptor (AChR) channels on clonal BC3H1 cells. We find that raised concentrations of acetylcholine (ACh; above 300 microM) or carbamylcholine (Carb; above 1,000 microM) produce a voltage- and concentration-dependent reduction in the mean single-channel current. Raised concentrations of suberyldicholine (Sub; above 3 microM) produce a voltage- and concentration-dependent increase in the number of brief duration low-conductance interruptions of open-channel currents. These observations can be quantitatively described by a model in which agonist molecules enter and transiently occlude the ion-channel of the AChR. PMID:6478036

  2. External Imaging of Cerebral Muscarinic Acetylcholine Receptors

    NASA Astrophysics Data System (ADS)

    Eckelman, William C.; Reba, Richard C.; Rzeszotarski, Waclaw J.; Gibson, Raymond E.; Hill, Thomas; Holman, B. Leonard; Budinger, Thomas; Conklin, James J.; Eng, Robert; Grissom, Michael P.

    1984-01-01

    A radioiodinated ligand that binds to muscarinic acetylcholine receptors was shown to distribute in the brain by a receptor-mediated process. With single-photon-emission imaging techniques, radioactivity was detected in the cerebrum but not in the cerebellum, whereas with a flow-limited radiotracer, radioactivity was detected in cerebrum and cerebellum. Single-photon-emission computed tomography showed good definition of the caudate putamen and cortex in man.

  3. External imaging of cerebral muscarinic acetylcholine receptors

    SciTech Connect

    Eckelman, W.C.; Reba, R.C.; Rzeszotarski, W.J.; Gibson, R.E.; Hill, T.; Holman, B.L.; Budinger, T.; Conklin, J.J.; Eng, R.; Grissom, M.P.

    1984-01-20

    A radioiodinated ligand that binds to muscarinic acetylcholine receptors was shown to distribute in the brain by a receptor-mediated process. With single-photon-emission imaging techniques, radioactivity was detected in the cerebrum but not in the cerebellum, whereas with a flow-limited radiotracer, radioactivity was detected in cerebrum and cerebellum. Single-photon-emission computed tomography showed good definition of the caudate putamen and cortex in man.

  4. Construction of a 3D rGO-collagen hybrid scaffold for enhancement of the neural differentiation of mesenchymal stem cells

    NASA Astrophysics Data System (ADS)

    Guo, Weibo; Wang, Shu; Yu, Xin; Qiu, Jichuan; Li, Jianhua; Tang, Wei; Li, Zhou; Mou, Xiaoning; Liu, Hong; Wang, Zhonglin

    2016-01-01

    The cell-material interface is one of the most important considerations in designing a high-performance tissue engineering scaffold because the surface of the scaffold can determine the fate of stem cells. A conductive surface is required for a scaffold to direct stem cells toward neural differentiation. However, most conductive polymers are toxic and not amenable to biological degradation, which restricts the design of neural tissue engineering scaffolds. In this study, we used a bioactive three-dimensional (3D) porcine acellular dermal matrix (PADM), which is mainly composed of type I collagen, as a basic material and successfully assembled a layer of reduced graphene oxide (rGO) nanosheets on the surface of the PADM channels to obtain a porous 3D, biodegradable, conductive and biocompatible PADM-rGO hybrid neural tissue engineering scaffold. Compared with the PADM scaffold, assembling the rGO into the scaffold did not induce a significant change in the microstructure but endowed the PADM-rGO hybrid scaffold with good conductivity. A comparison of the neural differentiation of rat bone-marrow-derived mesenchymal stem cells (MSCs) was performed by culturing the MSCs on PADM and PADM-rGO scaffolds in neuronal culture medium, followed by the determination of gene expression and immunofluorescence staining. The results of both the gene expression and protein level assessments suggest that the rGO-assembled PADM scaffold may promote the differentiation of MSCs into neuronal cells with higher protein and gene expression levels after 7 days under neural differentiation conditions. This study demonstrated that the PADM-rGO hybrid scaffold is a promising scaffold for neural tissue engineering; this scaffold can not only support the growth of MSCs at a high proliferation rate but also enhance the differentiation of MSCs into neural cells.The cell-material interface is one of the most important considerations in designing a high-performance tissue engineering scaffold

  5. Voluntary enhancement of neural signatures of affiliative emotion using FMRI neurofeedback.

    PubMed

    Moll, Jorge; Weingartner, Julie H; Bado, Patricia; Basilio, Rodrigo; Sato, João R; Melo, Bruno R; Bramati, Ivanei E; de Oliveira-Souza, Ricardo; Zahn, Roland

    2014-01-01

    In Ridley Scott's film "Blade Runner", empathy-detection devices are employed to measure affiliative emotions. Despite recent neurocomputational advances, it is unknown whether brain signatures of affiliative emotions, such as tenderness/affection, can be decoded and voluntarily modulated. Here, we employed multivariate voxel pattern analysis and real-time fMRI to address this question. We found that participants were able to use visual feedback based on decoded fMRI patterns as a neurofeedback signal to increase brain activation characteristic of tenderness/affection relative to pride, an equally complex control emotion. Such improvement was not observed in a control group performing the same fMRI task without neurofeedback. Furthermore, the neurofeedback-driven enhancement of tenderness/affection-related distributed patterns was associated with local fMRI responses in the septohypothalamic area and frontopolar cortex, regions previously implicated in affiliative emotion. This demonstrates that humans can voluntarily enhance brain signatures of tenderness/affection, unlocking new possibilities for promoting prosocial emotions and countering antisocial behavior.

  6. Enhanced neural responses to self-triggered voice pitch feedback perturbations

    PubMed Central

    Liu, Hanjun; Behroozmand, Roozbeh; Larson, Charles R.

    2013-01-01

    This study investigated the effect of self-triggered voice fundamental frequency (F0) feedback perturbation on auditory event-related potentials (ERPs) during vocalization and listening. Auditory ERPs were examined in response to self-triggered and computer-triggered −200 cents pitch-shift stimuli while participants vocalized or listened to the playback of their self-vocalizations. The stimuli were either presented with a delay of 500–1000 ms after the participants pressed a button or delivered by a computer with an interstimulus interval of 500–1000 ms. Results showed that self-triggered stimuli elicited larger ERPs compared with computer-triggered stimuli during both vocalization and listening conditions. These findings suggest that self-triggered perturbation of self-vocalization auditory feedback may enhance auditory responses to voice feedback pitch perturbation during vocalization and listening. PMID:20386347

  7. [Sites of synthesis of acetylcholine receptors in denervated muscles].

    PubMed

    Giacobini Robecchi, M G; Garelli, M; Filogamo, G

    1980-09-01

    Muscle fibres binding with 125I alpha-bungarotoxine from Bungarus Multicinctus, after treatment with saponine, shows (in electron microscope autoradiography) intracellular binding sites identifying sites of acetylcholine receptor synthesis. In innervated muscle, the acetylcholine receptor is located only at the neuromuscular junction. In denervated muscle the receptor is distributed along the whole sarcolemma; in this situation the acetylcholine receptor is synthesized "ex novo" in the membrane system over the whole length of the muscle fibre.

  8. The MMP-1/PAR-1 Axis Enhances Proliferation and Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells

    PubMed Central

    Valente, Maria Maddalena; Allen, Megan; Bortolotto, Valeria; Lim, Seung T.; Conant, Katherine; Grilli, Mariagrazia

    2015-01-01

    Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a role in varied forms of developmental and postnatal neuroplasticity. MMP substrates include protease-activated receptor-1 (PAR-1), a G-protein coupled receptor expressed in hippocampus. We examined proliferation and differentiation of adult neural progenitor cells (aNPCs) from hippocampi of mice that overexpress the potent PAR-1 agonist MMP-1. We found that, as compared to aNPCs from littermate controls, MMP-1 tg aNPCs display enhanced proliferation. Under differentiating conditions, these cells give rise to a higher percentage of MAP-2+ neurons and a reduced number of oligodendrocyte precursors, and no change in the number of astrocytes. The fact that these results are MMP and PAR-1 dependent is supported by studies with distinct antagonists. Moreover, JSH-23, an inhibitor of NF-κB p65 nuclear translocation, counteracted both the proliferation and differentiation changes seen in MMP-1 tg-derived NPCs. In complementary studies, we found that the percentage of Sox2+ undifferentiated progenitor cells is increased in hippocampi of MMP-1 tg animals, compared to wt mice. Together, these results add to a growing body of data suggesting that MMPs are effectors of hippocampal neuroplasticity in the adult CNS and that the MMP-1/PAR-1 axis may play a role in neurogenesis following physiological and/or pathological stimuli. PMID:26783471

  9. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease-like pathology.

    PubMed

    Zhang, Wei; Gu, Guo-Jun; Shen, Xing; Zhang, Qi; Wang, Gang-Min; Wang, Pei-Jun

    2015-03-01

    Mitochondrial dysfunction, especially a defect in mitochondrial biogenesis, is an early and prominent feature of Alzheimer's disease (AD). Previous studies demonstrated that the number of mitochondria is significantly reduced in susceptible hippocampal neurons from AD patients. Neural stem cell (NSC) transplantation in AD-like mice can compensate for the neuronal loss resulting from amyloid-beta protein deposition. The effects of NSC transplantation on mitochondrial biogenesis and cognitive function in AD-like mice, however, are poorly understood. In this study, we injected NSCs or vehicle into 12-month-old amyloid precursor protein (APP)/PS1 transgenic mice, a mouse model of AD-like pathology. The effects of NSC transplantation on cognitive function, the amount of mitochondrial DNA, the expression of mitochondrial biogenesis factors and mitochondria-related proteins, and mitochondrial morphology were investigated. Our results show that in NSC-injected APP/PS1 (Tg-NSC) mice, the cognitive function, number of mitochondria, and expression of mitochondria-related proteins, specifically the mitochondrial fission factors (dynamin-related protein 1 [Drp1] and fission 1 [Fis1]) and the mitochondrial fusion factor optic atrophy 1 (OPA1), were significantly increased compared with those in age-matched vehicle-injected APP/PS1 (Tg-Veh) mice, whereas the expression of mitochondrial fusion factors mitofusion 1 (Mfn1) and Mfn2 was significantly decreased. These data indicate that NSC transplantation may enhance mitochondria biogenesis and further rescue cognitive deficits in AD-like mice.

  10. Artificial Neural Network classification of operator workload with an assessment of time variation and noise-enhancement to increase performance.

    PubMed

    Casson, Alexander J

    2014-01-01

    Workload classification-the determination of whether a human operator is in a high or low workload state to allow their working environment to be optimized-is an emerging application of passive Brain-Computer Interface (BCI) systems. Practical systems must not only accurately detect the current workload state, but also have good temporal performance: requiring little time to set up and train the classifier, and ensuring that the reported performance level is consistent and predictable over time. This paper investigates the temporal performance of an Artificial Neural Network based classification system. For networks trained on little EEG data good classification accuracies (86%) are achieved over very short time frames, but substantial decreases in accuracy are found as the time gap between the network training and the actual use is increased. Noise-enhanced processing, where artificially generated noise is deliberately added to the testing signals, is investigated as a potential technique to mitigate this degradation without requiring the network to be re-trained using more data. Small stochastic resonance effects are demonstrated whereby the classification process gets better in the presence of more noise. The effect is small and does not eliminate the need for re-training, but it is consistent, and this is the first demonstration of such effects for non-evoked/free-running EEG signals suitable for passive BCI.

  11. Genetic dissection of neural circuits by Tol2 transposon-mediated Gal4 gene and enhancer trapping in zebrafish.

    PubMed

    Asakawa, Kazuhide; Suster, Maximiliano L; Mizusawa, Kanta; Nagayoshi, Saori; Kotani, Tomoya; Urasaki, Akihiro; Kishimoto, Yasuyuki; Hibi, Masahiko; Kawakami, Koichi

    2008-01-29

    Targeted gene expression is a powerful approach to study the function of genes and cells in vivo. In Drosophila, the P element-mediated Gal4-UAS method has been successfully used for this purpose. However, similar methods have not been established in vertebrates. Here we report the development of a targeted gene expression methodology in zebrafish based on the Tol2 transposable element and its application to the functional study of neural circuits. First, we developed gene trap and enhancer trap constructs carrying an engineered yeast Gal4 transcription activator (Gal4FF) and transgenic reporter fish carrying the GFP or the RFP gene downstream of the Gal4 recognition sequence (UAS) and showed that the Gal4FF can activate transcription through UAS in zebrafish. Second, by using this Gal4FF-UAS system, we performed large-scale screens and generated a large collection of fish lines that expressed Gal4FF in specific tissues, cells, and organs. Finally, we developed transgenic effector fish carrying the tetanus toxin light chain (TeTxLC) gene downstream of UAS, which is known to block synaptic transmission. We crossed the Gal4FF fish with the UAS:TeTxLC fish and analyzed double transgenic embryos for defects in touch response. From this analysis, we discovered that targeted expression of TeTxLC in distinct populations of neurons in the brain and the spinal cord caused distinct abnormalities in the touch response behavior. These studies illustrate that our Gal4FF gene trap and enhancer trap methods should be an important resource for genetic analysis of neuronal functions and behavior in vertebrates.

  12. Neural Progenitor Cell Transplantation Promotes Neuroprotection, Enhances Hippocampal Neurogenesis, and Improves Cognitive Outcomes after Traumatic Brain Injury

    PubMed Central

    Blaya, Meghan O.; Tsoulfas, Pantelis; Bramlett, Helen M.; Dietrich, W. Dalton

    2014-01-01

    Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1 week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism towards contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant

  13. Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury.

    PubMed

    Blaya, Meghan O; Tsoulfas, Pantelis; Bramlett, Helen M; Dietrich, W Dalton

    2015-02-01

    Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post-surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism toward contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant

  14. Immunocytochemical Detection of Acetylcholine in the Rat Central Nervous System

    NASA Astrophysics Data System (ADS)

    Geffard, M.; McRae-Degueurce, A.; Souan, Marie Laure

    1985-07-01

    A specific antibody to acetylcholine was raised and used as a marker for cholinergic neurons in the rat central nervous system. The acetylcholine conjugate was obtained by a two-step immunogen synthesis procedure. An enzyme-linked immunosorbent assay was used to test the specificity and affinity of the antibody in vitro; the results indicated high affinity. A chemical perfusion mixture of allyl alcohol and glutaraldehyde was used to fix the acetylcholine in the nervous tissue. Peroxidase-antiperoxidase immunocytochemistry showed many acetylcholine-immunoreactive cells and fibers in sections from the medial septum region.

  15. Situation-based social anxiety enhances the neural processing of faces: evidence from an intergroup context.

    PubMed

    Ofan, Renana H; Rubin, Nava; Amodio, David M

    2014-08-01

    Social anxiety is the intense fear of negative evaluation by others, and it emerges uniquely from a social situation. Given its social origin, we asked whether an anxiety-inducing social situation could enhance the processing of faces linked to the situational threat. While past research has focused on how individual differences in social anxiety relate to face processing, we tested the effect of manipulated social anxiety in the context of anxiety about appearing racially prejudiced in front of a peer. Visual processing of faces was indexed by the N170 component of the event-related potential. Participants viewed faces of Black and White males, along with nonfaces, either in private or while being monitored by the experimenter for signs of prejudice in a 'public' condition. Results revealed a difference in the N170 response to Black and Whites faces that emerged only in the public condition and only among participants high in dispositional social anxiety. These results provide new evidence that anxiety arising from the social situation modulates the earliest stages of face processing in a way that is specific to a social threat, and they shed new light on how anxiety effects on perception may contribute to the regulation of intergroup responses.

  16. Enhancing Executive Function and Neural Health in Bipolar Disorder through Reasoning Training

    PubMed Central

    Venza, Erin E.; Chapman, Sandra B.; Aslan, Sina; Zientz, Jennifer E.; Tyler, David L.; Spence, Jeffrey S.

    2016-01-01

    Cognitive deficits in executive function and memory among individuals with bipolar disorder (BD) are well-documented; however, only recently have efforts begun to address whether such cognitive deficits can be ameliorated through cognitive training. This pilot study examined the effects of a top–down, cognitive reasoning training program in adults with BD on both brain and cognitive measures. Twenty-seven participants (11 males, 16 females), aged 21–70 years old, completed the study. Participants completed neurocognitive testing and functional magnetic resonance imaging (fMRI) before and after training, consisting of 8 h (2 h/week) of training in small groups. The training delivered information processing strategies that were implemented and applicable to a variety of daily living contexts. Results indicated that participants showed significant gains in the primary outcome measure of complex abstraction, also referred to as gist reasoning, as well as in untrained domains of executive function and memory. We found a significant increase in resting cerebral blood flow (CBF) in left inferior frontal gyrus after cognitive training. We also found that resting CBF in the right frontal middle gyrus correlated positively with performance on the measure of complex abstraction. This feasibility study provides promising evidence that short-term reasoning training can enhance cognitive performance and brain health in adults with BD. These data motivate further efforts to explore adjuvant therapeutics to improve cognitive performance and underlying brain systems in bipolar, as well as other psychiatric disorders. Clinicaltrials.gov Identifier: NCT02843282, http://www.clinicaltrials.gov/ct2/show/NCT02843282 PMID:27847486

  17. Transplantation of Human Neural Progenitor Cells Expressing IGF-1 Enhances Retinal Ganglion Cell Survival

    PubMed Central

    Guo, Caiwei; Sun, Yu; Liao, Tiffany; Beattie, Ursula; López, Francisco J.; Chen, Dong Feng; Lashkari, Kameran

    2015-01-01

    We have previously characterized human neuronal progenitor cells (hNP) that can adopt a retinal ganglion cell (RGC)-like morphology within the RGC and nerve fiber layers of the retina. In an effort to determine whether hNPs could be used a candidate cells for targeted delivery of neurotrophic factors (NTFs), we evaluated whether hNPs transfected with an vector that expresses IGF-1 in the form of a fusion protein with tdTomato (TD), would increase RGC survival in vitro and confer neuroprotective effects in a mouse model of glaucoma. RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF-1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways. This study shows that neuronal progenitor cells that hone into the RGC and nerve fiber layers may be used as vehicles for local production and delivery of a desired NTF. Transplantation of hNPIGF-TD cells improves RGC survival in vitro and protects against RGC loss in a rodent model of glaucoma. Our findings have provided experimental evidence and form the basis for applying cell-based strategies for local delivery of NTFs into the retina. Application of cell-based delivery may be extended to other disease conditions beyond glaucoma. PMID:25923430

  18. Enhancing Executive Function and Neural Health in Bipolar Disorder through Reasoning Training.

    PubMed

    Venza, Erin E; Chapman, Sandra B; Aslan, Sina; Zientz, Jennifer E; Tyler, David L; Spence, Jeffrey S

    2016-01-01

    Cognitive deficits in executive function and memory among individuals with bipolar disorder (BD) are well-documented; however, only recently have efforts begun to address whether such cognitive deficits can be ameliorated through cognitive training. This pilot study examined the effects of a top-down, cognitive reasoning training program in adults with BD on both brain and cognitive measures. Twenty-seven participants (11 males, 16 females), aged 21-70 years old, completed the study. Participants completed neurocognitive testing and functional magnetic resonance imaging (fMRI) before and after training, consisting of 8 h (2 h/week) of training in small groups. The training delivered information processing strategies that were implemented and applicable to a variety of daily living contexts. Results indicated that participants showed significant gains in the primary outcome measure of complex abstraction, also referred to as gist reasoning, as well as in untrained domains of executive function and memory. We found a significant increase in resting cerebral blood flow (CBF) in left inferior frontal gyrus after cognitive training. We also found that resting CBF in the right frontal middle gyrus correlated positively with performance on the measure of complex abstraction. This feasibility study provides promising evidence that short-term reasoning training can enhance cognitive performance and brain health in adults with BD. These data motivate further efforts to explore adjuvant therapeutics to improve cognitive performance and underlying brain systems in bipolar, as well as other psychiatric disorders. Clinicaltrials.gov Identifier: NCT02843282, http://www.clinicaltrials.gov/ct2/show/NCT02843282.

  19. pH-dependent hydrolysis of acetylcholine: Consequences for non-neuronal acetylcholine.

    PubMed

    Wessler, Ignaz; Michel-Schmidt, Rosmarie; Kirkpatrick, Charles James

    2015-11-01

    Acetylcholine is inactivated by acetylcholinesterase and butyrylcholinesterase and thereby its cellular signalling is stopped. One distinguishing difference between the neuronal and non-neuronal cholinergic system is the high expression level of the esterase activity within the former and a considerably lower level within the latter system. Thus, any situation which limits the activity of both esterases will affect the non-neuronal cholinergic system to a much greater extent than the neuronal one. Both esterases are pH-dependent with an optimum at pH above 7, whereas at pH values below 6 particularly the specific acetylcholinesterase is more or less inactive. Thus, acetylcholine is prevented from hydrolysis at such low pH values. The pH of the surface of the human skin is around 5 and therefore non-neuronal acetylcholine released from keratinocytes can be detected in a non-invasive manner. Several clinical conditions like metabolic acidosis, inflammation, fracture-related haematomas, cardiac ischemia and malignant tumours are associated with local or systemic pH values below 7. Thus, the present article describes some consequences of an impaired inactivation of extracellular non-neuronal acetylcholine.

  20. Enhanced cholinergic suppression of previously strengthened synapses enables the formation of self-organized representations in olfactory cortex.

    PubMed

    Linster, Christiane; Maloney, Michaella; Patil, Madhvi; Hasselmo, Michael E

    2003-11-01

    Computational modeling assists in analyzing the specific functional role of the cellular effects of acetylcholine within cortical structures. In particular, acetylcholine may regulate the dynamics of encoding and retrieval of information by regulating the magnitude of synaptic transmission at excitatory recurrent connections. Many abstract models of associative memory function ignore the influence of changes in synaptic strength during the storage process and apply the effect of these changes only during a so-called recall-phase. Efforts to ensure stable activity with more realistic, continuous updating of the synaptic strength during the storage process have shown that the memory capacity of a realistic cortical network can be greatly enhanced if cholinergic modulation blocks transmission at synaptic connections of the association fibers during the learning process. We here present experimental data from an olfactory cortex brain slice preparation showing that previously potentiated fibers show significantly greater suppression (presynaptic inhibition) by the cholinergic agonist carbachol than unpotentiated fibers. We conclude that low suppression of non-potentiated fibers during the learning process ensures the formation of self-organized representations in the neural network while the higher suppression of previously potentiated fibers minimizes interference between overlapping patterns. We show in a computational model of olfactory cortex, that, together, these two phenomena reduce the overlap between patterns that are stored within the same neural network structure. These results further demonstrate the contribution of acetylcholine to mechanisms of cortical plasticity. The results are consistent with the extensive evidence supporting a role for acetylcholine in encoding of new memories and enhancement of response to salient sensory stimuli.

  1. Role of acetylcholine receptors in proliferation and differentiation of P19 embryonal carcinoma cells

    SciTech Connect

    Resende, R.R.; Alves, A.S.; Britto, L.R.G; Ulrich, H.

    2008-04-15

    Coordinated proliferation and differentiation of progenitor cells is the base for production of appropriate numbers of neurons and glia during neuronal development in order to establish normal brain functions. We have used murine embryonal carcinoma P19 cells as an in vitro model for early differentiation to study participation of nicotinic (nAChR) and muscarinic acetylcholine (mAChR) receptors in the proliferation of neural progenitor cells and their differentiation to neurons. We have previously shown that functional nicotinic acetylcholine receptors (nAChRs) already expressed in embryonic cells mediate elevations in cytosolic free calcium concentration ([Ca{sup 2+}]{sub i}) via calcium influx through nAChR channels whereas intracellular stores contribute to nAChR- and mAChR-mediated calcium fluxes in differentiated cells [Resende et al., Cell Calcium 43 (2008) 107-121]. In the present study, we have demonstrated that nicotine provoked inhibition of proliferation in embryonic cells as determined by BrdU labeling. However, in neural progenitor cells nicotine stimulated proliferation which was reversed in the presence of inhibitors of calcium mobilization from intracellular stores, indicating that liberation of intracellular calcium contributed to this proliferation induction. Muscarine induced proliferation stimulation in progenitor cells by activation of G{alpha}{sub q/11}-coupled M{sub 1}, M{sub 3} and M{sub 5} receptors and intracellular calcium stores, whereas G{alpha}{sub i/o}-protein coupled M{sub 2} receptor activity mediated neuronal differentiation.

  2. Synaptic modulation of excitatory synaptic transmission by nicotinic acetylcholine receptors in spinal ventral horn neurons.

    PubMed

    Mine, N; Taniguchi, W; Nishio, N; Izumi, N; Miyazaki, N; Yamada, H; Nakatsuka, T; Yoshida, M

    2015-04-02

    Nicotinic acetylcholine receptors (nAChRs) are distributed widely in the central nervous system and play important roles in higher brain functions, including learning, memory, and recognition. However, functions of the cholinergic system in spinal motoneurons remain poorly understood. In this study, we investigated the actions of presynaptic and postsynaptic nAChRs in spinal ventral horn neurons by performing whole-cell patch-clamp recordings on lumbar slices from male rats. The application of nicotine or acetylcholine generated slow inward currents and increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Slow inward currents by acetylcholine or nicotine were not inhibited by tetrodotoxin (TTX) or glutamate receptor antagonists. In the presence of TTX, the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) were also increased by acetylcholine or nicotine. A selective α4β2 nicotinic receptor antagonist, dihydro-β-erythroidine hydrobromide (DhβE), significantly decreased nicotine-induced inward currents without affecting the enhancement of sEPSCs and mEPSCs. In addition, a selective α7 nicotinic receptor antagonist, methyllycaconitine, did not affect either nicotine-induced inward currents or the enhancement of sEPSCs and mEPSCs. These results suggest that α4β2 AChRs are localized at postsynaptic sites in the spinal ventral horn, non-α4β2 and non-α7 nAChRs are located presynaptically, and nAChRs enhance excitatory synaptic transmission in the spinal ventral horn.

  3. Eating breakfast enhances the efficiency of neural networks engaged during mental arithmetic in school-aged children.

    PubMed

    Pivik, R T; Tennal, Kevin B; Chapman, Stephen D; Gu, Yuyuan

    2012-06-25

    To determine the influence of a morning meal on complex mental functions in children (8-11 y), time-frequency analyses were applied to electroencephalographic (EEG) activity recorded while children solved simple addition problems after an overnight fast and again after having either eaten or skipped breakfast. Power of low frequency EEG activity [2 Hertz (Hz) bands in the 2-12 Hz range] was determined from recordings over frontal and parietal brain regions associated with mathematical thinking during mental calculation of correctly answered problems. Analyses were adjusted for background variables known to influence or reflect the development of mathematical skills, i.e., age and measures of math competence and math fluency. Relative to fed children, those who continued to fast showed greater power increases in upper theta (6-8 Hz) and both alpha bands (8-10 Hz; 10-12 Hz) across sites. Increased theta suggests greater demands on working memory. Increased alpha may facilitate task-essential activity by suppressing non-task-essential activity. Fasting children also had greater delta (2-4 Hz) and greater lower-theta (4-6 Hz) power in left frontal recordings-indicating a region-specific emphasis on both working memory for mental calculation (theta) and activation of processes that suppress interfering activity (delta). Fed children also showed a significant increase in correct responses while children who continued to fast did not. Taken together the findings suggest that neural network activity involved in processing numerical information is functionally enhanced and performance is improved in children who have eaten breakfast, whereas greater mental effort is required for this mathematical thinking in children who skip breakfast.

  4. BMP, Wnt and FGF signals are integrated through evolutionarily conserved enhancers to achieve robust expression of Pax3 and Zic genes at the zebrafish neural plate border.

    PubMed

    Garnett, Aaron T; Square, Tyler A; Medeiros, Daniel M

    2012-11-01

    Neural crest cells generate a range of cells and tissues in the vertebrate head and trunk, including peripheral neurons, pigment cells, and cartilage. Neural crest cells arise from the edges of the nascent central nervous system, a domain called the neural plate border (NPB). NPB induction is known to involve the BMP, Wnt and FGF signaling pathways. However, little is known about how these signals are integrated to achieve temporally and spatially specific expression of genes in NPB cells. Furthermore, the timing and relative importance of these signals in NPB formation appears to differ between vertebrate species. Here, we use heat-shock overexpression and chemical inhibitors to determine whether, and when, BMP, Wnt and FGF signaling are needed for expression of the NPB specifiers pax3a and zic3 in zebrafish. We then identify four evolutionarily conserved enhancers from the pax3a and zic3 loci and test their response to BMP, Wnt and FGF perturbations. We find that all three signaling pathways are required during gastrulation for the proper expression of pax3a and zic3 in the zebrafish NPB. We also find that, although the expression patterns driven by the pax3a and zic3 enhancers largely overlap, they respond to different combinations of BMP, Wnt and FGF signals. Finally, we show that the combination of the two pax3a enhancers is less susceptible to signaling perturbations than either enhancer alone. Taken together, our results reveal how BMPs, FGFs and Wnts act cooperatively and redundantly through partially redundant enhancers to achieve robust, specific gene expression in the zebrafish NPB.

  5. Binding of rabies virus to purified Torpedo acetylcholine receptor.

    PubMed

    Lentz, T L; Benson, R J; Klimowicz, D; Wilson, P T; Hawrot, E

    1986-12-01

    The binding of 125I- and 35S-labeled rabies virus (CVS strain) to affinity-purified acetylcholine receptor from Torpedo electric organ was demonstrated. The binding of rabies virus to the acetylcholine receptor increased with increasing receptor concentration, was dependent on the pH of the incubation medium, and was saturable with increasing virus concentration. Binding of radioactively labeled virus was effectively competed by unlabeled homologous virus particles. Binding of 35S-labeled rabies virus to the AChR was inhibited up to 50% by alpha-bungarotoxin and up to 30% by (+)-tubocurarine but was not affected by atropine. These results demonstrate direct binding of rabies virus to a well-defined neurotransmitter receptor, namely the acetylcholine receptor and indicate that at least a portion of the virus interaction occurs near the acetylcholine binding site on the receptor. These findings support the hypothesis that the acetylcholine receptor may serve as a rabies virus receptor in vivo.

  6. Exercise and neuromodulators: choline and acetylcholine in marathon runners

    NASA Technical Reports Server (NTRS)

    Conlay, L. A.; Sabounjian, L. A.; Wurtman, R. J.

    1992-01-01

    Certain neurotransmitters (i.e., acetylcholine, catecholamines, and serotonin) are formed from dietary constituents (i.e., choline, tyrosine and tryptophan). Changing the consumption of these precursors alters release of their respective neurotransmitter products. The neurotransmitter acetylcholine is released from the neuromuscular junction and from brain. It is formed from choline, a common constituent in fish, liver, and eggs. Choline is also incorporated into cell membranes; membranes may likewise serve as an alternative choline source for acetylcholine synthesis. In trained athletes, running a 26 km marathon reduced plasma choline by approximately 40%, from 14.1 to 8.4 uM. Changes of similar magnitude have been shown to reduce acetylcholine release from the neuromuscular junction in vivo. Thus, the reductions in plasma choline associated with strenuous exercise may reduce acetylcholine release, and could thereby affect endurance or performance.

  7. Homology modeling of human muscarinic acetylcholine receptors.

    PubMed

    Thomas, Trayder; McLean, Kimberley C; McRobb, Fiona M; Manallack, David T; Chalmers, David K; Yuriev, Elizabeth

    2014-01-27

    We have developed homology models of the acetylcholine muscarinic receptors M₁R-M₅R, based on the β₂-adrenergic receptor crystal as the template. This is the first report of homology modeling of all five subtypes of acetylcholine muscarinic receptors with binding sites optimized for ligand binding. The models were evaluated for their ability to discriminate between muscarinic antagonists and decoy compounds using virtual screening using enrichment factors, area under the ROC curve (AUC), and an early enrichment measure, LogAUC. The models produce rational binding modes of docked ligands as well as good enrichment capacity when tested against property-matched decoy libraries, which demonstrates their unbiased predictive ability. To test the relative effects of homology model template selection and the binding site optimization procedure, we generated and evaluated a naïve M₂R model, using the M₃R crystal structure as a template. Our results confirm previous findings that binding site optimization using ligand(s) active at a particular receptor, i.e. including functional knowledge into the model building process, has a more pronounced effect on model quality than target-template sequence similarity. The optimized M₁R-M₅R homology models are made available as part of the Supporting Information to allow researchers to use these structures, compare them to their own results, and thus advance the development of better modeling approaches.

  8. Acetylcholine and choline levels in rabbit fetuses exposed to anticholinergics.

    PubMed

    McBride, W G; Hicks, L J

    1987-01-01

    It has been hypothesized that acetylcholine, choline acetylase and acetylcholinesterase may have an ontogenic and trophic influence in the embryo, and that therefore certain drugs may produce malformations via their effect on the acetylcholine and choline levels in the fetus. Thalidomide and the anticholinergics, scopolamine hydrobromide and orphenadrine hydrochloride, and doxylamine succinate, an antihistamine with secondary anticholinergic action, were administered to pregnant New Zealand White rabbit does from day 8 to day 15 of gestation. Cesarean sections were performed on gestational day 16, the fetuses removed and the acetylcholine and choline contents of the fetuses and placentas were estimated by organic extraction and derivation for injection into a GCMS. These acetylcholine and choline levels were compared with those of the fetuses and placentas of the control animals mated with the same buck on the same day as the treated animals. Thalidomide (50 mg/kg) did not affect acetylcholine or choline levels in the fetuses or the placentas obtained from the treated animal. Scopolamine (approximately 100 micrograms/kg) reduced the choline level in the placenta and fetus but not the acetylcholine levels. Orphenadrine (approximately 24 mg/kg) reduced acetylcholine and choline levels in the fetus and choline levels in the placenta. Doxylamine succinate (10 mg/kg) reduced the acetylcholine levels in the fetus and the choline levels in the placenta. The placenta is a fetal organ and the significance of acetylcholine production by the placenta is as yet unknown. The reduction in acetylcholine levels in the fetus exposed to drugs with an anticholinergic action may be of significance in the production of malformations.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors

    SciTech Connect

    Manceur, Aziza P.; Tseng, Michael; Holowacz, Tamara; Witterick, Ian; Weksberg, Rosanna; McCurdy, Richard D.; Warsh, Jerry J.; Audet, Julie

    2011-09-10

    The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro. GSK-3 inhibition was achieved using ATP-competitive (6-bromoindirubin-3'-oxime and CHIR99021) or substrate-competitive (TAT-eIF2B) inhibitors to eliminate potential confounding effects on cell fate due to off-target kinase inhibition. GSK-3 inhibitors decreased the number of neural precursor cells in OE cell cultures through a reduction in proliferation. Decreased proliferation was not associated with a reduction in cell survival but was accompanied by a reduction in nestin expression and a substantial increase in the expression of the neuronal differentiation markers MAP1B and neurofilament (NF-M) after 10 days in culture. Taken together, these results suggest that GSK-3 inhibition promotes the early stages of neuronal differentiation in cultures of adult human neural precursors and provide insights into the mechanisms by which alterations in GSK-3 signaling affect adult human neurogenesis, a cellular process strongly suspected to play a role in the etiology of neuropsychiatric disorders.

  10. “Controlled release of neurotrophin-3 from fibrin-based tissue engineering scaffolds enhances neural fiber sprouting following subacute spinal cord injury”†

    PubMed Central

    Johnson, Philip J; Parker, Stanley R; Sakiyama-Elbert, Shelly E.

    2009-01-01

    This study investigated whether delayed treatment of spinal cord injury with controlled release of neurotrophin-3 (NT-3) from fibrin scaffolds can stimulate enhanced neural fiber sprouting. Long Evans rats received a T9 dorsal hemisection spinal cord injury. Two weeks later, the injury site was re-exposed, and either a fibrin scaffold alone, a fibrin scaffold containing a heparin-based delivery system with different concentrations of NT-3 (500 and 1000 ng/mL), or a fibrin scaffold containing 1000 ng/mL of NT-3 (no delivery system) was implanted into the injury site. The injured spinal cords were evaluated for morphological differences using markers for neurons, astrocytes, and chondroitin sulfate proteoglycans 2 weeks after treatment. The addition of 500 ng/mL of NT-3 with the delivery system resulted in an increase in neural fiber density compared to fibrin alone. These results demonstrate that the controlled release of NT-3 from fibrin scaffolds can enhance neural fiber sprouting even when treatment is delayed 2 weeks following injury. PMID:19603426

  11. LIN28A enhances the therapeutic potential of cultured neural stem cells in a Parkinson's disease model.

    PubMed

    Rhee, Yong-Hee; Kim, Tae-Ho; Jo, A-Young; Chang, Mi-Yoon; Park, Chang-Hwan; Kim, Sang-Mi; Song, Jae-Jin; Oh, Sang-Min; Yi, Sang-Hoon; Kim, Hyeon Ho; You, Bo-Hyun; Nam, Jin-Wu; Lee, Sang-Hun

    2016-10-01

    The original properties of tissue-specific stem cells, regardless of their tissue origins, are inevitably altered during in vitro culturing, lessening the clinical and research utility of stem cell cultures. Specifically, neural stem cells derived from the ventral midbrain lose their dopamine neurogenic potential, ventral midbrain-specific phenotypes, and repair capacity during in vitro cell expansion, all of which are critical concerns in using the cultured neural stem cells in therapeutic approaches for Parkinson's disease. In this study, we observed that the culture-dependent changes of neural stem cells derived from the ventral midbrain coincided with loss of RNA-binding protein LIN28A expression. When LIN28A expression was forced and sustained during neural stem cell expansion using an inducible expression-vector system, loss of dopamine neurogenic potential and midbrain phenotypes after long-term culturing was blocked. Furthermore, dopamine neurons that differentiated from neural stem cells exhibited remarkable survival and resistance against toxic insults. The observed effects were not due to a direct action of LIN28A on the differentiated dopamine neurons, but rather its action on precursor neural stem cells as exogene expression was switched off in the differentiating/differentiated cultures. Remarkable and reproducible behavioural recovery was shown in all Parkinson's disease rats grafted with neural stem cells expanded with LIN28A expression, along with extensive engraftment of dopamine neurons expressing mature neuronal and midbrain-specific markers. These findings suggest that LIN28A expression during stem cell expansion could be used to prepare therapeutically competent donor cells.

  12. Neural mechanisms of selective auditory attention are enhanced by computerized training: Electrophysiological evidence from language-impaired and typically developing children

    PubMed Central

    Stevens, Courtney; Fanning, Jessica; Coch, Donna; Sanders, Lisa; Neville, Helen

    2008-01-01

    Recent proposals suggest that some interventions designed to improve language skills might also target or train selective attention. The present study examined whether six weeks of high-intensity (100 min/day) training with a computerized intervention program designed to improve language skills would also influence neural mechanisms of selective auditory attention previously shown to be deficient in children with specific language impairment (SLI). Twenty children received computerized training, including 8 children diagnosed with SLI and 12 children with typically developing language. An additional 13 children with typically developing language received no specialized training (NoTx control group) but were tested and retested after a comparable time period to control for maturational and test-retest effects. Before and after training (or a comparable delay period for the NoTx control group), children completed standardized language assessments and an event-related brain potential (ERP) measure of selective auditory attention. Relative to the NoTx control group, children receiving training showed increases in standardized measures of receptive language. In addition, children receiving training showed larger increases in the effects of attention on neural processing following training relative to the NoTx control group. The enhanced effect of attention on neural processing represented a large effect size (Cohen’s d = 0.8), and was specific to changes in signal enhancement of attended stimuli. These findings indicate that the neural mechanisms of selective auditory attention, previously shown to be deficient in children with SLI, can be remediated through training and can accompany improvements on standardized measures of language. Section Cognitive and Behavioral Neuroscience PMID:18353284

  13. Suitability of Nicotinic Acetylcholine Receptor α7 and Muscarinic Acetylcholine Receptor 3 Antibodies for Immune Detection

    PubMed Central

    Rommel, Frank R.; Raghavan, Badrinarayanan; Paddenberg, Renate; Kummer, Wolfgang; Tumala, Susanne; Lochnit, Günter; Gieler, Uwe

    2015-01-01

    Recent evidence reveals a crucial role for acetylcholine and its receptors in the regulation of inflammation, particularly of nicotinic acetylcholine receptor α7 (Chrna7) and muscarinic acetylcholine receptor 3 (Chrm3). Immunohistochemistry is a key tool for their cellular localization in functional tissues. We evaluated nine different commercially available antibodies on back skin tissue from wild-type (Wt) and gene-deficient (KO) mice. In the immunohistochemical analysis, we focused on key AChR-ligand sensitive skin cells (mast cells, nerve fibers and keratinocytes). All five antibodies tested for Chrm3 and the first three Chrna7 antibodies stained positive in both Wt and respective KO skin. With the 4th antibody (ab23832) nerve fibers were unlabeled in the KO mice. By western blot analysis, this antibody detected bands in both Wt and Chrna7 KO skin and brain. qRT-PCR revealed mRNA amplification with a primer set for the undeleted region in both Wt and KO mice, but none with a primer set for the deleted region in KO mice. By 2D electrophoresis, we found β-actin and β-enolase cross reactivity, which was confirmed by double immunolabeling. In view of the present results, the tested antibodies are not suitable for immunolocalization in skin and suggest thorough control of antibody specificity is required if histomorphometry is intended. PMID:25673288

  14. Acetylcholine receptors in the human retina

    SciTech Connect

    Hutchins, J.B.; Hollyfield, J.G.

    1985-11-01

    Evidence for a population of acetylcholine (ACh) receptors in the human retina is presented. The authors have used the irreversible ligand TH-propylbenzilylcholine mustard (TH-PrBCM) to label muscarinic receptors. TH- or SVI-alpha-bungarotoxin (alpha-BTx) was used to label putative nicotinic receptors. Muscarinic receptors are apparently present in the inner plexiform layer of the retina. Autoradiographic grain densities are reduced in the presence of saturating concentrations of atropine, quinuclidinyl benzilate or scopolamine; this indicates that TH-PrBCM binding is specific for a population of muscarinic receptors in the human retina. Binding sites for radiolabeled alpha-BTx are found predominantly in the inner plexiform layer of the retina. Grain densities are reduced in the presence of d-tubocurarine, indicating that alpha-BTx may bind to a pharmacologically relevant nicotinic ACh receptor. This study provides evidence for cholinergic neurotransmission in the human retina.

  15. Impulsive behavior and nicotinic acetylcholine receptors.

    PubMed

    Ohmura, Yu; Tsutsui-Kimura, Iku; Yoshioka, Mitsuhiro

    2012-01-01

    Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; α4β2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior.

  16. Conotoxins Targeting Nicotinic Acetylcholine Receptors: An Overview

    PubMed Central

    Lebbe, Eline K. M.; Peigneur, Steve; Wijesekara, Isuru; Tytgat, Jan

    2014-01-01

    Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide variety of ion channels such as voltage-gated sodium- (NaV), potassium- (KV), and calcium- (CaV) channels as well as nicotinic acetylcholine receptors (nAChRs) which are classified as ligand-gated ion channels. The mode of action of several conotoxins has been the subject of investigation, while for many others this remains unknown. This review aims to give an overview of the knowledge we have today on the molecular pharmacology of conotoxins specifically interacting with nAChRs along with the structure–function relationship data. PMID:24857959

  17. [Desensitization of the nicotinic acetylcholine receptor].

    PubMed

    Quiñonez, M; Rojas, L

    1994-01-01

    In biological membranes, ionic channels act speeding up ion movements. Each ionic channel is excited by a specific stimulus (i.e. electric, mechanical, chemical, etc.). Chemically activated ionic channels (CAIC), such as the nicotinic acetylcholine receptor (nAChR), suffer desensitization when the receptor site is still occupied by the agonist molecule. The desensitized CAIC is a non functional channel state regarded as a particular case of receptors rundown. CAIC desensitization only involve reduced activity and not their membrane elimination. Desensitization is important to control synaptic transmission and the development of the nervous system. In this review we discuss results related to its production, modulation and some aspects associated to models that consider it. Finally, an approach combining molecular biology and electrophysiology techniques to understand desensitization and its importance in biological systems is presented.

  18. Modulation of nicotinic acetylcholine receptors by strychnine

    PubMed Central

    García-Colunga, Jesús; Miledi, Ricardo

    1999-01-01

    Strychnine, a potent and selective antagonist at glycine receptors, was found to inhibit muscle (α1β1γδ, α1β1γ, and α1β1δ) and neuronal (α2β2 and α2β4) nicotinic acetylcholine receptors (AcChoRs) expressed in Xenopus oocytes. Strychnine alone (up to 500 μM) did not elicit membrane currents in oocytes expressing AcChoRs, but, when applied before, concomitantly, or during superfusion of acetylcholine (AcCho), it rapidly and reversibly inhibited the current elicited by AcCho (AcCho-current). Although in the three cases the AcCho-current was reduced to the same level, its recovery was slower when the oocytes were preincubated with strychnine. The amount of AcCho-current inhibition depended on the receptor subtype, and the order of blocking potency by strychnine was α1β1γδ > α2β4 > α2β2. With the three forms of drug application, the Hill coefficient was close to one, suggesting a single site for the receptor interaction with strychnine, and this interaction appears to be noncompetitive. The inhibitory effects on muscle AcChoRs were voltage-independent, and the apparent dissociation constant for AcCho was not appreciably changed by strychnine. In contrast, the inhibitory effects on neuronal AcChoRs were voltage-dependent, with an electrical distance of ≈0.35. We conclude that strychnine regulates reversibly and noncompetitively the embryonic type of muscle AcChoR and some forms of neuronal AcChoRs. In the former case, strychnine presumably inhibits allosterically the receptor by binding at an external domain whereas, in the latter case, it blocks the open receptor-channel complex. PMID:10097172

  19. Is the acetylcholine receptor a rabies virus receptor?

    PubMed

    Lentz, T L; Burrage, T G; Smith, A L; Crick, J; Tignor, G H

    1982-01-08

    Rabies virus was found on mouse diaphragms and on cultured chick myotubes in a distribution coinciding with that of the acetylcholine receptor. Treatment of the myotubes with alpha-bungarotoxin and d-tubocurarine before the addition of the virus reduced the number of myotubes that became infected with rabies virus. These findings together suggest that acetylcholine receptors may serve as receptors for rabies virus. The binding of virus to acetylcholine receptors, which are present in high density at the neuromuscular junction, would provide a mechanism whereby the virus could be locally concentrated at sites in proximity to peripheral nerves facilitating subsequent uptake and transfer to the central nervous system.

  20. Enhanced robust fractional order proportional-plus-integral controller based on neural network for velocity control of permanent magnet synchronous motor.

    PubMed

    Zhang, Bitao; Pi, YouGuo

    2013-07-01

    The traditional integer order proportional-integral-differential (IO-PID) controller is sensitive to the parameter variation or/and external load disturbance of permanent magnet synchronous motor (PMSM). And the fractional order proportional-integral-differential (FO-PID) control scheme based on robustness tuning method is proposed to enhance the robustness. But the robustness focuses on the open-loop gain variation of controlled plant. In this paper, an enhanced robust fractional order proportional-plus-integral (ERFOPI) controller based on neural network is proposed. The control law of the ERFOPI controller is acted on a fractional order implement function (FOIF) of tracking error but not tracking error directly, which, according to theory analysis, can enhance the robust performance of system. Tuning rules and approaches, based on phase margin, crossover frequency specification and robustness rejecting gain variation, are introduced to obtain the parameters of ERFOPI controller. And the neural network algorithm is used to adjust the parameter of FOIF. Simulation and experimental results show that the method proposed in this paper not only achieve favorable tracking performance, but also is robust with regard to external load disturbance and parameter variation.

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

    PubMed

    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.

  2. Acetylcholine induces voltage-independent increase of cytosolic calcium in mouse myotubes.

    PubMed Central

    Giovannelli, A; Grassi, F; Mattei, E; Mileo, A M; Eusebi, F; Giovanelli, A

    1991-01-01

    Electrophysiological, biochemical, and Ca2+ imaging studies of cultured mouse myotubes were used to investigate whether the neurotransmitter acetylcholine causes an increase in intracellular Ca2+ concentration ([Ca2+]i) through activation of a second messenger system. Bath applications of acetylcholine to myotubes (i) elicited a significant membrane current even in a Na(+)-free Ca2+ medium, when the current was carried mainly by calcium ions; (ii) caused a rapid and transient cytosolic accumulation of inositol 1,4,5-trisphosphate; (iii) evoked a conspicuous alpha-bungarotoxin-sensitive long-lasting [Ca2+]i enhancement even in the presence of Cd2+; and (iv) transiently increased [Ca2+]i when cells were equilibrated in a Ca(2+)-free atropine-containing medium. We propose that, in addition to opening ion channels, the nicotinic action of acetylcholine on the muscle cell membrane increases [Ca2+]i through activation of the inositol 1,4,5-trisphosphate second messenger system and mobilization of Ca2+ from intracellular stores. Images PMID:1946425

  3. Muscarinic acetylcholine receptor-mediated stimulation of retinal ganglion cell photoreceptors.

    PubMed

    Sodhi, Puneet; Hartwick, Andrew T E

    2016-09-01

    Melanopsin-dependent phototransduction in intrinsically photosensitive retinal ganglion cells (ipRGCs) involves a Gq-coupled phospholipase C (PLC) signaling cascade. Acetylcholine, released in the mammalian retina by starburst amacrine cells, can also activate Gq-PLC pathways through certain muscarinic acetylcholine receptors (mAChRs). Using multielectrode array recordings of rat retinas, we demonstrate that robust spiking responses can be evoked in neonatal and adult ipRGCs after bath application of the muscarinic agonist carbachol. The stimulatory action of carbachol on ipRGCs was a direct effect, as confirmed through calcium imaging experiments on isolated ipRGCs in purified cultures. Using flickering (6 Hz) yellow light stimuli at irradiances below the threshold for melanopsin activation, spiking responses could be elicited in ipRGCs that were suppressed by mAChR antagonism. Therefore, this work identified a novel melanopsin-independent pathway for stimulating sustained spiking in ganglion cell photoreceptors. This mAChR-mediated pathway could enhance ipRGC spiking responses in conditions known to evoke retinal acetylcholine release, such as those involving flickering or moving visual stimuli. Furthermore, this work identifies a pharmacological approach for light-independent ipRGC stimulation that could be targeted by mAChR agonists.

  4. Monitoring substrate and products in a bioprocess with FTIR spectroscopy coupled to artificial neural networks enhanced with a genetic-algorithm-based method for wavelength selection.

    PubMed

    Franco, Vanina G; Perín, Juan C; Mantovani, Víctor E; Goicoechea, Héctor C

    2006-01-15

    An experiment was developed as a simple alternative to existing analytical methods for the simultaneous quantitation of glucose (substrate) and glucuronic acid (main product) in the bioprocesses Kombucha by using FTIR spectroscopy coupled to multivariate calibration (partial least-squares, PLS-1 and artificial neural networks, ANNs). Wavelength selection through a novel ranked regions genetic algorithm (RRGA) was used to enhance the predictive ability of the chemometric models. Acceptable results were obtained by using the ANNs models considering the complexity of the sample and the speediness and simplicity of the method. The accuracy on the glucuronic acid determination was calculated by analysing spiked real fermentation samples (recoveries ca. 115%).

  5. The effect of acetylcholine-like biomimetic polymers on neuronal growth.

    PubMed

    Tu, Qin; Li, Li; Zhang, Yanrong; Wang, Jianchun; Liu, Rui; Li, Manlin; Liu, Wenming; Wang, Xueqin; Ren, Li; Wang, Jinyi

    2011-04-01

    Driven by clinical needs, nerve regeneration studies have recently become the focus of research and area of growth in tissue engineering. Biomimetic polymer synthesis and functional interface construction is a promising solution to induce neuritic sprouting and guide the regenerating nerve. However, few studies have been made on primary hippocampal neurons. In this study, a new type of acetylcholine-like biomimetic polymers for their potential in biomaterial-modulated nerve regeneration application is synthesized using click chemistry and free radical polymerization. The structure of the synthesized polymers includes a "bioactive" unit (acetylcholine-like unit) and a "bioinert" unit [poly(ethylene glycol) unit]. To explore the effects of the bioactive unit and the bioinert unit on neuronal growth, different ratios of the two initial monomers poly(ethylene glycol) monomethyl ether-glycidyl methacrylate (MePEG-GMA) and dimethylaminoethyl methacrylate (DMAEMA) were employed and five different polymers were synthesized. Their chemical structures were characterized using (1)H nuclear magnetic resonance and Fourier-transform infrared spectroscopy, and their physical properties (including molecular weight, polydispersity, glass transition temperature, and melting point) were determined using gel permeation chromatography and differential scanning calorimetry. Culturing of the primary rat hippocampal neurons on the polymeric surfaces show that the ratio of the two initial monomers utilized for polymer synthesis significantly affects neuronal growth. Rat hippocampal neurons show different growth morphologies on different polymeric surfaces. The polymeric surface prepared with 1:60 (mol/mol) of MePEG-GMA to DMAEMA induces neuronal regenerative responses similar to that on poly-l-lysine, a very common benchmark material for nerve cell cultures. These results suggest that acetylcholine-like biomimetic polymers are potential biomaterials for neural engineering applications

  6. Enhanced viability and neural differential potential in poor post-thaw hADSCs by agarose multi-well dishes and spheroid culture.

    PubMed

    Guo, Xiaoling; Li, Shanyi; Ji, Qingshan; Lian, Ruiling; Chen, Jiansu

    2015-10-01

    Human adipose-derived stem cells (hADSCs) are potential adult stem cells source for cell therapy. But hADSCs with multi-passage or cryopreservation often revealed poor growth performance. The aim of our work was to improve the activity of poor post-thaw hADSCs by simple and effective means. We describe here a simple method based on commercially available silicone micro-wells for creating hADSCs spheroids to improve viability and neural differentiation potential on poor post-thaw hADSCs. The isolated hADSCs positively expresse d CD29, CD44, CD105, and negatively expressed CD34, CD45, HLA-DR by flow cytometry. Meanwhile, they had adipogenic and osteogenic differentiation capacity. The post-thaw and post-spheroid hADSCs from poor growth status hADSCs showed a marked increase in cell proliferation by CKK-8 analysis, cell cycle analysis and Ki67/P27 quantitative polymerase chain reaction (qPCR) analysis. They also displayed an increase viability of anti-apoptosis by annexin v and propidium iodide assays and mitochondrial membrane potential assays. After 3 days of neural induction, the neural differentiation potential of post-thaw and post-spheroid hADSCs could be enhanced by qPCR analysis and western blotting analysis. These results suggested that the spheroid formation could improve the viability and neural differentiation potential of bad growth status hADSCs, which is conducive to ADSCs research and cell therapy.

  7. Anesthetics Target Interfacial Transmembrane Sites in Nicotinic Acetylcholine Receptors

    PubMed Central

    Forman, Stuart A.; Chiara, David C.; Miller, Keith W.

    2014-01-01

    General anesthetics are a heterogeneous group of small amphiphilic ligands that interact weakly at multiple allosteric sites on many pentameric ligand gated ion channels (pLGICs), resulting in either inhibition, potentiation of channel activity, or both. Allosteric principles imply that modulator sites must change configuration and ligand affinity during receptor state transitions. Thus, general anesthetics and related compounds are useful both as state-dependent probes of receptor structure and as potentially selective modulators of pLGIC functions. This review focuses on general anesthetic sites in nicotinic acetylcholine receptors, which were among the first anesthetic-sensitive pLGIC experimental models studied, with particular focus on sites formed by transmembrane domain elements. Structural models place many of these sites at interfaces between two or more pLGIC transmembrane helices both within subunits and between adjacent subunits, and between transmembrane helices and either lipids (the lipid-protein interface) or water (i.e. the ion channel). A single general anesthetic may bind at multiple allosteric sites in pLGICs, producing a net effect of either inhibition (e.g. blocking the ion channel) or enhanced channel gating (e.g. inter-subunit sites). Other general anesthetic sites identified by photolabeling or crystallography are tentatively linked to functional effects, including intra-subunit helix bundle sites and the lipid-protein interface. PMID:25316107

  8. Effects of acetylcholine and electrical stimulation on glial cell line-derived neurotrophic factor production in skeletal muscle cells.

    PubMed

    Vianney, John-Mary; Miller, Damon A; Spitsbergen, John M

    2014-11-07

    Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor required for survival of neurons in the central and peripheral nervous system. Specifically, GDNF has been characterized as a survival factor for spinal motor neurons. GDNF is synthesized and secreted by neuronal target tissues, including skeletal muscle in the peripheral nervous system; however, the mechanisms by which GDNF is synthesized and released by skeletal muscle are not fully understood. Previous results suggested that cholinergic neurons regulate secretion of GDNF by skeletal muscle. In the current study, GDNF production by skeletal muscle myotubes following treatment with acetylcholine was examined. Acetylcholine receptors on myotubes were identified with labeled alpha-bungarotoxin and were blocked using unlabeled alpha-bungarotoxin. The question of whether electrical stimulation has a similar effect to that of acetylcholine was also investigated. Cells were stimulated with voltage pulses; at 1 and 5 Hz frequencies for times ranging from 30 min to 48 h. GDNF content in myotubes and GDNF in conditioned culture medium were quantified by enzyme-linked immunosorbant assay. Results suggest that acetylcholine and short-term electrical stimulation reduce GDNF secretion, while treatment with carbachol or long-term electrical stimulation enhances GDNF production by skeletal muscle.

  9. Modal gating of muscle nicotinic acetylcholine receptors

    NASA Astrophysics Data System (ADS)

    Vij, Ridhima

    Many ion channels exhibit multiple patterns of kinetic activity in single-channel currents. This behavior is rare in WT mouse muscle nicotinic acetylcholine receptors (AChRs), where A2C↔A2O gating events are well-described by single exponentials. Also, single-channel open probability (PO) is essentially homogeneous at a given agonist concentration in the WT receptors. Here I report that perturbations of almost all the residues in loop C (alpha188-alpha199, at the agonist binding site) generate heterogeneity in PO ('modes'). Such unsettled activity was apparent with an alanine substitution at all positions in loop C (except alphaY190 and alphaY198) and with different side chain substitutions at alphaP197 for both adult- and fetal-type AChRs. I used single channel electrophysiology along with site-directed mutagenesis to study modal gating in AChRs consequent to mutations/deletions in loop C. The multiple patterns of kinetic activity arose from the difference in agonist affinity rather than in intrinsic AChR gating. Out of the four different agonists used to study the modal behavior, acetylcholine (ACh) showed a higher degree of kinetic heterogeneity compared to others. The time constant for switching between modes was long (~mins), suggesting that they arise from alternative, stable protein conformations. By studying AChRs having only 1 functional binding site, I attempted to find the source of the affinity difference, which was traced mainly to the alphadelta agonist site. Affinity at the neurotransmitter binding site is mainly determined by a core of five aromatic residues (alphaY93, alphaW149, alphaY190, alphaY198 and deltaW57). Phenylalanine substitutions at all aromatic residues except alphaY93 resulted in elimination of modes. Modes were also eliminated by alanine mutation at deltaW57 on the complementary side but not at other aromatics. Also, by substituting four gamma subunit residues into the delta subunit on the complementary beta sheet, I found that

  10. Acetylcholine Promotes Binding of α-Conotoxin MII for α3β2 Nicotinic Acetylcholine Receptors

    PubMed Central

    Sambasivarao, Somisetti V.; Roberts, Jessica; Bharadwaj, Vivek S.; Slingsby, Jason G.; Rohleder, Conrad; Mallory, Chris; Groome, James R.

    2014-01-01

    α-Conotoxin MII (α-CTxMII) is a 16 amino acid peptide with the sequence GCCSNPVCHLEHSNLC containing disulfide bonds between Cys2-Cys8 and Cys3-Cys16. This peptide, isolated from the venom of the marine cone snail Conus magus, is a potent and selective antagonist of neuronal nicotinic acetylcholine receptors (nAChRs). To evaluate the impact of channel-ligand interactions on ligand binding affinity, homology models of the heteropentameric α3β2-nAChR were constructed. The models were created in MODELLER using crystal structures of the Torpedo marmorata-nAChR (Tm-nAChR, PDB ID: 2BG9) and the Aplysia californica-acetylcholine binding protein (Ac-AChBP, PDB ID: 2BR8) as templates for the α3 and β2 subunit isoforms derived from rat neuronal nAChR primary amino acid sequences. Molecular docking calculations were performed with AutoDock to evaluate interactions of the heteropentameric nAChR homology models with the ligands acetylcholine (ACh) and α-CTxMII. The nAChR homology models described here bind ACh with commensurate binding energies to previously reported systems, and identify critical interactions that facilitate both ACh and α-CTxMII ligand binding. The docking calculations revealed an increased binding affinity of the α3β2-nAChR for α-CTxMII with ACh bound to the receptor, which was confirmed through two-electrode voltage clamp experiments on oocytes from Xenopus laevis. These findings provide insights into the inhibition and mechanism of electrostatically driven antagonist properties of the α-CTxMIIs on nAChRs. PMID:24420650

  11. Microtubule-disrupting chemotherapeutics result in enhanced proteasome-mediated degradation and disappearance of tubulin in neural cells.

    PubMed

    Huff, Lyn M; Sackett, Dan L; Poruchynsky, Marianne S; Fojo, Tito

    2010-07-15

    We sought to examine the effects of microtubule-targeting agents (MTA) on neural cells to better understand the problem of neurotoxicity, their principal side effect, and to possibly develop a model of clinical toxicity. Studies showed that microtubule-depolymerizing agents (MDA) not only disassembled microtubules in neural HCN2 cells but also led to rapid disappearance of tubulin, and that this was specific for MDAs. Tubulin levels decreased to 20% as early as 8 hours after adding vincristine, and to 1% to 30% (mean, 9.8 +/- 7.6%; median of 7%) after 100 nmol/L vincristine for 24 hours. This disappearance was reversible. An increase in both glu-terminated and acetylated tubulin, markers of stable tubulin, preceded reaccumulation of soluble tubulin, suggesting a priority for stabilizing tubulin first as microtubules before replenishing the soluble pool. Similar results were shown with other MDAs. Furthermore, microtubule reassembly did not arise from a central focus but instead appeared to involve dispersed nucleation, as evidenced by the appearance of small, stable microtubule stubs throughout the cytoplasm. In contrast, experiments with four nonneural "normal" cell lines and four cancer cell lines resulted in microtubule destabilization but only modest tubulin degradation. Evidence for proteasome-mediated degradation was obtained by demonstrating that adding a proteasome inhibitor before vincristine prevented tubulin disappearance. In summary, MDAs lead to rapid disappearance of tubulin in neural but not in other normal or cancer cells. These results underscore the fine control that occurs in neural cells and may further our understanding of neurotoxicity following MDAs.

  12. A supervised 'lesion-enhancement' filter by use of a massive-training artificial neural network (MTANN) in computer-aided diagnosis (CAD)

    NASA Astrophysics Data System (ADS)

    Suzuki, Kenji

    2009-09-01

    Computer-aided diagnosis (CAD) has been an active area of study in medical image analysis. A filter for the enhancement of lesions plays an important role for improving the sensitivity and specificity in CAD schemes. The filter enhances objects similar to a model employed in the filter; e.g. a blob-enhancement filter based on the Hessian matrix enhances sphere-like objects. Actual lesions, however, often differ from a simple model; e.g. a lung nodule is generally modeled as a solid sphere, but there are nodules of various shapes and with internal inhomogeneities such as a nodule with spiculations and ground-glass opacity. Thus, conventional filters often fail to enhance actual lesions. Our purpose in this study was to develop a supervised filter for the enhancement of actual lesions (as opposed to a lesion model) by use of a massive-training artificial neural network (MTANN) in a CAD scheme for detection of lung nodules in CT. The MTANN filter was trained with actual nodules in CT images to enhance actual patterns of nodules. By use of the MTANN filter, the sensitivity and specificity of our CAD scheme were improved substantially. With a database of 69 lung cancers, nodule candidate detection by the MTANN filter achieved a 97% sensitivity with 6.7 false positives (FPs) per section, whereas nodule candidate detection by a difference-image technique achieved a 96% sensitivity with 19.3 FPs per section. Classification-MTANNs were applied for further reduction of the FPs. The classification-MTANNs removed 60% of the FPs with a loss of one true positive; thus, it achieved a 96% sensitivity with 2.7 FPs per section. Overall, with our CAD scheme based on the MTANN filter and classification-MTANNs, an 84% sensitivity with 0.5 FPs per section was achieved. First presented at the Seventh International Conference on Machine Learning and Applications, San Diego, CA, USA, 11-13 December 2008.

  13. Gelatin Directly Enhances Neurogenic Differentiation Potential in Bone Marrow-Derived Mesenchymal Stem Cells Without Stimulation of Neural Progenitor Cell Proliferation.

    PubMed

    Lee, Hyun; Han, Na Rae; Hwang, Jae Yeon; Yun, Jung Im; Kim, Choonghyo; Park, Kyu Hyun; Lee, Seung Tae

    2016-09-01

    Gelatin has been reported to induce generation of mesenchymal stem cells (MSCs) with enhanced potential of differentiation into neuronal lineage cells. However, the presence of various cell types besides MSCs in bone marrow has raised doubts about the effects of gelatin. In the following report, we determined whether gelatin can directly enhance neurogenic differentiation potential in MSCs without proliferation of neural progenitor cells (NPCs). MSCs comprised a high proportion of bone marrow-derived primary cells (BMPCs) and gelatin induced significant increases in MSC proliferation during primary culture, and the proportion of MSCs was maintained at more than 99% throughout the subculture. However, NPCs comprised a low percentage of BMPCs and a decrease in proliferation was detected despite gelatin treatment during the primary culture, and the proportion of subcultured NPCs gradually decreased. In a similar manner, MSCs exposed to gelatin during primary culture showed more enhanced neurogenic differentiation ability than those not exposed to gelatin. Together, these results demonstrate that gelatin directly enhances neurogenic differentiation in bone marrow-derived MSCs without stimulating NPC proliferation.

  14. FN-DFE: fuzzy-neural data fusion engine for enhanced resilient state-awareness of hybrid energy systems.

    PubMed

    Wijayasekara, Dumidu; Linda, Ondrej; Manic, Milos; Rieger, Craig

    2014-11-01

    Resiliency and improved state-awareness of modern critical infrastructures, such as energy production and industrial systems, is becoming increasingly important. As control systems become increasingly complex, the number of inputs and outputs increase. Therefore, in order to maintain sufficient levels of state-awareness, a robust system state monitoring must be implemented that correctly identifies system behavior even when one or more sensors are faulty. Furthermore, as intelligent cyber adversaries become more capable, incorrect values may be fed to the operators. To address these needs, this paper proposes a fuzzy-neural data fusion engine (FN-DFE) for resilient state-awareness of control systems. The designed FN-DFE is composed of a three-layered system consisting of: 1) traditional threshold based alarms; 2) anomalous behavior detector using self-organizing fuzzy logic system; and 3) artificial neural network-based system modeling and prediction. The improved control system state-awareness is achieved via fusing input data from multiple sources and combining them into robust anomaly indicators. In addition, the neural network-based signal predictions are used to augment the resiliency of the system and provide coherent state-awareness despite temporary unavailability of sensory data. The proposed system was integrated and tested with a model of the Idaho National Laboratory's hybrid energy system facility known as HYTEST. Experiment results demonstrate that the proposed FN-DFE provides timely plant performance monitoring and anomaly detection capabilities. It was shown that the system is capable of identifying intrusive behavior significantly earlier than conventional threshold-based alarm systems.

  15. The advantage of ambiguity? Enhanced neural responses to multi-stable percepts correlate with the degree of perceived instability.

    PubMed

    Dyson, Benjamin J

    2011-01-01

    Artwork can often pique the interest of the viewer or listener as a result of the ambiguity or instability contained within it. Our engagement with uncertain sensory experiences might have its origins in early cortical responses, in that perceptually unstable stimuli might preclude neural habituation and maintain activity in early sensory areas. To assess this idea, participants engaged with an ambiguous visual stimulus wherein two squares alternated with one another, in terms of simultaneously opposing vertical and horizontal locations relative to fixation (i.e., stroboscopic alternating motion; von Schiller, 1933). At each trial, participants were invited to interpret the movement of the squares in one of five ways: traditional vertical or horizontal motion, novel clockwise or counter-clockwise motion, and, a free-view condition in which participants were encouraged to switch the direction of motion as often as possible. Behavioral reports of perceptual stability showed clockwise and counter-clockwise motion to possess an intermediate level of stability compared to relatively stable vertical and horizontal motion, and, relatively unstable motion perceived during free-view conditions. Early visual evoked components recorded at parietal-occipital sites such as C1, P1, and N1 modulated as a function of visual intention. Both at a group and individual level, increased perceptual instability was related to increased negativity in all three of these early visual neural responses. Engagement with increasingly ambiguous input may partly result from the underlying exaggerated neural response to it. The study underscores the utility of combining neuroelectric recording with the presentation of perceptually multi-stable yet physically identical stimuli, in revealing brain activity associated with the purely internal process of interpreting and appreciating the sensory world that surrounds us.

  16. FN-DFE: Fuzzy-Neural Data Fusion Engine for Enhanced State-Awareness of Resilient Hybrid Energy System

    SciTech Connect

    Ondrej Linda; Dumidu Wijayasekara; Milos Manic; Craig Rieger

    2014-11-01

    Resiliency and improved state-awareness of modern critical infrastructures, such as energy production and industrial systems, is becoming increasingly important. As control systems become increasingly complex, the number of inputs and outputs increase. Therefore, in order to maintain sufficient levels of state-awareness, a robust system state monitoring must be implemented that correctly identifies system behavior even when one or more sensors are faulty. Furthermore, as intelligent cyber adversaries become more capable, incorrect values may be fed to the operators. To address these needs, this paper proposes a Fuzzy-Neural Data Fusion Engine (FN-DFE) for resilient state-awareness of control systems. The designed FN-DFE is composed of a three-layered system consisting of: 1) traditional threshold based alarms, 2) anomalous behavior detector using self-organizing fuzzy logic system, and 3) artificial neural network based system modeling and prediction. The improved control system state-awareness is achieved via fusing input data from multiple sources and combining them into robust anomaly indicators. In addition, the neural network based signal predictions are used to augment the resiliency of the system and provide coherent state-awareness despite temporary unavailability of sensory data. The proposed system was integrated and tested with a model of the Idaho National Laboratory’s (INL) hybrid energy system facility know as HYTEST. Experimental results demonstrate that the proposed FN-DFE provides timely plant performance monitoring and anomaly detection capabilities. It was shown that the system is capable of identifying intrusive behavior significantly earlier than conventional threshold based alarm systems.

  17. Effects of a monoclonal anti-acetylcholine receptor antibody on the avian end-plate.

    PubMed Central

    Maselli, R A; Nelson, D J; Richman, D P

    1989-01-01

    1. The effects of anti-acetylcholine receptor (AChR) monoclonal antibodies (mAbs) 370 and 132A on miniature end-plate potentials (MEPPs) and end-plate currents (EPCs) in the posterior latissimus dorsi muscle of adult chickens were investigated. 2. After incubation of the electrophysiological preparation with mAb 370 (5-50 micrograms/ml), which blocks both agonist (carbamylcholine) and alpha-bungarotoxin (alpha-BTX) binding and induces a hyperacute form of experimental autoimmune myasthenia gravis (EAMG), MEPP and EPC amplitudes were irreversibly reduced. 3. This effect was not associated with any significant change in the time constant describing EPC decay (tau EPC), current reversal potential, or the voltage dependence of tau EPC. The tau EPC at -80 mV was 5.9 +/- 0.6 ms before incubation with mAb 370 (50 micrograms/ml) and 6.0 +/- 0.9 ms afterwards. Current reversal potential was -3.9 +/- 0.4 mV before mAb incubation and -4.8 +/- 1.5 mV afterwards. The change in membrane potential required to produce an e-fold change in tau EPC was 128 +/- 2.3 mV before antibody incubation compared to 125 +/- 6.6 mV after incubation. 4. A second anti-AChR mAb, 132A (50 micrograms/ml), which is capable of inducing the classically described form of EAMG without blocking agonist or alpha-BTX binding, or inducing hyperacute EAMG, produced no significant change in MEPP amplitude, EPC amplitude, tau EPC or EPC reversal potentials. 5. The mAb 370 (50 micrograms/ml) induced a partially reversible decrease of the quantal content of the neurally evoked end-plate potential (EPP). This effect was not observed with mAb 132A, (+)tubocurarine (10(-7)-10(-5) g/ml) or an irrelevant anti-oestrogen receptor mAb. 6. These data suggest that the rapid onset of weakness observed in chicken hatchlings after the injection of mAb 370 (Gomez & Richman, 1983) can be attributed to a combined effect of a block of acetylcholine (ACh)-induced ion channel activity in the postsynaptic membrane and a reduction of

  18. The mechanism of acetylcholine receptor in binding MuSK in myasthenia gravis and the role of HSP90 molecular chaperone.

    PubMed

    Chen, Rongbo; Chen, Siqia; Liao, Juan; Chen, Xiaopu; Xu, Xiaoling

    2016-01-01

    As an autoimmune disease, myasthenia gravis is caused by the dysfunction of neural transmission. Acetylcholine is known to exert its function after entering into synaptic cleft through binding onto postsynaptic membrane. The role of acetylcholine in binding MuSK in myasthenia gravis, however, remains unknown. A total of 38 myasthenia gravis patients and 27 healthy controls were included in this study for the detection of the expression of MuSK using immunofluorescent method. Expression of both MuSK and interleukin-6 (IL-6) were measured by Western blot, followed by the correlation analysis between heat shock protein 90 (HSP90) and IL-6 which were measured by enzyme-linked immunosorbent assay (ELISA). In myasthenia gravis patients, MuSK was co-localized with acetylcholine at the postsynaptic membrane. Such accumulation of MuSK, however, did not occur in normal people. Meanwhile we also observed elevated expression of IL-6 in myasthenia gravis patients (p<0.05). ELISA assay showed higher expression of HSP90 in patients. Further signaling pathway screening revealed the activation of IL-6-mediated pathways including STAT3 and SPH2. In conclusion, MuSK was co-localized with acetylcholine in myasthenia gravis patients, with elevated expression. HSP90 in disease people can activate IL-6 mediated signaling pathways.

  19. Diversity of insect nicotinic acetylcholine receptor subunits.

    PubMed

    Jones, Andrew K; Sattelle, David B

    2010-01-01

    Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate fast synaptic transmission in the insect nervous system and are targets of a major group of insecticides, the neonicotinoids. They consist of five subunits arranged around a central ion channeL Since the subunit composition determines the functional and pharmacological properties of the receptor the presence of nAChR families comprising several subunit-encodinggenes provides a molecular basis for broad functional diversity. Analyses of genome sequences have shown that nAChR gene families remain compact in diverse insect species, when compared to their nematode andvertebrate counterparts. Thus, the fruit fly (Drosophila melanogaster), malaria mosquito (Anopheles gambiae), honey bee (Apis mellifera), silk worm (Bombyx mon) and the red flour beetle (Tribolium castaneum) possess 10-12 nAChR genes while human and the nematode Caenorhabditis elegans have 16 and 29 respectively. Although insect nAChRgene families are amongst the smallest known, receptor diversity can be considerably increased by the posttranscriptional processes alternative splicing and mRNA A-to-I editingwhich can potentially generate protein products which far outnumber the nAChR genes. These two processes can also generate species-specific subunit isoforms. In addition, each insect possesses at least one highly divergent nAChR subunit which may perform species-specific functions. Species-specific subunit diversification may offer promising targets for future rational design of insecticides that target specific pest insects while sparing beneficial species.

  20. Allosteric binding sites on muscarinic acetylcholine receptors.

    PubMed

    Wess, Jürgen

    2005-12-01

    In this issue of Molecular Pharmacology, Tränkle et al. (p. 1597) present new findings regarding the existence of a second allosteric site on the M2 muscarinic acetylcholine receptor (M2 mAChR). The M2 mAChR is a prototypic class A G protein-coupled receptor (GPCR) that has proven to be a very useful model system to study the molecular mechanisms involved in the binding of allosteric GPCR ligands. Previous studies have identified several allosteric muscarinic ligands, including the acetylcholinesterase inhibitor tacrine and the bis-pyridinium derivative 4,4'-bis-[(2,6-dichloro-benzyloxy-imino)-methyl]-1,1'-propane-1,3-diyl-bis-pyridinium dibromide (Duo3), which, in contrast to conventional allosteric muscarinic ligands, display concentration-effect curves with slope factors >1. By analyzing the interactions of tacrine and Duo3 with other allosteric muscarinic agents predicted to bind to the previously identified ;common' allosteric binding site, Tränkle et al. provide evidence suggesting that two allosteric agents and one orthosteric ligand may be able to bind to the M2 mAChR simultaneously. Moreover, studies with mutant mAChRs indicated that the M2 receptor epitopes involved in the binding of tacrine and Duo3 may not be identical. Molecular modeling and ligand docking studies suggested that the additional allosteric site probably represents a subdomain of the receptor's allosteric binding cleft. Because allosteric binding sites have been found on many other GPCRs and drugs interacting with these sites are thought to have great therapeutic potential, the study by Tränkle et al. should be of considerable general interest.

  1. Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders.

    PubMed

    Ong, Peter; Athanasiadis, Anastasios; Sechtem, Udo

    2016-08-18

    Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the catheterization laboratory which was introduced more than 30 years ago. Due to the short half-life of acetylcholine it can only be applied directly into the coronary arteries. Several studies have demonstrated the safety and clinical usefulness of this test. However, acetylcholine testing is only rarely applied in the U.S. or Europe. Nevertheless, it has been shown that 62% of Caucasian patients with stable angina and unobstructed coronary arteries on coronary angiography suffer from coronary vasomotor disorders that can be diagnosed with acetylcholine testing. In recent years it has been appreciated that the ACH-test not only assesses the presence of epicardial spasm but that it can also be useful for the detection of coronary microvascular spam. In such cases no epicardial spasm is seen after injection of acetylcholine but ischemic ECG shifts are present together with a reproduction of the patient's symptoms during the test. This article describes the experience with the ACH-test and its implementation in daily clinical routine.

  2. Alternative splicing in nicotinic acetylcholine receptor subunits from Locusta migratoria and its influence on acetylcholine potencies.

    PubMed

    Zhang, Yixi; Liu, Yang; Bao, Haibo; Sun, Huahua; Liu, Zewen

    2017-01-18

    Due to the great abundance within insect central nervous system (CNS), nicotinic acetylcholine receptors (nAChRs) play key roles in insect CNS, which makes it to be the targets of several classes of insecticides, such as neonicotinoids. Insect nAChRs are pentameric complexes consisting of five subunits, and a dozen subunits in one insect species can theoretically comprise diverse nAChRs. The alternative splicing in insect nAChR subunits may increase the diversity of insect nAChRs. In the oriental migratory locust (Locusta migratoria manilensis Meyen), a model insect species with agricultural importance, the alternative splicing was found in six α subunits among nine α and two β subunits, such as missing conserved residues in Loop D from Locα1, Locα6 and Locα9, a 34-residue insertion in Locα8 cytoplasmic loop, and truncated transcripts for Locα4, Locα7 and Locα9. Hybrid nAChRs were successfully constructed in Xenopus oocytes through co-expression with rat β2 and one α subunit from L. migratoria, which included Locα1, Locα2, Locα3, Locα4, Locα5, Locα8 and Locα9. Influences of alternative splicing in Locα1, Locα8 and Locα9 on acetylcholine potency were tested on hybrid nAChRs. The alternative splicing in Locα1 and Locα9 could increase acetylcholine sensitivities on recombinant receptors, while the splicing in Locα8 showed significant influences on the current amplitudes of oocytes. The results revealed that the alternative splicing at or close to the ligand-binding sites, as well as at cytoplasmic regions away from the ligand-binding sites, in insect nAChR subunits would change the agonist potencies on the receptors, which consequently increased nAChR diversity in functional and pharmacological properties.

  3. Neuronal nicotinic acetylcholine receptors are modulated by zinc.

    PubMed

    Vázquez-Gómez, Elizabeth; García-Colunga, Jesús

    2009-01-01

    It is known that zinc modulates nicotinic acetylcholine receptors (nAChRs). Here, we studied the effects of zinc on neuronal alpha4beta4 nAChRs, expressed in Xenopus oocytes and activated by nicotine. Membrane ion currents elicited by nicotine (10 nM to 100 microM) were enhanced by zinc (100 microM). Maximal zinc potentiation of the nicotine-activated current (2530%) occurred at 50 nM nicotine, and potentiation gradually decreased as the nicotine concentration increased. The EC(50) and IC(50) for the nicotine-activated current were 639 nM and 14.7 microM nicotine, respectively. Both parameters decreased in the presence of zinc to 160 nM and 4.6 microM, respectively, probably due to an increase of sensitivity of nAChRs for nicotine. We used different concentrations and durations of exposure to nicotine, due to desensitization of nAChRs directly depends on both these factors. With 500 nM nicotine and 20 min washing periods between nicotine applications, zinc potentiation remained constant, 901% for 2 min and 813% for 20 min of nicotine exposure. With continuous application of nicotine, zinc potentiation decreased as the time of nicotine exposure increased, 721% for 2 min and 254% for 48 min of nicotine exposure. Our results indicate that zinc-potentiating effects on alpha4beta4 nAChRs strongly depend on both concentration and time of exposure to nicotine, suggesting that zinc potentiation depends on the degree of desensitization.

  4. Endoplasmic reticulum stress contributes to acetylcholine receptor degradation by promoting endocytosis in skeletal muscle cells.

    PubMed

    Du, Ailian; Huang, Shiqian; Zhao, Xiaonan; Zhang, Yun; Zhu, Lixun; Ding, Ji; Xu, Congfeng

    2016-01-15

    After binding by acetylcholine released from a motor neuron, a nicotinic acetylcholine receptor at the neuromuscular junction produces a localized end-plate potential, which leads to muscle contraction. Improper turnover and renewal of acetylcholine receptors contributes to the pathogenesis of myasthenia gravis. In the present study, we demonstrate that endoplasmic reticulum (ER) stress contributes to acetylcholine receptor degradation in C2C12 myocytes. We further show that ER stress promotes acetylcholine receptor endocytosis and lysosomal degradation, which was dampened by blocking endocytosis or treating with lysosome inhibitor. Knockdown of ER stress proteins inhibited acetylcholine receptor endocytosis and degradation, while rescue assay restored its endocytosis and degradation, confirming the effects of ER stress on promoting endocytosis-mediated degradation of junction acetylcholine receptors. Thus, our studies identify ER stress as a factor promoting acetylcholine receptor degradation through accelerating endocytosis in muscle cells. Blocking ER stress and/or endocytosis might provide a novel therapeutic approach for myasthenia gravis.

  5. Enhanced selective gene delivery to neural stem cells in vivo by an adeno-associated viral variant.

    PubMed

    Kotterman, Melissa A; Vazin, Tandis; Schaffer, David V

    2015-05-15

    Neural stem cells (NSCs) are defined by their ability to self-renew and to differentiate into mature neuronal and glial cell types. NSCs are the subject of intense investigation, owing to their crucial roles in neural development and adult brain function and because they present potential targets for gene and cell replacement therapies following injury or disease. Approaches to specifically genetically perturb or modulate NSC function would be valuable for either motivation. Unfortunately, most gene delivery vectors are incapable of efficient or specific gene delivery to NSCs in vivo. Vectors based on adeno-associated virus (AAV) present a number of advantages and have proven increasingly successful in clinical trials. However, natural AAV variants are inefficient in transducing NSCs. We previously engineered a novel AAV variant (AAV r3.45) capable of efficient transduction of adult NSCs in vitro. Here, to build upon the initial promise of this variant, we investigated its in vitro and in vivo infectivity. AAV r3.45 was more selective for NSCs than mature neurons in a human embryonic stem cell-derived culture containing a mixture of cell types, including NSCs and neurons. It was capable of more efficient and selective transduction of rat and mouse NSCs in vivo than natural AAV serotypes following intracranial vector administration. Delivery of constitutively active β-catenin yielded insights into mechanisms by which this key regulator modulates NSC function, indicating that this engineered AAV variant can be harnessed for preferential modulation of adult NSCs in the hippocampus. The capacity to rapidly genetically modify these cells might greatly accelerate in vivo investigations of adult neurogenesis.

  6. Acetylcholine elongates neuronal growth cone filopodia via activation of nicotinic acetylcholine receptors.

    PubMed

    Zhong, Lei Ray; Estes, Stephen; Artinian, Liana; Rehder, Vincent

    2013-07-01

    In addition to acting as a classical neurotransmitter in synaptic transmission, acetylcholine (ACh) has been shown to play a role in axonal growth and growth cone guidance. What is not well understood is how ACh acts on growth cones to affect growth cone filopodia, structures known to be important for neuronal pathfinding. We addressed this question using an identified neuron (B5) from the buccal ganglion of the pond snail Helisoma trivolvis in cell culture. ACh treatment caused pronounced filopodial elongation within minutes, an effect that required calcium influx and resulted in the elevation of the intracellular calcium concentration ([Ca]i ). Whole-cell patch clamp recordings showed that ACh caused a reduction in input resistance, a depolarization of the membrane potential, and an increase in firing frequency in B5 neurons. These effects were mediated via the activation of nicotinic acetylcholine receptors (nAChRs), as the nAChR agonist dimethylphenylpiperazinium (DMPP) mimicked the effects of ACh on filopodial elongation, [Ca]i elevation, and changes in electrical activity. Moreover, the nAChR antagonist tubucurarine blocked all DMPP-induced effects. Lastly, ACh acted locally at the growth cone, because growth cones that were physically isolated from their parent neuron responded to ACh by filopodial elongation with a similar time course as growth cones that remained connected to their parent neuron. Our data revealed a critical role for ACh as a modulator of growth cone filopodial dynamics. ACh signaling was mediated via nAChRs and resulted in Ca influx, which, in turn, caused filopodial elongation.

  7. Mechanisms determining cholinergic neural responses in airways of young and mature rabbits.

    PubMed

    Larsen, Gary L; Loader, Joan; Nguyen, Dee Dee; Fratelli, Cori; Dakhama, Azzeddine; Colasurdo, Giuseppe N

    2004-08-01

    Neural pathways help control airway caliber and responsiveness. Yet little is known of how neural control changes as a function of development. In rabbits, we found electrical field stimulation (EFS) of airway nerves led to more marked contractile responses in 2- vs. 13-week-old animals. This enhanced response to EFS may be due to prejunctional, junctional, and/or postjunctional neural mechanisms. We assessed these mechanisms in airways of 2- and 13-week-old rabbits. The contractile responses to methacholine did not differ in the groups, suggesting postjunctional neural events are not primarily responsible for differing responses to EFS. To address junctional events, acetylcholinesterase (AChE) was measured (spectrophotometry). AChE was elevated in 2-week-olds. However, this should lead to less and not greater responses. Prejunctionally, EFS-induced acetylcholine (ACh) release was assessed by HPLC. Airways of 2-week-old rabbits released significantly more ACh than airways from mature rabbits. Choline acetyltransferase, a marker of cholinergic nerves, was not different between groups, suggesting that more ACh release in young rabbits was not due to increased nerve density. ACh release in the presence of polyarginine increased significantly in both groups, supporting the presence of functional muscarinic autoreceptors (M2) at both ages. Because substance P (SP) increases release of ACh, SP was measured by ELISA. This neuropeptide was significantly elevated in airways of younger rabbits. Nerve growth factor (NGF) increased SP and was also significantly increased in airways from younger rabbits. This work suggests that increases in EFS-induced responsiveness in young rabbits are likely due to prejunctional events with enhanced release of ACh. Increases in NGF and SP early in life may contribute to this increased responsiveness.

  8. Involvement of β3-adrenoceptors in the inhibitory control of cholinergic activity in human bladder: Direct evidence by [(3)H]-acetylcholine release experiments in the isolated detrusor.

    PubMed

    D' Agostino, Gianluigi; Maria Condino, Anna; Calvi, Paolo

    2015-07-05

    Bladder overactivity (OAB) is a multifactorial bladder disorder that requires therapeutics superior to the current pharmacological treatment with muscarinic antagonists. β3-adrenoceptor (β3-ADR) agonists represent a novel promising approach that differently addresses the parasympathetic pathway, but the clinical efficacy of these drugs has not been fully elucidated to date. Therefore, we aimed to study the pharmacological mechanisms activated by β3-ADR agonists at muscular and neural sites in the isolated human bladder. Detrusor smooth muscle strips obtained from male patients undergoing total cystectomy were labelled with tritiated choline and stimulated with electrical field stimulation (EFS). EFS produced smooth muscle contraction and simultaneous acetylcholine ([(3)H]-ACh) release, which mostly reflects the neural origin of acetylcholine. Isoprenaline (INA), BRL37344 and mirabegron inhibited the EFS-evoked contraction and [(3)H]-ACh release in a concentration-dependent manner, yielding concentration-response curves (CRCs) that were shifted to the right by the selective β3-ADR antagonists L-748,337 and SR59230A. Based on the agonist potency estimates (pEC50) and apparent affinities (pKb) of antagonists evaluated from the CRCs of agonists, our data confirm the occurrence of β3-ADRs at muscle sites. Moreover, our data are consistent with the presence of inhibitory β3-ADRs that are functionally expressed at the neural site. Taken together, these findings elucidate the mechanisms activated by β3-ADR agonists because neural β3-ADRs participate in the inhibition of detrusor motor drive by reducing the amount of acetylcholine involved in the cholinergic pathway.

  9. Enhanced antibiotic production by Streptomyces sindenensis using artificial neural networks coupled with genetic algorithm and Nelder-Mead downhill simplex.

    PubMed

    Tripathi, C K M; Khan, Mahvish; Praveen, Vandana; Khan, Saif; Srivastava, Akanksha

    2012-07-01

    Antibiotic production with Streptomyces sindenensis MTCC 8122 was optimized under submerged fermentation conditions by artificial neural network (ANN) coupled with genetic algorithm (GA) and Nelder-Mead downhill simplex (NMDS). Feed forward back-propagation ANN was trained to establish the mathematical relationship among the medium components and length of incubation period for achieving maximum antibiotic yield. The optimization strategy involved growing the culture with varying concentrations of various medium components for different incubation periods. Under non-optimized condition, antibiotic production was found to be 95 microgram/ml, which nearly doubled (176 microgram/ml) with the ANN-GA optimization. ANN-NMDS optimization was found to be more efficacious, and maximum antibiotic production (197 microgram/ml) was obtained by cultivating the cells with (g/l) fructose 2.7602, MgSO4 1.2369, (NH4)2PO4 0.2742, DL-threonine 3.069%, and soyabean meal 1.952%, for 9.8531 days of incubation, which was roughly 12% higher than the yield obtained by ANN coupled with GA under the same conditions.

  10. β-adrenoceptor pathway enhances mitochondrial function in human neural stem cells via rotary cell culture system.

    PubMed

    Chiang, Ming-Chang; Lin, Heng; Cheng, Yi-Chuan; Yen, Chia-Hui; Huang, Rong-Nan; Lin, Kuan-Hung

    2012-06-15

    The structure and function of the human nervous system are altered in space when compared with their state on earth. To investigate directly the influence of simulated microgravity conditions which may be beneficial for cultivation and proliferation of human neural stem cells (hNSCs), the rotary cell culture system (RCCS) developed at the National Aeronautics and Space Administration (NASA) was used. RCCS allows the creation of a unique microgravity environment of low shear force, high-mass transfer and enables three-dimensional (3D) cell culture of dissimilar cell types. The results show that simulated microgravity using an RCCS would induce β-adrenoceptor, upregulate cAMP formation and activate both PKA and CREB (cAMP response element binding protein) pathways. The expression of intracellular mitochondrial genes, including PGC1α (PPAR coactivator 1α), nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and mitochondrial transcription factor A (Tfam), regulated by CREB, were all significantly increased at 72 h after the onset of microgravity. Accordingly and importantly, the ATP level and amount of mitochondrial mass were also increased. These results suggest that exposure to simulated microgravity using an RCCS would induce cellular proliferation in hNSCs via an increased mitochondrial function. In addition, the RCCS bioreactor would support hNSCs growth, which may have the potential for cell replacement therapy in neurological disorders.

  11. Beyond Neural Cubism: Promoting a Multidimensional View of Brain Disorders by Enhancing the Integration of Neurology and Psychiatry in Education

    PubMed Central

    Taylor, Joseph J.; Williams, Nolan R.; George, Mark S.

    2014-01-01

    Cubism was an influential early 20th century art movement characterized by angular, disjointed imagery. The two-dimensional appearance of Cubist figures and objects is created through juxtaposition of angles. The authors posit that the constrained perspectives found in Cubism may also be found in the clinical classification of brain disorders. Neurological disorders are often separated from psychiatric disorders as if they stem from different organ systems. Maintaining two isolated clinical disciplines fractionalizes the brain in the same way that Pablo Picasso fractionalized figures and objects in his Cubist art. This Neural Cubism perpetuates a clinical divide that does not reflect the scope and depth of neuroscience. All brain disorders are complex and multidimensional, with aberrant circuitry and resultant psychopharmacology manifesting as altered behavior, affect, mood or cognition. Trainees should receive a multidimensional education based on modern neuroscience, not a partial education based on clinical precedent. The authors briefly outline the rationale for increasing the integration of neurology and psychiatry and discuss a nested model with which clinical neuroscientists (neurologists and psychiatrists) can approach and treat brain disorders. PMID:25340364

  12. Enhancement of noradrenergic neural transmission: an effective therapy of myasthenia gravis: a report on 52 consecutive patients.

    PubMed

    Lechin, F; van der Dijs, B; Pardey-Maldonado, B; John, E; Jimenez, V; Orozco, B; Baez, S; Lechin, M E

    2000-01-01

    Neurochemical, neuroautonomic and neuropharmacological assessments carried out on all our myasthenia gravis (MG) patients showed that they presented a neural sympathetic deficit plus excessive adrenal-sympathetic activity. These abnormalities were registered during the basal (supine-resting) state, as well as after several stress tests (orthostasis, exercise, oral glucose and buspirone). In addition, MG patients showed increased levels of free-serotonin (f5HT) in the plasma, supposedly associated with the increased platelet aggregability which we found in all MG patients. As the above trio of neurochemical disorders (low noradrenergic-activity + high adrenergic-activity + increased f-5HT plasma levels) is known to favor Th-1 immunosuppression + Th-2 predominance, we outlined a neuropharmacological strategy for reverting the above neurochemical disorder. This treatment provoked sudden (acute), and late sustained improvements. Acute effects have been attributed to the increase of alpha-1 activity at the spinal motoneuron level. Late improvements always paralleled a significant normalization of immunological disorders. Complete normalization was registered only in non-thymectomized MG patients.

  13. Beyond neural cubism: promoting a multidimensional view of brain disorders by enhancing the integration of neurology and psychiatry in education.

    PubMed

    Taylor, Joseph J; Williams, Nolan R; George, Mark S

    2015-05-01

    Cubism was an influential early-20th-century art movement characterized by angular, disjointed imagery. The two-dimensional appearance of Cubist figures and objects is created through juxtaposition of angles. The authors posit that the constrained perspectives found in Cubism may also be found in the clinical classification of brain disorders. Neurological disorders are often separated from psychiatric disorders as if they stemmed from different organ systems. Maintaining two isolated clinical disciplines fractionalizes the brain in the same way that Pablo Picasso fractionalized figures and objects in his Cubist art. This Neural Cubism perpetuates a clinical divide that does not reflect the scope and depth of neuroscience. All brain disorders are complex and multidimensional, with aberrant circuitry and resultant psychopharmacology manifesting as altered behavior, affect, mood, or cognition. Trainees should receive a multidimensional education based on modern neuroscience, not a partial education based on clinical precedent. The authors briefly outline the rationale for increasing the integration of neurology and psychiatry and discuss a nested model with which clinical neuroscientists (neurologists and psychiatrists) can approach and treat brain disorders.

  14. Neural mechanisms underlying the reward-related enhancement of motivation when remembering episodic memories with high difficulty.

    PubMed

    Shigemune, Yayoi; Tsukiura, Takashi; Nouchi, Rui; Kambara, Toshimune; Kawashima, Ryuta

    2017-04-04

    The motivation to receive rewards enhances episodic memories, and the motivation is modulated by task difficulty. In episodic retrieval, however, functional neuroimaging evidence regarding the motivation that mediates interactions between reward and task difficulty is scarce. The present fMRI study investigated this issue. During encoding performed without fMRI, participants encoded Japanese words using either deep or shallow strategies, which led to variation in difficulty level during subsequent retrieval. During retrieval with fMRI, participants recognized the target words in either high or low monetary reward conditions. In the behavioral results, a reward-related enhancement of memory was found only when the memory retrieval was difficult, and the rewarding effect on subjective motivation was greater in the retrieval of memories with high difficulty than those with low difficulty. The fMRI data showed that reward-related increases in the activation of the substantia nigra/ventral tegmental area (SN/VTA), medial temporal lobe (MTL), dorsomedial prefrontal cortex (dmPFC), and dorsolateral prefrontal cortex (dlPFC) were greater during the retrieval of memories with high difficulty than those with low difficulty. Furthermore, reward-related enhancement of functional connectivity between the SN/VTA and MTL and between the SN/VTA and dmPFC during the retrieval of memories with high difficulty was significantly correlated with reward-related increases of retrieval accuracy and subjective motivation. The reward-related enhancement of episodic retrieval and retrieval-related motivation could be most effective when the level of retrieval difficulty is optimized. Such reward-related enhancement of memory and motivation could be modulated by a network including the reward-related SN/VTA, motivation-related dmPFC, and memory-related MTL. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

  15. Changes in Acetylcholine Extracellular Levels during Cognitive Processes

    ERIC Educational Resources Information Center

    Pepeu, Giancarlo; Giovannini, Maria Grazia

    2004-01-01

    Measuring the changes in neurotransmitter extracellular levels in discrete brain areas is considered a tool for identifying the neuronal systems involved in specific behavioral responses or cognitive processes. Acetylcholine (ACh) is the first neurotransmitter whose diffusion from the central nervous system was investigated and whose extracellular…

  16. Mechanisms of Action of Anticholinesterases and Oximes on Acetylcholine Receptors

    DTIC Science & Technology

    1988-07-23

    J.F. and D.B. Sanders. The management of patients with myasthenia gravis , in Myasthenia Gravis (E.X. Albuquerque and A.T. Eldefrawi, eds.), Chapman...Eldefrawi. Affinity of myasthenia drugs to acetylcholinesterase and acetylcholine receptor. Biochem. Med. 10:258-265 (1974). 9. Carpenter, D.O., L.A

  17. Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors.

    PubMed

    Schmeller, T; Sauerwein, M; Sporer, F; Wink, M; Müller, W E

    1994-09-01

    Fourteen quinolizidine alkaloids, isolated from Lupinus albus, L. mutabilis, and Anagyris foetida, were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. Of the compounds tested, the alpha-pyridones, N-methylcytisine and cytisine, showed the highest affinities at the nicotinic receptor, while several quinolizidine alkaloid types were especially active at the muscarinic receptor.

  18. Human Neural Stem Cell Transplantation Rescues Cognitive Defects in APP/PS1 Model of Alzheimer’s Disease by Enhancing Neuronal Connectivity and Metabolic Activity

    PubMed Central

    Li, Xueyuan; Zhu, Hua; Sun, Xicai; Zuo, Fuxing; Lei, Jianfeng; Wang, Zhanjing; Bao, Xinjie; Wang, Renzhi

    2016-01-01

    Alzheimer’s disease (AD), the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC) transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs) into bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD to test the effects of hNSC transplantation on Alzheimer’s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system (CNS). The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in vivo magnetic resonance spectroscopy (MRS) showed that hNSC-treated mice had notably increased levels of N-acetylaspartate (NAA) and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer’s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This

  19. In Vivo Tracking of Human Neural Progenitor Cells in the Rat Brain Using Magnetic Resonance Imaging Is Not Enhanced by Ferritin Expression.

    PubMed

    Bernau, Ksenija; Lewis, Christina M; Petelinsek, Anna M; Reagan, Matthew S; Niles, David J; Mattis, Virginia B; Meyerand, M Elizabeth; Suzuki, Masatoshi; Svendsen, Clive N

    2016-01-01

    Rapid growth in the field of stem cell research has generated a lot of interest in their therapeutic use, especially in the treatment of neurodegenerative diseases. Specifically, human neural progenitor cells (hNPCs), unique in their capability to differentiate into cells of the neural lineage, have been widely investigated due to their ability to survive, thrive, and migrate toward injured tissues. Still, one of the major roadblocks for clinical applicability arises from the inability to monitor these cells following transplantation. Molecular imaging techniques, such as magnetic resonance imaging (MRI), have been explored to assess hNPC transplant location, migration, and survival. Here we investigated whether inducing hNPCs to overexpress ferritin (hNPCs(Fer)), an iron storage protein, is sufficient to track these cells long term in the rat striatum using MRI. We found that increased hypointensity on MRI images could establish hNPC(Fer) location. Unexpectedly, however, wild-type hNPC transplants were detected in a similar manner, which is likely due to increased iron accumulation following transplantation-induced damage. Hence, we labeled hNPCs with superparamagnetic iron oxide (SPIO) nanoparticles to further increase iron content in an attempt to enhance cell contrast in MRI. SPIO-labeling of hNPCs (hNPCs-SPIO) achieved increased hypointensity, with significantly greater area of decreased T2* compared to hNPC(Fer) (p < 0.0001) and all other controls used. However, none of the techniques could be used to determine graft rejection in vivo, which is imperative for understanding cell behavior following transplantation. We conclude that in order for cell survival to be monitored in preclinical and clinical settings, another molecular imaging technique must be employed, including perhaps multimodal imaging, which would utilize MRI along with another imaging modality.

  20. Integration-Enhanced Zhang Neural Network for Real-Time-Varying Matrix Inversion in the Presence of Various Kinds of Noises.

    PubMed

    Jin, Long; Zhang, Yunong; Li, Shuai

    2016-12-01

    Matrix inversion often arises in the fields of science and engineering. Many models for matrix inversion usually assume that the solving process is free of noises or that the denoising has been conducted before the computation. However, time is precious for the real-time-varying matrix inversion in practice, and any preprocessing for noise reduction may consume extra time, possibly violating the requirement of real-time computation. Therefore, a new model for time-varying matrix inversion that is able to handle simultaneously the noises is urgently needed. In this paper, an integration-enhanced Zhang neural network (IEZNN) model is first proposed and investigated for real-time-varying matrix inversion. Then, the conventional ZNN model and the gradient neural network model are presented and employed for comparison. In addition, theoretical analyses show that the proposed IEZNN model has the global exponential convergence property. Moreover, in the presence of various kinds of noises, the proposed IEZNN model is proven to have an improved performance. That is, the proposed IEZNN model converges to the theoretical solution of the time-varying matrix inversion problem no matter how large the matrix-form constant noise is, and the residual errors of the proposed IEZNN model can be arbitrarily small for time-varying noises and random noises. Finally, three illustrative simulation examples, including an application to the inverse kinematic motion planning of a robot manipulator, are provided and analyzed to substantiate the efficacy and superiority of the proposed IEZNN model for real-time-varying matrix inversion.

  1. Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement.

    PubMed

    Kandalam, Saikrishna; Sindji, Laurence; Delcroix, Gaëtan J-R; Violet, Fabien; Garric, Xavier; André, Emilie M; Schiller, Paul C; Venier-Julienne, Marie-Claire; des Rieux, Anne; Guicheux, Jérôme; Montero-Menei, Claudia N

    2017-02-01

    Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device. It should direct the survival and/or neuronal differentiation of the grafted cells, to safely transplant them in the central nervous system, and enhance their tissue repair properties. A model protein was used to optimize the nanoprecipitation conditions of the neuroprotective brain-derived neurotrophic factor (BDNF). BDNF nanoprecipitate was encapsulated in fibronectin-coated (FN) PAMs and the in vitro release profile evaluated. It showed a prolonged, bi-phasic, release of bioactive BDNF, without burst effect. We demonstrated that PAMs and the Si-HPMC hydrogel increased the expression of neural/neuronal differentiation markers of MIAMI cells after 1week. Moreover, the 3D environment (PAMs or hydrogel) increased MIAMI cells secretion of growth factors (b-NGF, SCF, HGF, LIF, PlGF-1, SDF-1α, VEGF-A & D) and chemokines (MIP-1α & β, RANTES, IL-8). These results show that PAMs delivering BDNF combined with Si-HPMC hydrogel represent a useful novel local delivery tool in the context of neurological disorders. It not only provides neuroprotective BDNF but also bone marrow-derived stem cells that benefit from that environment by displaying neural commitment and an improved neuroprotective/reparative secretome. It provides preliminary evidence of a promising pro-angiogenic, neuroprotective and axonal growth-promoting device for the nervous system.

  2. Acetylcholine receptors in the retinas of the α7 nicotinic acetylcholine receptor knockout mouse

    PubMed Central

    Souza, Fred G. Oliveira; Bruce, Kady S.; Strang, Christianne E.; Morley, Barbara J.; Keyser, Kent T.

    2014-01-01

    Purpose The α7 nicotinic acetylcholine receptor (nAChR) is widely expressed in the nervous system, including in the inner retinal neurons in all species studied to date. Although reductions in the expression of α7 nAChRs are thought to contribute to the memory and visual deficits reported in Alzheimer’s disease (AD) and schizophrenia , the α7 nAChR knockout (KO) mouse is viable and has only slight visual dysfunction. The absence of a major phenotypic abnormality may be attributable to developmental mechanisms that serve to compensate for α7 nAChR loss. We hypothesized that the upregulation of genes encoding other nAChR subunits or muscarinic acetylcholine receptor (mAChR) subtypes during development partially accounts for the absence of major deficiencies in the α7 nAChR KO mouse. The purpose of this study was to determine whether the deletion of the α7 nAChR subunit in a mouse model resulted in changes in the regulation of other cholinergic receptors or other ion channels in an α7 nAChR KO mouse when compared to a wild-type (WT) mouse. Methods To examine gene expression changes, we employed a quantitative real-time polymerase chain reaction (qPCR) using whole retina RNA extracts as well as RNA extracted from selected regions of the retina. These extracts were collected using laser capture microdissection (LCM). The presence of acetylcholine receptor (AChR) subunit and subtype proteins was determined via western blotting. To determine any differences in the number and distribution of choline acetyltransferase (ChAT) amacrine cells, we employed wholemount and vertical immunohistochemistry (IHC) and cell counting. Additionally, in both WT and α7 nAChR KO mouse retinas, the distribution of the nAChR subunit and mAChR subtype proteins were determined via IHC for those KO mice that experienced mRNA changes. Results In the whole retina, there was a statistically significant upregulation of α2, α9, α10, β4, nAChR subunit, and m1 and m4 mAChR subtype

  3. GLUTAMATERGIC SYNAPSE FORMATION IS PROMOTED BY α7-CONTAINING NICOTINIC ACETYLCHOLINE RECEPTORS

    PubMed Central

    Lozada, Adrian F.; Wang, Xulong; Gounko, Natalia V.; Massey, Kerri A.; Duan, Jingjing; Liu, Zhaoping; Berg, Darwin K.

    2012-01-01

    Glutamate is the primary excitatory transmitter in adult brain, acting through synapses on dendritic spines and shafts. Early in development, however, when glutamatergic synapses are only beginning to form, nicotinic cholinergic excitation is already widespread; it is mediated by acetylcholine activating nicotinic acetylcholine receptors (nAChRs) that generate waves of activity across brain regions. A major class of nAChRs contributing at this time is a species containing α7 subunits (α7-nAChRs). These receptors are highly permeable to calcium, influence a variety of calcium-dependent events, and are diversely distributed throughout the developing CNS. Here we show that α7-nAChRs unexpectedly promote formation of glutamatergic synapses during development. The dependence on α7-nAChRs becomes clear when comparing wild-type mice with mice constitutively lacking the α7-nAChR gene. Ultrastructural analysis, immunostaining, and patch-clamp recording all reveal synaptic deficits when α7-nAChR input is absent. Similarly, nicotinic activation of α7-nAChRs in wild-type organotypic culture, as well as cell culture, increases the number of glutamatergic synapses. RNA interference demonstrates that the α7-nAChRs must be expressed in the neuron being innervated for normal innervation to occur. Moreover the deficits persist throughout the developmental period of major de novo synapse formation and are still fully apparent in the adult. GABAergic synapses, in contrast, are undiminished in number under such conditions. As a result, mice lacking α7-nAChRs have an altered balance in the excitatory/inhibitory input they receive. This ratio represents a fundamental feature of neural networks and shows for the first time that endogenous nicotinic cholinergic signaling plays a key role in network construction. PMID:22649244

  4. beta-Chemokine production by neural and glial progenitor cells is enhanced by HIV-1 Tat: effects on microglial migration.

    PubMed

    Hahn, Yun Kyung; Vo, Phu; Fitting, Sylvia; Block, Michelle L; Hauser, Kurt F; Knapp, Pamela E

    2010-07-01

    Human immunodeficiency virus (HIV)-1 neuropathology results from collective effects of viral proteins and inflammatory mediators on several cell types. Significant damage is mediated indirectly through inflammatory conditions promulgated by glial cells, including microglia that are productively infected by HIV-1, and astroglia. Neural and glial progenitors exist in both developing and adult brains. To determine whether progenitors are targets of HIV-1, a multi-plex assay was performed to assess chemokine/cytokine expression after treatment with viral proteins transactivator of transcription (Tat) or glycoprotein 120 (gp120). In the initial screen, ten analytes were basally released by murine striatal progenitors. The beta-chemokines CCL5/regulated upon activation, normal T cell expressed and secreted, CCL3/macrophage inflammatory protein-1alpha, and CCL4/macrophage inflammatory protein-1beta were increased by 12-h exposure to HIV-1 Tat. Secreted factors from Tat-treated progenitors were chemoattractive towards microglia, an effect blocked by 2D7 anti-CCR5 antibody pre-treatment. Tat and opiates have interactive effects on astroglial chemokine secretion, but this interaction did not occur in progenitors. gp120 did not affect chemokine/cytokine release, although both CCR5 and CXCR4, which serve as gp120 co-receptors, were detected in progenitors. We postulate that chemokine production by progenitors may be a normal, adaptive process that encourages immune inspection of newly generated cells. Pathogens such as HIV might usurp this function to create a maladaptive state, especially during development or regeneration, when progenitors are numerous.

  5. MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells.

    PubMed

    Fan, Zheng; Lu, Ming; Qiao, Chen; Zhou, Yan; Ding, Jian-Hua; Hu, Gang

    2016-12-01

    α-Synuclein (α-syn) has been recognized to induce neuroinflammation and to disturb nerve repair process in Parkinson's disease. However, the potential mechanisms underlying α-syn-induced impairment of adult neurogenesis remain unclear. In the present study, A53T mutant α--synuclein transgenic (A53T(tg/tg)) mice, caspase-1 knockout mice, and A53T(tg/tg);caspase-1(-/-) double transgenic mice were used to prepare adult neural stem cells (ANSCs) and to investigate inflammasome-related mechanism for α-syn-impaired neurogenesis in mouse subventricular zone (SVZ). We showed that α-syn inhibited neurogenesis in the SVZ of A53T(tg/tg) mice and impaired proliferation and differentiation in ANSCs cultured in vitro, accompanied by reduced microRNA-7 (miR-7) expression levels. We further found that ANSC expressed NLRP3-containing inflammasome and α-syn activated both TLR4/NF-κB and NLRP3/caspase-1 signals in ANSCs. Either Nlrp3 knockdown or Caspase-1 knockout could attenuate the inhibition of proliferation in ANSCs induced by α-syn. Furthermore, we demonstrated that miR-7 post-transcriptionally controlled Nlrp3 expression besides targeting α-syn. Most notably, stereotactic injection of miR-7 mimics into lateral ventricles significantly inhibited NLRP3 inflammasome activation and improved adult neurogenesis in mouse SVZ. Our study provides a direct link between NLRP3 inflammasome activation and α-syn-impaired neurogenesis in the pathogenesis of α-synucleinopathies.

  6. Rethinking inflammation: neural circuits in the regulation of immunity

    PubMed Central

    Olofsson, Peder S.; Rosas-Ballina, Mauricio; Levine, Yaakov A.; Tracey, Kevin J.

    2015-01-01

    Summary Neural reflex circuits regulate cytokine release to prevent potentially damaging inflammation and maintain homeostasis. In the inflammatory reflex, sensory input elicited by infection or injury travels through the afferent vagus nerve to integrative regions in the brainstem, and efferent nerves carry outbound signals that terminate in the spleen and other tissues. Neurotransmitters from peripheral autonomic nerves subsequently promote acetylcholine-release from a subset of CD4+ T cells that relay the neural signal to other immune cells, e.g. through activation of α7 nicotinic acetylcholine receptors on macrophages. Here, we review recent progress in the understanding of the inflammatory reflex and discuss potential therapeutic implications of current findings in this evolving field. PMID:22725962

  7. Acetylcholine induces neurite outgrowth and modulates matrix metalloproteinase 2 and 9.

    PubMed

    Anelli, Tonino; Mannello, Ferdinando; Salani, Monica; Tonti, Gaetana A; Poiana, Giancarlo; Biagioni, Stefano

    2007-10-19

    The matrix metalloproteinases (MMPs), responsible for the degradation of extracellular matrix (ECM) proteins, may regulate brain cellular functions. Choline acetyltransferase (ChAT) transfected murine neuroblastoma cell line N18TG2, that synthesize acetylcholine and show enhancement of several neurospecific markers (i.e., sinapsin I, voltage gated Na(+) channels, high affinity choline uptake) and fiber outgrowth, were studied for the MMP regulation during neuronal differentiation. Zymography of N18TG2 culture medium revealed no gelatinolytic activity, whereas after carbachol treatment of cells both MMP-9 and activated MMP-2 forms were detected. ChAT-transfected clone culture medium contains three MMP forms at 230, 92, and 66kDa. Carbachol treatment increased MMP-2 and MMP-9 gene expression in N18TG2 cells and higher levels for both genes were also observed in ChAT transfected cells. The data are consistent with the hypothesis that acetylcholine brings about the activation of an autocrine loop modulating MMP expression.

  8. Protease inhibitor homologues from mamba venoms: facilitation of acetylcholine release and interactions with prejunctional blocking toxins.

    PubMed

    Harvey, A L; Karlsson, E

    1982-09-01

    1 Five polypeptides, which were isolated from elapid snake venoms and which are structurally related to protease inhibitors, were tested for action on isolated biventer cervicis nerve-muscle preparations of the chick. 2 Dendrotoxin from the Eastern green mamba (Dendroaspis angusticeps) and toxins K and I from the black mamba (Dendroaspis polylepis polylepis) increased to indirect stimulation without affecting responses to exogenous acetylcholine, carbachol of KCl. 3 The two other protease inhibitor homologues, HHV-II from Ringhals cobra (Hemachatus haemachatus) and NNV-II from Cape cobra (Naja nivea) did not increase responses to nerve stimulation. Trypsin inhibitor from bovine pancreas also had no facilitatory effects on neuromuscular transmission. 4 The facilitatory toxins from mamba venoms interacted with the prejunctional blocking toxins, beta-bungarotoxin, crotoxin and notexin, but not with taipoxin. The blocking effects of beta-bungarotoxin were reduced by pretreatment with the mamba toxins, whereas the blocking actions of crotoxin and notexin were enhanced. 5 The results indicate that protease inhibitor homologues from mamba venoms form a new class of neurotoxin, which acts to increase the release of acetylcholine in response to motor nerve stimulation. 6 From the interaction studies it is concluded that the facilitatory toxins bind to motor nerve terminals at sites related to those occupied by the prejunctional blocking toxins. However, differences in interactions with individual toxins suggest that there must be several related binding sites on the nerve terminals.

  9. Effect of externally added carnitine on the synthesis of acetylcholine in rat cerebral cortex cells.

    PubMed

    Wawrzeńczyk, A; Nałecz, K A; Nałecz, M J

    1995-06-01

    Acetylcholine synthesis from radiolabelled glucose was monitored in cerebral cortex cells isolated from brains of suckling and adult rats. Acetylcholine synthesis was found much higher in suckling animals, both in the absence and presence of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) inhibitor, paraoxon. Together with choline (20 microM), carnitine was found to stimulate acetylcholine synthesis in a synergistic way in cortex cells from adult rats (18%). Choline, however, was incapable of reversing an inhibitory effect exerted by carnitine on acetylcholine synthesis in cortex cells from suckling animals. Distribution of carnitine derivatives was found significantly different in the cells from young and old animals, the content of acetylcarnitine decreased with age with a corresponding increase of free carnitine. The observed differences in carnitine effect on acetylcholine synthesis suggested that high acetylcarnitine in cells capable of beta-oxidation might be correlated with the lower level of acetylcholine synthesis.

  10. Ketanserin and Naftopidil Enhance the Potentiating Effect of Alpha-Methyl-Serotonin on the Neurally-Induced Contraction of Human Isolated Urinary Bladder Muscle Strips

    PubMed Central

    2017-01-01

    Purpose The aim of this study was to assess the potential involvement of a specific subtype of 5-hydroxytryptamine (5-HT), 5HT2 receptors in neurally-induced contractions of the human detrusor. Methods Contractile responses to electrical field stimulation (EFS) were examined in human isolated urinary bladder muscle strips. The potentiation of EFS-induced detrusor contraction was examined by adding cumulative concentrations of a 5-HT and 5-HT2 receptor agonist, α-methyl-serotonin (α-Me-5-HT) (1nM–100μM) in the presence or absence of a 5-HT2 antagonist, ketanserin (5-HT2A>5-HT2C) or naftopidil (5-HT2B>5-HT2A) (0.3–3μM). Results 5-HT and α-Me-5-HT potentiated EFS-induced contraction with a maximal effect (Emax) of 37.6% and 38.6%, respectively, and with pEC50 (negative logarithm of the concentration required for a half-maximal response to an agonist) values of 8.3 and 6.8, respectively. Neither ketanserin nor naftopidil at any concentration produced a rightward displacement of the α-Me-5-HT concentration response curve. Instead, the Emax of α-Me-5-HT increased in the presence of ketanserin at 0.3–1μM and in the presence of naftopidil at 1μM to 51% and 56%, respectively, while the Emax in the presence of vehicle alone was 36%. The highest concentration (3μM) of either drug, however, fully reversed the enhancement. Conclusions The potentiating effect of α-Me-5-HT on neurally-induced contraction of human urinary bladder muscle strips was not found to be mediated via any 5-HT2 receptor subtypes. The underlying mechanism for the enhancement of the α-Me-5-HT potentiating effect on detrusor contractility by ketanserin and naftopidil remains unknown; however, our results suggest that these drugs may be useful for treating contractile dysfunction of the detrusor, as manifested in conditions such as underactive bladder. PMID:28361518

  11. Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

    NASA Astrophysics Data System (ADS)

    Lyukmanova, E. N.; Shulepko, M. A.; Shenkarev, Z. O.; Bychkov, M. L.; Paramonov, A. S.; Chugunov, A. O.; Kulbatskii, D. S.; Arvaniti, M.; Dolejsi, Eva; Schaer, T.; Arseniev, A. S.; Efremov, R. G.; Thomsen, M. S.; Dolezal, V.; Bertrand, D.; Dolgikh, D. A.; Kirpichnikov, M. P.

    2016-08-01

    Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a ‘three-finger’ fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC50 ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with α3β2-nAChRs, while it inhibited cell growth via α7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the ‘classical’ orthosteric agonist/antagonist binding sites at α7 and α3β2-nAChRs.

  12. Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

    PubMed Central

    Lyukmanova, E. N.; Shulepko, M. A.; Shenkarev, Z. O.; Bychkov, M. L.; Paramonov, A. S.; Chugunov, A. O.; Kulbatskii, D. S.; Arvaniti, M.; Dolejsi, Eva; Schaer, T.; Arseniev, A. S.; Efremov, R. G.; Thomsen, M. S.; Dolezal, V.; Bertrand, D.; Dolgikh, D. A.; Kirpichnikov, M. P.

    2016-01-01

    Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a ‘three-finger’ fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC50 ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with α3β2-nAChRs, while it inhibited cell growth via α7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the ‘classical’ orthosteric agonist/antagonist binding sites at α7 and α3β2-nAChRs. PMID:27485575

  13. Phase Detection Using Neural Networks.

    DTIC Science & Technology

    1997-03-10

    A likelihood of detecting a reflected signal characterized by phase discontinuities and background noise is enhanced by utilizing neural networks to...identify coherency intervals. The received signal is processed into a predetermined format such as a digital time series. Neural networks perform

  14. Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism

    PubMed Central

    Gordon, Ilanit; Jack, Allison; Pretzsch, Charlotte M.; Vander Wyk, Brent; Leckman, James F.; Feldman, Ruth; Pelphrey, Kevin A.

    2016-01-01

    Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain’s reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation—one that could, in future, be harnessed to augment behavioral treatments for ASD. PMID:27845765

  15. Achieving Acetylcholine Receptor Clustering in Tissue-Engineered Skeletal Muscle Constructs In vitro through a Materials-Directed Agrin Delivery Approach

    PubMed Central

    Scott, John B.; Ward, Catherine L.; Corona, Benjamin T.; Deschenes, Michael R.; Harrison, Benjamin S.; Saul, Justin M.; Christ, George J.

    2017-01-01

    Volumetric muscle loss (VML) can result from trauma, infection, congenital anomalies, or surgery, and produce permanent functional and cosmetic deficits. There are no effective treatment options for VML injuries, and recent advances toward development of muscle constructs lack the ability to achieve innervation necessary for long-term function. We sought to develop a proof-of-concept biomaterial construct that could achieve acetylcholine receptor (AChR) clustering on muscle-derived cells (MDCs) in vitro. The approach consisted of the presentation of neural (Z+) agrin from the surface of microspheres embedded with a fibrin hydrogel to muscle cells (C2C12 cell line or primary rat MDCs). AChR clustering was spatially restricted to areas of cell (C2C12)-microsphere contact when the microspheres were delivered in suspension or when they were incorporated into a thin (2D) fibrin hydrogel. AChR clusters were observed from 16 to 72 h after treatment when Z+ agrin was adsorbed to the microspheres, and for greater than 120 h when agrin was covalently coupled to the microspheres. Little to no AChR clustering was observed when agrin-coated microspheres were delivered from specially designed 3D fibrin constructs. However, cyclic stretch in combination with agrin-presenting microspheres led to dramatic enhancement of AChR clustering in cells cultured on these 3D fibrin constructs, suggesting a synergistic effect between mechanical strain and agrin stimulation of AChR clustering in vitro. These studies highlight a strategy for maintaining a physiological phenotype characterized by motor endplates of muscle cells used in tissue engineering strategies for muscle regeneration. As such, these observations may provide an important first step toward improving function of tissue-engineered constructs for treatment of VML injuries. PMID:28123368

  16. Achieving Acetylcholine Receptor Clustering in Tissue-Engineered Skeletal Muscle Constructs In vitro through a Materials-Directed Agrin Delivery Approach.

    PubMed

    Scott, John B; Ward, Catherine L; Corona, Benjamin T; Deschenes, Michael R; Harrison, Benjamin S; Saul, Justin M; Christ, George J

    2016-01-01

    Volumetric muscle loss (VML) can result from trauma, infection, congenital anomalies, or surgery, and produce permanent functional and cosmetic deficits. There are no effective treatment options for VML injuries, and recent advances toward development of muscle constructs lack the ability to achieve innervation necessary for long-term function. We sought to develop a proof-of-concept biomaterial construct that could achieve acetylcholine receptor (AChR) clustering on muscle-derived cells (MDCs) in vitro. The approach consisted of the presentation of neural (Z+) agrin from the surface of microspheres embedded with a fibrin hydrogel to muscle cells (C2C12 cell line or primary rat MDCs). AChR clustering was spatially restricted to areas of cell (C2C12)-microsphere contact when the microspheres were delivered in suspension or when they were incorporated into a thin (2D) fibrin hydrogel. AChR clusters were observed from 16 to 72 h after treatment when Z+ agrin was adsorbed to the microspheres, and for greater than 120 h when agrin was covalently coupled to the microspheres. Little to no AChR clustering was observed when agrin-coated microspheres were delivered from specially designed 3D fibrin constructs. However, cyclic stretch in combination with agrin-presenting microspheres led to dramatic enhancement of AChR clustering in cells cultured on these 3D fibrin constructs, suggesting a synergistic effect between mechanical strain and agrin stimulation of AChR clustering in vitro. These studies highlight a strategy for maintaining a physiological phenotype characterized by motor endplates of muscle cells used in tissue engineering strategies for muscle regeneration. As such, these observations may provide an important first step toward improving function of tissue-engineered constructs for treatment of VML injuries.

  17. Neural correlates of retrieval-based memory enhancement: an fMRI study of the testing effect.

    PubMed

    Wing, Erik A; Marsh, Elizabeth J; Cabeza, Roberto

    2013-10-01

    Restudying material is a common method for learning new information, but not necessarily an effective one. Research on the testing effect shows that practice involving retrieval from memory can facilitate later memory in contrast to passive restudy. Despite extensive behavioral work, the brain processes that make retrieval an effective learning strategy remain unclear. In the present experiment, we explored how initially retrieving items affected memory a day later as compared to a condition involving traditional restudy. In contrast to restudy, initial testing that contributed to future memory success was associated with engagement of several regions including the anterior hippocampus, lateral temporal cortices, and medial prefrontal cortex (PFC). Additionally, testing enhanced hippocampal connectivity with ventrolateral PFC and midline regions. These findings indicate that the testing effect may be contingent on processes that are typically thought to support memory success at encoding (e.g. relational binding, selection and elaboration of semantically-related information) in addition to those more often associated with retrieval (e.g. memory search).

  18. Neural correlates of retrieval-based memory enhancement: An fMRI study of the testing effect

    PubMed Central

    Wing, Erik A.; Marsh, Elizabeth J.; Cabeza, Roberto

    2013-01-01

    Restudying material is a common method for learning new information, but not necessarily an effective one. Research on the testing effect shows that practice involving retrieval from memory can facilitate later memory in contrast to passive restudy. Despite extensive behavioral work, the brain processes that make retrieval an effective learning strategy remain unclear. In the present experiment, we explored how initially retrieving items affected memory a day later as compared to a condition involving traditional restudy. In contrast to restudy, initial testing that contributed to future memory success was associated with engagement of several regions including the anterior hippocampus, lateral temporal cortices, and medial prefrontal cortex (PFC). Additionally, testing enhanced hippocampal connectivity with ventrolateral PFC and midline regions. These findings indicate that the testing effect may be contingent on processes that are typically thought to support memory success at encoding (e.g. relational binding, selection and elaboration of semantically-related information) in addition to those more often associated with retrieval (e.g. memory search). PMID:23607935

  19. Nicotinic acetylcholine receptors control acetylcholine and noradrenaline release in the rodent habenulo-interpeduncular complex

    PubMed Central

    Beiranvand, F; Zlabinger, C; Orr-Urtreger, A; Ristl, R; Huck, S; Scholze, P

    2014-01-01

    Background and purpose Nicotinic acetylcholine receptors (nACh receptors) play a central role in the habenulo-interpeduncular system. We studied nicotine-induced release of NA and ACh in the habenula and interpeduncular nucleus (IPN). Experimental approach The habenula and IPN were loaded with [3H]-choline or [3H]-NA and placed in superfusion chambers. [3H]-ACh release was also stimulated using nicotinic agonists, electrical pulses and elevated [KCl]o in hippocampal and cortical slices from rats, wild-type mice and mice lacking α5, α7, β2, or β4 nACh receptor subunits. Finally, we analysed nACh receptor subtypes in the IPN using immunoprecipitation. Key results Nicotine induced release of [3H]-ACh in the IPN of rats and mice. This release was calcium-dependent but not blocked by tetrodotoxin (TTX); moreover, [3H]-ACh release was abolished in β4-knockout mice but was unaffected in β2- and α5-knockout mice. In contrast, nicotine-induced release of [3H]-NA in the IPN and habenula was blocked by TTX and reduced in both β2-knockout and β4-knockout mice, and dose–response curves were right-shifted in α5-knockout mice. Although electrical stimuli triggered the release of both transmitters, [3H]-ACh release required more pulses delivered at a higher frequency. Conclusions and implications Our results confirm previous findings that β4-containing nACh receptors are critical for [3H]-ACh release in the mouse IPN. Experiments using α5-knockout mice also revealed that unlike in the hippocampus, nicotine-induced [3H]-NA release in the habenulo-interpeduncular system is altered in this knockout model. As α5-containing nACh receptors play a key role in nicotine intake, our results add NA to the list of transmitters involved in this mechanism. PMID:25041479

  20. A Dynamical Role for Acetylcholine in Synaptic Renormalization

    PubMed Central

    Fink, Christian G.; Murphy, Geoffrey G.; Zochowski, Michal; Booth, Victoria

    2013-01-01

    Although sleep is a fundamental behavior observed in virtually all animal species, its functions remain unclear. One leading proposal, known as the synaptic renormalization hypothesis, suggests that sleep is necessary to counteract a global strengthening of synapses that occurs during wakefulness. Evidence for sleep-dependent synaptic downscaling (or synaptic renormalization) has been observed experimentally, but the physiological mechanisms which generate this phenomenon are unknown. In this study, we propose that changes in neuronal membrane excitability induced by acetylcholine may provide a dynamical mechanism for both wake-dependent synaptic upscaling and sleep-dependent downscaling. We show in silico that cholinergically-induced changes in network firing patterns alter overall network synaptic potentiation when synaptic strengths evolve through spike-timing dependent plasticity mechanisms. Specifically, network synaptic potentiation increases dramatically with high cholinergic concentration and decreases dramatically with low levels of acetylcholine. We demonstrate that this phenomenon is robust across variation of many different network parameters. PMID:23516342

  1. Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors

    NASA Astrophysics Data System (ADS)

    Tochitsky, Ivan; Banghart, Matthew R.; Mourot, Alexandre; Yao, Jennifer Z.; Gaub, Benjamin; Kramer, Richard H.; Trauner, Dirk

    2012-02-01

    Advances in synthetic chemistry, structural biology, molecular modelling and molecular cloning have enabled the systematic functional manipulation of transmembrane proteins. By combining genetically manipulated proteins with light-sensitive ligands, innately ‘blind’ neurobiological receptors can be converted into photoreceptors, which allows them to be photoregulated with high spatiotemporal precision. Here, we present the optochemical control of neuronal nicotinic acetylcholine receptors (nAChRs) with photoswitchable tethered agonists and antagonists. Using structure-based design, we produced heteromeric α3β4 and α4β2 nAChRs that can be activated or inhibited with deep-violet light, but respond normally to acetylcholine in the dark. The generation of these engineered receptors should facilitate investigation of the physiological and pathological functions of neuronal nAChRs and open a general pathway to photosensitizing pentameric ligand-gated ion channels.

  2. Spin labeled acetylcholine analogs: studies of cholinergic receptor.

    PubMed

    Rosen, G M; Abou-Donia, M B; Yeh, J Z; Menzel, D B

    1975-10-01

    Some spin-labeled acetylcholine analogs, in which the number of methylene groups between the quaternary nitrogen and the ether oxygen ranged between 1-5, were synthesized to study drug interacitons with acetylcholine receptors. None of the compounds tested, with the exception of the one that contained 2 methylene groups (SL-2) had any cholinergic activity. SL-2 was not capable of producing any nicotinic cholinomimetic activity. On the other hand it proved to have a very weak nicotinic cholinolytic activity on the receptors of the frog satorius muscle. This compound exhibited strong antagonism against muscarinic receptors of the isolated frog heart. The muscarinic cholinolytic action of the spin-label ACh analog is discussed in terms of the molecular perturbation theory of drug action.

  3. Neural dynamics based on the recognition of neural fingerprints

    PubMed Central

    Carrillo-Medina, José Luis; Latorre, Roberto

    2015-01-01

    Experimental evidence has revealed the existence of characteristic spiking features in different neural signals, e.g., individual neural signatures identifying the emitter or functional signatures characterizing specific tasks. These neural fingerprints may play a critical role in neural information processing, since they allow receptors to discriminate or contextualize incoming stimuli. This could be a powerful strategy for neural systems that greatly enhances the encoding and processing capacity of these networks. Nevertheless, the study of information processing based on the identification of specific neural fingerprints has attracted little attention. In this work, we study (i) the emerging collective dynamics of a network of neurons that communicate with each other by exchange of neural fingerprints and (ii) the influence of the network topology on the self-organizing properties within the network. Complex collective dynamics emerge in the network in the presence of stimuli. Predefined inputs, i.e., specific neural fingerprints, are detected and encoded into coexisting patterns of activity that propagate throughout the network with different spatial organization. The patterns evoked by a stimulus can survive after the stimulation is over, which provides memory mechanisms to the network. The results presented in this paper suggest that neural information processing based on neural fingerprints can be a plausible, flexible, and powerful strategy. PMID:25852531

  4. Identification of a family of muscarinic acetylcholine receptor genes

    SciTech Connect

    Bonner, T.I.; Buckley, N.J.; Young, A.C.; Brann, M.R.

    1987-07-31

    Complementary DNAs for three different muscarinic acetylcholine receptors were isolated from a rat cerebral cortex library, and the cloned receptors were expressed in mammalian cells. Analysis of human and rat genomic clones indicates that there are at least four functional muscarinic receptor genes and that these genes lack introns in the coding sequence. This gene family provides a new basis for evaluating the diversity of muscarinic mechanisms in the nervous system.

  5. Acetylcholine in the rat pituitary: a possible humoral factor.

    PubMed

    Egozi, Y; Kloog, Y; Fleminger, G; Sokolovsky, M

    1988-12-20

    Significant amounts of acetylcholine (ACh) were detected in each of the 3 lobes of the rat pituitary (3-6 pmol/anterior lobe, 3 pmol/intermediate lobe and 1.8 pmol/posterior lobe). In the anterior lobes of cyclic rats the levels of ACh varied with the estrous cycle, with daily peaks being observed on the days of proestrus and estrus. The occurrence of ACh, apparently as a humoral factor, appears to be unique to the anterior pituitary.

  6. A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis.

    PubMed

    Allouche-Arnon, Hyla; Gamliel, Ayelet; Barzilay, Claudia M; Nalbandian, Ruppen; Gomori, J Moshe; Karlsson, Magnus; Lerche, Mathilde H; Katz-Brull, Rachel

    2011-01-01

    Choline as a reporter molecule has been investigated by in vivo magnetic resonance for almost three decades. Accumulation of choline metabolites (mainly the phosphorylated forms) had been observed in malignancy in preclinical models, ex-vivo, in vivo and in patients. The combined choline metabolite signal appears in (1) H-MRS of the brain and its relative intensity had been used as a diagnostic factor in various conditions. The advent of spin hyperpolarization methods for in vivo use has raised interest in the ability to follow the physiological metabolism of choline into acetylcholine in the brain. Here we present a stable-isotope labeled choline analog, [1,1,2,2-D(4) ,2-(13) C]choline chloride, that is suitable for this purpose. In this analog, the (13) C position showed 24% polarization in the liquid state, following DNP hyperpolarization. This nucleus also showed a long T(1) (35 s) at 11.8 T and 25 °C, which is a prerequisite for hyperpolarized studies. The chemical shift of this (13) C position differentiates choline and acetylcholine from each other and from the other water-soluble choline metabolites, namely phosphocholine and betaine. Enzymatic studies using an acetyltransferase enzyme showed the synthesis of the deuterated-acetylcholine form at thermal equilibrium conditions and in a hyperpolarized state. Analysis using a comprehensive model showed that the T(1) of the formed hyperpolarized [1,1,2,2-D(4) ,2-(13) C]acetylcholine was 34 s at 14.1 T and 37 °C. We conclude that [1,1,2,2-D(4) ,2-(13) C]choline chloride is a promising new molecular probe for hyperpolarized metabolic studies and discuss the factors related to its possible use in vivo.

  7. Effect of oxotremorine, physostigmine, and scopolamine on brain acetylcholine synthesis: a study using HPLC

    SciTech Connect

    Bertrand, N.; Beley, A. )

    1990-11-01

    The synthesis rate of brain acetylcholine (ACh) was estimated in mice following i.v. administration of ({sup 3}H)choline (Ch). The measurements were performed 1 min after the tracer injection, using the ({sup 3}H)ACh/({sup 3}H)Ch specific radioactivity ratio as an index of ACh synthesis rate. Endogenous and labeled Ch and ACh were quantified using HPLC methodology. Oxotremorine and physostigmine (0.5 mg/kg, i.p.) increased the steady state concentration of brain ACh by + 130% and 84%, respectively and of Ch by + 60% (oxotremorine); they decreased ACh synthesis by 62 and 55%, respectively. By contrast, scopolamine (0.7 mg/kg, i.p.) decreased the cerebral content of Ch by - 26% and of ACh by - 23% without enhancing the synthesis of ACh. The results show the utility of HPLC methodology in the investigation of ACh turnover.

  8. Acetylcholine-induced phosphorylation in isolated outer hair cells.

    PubMed

    Szõnyi, M; Csermely, P; Sziklai, I

    1999-03-01

    Two groups of isolated, surviving outer hair cells (OHCs) of guinea pig cochleas (n = 20, for each group) were treated with 10 microM acetylcholine or acetylcholine plus strichnine (an alpha9 nAChR antagonist), respectively, under short-term tissue culture conditions. The protein content of the cell homogenates was separated by SDS-polyacrylamide gel electrophoresis, Western blotted and labelled with an antibody against phosphoserine residues. Signals were detected using the ECL system. Acetylcholine challenge of the OHCs resulted in a difference in the pattern of phosphorylated proteins from those of strichnine pretreated cells. A 220 kDa and a 120 kDa protein expressed a more intense phosphorylated state in the ACh group compared with the ACh plus strichnine group. The 220 kDa phosphoprotein is in the range of the cytoskeletal protein beta-fodrin, whereas the 120 kDa fraction is similar to alpha-fodrin or an ankyrin isoform. Phosphorylation of proteins due to activation of the AChR by agonist can play a role in the signalling mechanism between receptor activation and increase in the electromotile capability of isolated OHCs.

  9. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory

    PubMed Central

    Hornick, A.; Lieb, A.; Vo, N.P.; Rollinger, J.M.; Stuppner, H.; Prast, H.

    2011-01-01

    In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (Emax: 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (Emax: 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist d, l-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15–18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus. PMID:21945033

  10. Neural Networks

    DTIC Science & Technology

    1990-01-01

    FUNDING NUMBERS PROGRAM PROJECT TASK WORK UNIT ELEMENT NO. NO. NO. ACCESSION NO 11 TITLE (Include Security Classification) NEURAL NETWORKS 12. PERSONAL...SUB-GROUP Neural Networks Optical Architectures Nonlinear Optics Adaptation 19. ABSTRACT (Continue on reverse if necessary and identify by block number...341i Y C-odes , lo iii/(iv blank) 1. INTRODUCTION Neural networks are a type of distributed processing system [1

  11. Formate supplementation enhances folate-dependent nucleotide biosynthesis and prevents spina bifida in a mouse model of folic acid-resistant neural tube defects.

    PubMed

    Sudiwala, Sonia; De Castro, Sandra C P; Leung, Kit-Yi; Brosnan, John T; Brosnan, Margaret E; Mills, Kevin; Copp, Andrew J; Greene, Nicholas D E

    2016-07-01

    The curly tail mouse provides a model for neural tube defects (spina bifida and exencephaly) that are resistant to prevention by folic acid. The major ct gene, responsible for spina bifida, corresponds to a hypomorphic allele of grainyhead-like 3 (Grhl3) but the frequency of NTDs is strongly influenced by modifiers in the genetic background. Moreover, exencephaly in the curly tail strain is not prevented by reinstatement of Grhl3 expression. In the current study we found that expression of Mthfd1L, encoding a key component of mitochondrial folate one-carbon metabolism (FOCM), is significantly reduced in ct/ct embryos compared to a partially congenic wild-type strain. This expression change is not attributable to regulation by Grhl3 or the genetic background at the Mthfd1L locus. Mitochondrial FOCM provides one-carbon units as formate for FOCM reactions in the cytosol. We found that maternal supplementation with formate prevented NTDs in curly tail embryos and also resulted in increased litter size. Analysis of the folate profile of neurulation-stage embryos showed that formate supplementation resulted in an increased proportion of formyl-THF and THF but a reduction in proportion of 5-methyl THF. In contrast, THF decreased and 5-methyl THF was relatively more abundant in the liver of supplemented dams than in controls. In embryos cultured through the period of spinal neurulation, incorporation of labelled thymidine and adenine into genomic DNA was suppressed by supplemental formate, suggesting that de novo folate-dependent biosynthesis of nucleotides (thymidylate and purines) was enhanced. We hypothesise that reduced Mthfd1L expression may contribute to susceptibility to NTDs in the curly tail strain and that formate acts as a one-carbon donor to prevent NTDs.

  12. Comparison of (/sup 3/H)nicotine and (/sup 3/H)acetylcholine binding in mouse brain: regional distribution

    SciTech Connect

    Sershen, H.; Reith, M.E.; Hashim, A.; Lajtha, A.

    1985-06-01

    In a continuing study of nicotine binding sites, the authors determined the relative amount of nicotine binding and acetylcholine binding in various brain regions of C57/BL and of DBA mice. Although midbrain showed the highest and cerebellum the lowest binding for both (/sup 3/H)nicotine and (/sup 3/H)acetylcholine, the ratio of nicotine to acetylcholine binding showed a three-fold regional variation. Acetylcholine inhibition of (/sup 3/H)nicotine binding indicated that a portion of nicotine binding was not inhibited by acetylcholine. These results indicate important differences between the binding of (+/-)-(/sup 3/H)nicotine and that of (/sup 3/H)acetylcholine.

  13. The effects of postnatal alcohol exposure and galantamine on the context pre-exposure facilitation effect and acetylcholine efflux using in vivo microdialysis.

    PubMed

    Perkins, Amy E; Fadel, Jim R; Kelly, Sandra J

    2015-05-01

    Fetal alcohol spectrum disorders (FASD) are characterized by damage to multiple brain regions, including the hippocampus, which is involved in learning and memory. The acetylcholine neurotransmitter system provides major input to the hippocampus and is a possible target of developmental alcohol exposure. Alcohol (3.0 g/kg/day) was administered via intubation to male rat pups (postnatal day [PD] 2-10; ethanol-treated [ET]). Controls received a sham intubation (IC) or no treatment (NC). Acetylcholine efflux was measured using in vivo microdialysis (PD 32-35). ET animals were not different at baseline, but had decreased K(+)/Ca(2+)-induced acetylcholine efflux compared to NC animals and an enhanced acetylcholine response to galantamine (acetylcholinesterase inhibitor; 2.0 mg/kg) compared to both control groups. A separate cohort of animals was tested in the context pre-exposure facilitation effect task (CPFE; PD 30-32) following postnatal alcohol exposure and administration of galantamine (2.0 mg/kg; PD 11-30). Neither chronic galantamine nor postnatal alcohol exposure influenced performance in the CPFE task. Using immunohistochemistry, we found that neither alcohol exposure nor behavioral testing significantly altered the density of vesicular acetylcholine transporter or alpha7 nicotinic acetylcholine receptor in the ventral hippocampus (CA1). In the medial septum, the average number of choline acetyltransferase (ChAT+) cells was increased in ET animals that displayed the context-shock association; there were no changes in IC and NC animals that learned the context-shock association or in any animals that were in the control task that entailed no learning. Taken together, these results indicate that the hippocampal acetylcholine system is significantly disrupted under conditions of pharmacological manipulations (e.g., galantamine) in alcohol-exposed animals. Furthermore, ChAT was up‑regulated in ET animals that learned the CPFE, which may account for their ability

  14. Acetylcholine receptors and concanavalin A-binding sites on cultured Xenopus muscle cells: electrophoresis, diffusion, and aggregation [corrected and republished article originally printed in J Cell Biol 1988 May;106(5):1723-34

    PubMed Central

    1988-01-01

    Using digitally analyzed fluorescence videomicroscopy, we have examined the behavior of acetylcholine receptors and concanavalin A binding sites in response to externally applied electric fields. The distributions of these molecules on cultured Xenopus myoballs were used to test a simple model which assumes that electrophoresis and diffusion are the only important processes involved. The model describes the distribution of concanavalin A sites quite well over a fourfold range of electric field strengths; the results suggest an average diffusion constant of approximately 2.3 X 10(-9) cm2/s. At higher electric field strengths, the asymmetry seen is substantially less than that predicted by the model. Acetylcholine receptors subjected to electric fields show distributions substantially different from those predicted on the basis of simple electrophoresis and diffusion, and evidence a marked tendency to aggregate. Our results suggest that this aggregation is due to lateral migration of surface acetylcholine receptors, and is dependent on surface interactions, rather than the rearrangement of microfilaments or microtubules. The data are consistent with a diffusion-trap mechanism of receptor aggregation, and suggest that the event triggering receptor localization is a local increase in the concentration of acetylcholine receptors, or the electrophoretic concentration of some other molecular species. These observations suggest that, whatever mechanism(s) trigger initial clustering events in vivo, the accumulation of acetylcholine receptors can be substantially enhanced by passive, diffusion-mediated aggregation. PMID:3170634

  15. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy

    PubMed Central

    Palma, Eleonora; Reyes-Ruiz, Jorge Mauricio; Lopergolo, Diego; Roseti, Cristina; Bertollini, Cristina; Ruffolo, Gabriele; Cifelli, Pierangelo; Onesti, Emanuela; Limatola, Cristina; Miledi, Ricardo; Inghilleri, Maurizio

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. By microtransplanting muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of acetylcholine-evoked currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. The expression of human recombinant α1β1γδ (γ-AChRs) and α1β1εδ AChRs (ε-AChRs) in Xenopus oocytes revealed that PEA selectively affected the rundown of ACh currents in ε-AChRs. A clear up-regulation of the α1 subunit in muscle from ALS patients compared with that from non-ALS patients was found by quantitative PCR, but no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease. PMID:26929355

  16. Modes of action, resistance and toxicity of insecticides targeting nicotinic acetylcholine receptors.

    PubMed

    Ihara, Makoto; Buckingham, Steven D; Matsuda, Kazuhiko; Sattelle, David B

    2017-02-06

    Nicotinic acetylcholine receptors (nAChRs) are members of the cys-loop superfamily of ligand-gated ion channels (cys-loop LGICs) and mediate fast cholinergic synaptic transmission in the nervous system of insects. The completion of many insect genome projects has greatly enhanced our understanding of the individual subunits that make up nAChR gene families from an insect genetic model organism (Drosophila melanogaster), crop pests, disease vectors and beneficial (pollinator) species. In addition to considerable insect nAChR subunit diversity, individual subunits can be subject to alternative splicing and RNA editing and these post-transcriptional modifications can add significantly to the diversity of nAChR receptor subtypes. The actions of insecticides targeting nAChRs, notably cartap, neonicotinoids, sulfoximines, flupyradifurone, spinosyns and triflumezopyrim are reviewed. Structural studies obtained using an acetylcholine binding protein (AChBP) co-crystallised with neonicotinoids have yielded important new insights into the requirements for neonicotinoid insecticide - nAChR interactions. The persistent application of insecticides to crop pests leads to the onset of resistance and several examples of resistance to insecticides targeting nAChRs have been documented. Understanding the molecular basis of resistance can inform our understanding of the mechanism of insecticide action. It also provides an important driver for the development of new chemistry, diagnostic tests for resistance and the adoption of application strategies designed to attenuate such problems. Finally, we consider toxicity issues relating to nAChR-active insecticides, with particular reference to beneficial insect species (pollinators) as well as mammalian and avian toxicity. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity.".

  17. Functional characterisation of a nicotinic acetylcholine receptor α subunit from the brown dog tick, Rhipicephalus sanguineus☆

    PubMed Central

    Lees, Kristin; Jones, Andrew K.; Matsuda, Kazuhiko; Akamatsu, Miki; Sattelle, David B.; Woods, Debra J.; Bowman, Alan S.

    2014-01-01

    Ticks and tick-borne diseases have a major impact on human and animal health worldwide. Current control strategies rely heavily on the use of chemical acaricides, most of which target the CNS and with increasing resistance, new drugs are urgently needed. Nicotinic acetylcholine receptors (nAChRs) are targets of highly successful insecticides. We isolated a full-length nAChR α subunit from a normalised cDNA library from the synganglion (brain) of the brown dog tick, Rhipicephalus sanguineus. Phylogenetic analysis has shown this R. sanguineus nAChR to be most similar to the insect α1 nAChR group and has been named Rsanα1. Rsanα1 is distributed in multiple tick tissues and is present across all life-stages. When expressed in Xenopus laevis oocytes Rsanα1 failed to function as a homomer, with and without the addition of either Caenorhabditis elegans resistance-to-cholinesterase (RIC)-3 or X. laevis RIC-3. When co-expressed with chicken β2 nAChR, Rsanα1 evoked concentration-dependent, inward currents in response to acetylcholine (ACh) and showed sensitivity to nicotine (100 μM) and choline (100 μM). Rsanα1/β2 was insensitive to both imidacloprid (100 μM) and spinosad (100 μM). The unreliable expression of Rsanα1 in vitro suggests that additional subunits or chaperone proteins may be required for more robust expression. This study enhances our understanding of nAChRs in arachnids and may provide a basis for further studies on the interaction of compounds with the tick nAChR as part of a discovery process for novel acaricides. PMID:24291321

  18. Towards timely Alzheimer diagnosis: A self-powered amperometric biosensor for the neurotransmitter acetylcholine.

    PubMed

    Moreira, Felismina T C; Sale, M Goreti F; Di Lorenzo, Mirella

    2017-01-15

    Serious brain disorders, such as the Alzheimer's Disease (AD), are associated with a marked drop in the levels of important neurotransmitters, such as acetylcholine (ACh). Real time monitoring of such biomarkers can therefore play a critical role in enhancing AD therapies by allowing timely diagnosis, verifications of treatment effectiveness, and developments of new medicines. In this study, we present the first acetylcholine/oxygen hybrid enzymatic fuel cell for the self-powered on site detection of ACh in plasma, which is based on the combination of an enzymatic anode with a Pt cathode. Firstly, an effective acetylcholinesterase immobilized electrode was developed and its electrochemical performance evaluated. Highly porous gold was used as the electrode material, and the enzyme was immobilized via a one step rapid and simple procedure that does not require the use of harsh chemicals or any electrode/enzyme pre-treatments. The resulting enzymatic electrode was subsequently used as the anode of a miniature flow-through membrane-less fuel cell and showed excellent response to varying concentrations of ACh. The peak power generated by the fuel cell was 4nW at a voltage of 260mV and with a current density of 9μAcm(-2). The limit of detection of the fuel cell sensor was 10μM, with an average response time as short as 3min. These exciting results open new horizons for point-of-care Alzheimer diagnosis and provide an attractive potential alternative to established methods that require laborious and time-consuming sample treatments and expensive instruments.

  19. CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory.

    PubMed

    Wake, G; Court, J; Pickering, A; Lewis, R; Wilkins, R; Perry, E

    2000-02-01

    Certain Lamiaceous and Asteraceous plants have long histories of use as restoratives of lost or declining cognitive functions in western European systems of traditional medicine. Investigations were carried out to evaluate human CNS cholinergic receptor binding activity in extracts of those European medicinal plants reputed to enhance or restore mental functions including memory. Ethanolic extracts were prepared from accessions of these plants and a number of other species related by genus. Amongst the plant extracts screened for contents able to displace [3H]-(N)-nicotine and [3H]-(N)-scopolamine from nicotinic receptors and muscarinic receptors, respectively in homogenates of human cerebral cortical cell membranes, the most potent extracts, prepared from one accession of Melissa officinalis, three Salvia species and Artemisia absinthium had IC50 concentrations of < 1 mg/ml. The displacement curves of some extracts were comparable with that of carbamylcholine chloride, a potent acetylcholine analogue. Choline, a weak nicotinic ligand (IC50 = 3 x 10(-4) M) was found in extracts of all plants studied at concentrations of 10(-6)-10(-5) M. These concentrations could not account for not more than 5% of the displacement activity observed. Some extracts displayed differential displacement at nicotinic and muscarinic acetylcholine receptors, with M. officinalis 0033 having the highest [3H]-(N)-nicotine displacement value and Salvia elegans with the highest [3H]-(N)-scopolamine displacement value. There was also considerable variation in cholinoreceptor interactions between different accessions of a single plant species. Although most plant extracts screened showed some nicotinic and muscarinic activity, only some showed dose-dependent receptor activity typical of materials with genuine cholinergic activity.

  20. Pulmonary Inflammation Is Regulated by the Levels of the Vesicular Acetylcholine Transporter

    PubMed Central

    Perini, Adenir; Câmara, Niels O. S.; Costa, Soraia K. P.; Alonso-Vale, Maria Isabel C.; Caperuto, Luciana C.; Tibério, Iolanda F. L. C.; Prado, Marco Antônio M.; Martins, Mílton A.; Prado, Vânia F.; Prado, Carla M.

    2015-01-01

    Acetylcholine (ACh) plays a crucial role in physiological responses of both the central and the peripheral nervous system. Moreover, ACh was described as an anti-inflammatory mediator involved in the suppression of exacerbated innate response and cytokine release in various organs. However, the specific contributions of endogenous release ACh for inflammatory responses in the lung are not well understood. To address this question we have used mice with reduced levels of the vesicular acetylcholine transporter (VAChT), a protein required for ACh storage in secretory vesicles. VAChT deficiency induced airway inflammation with enhanced TNF-α and IL-4 content, but not IL-6, IL-13 and IL-10 quantified by ELISA. Mice with decreased levels of VAChT presented increased collagen and elastic fibers deposition in airway walls which was consistent with an increase in inflammatory cells positive to MMP-9 and TIMP-1 in the lung. In vivo lung function evaluation showed airway hyperresponsiveness to methacholine in mutant mice. The expression of nuclear factor-kappa B (p65-NF-kB) in lung of VAChT-deficient mice were higher than in wild-type mice, whereas a decreased expression of janus-kinase 2 (JAK2) was observed in the lung of mutant animals. Our findings show the first evidence that cholinergic deficiency impaired lung function and produce local inflammation. Our data supports the notion that cholinergic system modulates airway inflammation by modulation of JAK2 and NF-kB pathway. We proposed that intact cholinergic pathway is necessary to maintain the lung homeostasis. PMID:25816137

  1. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy.

    PubMed

    Palma, Eleonora; Reyes-Ruiz, Jorge Mauricio; Lopergolo, Diego; Roseti, Cristina; Bertollini, Cristina; Ruffolo, Gabriele; Cifelli, Pierangelo; Onesti, Emanuela; Limatola, Cristina; Miledi, Ricardo; Inghilleri, Maurizio

    2016-03-15

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. By microtransplanting muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of acetylcholine-evoked currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. The expression of human recombinant α1β1γδ (γ-AChRs) and α1β1εδ AChRs (ε-AChRs) in Xenopus oocytes revealed that PEA selectively affected the rundown of ACh currents in ε-AChRs. A clear up-regulation of the α1 subunit in muscle from ALS patients compared with that from non-ALS patients was found by quantitative PCR, but no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease.

  2. Nicotinic acetylcholine receptors: from basic science to therapeutics.

    PubMed

    Hurst, Raymond; Rollema, Hans; Bertrand, Daniel

    2013-01-01

    Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic.

  3. Single acetylcholine receptor channel currents recorded at high hydrostatic pressures.

    PubMed Central

    Heinemann, S H; Stühmer, W; Conti, F

    1987-01-01

    A technique for performing patch-clamp experiments under high hydrostatic (oil) pressure is described. The method allows the transfer of whole cell or membrane patches in a recording configuration into a pressure vessel, where pressure can be increased up to 60 MPa (approximately equal to 600 bar). We have studied in this way the pressure dependence of single acetylcholine receptor channels in excised "outside-out" membrane patches from cultured rat muscle cells. In the range of 0.1 to 60 MPa the open channel conductance in 140 mM NaCl solutions did not vary by more than 2%, which implies that the translocation of sodium ions through the channel pore does not involve steps with significant activation volumes. At high acetylcholine concentrations (20 microM) bursts of single-channel activity allowed measurements of the mean open and mean closed times of the channel. Pressurization to 40 MPa increased both mean open and mean closed times giving apparent activation volumes of about 59 and 139 A3, respectively. This implies a net volume increase of 80 A3, associated with the transition from the agonist-free state to the open state of the channel, which may be partially associated with the agonist-binding step. All the observed pressure effects were reversible. The activation volumes for the gating of acetylcholine receptor channels are comparable to those of sodium and potassium channels in the squid giant axon, suggesting that there is some basic common mechanism in the operation of ion-channel proteins. Images PMID:2437577

  4. Synthesis, Trafficking, and Localization of Muscarinic Acetylcholine Receptors

    PubMed Central

    Nathanson, Neil M.

    2008-01-01

    Muscarinic acetylcholine receptors are members of the G-protein coupled receptor superfamily that are expressed in and regulate the function of neurons, cardiac and smooth muscle, glands, and many other cell types and tissues. The correct trafficking of membrane proteins to the cell surface and their subsequent localization at appropriate sites in polarized cells are required for normal cellular signaling and physiological responses. This review will summarize work on the synthesis and trafficking of muscarinic receptors to the plasma membrane and their localization at the cell surface. PMID:18558434

  5. Polyethylene glycol-based homologated ligands for nicotinic acetylcholine receptors☆

    PubMed Central

    Scates, Bradley A.; Lashbrook, Bethany L.; Chastain, Benjamin C.; Tominaga, Kaoru; Elliott, Brandon T.; Theising, Nicholas J.; Baker, Thomas A.; Fitch, Richard W.

    2010-01-01

    A homologous series of polyethylene glycol (PEG) monomethyl ethers were conjugated with three ligand series for nicotinic acetylcholine receptors. Conjugates of acetylaminocholine, the cyclic analog 1-acetyl-4,4-dimethylpiperazinium, and pyridyl ether A-84543 were prepared. Each series was found to retain significant affinity at nicotinic receptors in rat cerebral cortex with tethers of up to six PEG units. Such compounds are hydrophilic ligands which may serve as models for fluorescent/affinity probes and multivalent ligands for nAChR. PMID:19006672

  6. Effects of isoflurane on the actions of neuromuscular blockers on the muscle nicotine acetylcholine receptors.

    PubMed

    Li, Chuanxiang; Yao, Shanglong; Nie, Hui; Lü, Bin

    2004-01-01

    In this study, we tested the hypothesis that volatile anesthetic enhancement of muscle relaxation is the result of combined drug effects on the nicotinic acetylcholine receptors. The poly A m RNA from muscle by isolation were microinjected into Xenopus oocytes for receptor expression. Concentration-effect curves for the inhibition of Ach-induced currents were established for vecuronium, rocuranium, and isoflurane. Subsequently, inhibitory effects of NDMRs were studied in the presence of the isoflurane at a concentration equivalent to half the concentration producing a 50% inhibition alone. All tested drugs produced rapid and readily reversible concentration-dependent inhibition. The 50% inhibitory concentration values were 889 micromol/L (95% CI: 711-1214 micromol). 33.4 micromol (95% CI: 27.1-41.7 nmol) and 9.2 nmol (95% CI: 7.9-12.3 nmol) for isoflurane. rocuranium and vecuronium, respectively. Coapplication of isoflurane significantly enhanced the inhibitory effects of rocuranium and vecuronium, and it was especially so at low concentration of NMDRs. Isoflurane increases the potency of NDMRs, possibly by enhancing antagonist affinity at the receptor site.

  7. Release of acetylcholine by syringin, an active principle of Eleutherococcus senticosus, to raise insulin secretion in Wistar rats.

    PubMed

    Liu, Ko Yu; Wu, Yang-Chang; Liu, I-Min; Yu, Wen Chen; Cheng, Juei-Tang

    2008-03-28

    The present study is designed to screen the effect of syringin, an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae), on the plasma glucose and investigate the possible mechanisms. Plasma glucose decreased in a dose-dependent manner 60 min after intravenous injection of syringin into fasting Wistar rats. In parallel to the decrease of plasma glucose, increases of plasma insulin level as well as the plasma C-peptide was also observed in rats receiving same treatment. Both the plasma glucose lowering action and the raised plasma levels of insulin and C-peptide induced by syringin were also inhibited by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP), the antagonist of the muscarinic M3 receptors, but not affected by the ganglionic nicotinic antagonist, pentolinium or hexamethonium. Moreover, disruption of synaptic available acetylcholine (ACh) using an inhibitor of choline uptake, hemicholinium-3, or vesicular acetylcholine transport, vesamicol, abolished these actions of syringin. Also, physostigmine at concentration sufficient to inhibit acetylcholinesterase enhanced the actions of syringin. Mediation of ACh release from the nerve terminals to enhance insulin secretion by syringin can thus be considered. The results suggest that syringin has an ability to raise the release of ACh from nerve terminals, which in turn to stimulate muscarinic M3 receptors in pancreatic cells and augment the insulin release to result in plasma glucose lowering action.

  8. Designer Self-Assemble Peptides Maximize the Therapeutic Benefits of Neural Stem Cell Transplantation for Alzheimer's Disease via Enhancing Neuron Differentiation and Paracrine Action.

    PubMed

    Cui, Guo-hong; Shao, Shui-jin; Yang, Jia-jun; Liu, Jian-ren; Guo, Hai-dong

    2016-03-01

    The neuropathological hallmarks of Alzheimer's disease (AD) include the presence of extracellular amyloid-β peptide (Aβ) in the form of amyloid plaques and neuronal loss. Neural stem cell (NSC) is being scrutinized as a promising cell replacement therapy for various neurodegenerative diseases. However, the unfavorable niche at the site of degenerative disease is hostile to the survival and differentiation of transplanted cells. Here, we undertook in vitro and in vivo works to examine whether a designer self-assemble peptide (DSP), which contains one functional domain Tyr-Ile-Gly-Ser-Arg (YIGSR) derived from laminin, promotes the survival and neuronal differentiation of NSC and behavioral improvement. We found that DSP could undergo spontaneous assembly into well-ordered nanofibers, and it not only facilitated the cell viability in normal culture condition, but also decreased the number of apoptotic cells induced by Aβ in vitro. NSC seeded in DSP showed much more neuronal differentiation than that seeded in self-assemble peptide (SP) or alone. In the AD model, NSC transplantation in DSP-treated AD rats demonstrated much more obvious cognitive rescue with restoration of learning/memory function compared with NSC transplantation in SP, NSC alone, or DSP alone treated ones. Interestingly, DSP enhanced the survival and neuronal differentiation of transplanted NSC. Apoptosis levels in the CA1 region and Aβ level in the hippocampus were significantly decreased in the group of NSC transplantation in DSP. Moreover, synaptic function, indicated by the expression of pre-synaptic protein synapsin-1, was restored and the secretion of anti-inflammatory and neurotrophic factors were increased, such as IL-10, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin-like growth factor 1 (IGF-1), while the expression of pro-inflammatory factors were decreased, such as TNF-α and IL-1β. These data firstly unveiled that the biomaterial DSP can

  9. Acetylcholine receptors and cholinergic ligands: biochemical and genetic aspects in Torpedo californica and Drosophila melanogaster

    SciTech Connect

    Rosenthal, L.S.

    1987-01-01

    This study evaluates the biochemical and genetic aspects of the acetylcholine receptor proteins and cholinergic ligands in Drosophila melanogaster and Torpedo californica. Included are (1) a comparative study of nicotinic ligand-induced cation release from acetylcholine receptors isolated from Torpedo californica and from Drosophila melanogaster, (2) solution studies of the cholinergic ligands, nikethamide and ethamivan, aimed at measuring internal molecular rotational barriers in solvents of different polarity; and (3) the isolation and characterization of the gene(s) for the acetylcholine receptor in Drosophila melasogaster. Acetylcholine receptor proteins isolated from Drosphila melanogaster heads were found to behave kinetically similar (with regards to cholinergic ligand-induced /sup 155/Eu:/sup 3 +/ displacement from prelabeled proteins) to receptor proteins isolated from Torpedo californica electric tissue, providing additional biochemical evidence for the existence of a Drosophila acetylcholine receptor.

  10. Organophosphate acetylcholine esterase inhibitor poisoning from a home-made shampoo.

    PubMed

    Sadaka, Yair; Broides, Arnon; Tzion, Raffi Lev; Lifshitz, Matitiahu

    2011-07-01

    Organophosphate acetylcholine esterase inhibitor poisoning is a major health problem in children. We report an unusual cause of organophosphate acetylcholine esterase inhibitor poisoning. Two children were admitted to the pediatric intensive care unit due to organophosphate acetylcholine esterase inhibitor poisoning after exposure from a home-made shampoo that was used for the treatment of head lice. Owing to no obvious source of poisoning, the diagnosis of organophosphate acetylcholine esterase inhibitor poisoning in one of these patients was delayed. Both patients had an uneventful recovery. Organophosphate acetylcholine esterase inhibitor poisoning from home-made shampoo is possible. In cases where the mode of poisoning is unclear, direct questioning about the use of home-made shampoo is warranted, in these cases the skin and particularly the scalp should be rinsed thoroughly as soon as possible.

  11. Sharpened cortical tuning and enhanced cortico-cortical communication contribute to the long-term neural mechanisms of visual motion perceptual learning.

    PubMed

    Chen, Nihong; Bi, Taiyong; Zhou, Tiangang; Li, Sheng; Liu, Zili; Fang, Fang

    2015-07-15

    Much has been debated about whether the neural plasticity mediating perceptual learning takes place at the sensory or decision-making stage in the brain. To investigate this, we trained human subjects in a visual motion direction discrimination task. Behavioral performance and BOLD signals were measured before, immediately after, and two weeks after training. Parallel to subjects' long-lasting behavioral improvement, the neural selectivity in V3A and the effective connectivity from V3A to IPS (intraparietal sulcus, a motion decision-making area) exhibited a persistent increase for the trained direction. Moreover, the improvement was well explained by a linear combination of the selectivity and connectivity increases. These findings suggest that the long-term neural mechanisms of motion perceptual learning are implemented by sharpening cortical tuning to trained stimuli at the sensory processing stage, as well as by optimizing the connections between sensory and decision-making areas in the brain.

  12. The acetylcholine receptor as a cellular receptor for rabies virus.

    PubMed

    Lentz, T L; Burrage, T G; Smith, A L; Tignor, G H

    1983-01-01

    Characterization of specific host cell receptors for enveloped viruses is a difficult problem because many enveloped viruses bind to a variety of substrates which are not obviously related to tissue tropisms in the intact host. Viruses with a limited cellular tropism in infected animals present useful models for studying the mechanisms by which virus attachment regulates the disease process. Rabies virus is a rhabdovirus which exhibits a marked neuronotropism in infected animals. Limited data suggest that spread occurs by transsynaptic transfer of virus. The results of recent experiments at Yale suggest that viral antigen is localized very soon after injection at neuromuscular junctions, the motor nerve endings on muscle tissue. On cultured muscle cells, similar co-localization with the acetylcholine receptor is seen both before and after virus multiplication. Pretreatment of these cells with some ligands of the acetylcholine receptor results in reduced viral infection. These findings suggest that a neurotransmitter receptor or a closely associated molecule may serve as a specific host cell receptor for rabies virus and thus may be responsible for the tissue tropism exhibited by this virus. In addition to clarifying aspects of rabies virus pathogenesis, these studies have broad implications regarding the mechanism by which other viruses or viral immunizations might mediate autoimmune diseases such as myasthenia gravis.

  13. Caenorhabditis elegans nicotinic acetylcholine receptors are required for nociception

    PubMed Central

    Cohen, Emiliano; Chatzigeorgiou, Marios; Husson, Steven J.; Steuer-Costa, Wagner; Gottschalk, Alexander; Schafer, William R.; Treinin, Millet

    2014-01-01

    Polymodal nociceptors sense and integrate information on injurious mechanical, thermal, and chemical stimuli. Chemical signals either activate nociceptors or modulate their responses to other stimuli. One chemical known to activate or modulate responses of nociceptors is acetylcholine (ACh). Across evolution nociceptors express subunits of the nicotinic acetylcholine receptor (nAChR) family, a family of ACh-gated ion channels. The roles of ACh and nAChRs in nociceptor function are, however, poorly understood. Caenorhabditis elegans polymodal nociceptors, PVD, express nAChR subunits on their sensory arbor. Here we show that mutations reducing ACh synthesis and mutations in nAChR subunits lead to defects in PVD function and morphology. A likely cause for these defects is a reduction in cytosolic calcium measured in ACh and nAChR mutants. Indeed, overexpression of a calcium pump in PVD mimics defects in PVD function and morphology found in nAChR mutants. Our results demonstrate, for the first time, a central role for nAChRs and ACh in nociceptor function and suggest that calcium permeating via nAChRs facilitates activity of several signaling pathways within this neuron. PMID:24518198

  14. Corelease of acetylcholine and GABA from cholinergic forebrain neurons

    PubMed Central

    Saunders, Arpiar; Granger, Adam J; Sabatini, Bernardo L

    2015-01-01

    Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons. DOI: http://dx.doi.org/10.7554/eLife.06412.001 PMID:25723967

  15. Expression of cloned α6* nicotinic acetylcholine receptors.

    PubMed

    Wang, Jingyi; Kuryatov, Alexander; Lindstrom, Jon

    2015-09-01

    Nicotinic acetylcholine receptors (AChRs) are ACh-gated ion channels formed from five homologous subunits in subtypes defined by their subunit composition and stoichiometry. Some subtypes readily produce functional AChRs in Xenopus oocytes and transfected cell lines. α6β2β3* AChRs (subtypes formed from these subunits and perhaps others) are not easily expressed. This may be because the types of neurons in which they are expressed (typically dopaminergic neurons) have unique chaperones for assembling α6β2β3* AChRs, especially in the presence of the other AChR subtypes. Because these relatively minor brain AChR subtypes are of major importance in addiction to nicotine, it is important for drug development as well as investigation of their functional properties to be able to efficiently express human α6β2β3* AChRs. We review the issues and progress in expressing α6* AChRs. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

  16. Physiological characterization of human muscle acetylcholine receptors from ALS patients.

    PubMed

    Palma, Eleonora; Inghilleri, Maurizio; Conti, Luca; Deflorio, Cristina; Frasca, Vittorio; Manteca, Alessia; Pichiorri, Floriana; Roseti, Cristina; Torchia, Gregorio; Limatola, Cristina; Grassi, Francesca; Miledi, Ricardo

    2011-12-13

    Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons leading to muscle paralysis. Research in transgenic mice suggests that the muscle actively contributes to the disease onset, but such studies are difficult to pursue in humans and in vitro models would represent a good starting point. In this work we show that tiny amounts of muscle from ALS or from control denervated muscle, obtained by needle biopsy, are amenable to functional characterization by two different technical approaches: "microtransplantation" of muscle membranes into Xenopus oocytes and culture of myogenic satellite cells. Acetylcholine (ACh)-evoked currents and unitary events were characterized in oocytes and multinucleated myotubes. We found that ALS acetylcholine receptors (AChRs) retain their native physiological characteristics, being activated by ACh and nicotine and blocked by α-bungarotoxin (α-BuTX), d-tubocurarine (dTC), and galantamine. The reversal potential of ACh-evoked currents and the unitary channel behavior were also typical of normal muscle AChRs. Interestingly, in oocytes injected with muscle membranes derived from ALS patients, the AChRs showed a significant decrease in ACh affinity, compared with denervated controls. Finally, riluzole, the only drug currently used against ALS, reduced, in a dose-dependent manner, the ACh-evoked currents, indicating that its action remains to be fully characterized. The two methods described here will be important tools for elucidating the role of muscle in ALS pathogenesis and for developing drugs to counter the effects of this disease.

  17. Binding of Alpha-Bungarotoxin to Single Identified Neurons of ’Aplysia’ which have Different Ionic Responses to Acetylcholine,

    DTIC Science & Technology

    1976-09-01

    Identifiable Aplysia neurons have one or more of three different ionic responses to acetylcholine, due to Na, Cl, and K conductance increases... Aplysia acetylcholine receptors. Thus the inhibition of the Na response by hexamethonium may be a result of the binding to a site which prevent the conductance change rather than preventing acetylcholine from binding to its receptor.

  18. Evolvable synthetic neural system

    NASA Technical Reports Server (NTRS)

    Curtis, Steven A. (Inventor)

    2009-01-01

    An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

  19. Neural Networks

    SciTech Connect

    Smith, Patrick I.

    2003-09-23

    Physicists use large detectors to measure particles created in high-energy collisions at particle accelerators. These detectors typically produce signals indicating either where ionization occurs along the path of the particle, or where energy is deposited by the particle. The data produced by these signals is fed into pattern recognition programs to try to identify what particles were produced, and to measure the energy and direction of these particles. Ideally, there are many techniques used in this pattern recognition software. One technique, neural networks, is particularly suitable for identifying what type of particle caused by a set of energy deposits. Neural networks can derive meaning from complicated or imprecise data, extract patterns, and detect trends that are too complex to be noticed by either humans or other computer related processes. To assist in the advancement of this technology, Physicists use a tool kit to experiment with several neural network techniques. The goal of this research is interface a neural network tool kit into Java Analysis Studio (JAS3), an application that allows data to be analyzed from any experiment. As the final result, a physicist will have the ability to train, test, and implement a neural network with the desired output while using JAS3 to analyze the results or output. Before an implementation of a neural network can take place, a firm understanding of what a neural network is and how it works is beneficial. A neural network is an artificial representation of the human brain that tries to simulate the learning process [5]. It is also important to think of the word artificial in that definition as computer programs that use calculations during the learning process. In short, a neural network learns by representative examples. Perhaps the easiest way to describe the way neural networks learn is to explain how the human brain functions. The human brain contains billions of neural cells that are responsible for processing

  20. Roles for N-terminal extracellular domains of nicotinic acetylcholine receptor (nAChR) β3 subunits in enhanced functional expression of mouse α6β2β3- and α6β4β3-nAChRs.

    PubMed

    Dash, Bhagirathi; Li, Ming D; Lukas, Ronald J

    2014-10-10

    Functional heterologous expression of naturally expressed mouse α6*-nicotinic acetylcholine receptors (mα6*-nAChRs; where "*" indicates the presence of additional subunits) has been difficult. Here we expressed and characterized wild-type (WT), gain-of-function, chimeric, or gain-of-function chimeric nAChR subunits, sometimes as hybrid nAChRs containing both human (h) and mouse (m) subunits, in Xenopus oocytes. Hybrid mα6mβ4hβ3- (∼ 5-8-fold) or WT mα6mβ4mβ3-nAChRs (∼ 2-fold) yielded higher function than mα6mβ4-nAChRs. Function was not detected when mα6 and mβ2 subunits were expressed together or in the additional presence of hβ3 or mβ3 subunits. However, function emerged upon expression of mα6mβ2mβ3(V9'S)-nAChRs containing β3 subunits having gain-of-function V9'S (valine to serine at the 9'-position) mutations in transmembrane domain II and was further elevated 9-fold when hβ3(V9'S) subunits were substituted for mβ3(V9'S) subunits. Studies involving WT or gain-of-function chimeric mouse/human β3 subunits narrowed the search for domains that influence functional expression of mα6*-nAChRs. Using hβ3 subunits as templates for site-directed mutagenesis studies, substitution with mβ3 subunit residues in extracellular N-terminal domain loops "C" (Glu(221) and Phe(223)), "E" (Ser(144) and Ser(148)), and "β2-β3" (Gln(94) and Glu(101)) increased function of mα6mβ2*- (∼ 2-3-fold) or mα6mβ4* (∼ 2-4-fold)-nAChRs. EC50 values for nicotine acting at mα6mβ4*-nAChR were unaffected by β3 subunit residue substitutions in loop C or E. Thus, amino acid residues located in primary (loop C) or complementary (loops β2-β3 and E) interfaces of β3 subunits are some of the molecular impediments for functional expression of mα6mβ2β3- or mα6mβ4β3-nAChRs.

  1. Functional characterization of mongoose nicotinic acetylcholine receptor alpha-subunit: resistance to alpha-bungarotoxin and high sensitivity to acetylcholine.

    PubMed

    Asher, O; Lupu-Meiri, M; Jensen, B S; Paperna, T; Fuchs, S; Oron, Y

    1998-07-24

    The mongoose is resistant to snake neurotoxins. The mongoose muscle nicotinic acetylcholine receptor (AChR) alpha-subunit contains a number of mutations in the ligand-binding domain and exhibits poor binding of alpha-bungarotoxin (alpha-BTX). We characterized the functional properties of a hybrid (alpha-mongoose/beta gamma delta-rat) AChR. Hybrid AChRs, expressed in Xenopus oocytes, respond to acetylcholine with depolarizing current, the mean maximal amplitude of which was greater than that mediated by the rat AChR. The IC50 of alpha-BTX to the hybrid AChR was 200-fold greater than that of the rat, suggesting much lower affinity for the toxin. Hybrid AChRs exhibited an apparent higher rate of desensitization and higher affinity for ACh (EC50 1.3 vs. 23.3 microM for the rat AChR). Hence, changes in the ligand-binding domain of AChR not only affect the binding properties of the receptor, but also result in marked changes in the characteristics of the current.

  2. Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

    EPA Science Inventory

    Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

  3. In vitro enhanced differentiation of neural networks in ES gut-like organ from mouse ES cells by a 5-HT4-receptor activation.

    PubMed

    Takaki, Miyako; Misawa, Hiromi; Matsuyoshi, Hiroko; Kawahara, Isao; Goto, Kei; Zhang, Guo-Xing; Obata, Koji; Kuniyasu, Hiroki

    2011-03-25

    Using an embryoid body (EB) culture system, we developed a functional organ-like cluster, a "gut", from mouse embryonic stem (ES) cells (ES gut). Each ES gut exhibited various types of spontaneous movements. In these spontaneously contracting ES guts, dense distributions of interstitial cells of Cajal (ICC) (c-kit, a transmembrane receptor that has tyrosine kinase activity, positive cells; gut pacemaker cells) and smooth muscle cells were discernibly identified, but enteric neural networks were not identified. In the present study, we succeeded in forming dense enteric neural networks by a 5-HT(4)-receptor (SR4) agonist, mosapride citrate (1-10 μM) added only during EB formation. Addition of an SR4-antagonist, GR113808 (10 μM) abolished the SR4-agonist-induced formation of enteric neural networks. The SR4-agonist (1 μM) up-regulated the expression of mRNA of SR4 and the SR4-antagonist abolished this upregulation. 5-HT per se exerted similar effects to those of SR4-agonist, though less potent. These results suggest SR4-agonist differentiated enteric neural networks, mediated via activation of SR4 in the ES gut.

  4. Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development.

    PubMed Central

    Bigbee, J W; Sharma, K V; Gupta, J J; Dupree, J L

    1999-01-01

    Acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine at cholinergic synapses and neuromuscular junctions. However, results from our laboratory and others indicate that AChE has an extrasynaptic, noncholinergic role during neural development. This article is a review of our findings demonstrating the morphogenic role of AChE, using a neuronal cell culture model. We also discuss how these data suggest that AChE has a cell adhesive function during neural development. These results could have additional significance as AChE is the target enzyme of agricultural organophosphate and carbamate pesticides as well as the commonly used household organophosphate chlorpyrifos (Dursban). Prenatal exposure to these agents could have adverse effects on neural development by interfering with the morphogenic function of AChE. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6 Figure 7 PMID:10229710

  5. Acetylcholine-producing T cells in the intestine regulate antimicrobial peptide expression and microbial diversity.

    PubMed

    Dhawan, Shobhit; De Palma, Giada; Willemze, Rose A; Hilbers, Francisca W; Verseijden, Caroline; Luyer, Misha D; Nuding, Sabine; Wehkamp, Jan; Souwer, Yuri; de Jong, Esther C; Seppen, J; van den Wijngaard, René M; Wehner, Sven; Verdu, Elena; Bercik, Premek; de Jonge, Wouter J

    2016-11-01

    The cholinergic anti-inflammatory pathway reduces systemic tumor necrosis factor (TNF) via acetylcholine-producing memory T cells in the spleen. These choline acetyltransferase (ChAT)-expressing T cells are also found in the intestine, where their function is unclear. We aimed to characterize these cells in mouse and human intestine and delineate their function. We made use of the ChAT-enhanced green fluorescent protein (eGFP) reporter mice. CD4(Cre) mice were crossed to ChAT(fl/fl) mice to achieve specific deletion of ChAT in CD4(+) T cells. We observed that the majority of ChAT-expressing T cells in the human and mouse intestine have characteristics of Th17 cells and coexpress IL17A, IL22, and RORC The generation of ChAT-expressing T cells was skewed by dendritic cells after activation of their adrenergic receptor β2 To evaluate ChAT T cell function, we generated CD4-specific ChAT-deficient mice. CD4ChAT(-/-) mice showed a reduced level of epithelial antimicrobial peptides lysozyme, defensin A, and ang4, which was associated with an enhanced bacterial diversity and richness in the small intestinal lumen in CD4ChAT(-/-) mice. We conclude that ChAT-expressing T cells in the gut are stimulated by adrenergic receptor activation on dendritic cells. ChAT-expressing T cells may function to mediate the host AMP secretion, microbial growth and expansion.

  6. Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism.

    PubMed

    Karvat, Golan; Kimchi, Tali

    2014-03-01

    Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

  7. Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

    PubMed Central

    Prestori, Francesca; Bonardi, Claudia; Mapelli, Lisa; Lombardo, Paola; Goselink, Rianne; De Stefano, Maria Egle; Gandolfi, Daniela; Mapelli, Jonathan; Bertrand, Daniel; Schonewille, Martijn; De Zeeuw, Chris; D’Angelo, Egidio

    2013-01-01

    The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation. PMID:23741401

  8. Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

    SciTech Connect

    Supavilai, P.; Karobath, M.

    1985-02-04

    GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.

  9. Acetylcholine promotes the emergence and elongation of lateral roots of Raphanus sativus.

    PubMed

    Sugiyama, Kou-ichi; Tezuka, Takafumi

    2011-10-01

    Radish (Raphanus sativus L.) was grown on four layers of paper towel moistened with distilled water with and without acetylcholine (ACh) for five days in the dark after sowing. ACh at 1 nM promoted the growth (emergence and elongation) of lateral roots of radish plants, but had no effect on the stems and main roots. Moreover, ACh enhanced the dry weight of roots [main (primary) + lateral roots]. Neostigmine, an inhibitor of acetylcholinesterase (AChE) also promoted the emergence and elongation of lateral roots, and atropine, a competitive inhibitor of ACh receptor, suppressed the emergence and elongation. ACh suppressed the activity of AChE and increased the amount of proteins and pyridine nucleotides (NAD and NADH) in the roots of the seedlings. It also increased the activities of NAD-forming enzymes [NAD synthetase and ATP-nicotinamide mononucleotide (ATP-NMN) adenyltransferase], and enhanced the amount of DNA in the roots of the seedlings. The relationship between ACh and the emergence and growth of lateral roots was discussed from a biochemical viewpoint.

  10. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine

    PubMed Central

    Martella, Giuseppina; Tassone, Annalisa; Sciamanna, Giuseppe; Platania, Paola; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Cacci, Emanuele; Biagioni, Stefano; Usiello, Alessandro; Bernardi, Giorgio; Sharma, Nutan

    2009-01-01

    DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been

  11. The science of neural interface systems.

    PubMed

    Hatsopoulos, Nicholas G; Donoghue, John P

    2009-01-01

    The ultimate goal of neural interface research is to create links between the nervous system and the outside world either by stimulating or by recording from neural tissue to treat or assist people with sensory, motor, or other disabilities of neural function. Although electrical stimulation systems have already reached widespread clinical application, neural interfaces that record neural signals to decipher movement intentions are only now beginning to develop into clinically viable systems to help paralyzed people. We begin by reviewing state-of-the-art research and early-stage clinical recording systems and focus on systems that record single-unit action potentials. We then address the potential for neural interface research to enhance basic scientific understanding of brain function by offering unique insights in neural coding and representation, plasticity, brain-behavior relations, and the neurobiology of disease. Finally, we discuss technical and scientific challenges faced by these systems before they are widely adopted by severely motor-disabled patients.

  12. Methamphetamine exposure during brain development alters the brain acetylcholine system in adolescent mice.

    PubMed

    Siegel, Jessica A; Park, Byung S; Raber, Jacob

    2011-10-01

    Children exposed to methamphetamine during brain development as a result of maternal drug use have long-term hippocampus-dependent cognitive impairments, but the mechanisms underlying these impairments are not understood. The acetylcholine system plays an important role in cognitive function and potential methamphetamine-induced acetylcholine alterations may be related to methamphetamine-induced cognitive impairments. In this study, we investigated the potential long-term effects of methamphetamine exposure during hippocampal development on the acetylcholine system in adolescence mice on postnatal day 30 and in adult mice on postnatal day 90. Methamphetamine exposure increased the density of acetylcholine neurons in regions of the basal forebrain and the area occupied by acetylcholine axons in the hippocampus in adolescent female mice. In contrast, methamphetamine exposure did not affect the density of GABA cells or total neurons in the basal forebrain. Methamphetamine exposure also increased the number of muscarinic acetylcholine receptors in the hippocampus of adolescent male and female mice. Our results demonstrate for the first time that methamphetamine exposure during hippocampal development affects the acetylcholine system in adolescent mice and that these changes are more profound in females than males.

  13. Acetylcholine receptor extracellular domain determines sensitivity to nicotine-induced inactivation.

    PubMed

    Kuryatov, A; Olale, F A; Choi, C; Lindstrom, J

    2000-03-30

    We have shown previously that chronic exposure to submicromolar concentrations of nicotine permanently inactivates alpha4beta2 and alpha7 neuronal nicotinic acetylcholine receptors while alpha3beta2 acetylcholine receptors are resistant to inactivation. Phosphorylation of the large cytoplasmic domain has been proposed to mediate functional inactivation. Chimeric subunits consisting of human alpha4 sequence from their N-terminus to either the beginning of the first transmembrane domain or the large cytoplasmic domain and alpha3 sequences thereafter formed acetylcholine receptors with beta2 subunits which were as susceptible to nicotine-induced inactivation as wild-type alpha4 acetylcholine receptors. The converse chimeras, containing the N-terminal parts of the alpha3 subunit and the C-terminal parts of the alpha4 subunit, formed acetylcholine receptors with beta2 subunits which were as resistant to nicotine-induced inactivation as wild-type alpha3beta2 acetylcholine receptors. Thus, inactivation of acetylcholine receptors produced by chronic exposure to nicotine results primarily from effects of the agonist on the extracellular and transmembrane domains of the alpha subunit.

  14. Specific Stimulated Uptake of Acetylcholine by Torpedo Electric Organ Synaptic Vesicles

    NASA Astrophysics Data System (ADS)

    Parsons, Stanley M.; Koenigsberger, Robert

    1980-10-01

    The specificity of acetylcholine uptake by synaptic vesicles isolated from the electric organ of Torpedo californica was studied. In the absence of cofactors, [3H]acetylcholine was taken up identically to [14C]choline in the same solution (passive uptake), and the equilibrium concentration achieved inside the vesicles was equal to the concentration outside. In the presence of MgATP, [3H]acetylcholine and [14C]choline in the same solution were taken up identically, except only about half as much of each was taken up (suppressed uptake). [3H]Acetylcholine uptake was stimulated by MgATP and HCO3 about 4-fold relative to suppressed uptake, for a net concentrative uptake of about 2:1 (stimulated uptake). Uptake of [14C]choline in the same solution remained at the suppressed level. [3H]Acetylcholine taken up under stimulated conditions migrated with vesicles containing [14C]mannitol on analytical glycerol density gradients during centrifugation. Vesicles were treated with nine protein modification reagents under mild conditions. Two reagents had no effect on, dithiothreitol potentiated, and six reagents strongly inhibited subsequent stimulated uptake of [3H]acetylcholine. The results indicate that uptake of acetylcholine is conditionally specific for the transported substrate, is carried out by the synaptic vesicles rather than a contaminant of the preparation, and requires a functional protein system containing a critical sulfhydryl group.

  15. Stimulation of the Nonneuronal Cholinergic System by Highly Diluted Acetylcholine in Keratinocytes.

    PubMed

    Uberti, Francesca; Bardelli, Claudio; Morsanuto, Vera; Ghirlanda, Sabrina; Cochis, Andrea; Molinari, Claudio

    2017-01-01

    The physiological effects of acetylcholine on keratinocytes depend on the presence of nicotinic and muscarinic receptors. The role of nonneuronal acetylcholine in keratinocytes could have important clinical implications for patients with various skin disorders such as nonhealing wounds. In order to evaluate the efficacy of highly diluted acetylcholine solutions obtained by sequential kinetic activation, we aimed to investigate the effects of these solutions on normal human keratinocytes. Two different concentrations (10 fg/mL and 1 pg/mL) and formulations (kinetically activated and nonkinetically activated) of acetylcholine were used to verify keratinocyte viability, proliferation, and migration and the intracellular pathways involved using MTT, crystal violet, wound healing, and Western blot compared to 147 ng/mL acetylcholine. The activated formulations (1 pg/mL and 10 fg/mL) revealed a significant capacity to increase migration, cell viability, and cell proliferation compared to 147 ng/mL acetylcholine, and these effects were more evident after a single administration. Sequential kinetic activation resulted in a statistically significant decrease in reactive oxygen species production accompanied by an increase in mitochondrial membrane potential and a decrease in oxygen consumption compared to 147 ng/mL acetylcholine. The M1 muscarinic receptor was involved in these effects. Finally, the involvement of ERK/mitogen-activated protein kinases (MAPK) and KI67 confirmed the effectiveness of the single treatment on cell proliferation. The intracellular pathways of calcium were investigated as well. Our results indicate for the first time that highly diluted and kinetically activated acetylcholine seems to play an active role in an in vitro model of wound healing. Moreover, the administration of acetylcholine within the physiological range may not only be effective but is also likely to be safe.

  16. Mef2c-F10N enhancer driven β-galactosidase (LacZ) and Cre recombinase mice facilitate analyses of gene function and lineage fate in neural crest cells

    PubMed Central

    Aoto, Kazushi; Sandell, Lisa L.; Butler Tjaden, Naomi E.; Yuen, Kobe C.; Noack Watt, Kristin E.; Black, Brian L.; Durnin, Michael; Trainor, Paul A.

    2015-01-01

    Neural crest cells (NCC) comprise a multipotent, migratory stem cell and progenitor population that gives rise to numerous cell and tissue types within a developing embryo, including craniofacial bone and cartilage, neurons and glia of the peripheral nervous system, and melanocytes within the skin. Here we describe two novel stable transgenic mouse lines suitable for lineage tracing and analysis of gene function in NCC. Firstly, using the F10N enhancer of the Mef2c gene (Mef2c-F10N) linked to LacZ, we generated transgenic mice (Mef2c-F10N-LacZ) that express LacZ in the majority, if not all migrating NCC that delaminate from the neural tube. Mef2c-F10N-LacZ then continues to be expressed primarily in neurogenic, gliogenic and melanocytic NCC and their derivatives, but not in ectomesenchymal derivatives. Secondly, we used the same Mef2c-F10N enhancer together with Cre recombinase to generate transgenic mice (Mef2c-F10N-Cre) that can be used to indelibly label, or alter gene function in, migrating NCC and their derivatives. At early stages of development, Mef2c-F10N-LacZ and Mef2c-F10N-Cre label NCC in a pattern similar to Wnt1-Cre mice, with the exception that Mef2c-F10N-LacZ and Mef2c-F10N-Cre specifically label NCC that have delaminated from the neural plate, while premigratory NCC are not labeled. Thus, our Mef2c-F10N-LacZ and Mef2c-F10N-Cre transgenic mice provide new resources for tracing migratory NCC and analyzing gene function in migrating and differentiating NCC independently of NCC formation. PMID:25794678

  17. A model of the human M2 muscarinic acetylcholine receptor

    NASA Astrophysics Data System (ADS)

    Jöhren, Kirstin; Höltje, Hans-Dieter

    2002-11-01

    The M2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M2 were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.

  18. Naturally occurring and synthetic peptides acting on nicotinic acetylcholine receptors.

    PubMed

    Kasheverov, Igor E; Utkin, Yuri N; Tsetlin, Victor I

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are pentameric membrane-bound proteins belonging to the large family of ligand-gated ion channels. nAChRs possess various binding sites which interact with compounds of different chemical nature, including peptides. Historically first peptides found to act on nAChR were synthetic fragments of snake alpha-neurotoxins, competitive receptor antagonists. Later it was shown that fragments of glycoprotein from rabies virus, having homology to alpha-neurotoxins, and polypeptide neurotoxins waglerins from the venom of Wagler's pit viper Trimeresurus (Tropidolaemus) wagleri bind in a similar way, waglerins being efficient blockers of muscle-type nAChRs. Neuropeptide substance P appears to interact with the channel moiety of nAChR. beta-Amyloid, a peptide forming senile plaques in Alzheimer's disease, also can bind to nAChR, although the mode of binding is still unclear. However, the most well-studied peptides interacting with the ligand-binding sites of nAChRs are so-called alpha-conotoxins, peptide neurotoxins from marine snails of Conus genus. First alpha-conotoxins were discovered in the late 1970s, and now it is a rapidly growing family due to isolation of peptides from multiple Conus species, as well as to cloning, and chemical synthesis of new analogues. Because of their unique selectivity towards distinct nAChR subtypes, alpha-conotoxins became valuable tools in nAChR research. Recent X-ray structures of alpha-conotoxin complexes with acetylcholine-binding protein, a model of nAChR ligand-binding domains, revealed the details of the nAChR ligand-binding sites and provided the basis for design of novel ligands.

  19. Characterization and photoaffinity labeling of the muscarinic acetylcholine receptor

    SciTech Connect

    Cremo, C.R.

    1983-01-01

    The muscarinic acetylcholine receptor, identified by tritiated L-quinuclidinyl benzilate (L-(/sup 3/H)QNB) binding, was solubilized from porcine atrial membranes using a 5:1 (w/w) ratio of digitonin and cholate. Specific binding activities of the solubilized receptor solutions usually exceeded 1.0 nmol L-(/sup 3/H)QNB sites per gram of protein, representing 75-98% total site recovery and a two- to three-fold enrichment over untreated atrial membranes. Two rapid assays for measuring the binding activities of detergent extracts were devised and compared with equilibrium dialysis. All three methods gave similar results. The equilibrium dissociation constant of the solubilized receptor for L-(/sup 3/H)QNB as determined by the three methods varied from 230 to 450 pM depending on the method and temperature. The interaction of alkyl quanidines and decahydrohistrionicotoxin with the membrane-bound and solubilized muscarinic acetylcholine receptor (mAcChR) from porcine atria was described. Alkyl guanidines with alkyl chain lengths from one to ten carbons displaced (/sup 3/H)L-quinuclidinyl bensilate ((/sup 3/H)L-QNB) competitively from a single class of sites for the membrane-bound mAcChR. From a plot of -1n K/sub i/ versus alkyl carbon chain number, a value of -(473 +/- 30) cal/mol was estimated as the energetic contribution per methylene group to the total binding energy. The synthesis and properties of a radiolabeled muscarinic antagonist photoaffinity probe, (/sup 3/H) p-azidoatropine methyl iodide were reported.

  20. Structure and dynamics of the M3 muscarinic acetylcholine receptor

    SciTech Connect

    Kruse, Andrew C.; Hu, Jianxin; Pan, Albert C.; Arlow, Daniel H.; Rosenbaum, Daniel M.; Rosemond, Erica; Green, Hillary F.; Liu, Tong; Chae, Pil Seok; Dror, Ron O.; Shaw, David E.; Weis, William I.; Wess, Jürgen; Kobilka, Brian K.

    2012-03-01

    Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G{sub q/11}-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G{sub i/o}-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.

  1. Morphine Increases Acetylcholine Release in the Trigeminal Nuclear Complex

    PubMed Central

    Zhu, Zhenghong; Bowman, Heather R.; Baghdoyan, Helen A.; Lydic, Ralph

    2008-01-01

    Study Objectives: The trigeminal nuclear complex (V) contains cholinergic neurons and includes the principal sensory trigeminal nucleus (PSTN) which receives sensory input from the face and jaw, and the trigeminal motor nucleus (MoV) which innervates the muscles of mastication. Pain associated with pathologies of V is often managed with opioids but no studies have characterized the effect of opioids on acetylcholine (ACh) release in PSTN and MoV. Opioids can increase or decrease ACh release in brainstem nuclei. Therefore, the present experiments tested the 2-tailed hypothesis that microdialysis delivery of opioids to the PSTN and MoV significantly alters ACh release. Design: Using a within-subjects design and isoflurane-anesthetized Wistar rats (n = 53), ACh release in PSTN during microdialysis with Ringer's solution (control) was compared to ACh release during dialysis delivery of the sodium channel blocker tetrodotoxin, muscarinic agonist bethanechol, opioid agonist morphine, mu opioid agonist DAMGO, antagonists for mu (naloxone) and kappa (nor-binaltorphimine; nor-BNI) opioid receptors, and GABAA antagonist bicuculline. Measurements and Results: Tetrodotoxin decreased ACh, confirming action potential-dependent ACh release. Bethanechol and morphine caused a concentration-dependent increase in PSTN ACh release. The morphine-induced increase in ACh release was blocked by nor-BNI but not by naloxone. Bicuculline delivered to the PSTN also increased ACh release. ACh release in the MoV was increased by morphine, and this increase was not blocked by naloxone or nor-BNI. Conclusions: These data comprise the first direct measures of ACh release in PSTN and MoV and suggest synaptic disinhibition as one possible mechanism by which morphine increases ACh release in the trigeminal nuclei. Citation: Zhu Z; Bowman HR; Baghdoyan HA; Lydic R. Morphine increases acetylcholine release in the trigeminal nuclear complex. SLEEP 2008;31(12):1629–1637. PMID:19090318

  2. Physiological characterization of human muscle acetylcholine receptors from ALS patients

    PubMed Central

    Palma, Eleonora; Inghilleri, Maurizio; Conti, Luca; Deflorio, Cristina; Frasca, Vittorio; Manteca, Alessia; Pichiorri, Floriana; Roseti, Cristina; Torchia, Gregorio; Limatola, Cristina; Grassi, Francesca; Miledi, Ricardo

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons leading to muscle paralysis. Research in transgenic mice suggests that the muscle actively contributes to the disease onset, but such studies are difficult to pursue in humans and in vitro models would represent a good starting point. In this work we show that tiny amounts of muscle from ALS or from control denervated muscle, obtained by needle biopsy, are amenable to functional characterization by two different technical approaches: “microtransplantation” of muscle membranes into Xenopus oocytes and culture of myogenic satellite cells. Acetylcholine (ACh)-evoked currents and unitary events were characterized in oocytes and multinucleated myotubes. We found that ALS acetylcholine receptors (AChRs) retain their native physiological characteristics, being activated by ACh and nicotine and blocked by α-bungarotoxin (α-BuTX), d-tubocurarine (dTC), and galantamine. The reversal potential of ACh-evoked currents and the unitary channel behavior were also typical of normal muscle AChRs. Interestingly, in oocytes injected with muscle membranes derived from ALS patients, the AChRs showed a significant decrease in ACh affinity, compared with denervated controls. Finally, riluzole, the only drug currently used against ALS, reduced, in a dose-dependent manner, the ACh-evoked currents, indicating that its action remains to be fully characterized. The two methods described here will be important tools for elucidating the role of muscle in ALS pathogenesis and for developing drugs to counter the effects of this disease. PMID:22128328

  3. Acetylcholine receptors at neuromuscular synapses: phylogenetic differences detected by snake alpha-neurotoxins.

    PubMed Central

    Burden, S J; Hartzell, H C; Yoshikami, D

    1975-01-01

    Phylogenetic differences in acetylcholine receptors from skeletal neuromuscular synapses of various species of snakes and lizards have been investigated, using the snake venom alpha-neurotoxins alpha-atratoxin (cobrotoxin) and alpha-bungarotoxin. The acetylcholine receptors of the phylogenetically primitive lizards, like those from all other vertebrates previously tested, are blocked by these alpha-neurotoxins. In contrast, receptors from snakes and advanced lizards are insensitive to one or both of the toxins. It is suggested that toxin-resistant acetylcholine receptors appeared early in the evolution of Squamata and preceded the appearance of alpha-neurotoxins. Images PMID:1081230

  4. Immunological relationship between acetylcholine receptor and thymus: a possible significance in myasthenia gravis.

    PubMed Central

    Aharonov, A; Tarrab-Hazdai, R; Abramsky, O; Fuchs, S

    1975-01-01

    A defined immunological cross-reaction was observed between acetylcholine receptor fraction from the electric eel, Electrophorus electricus, and two calf thymus fractions. The cross-reaction was demonstrated on the cellular level by means of the lymphocyte transformation technique, and on the humoral level, by means of the microcomplement fixation assay. In the human disease myasthenia gravis both acetylcholine receptor at the neuromuscular junction and the thymus are affected, probably by an autoimmune mechanism. The immunological cross-reaction between acetylcholine receptor and thymic components may explain the association between endplate and thymus disorders in myasthenia gravis. PMID:1055418

  5. Base-catalyzed and cholinesterase-catalyzed hydrolysis of acetylcholine and optically active analogs.

    PubMed

    Schowen, K B; Smissman, E E; Stephen, W F

    1975-03-01

    The base- and cholinestrase-catalyzed hydrolyses of the following optically active analogs of acetylcholine were studied: 3 (a)-trimethylammonium-2(a)-acetoxy-trans-decalin iodide, threo- and erythro-alpha, beta-dimethylacetylcholine iodide, alpha-methylacetylcholine, and beta-methylacetylcholine. Evidence that the optimum dihedral +N-C-C-O angle in the transition state for acetylcholinesterase hydrolysis of acetylcholine analogs is positive and anticlinal is given. The data obtained suggest that acetylcholine undergoes a geometrically flexible mode of attachment to the enzyme.

  6. Synergistic effect of choline and carnitine on acetylcholine synthesis in neuroblastoma NB-2a cells.

    PubMed

    Wawrzeńczyk, A; Nałecz, K A; Nałecz, M J

    1994-07-15

    An influence of carnitine on acetylcholine synthesis from radiolabeled glucose was monitored in neuroblastoma NB-2a cells. Upon addition of carnitine the distribution of its derivatives was found significantly different than the values published for brain, the level of long-chain acyl derivatives being much higher and reaching 60%. Carnitine itself did not change acetylcholine level. Together with choline (20 microM), carnitine was observed to stimulate (by 36%) acetylcholine synthesis in a synergistic way, which indicated that both substrates could be limiting factors of this process in NB-2a cell line of neuroblastoma.

  7. Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion*

    PubMed Central

    Ziegler, Amber N.; Chidambaram, Shravanthi; Forbes, Briony E.; Wood, Teresa L.; Levison, Steven W.

    2014-01-01

    The objective of this study was to employ genetically engineered IGF-II analogs to establish which receptor(s) mediate the stemness promoting actions of IGF-II on mouse subventricular zone neural precursors. Neural precursors from the subventricular zone were propagated in vitro in culture medium supplemented with IGF-II analogs. Cell growth and identity were analyzed using sphere generation and further analyzed by flow cytometry. F19A, an analog of IGF-II that does not bind the IGF-2R, stimulated an increase in the proportion of neural stem cells (NSCs) while decreasing the proportion of the later stage progenitors at a lower concentration than IGF-II. V43M, which binds to the IGF-2R with high affinity but which has low binding affinity to the IGF-1R and to the A isoform of the insulin receptor (IR-A) failed to promote NSC growth. The positive effects of F19A on NSC growth were unaltered by the addition of a functional blocking antibody to the IGF-1R. Altogether, these data lead to the conclusion that IGF-II promotes stemness of NSCs via the IR-A and not through activation of either the IGF-1R or the IGF-2R. PMID:24398690

  8. Substituted 2-Aminopyrimidines Selective for α7-Nicotinic Acetylcholine Receptor Activation and Association with Acetylcholine Binding Proteins.

    PubMed

    Kaczanowska, Katarzyna; Camacho Hernandez, Gisela Andrea; Bendiks, Larissa; Kohs, Larissa; Cornejo-Bravo, Jose Manuel; Harel, Michal; Finn, M G; Taylor, Palmer

    2017-03-15

    Through studies with ligand binding to the acetylcholine binding protein (AChBP), we previously identified a series of 4,6-substituted 2-aminopyrimidines that associate with this soluble surrogate of the nicotinic acetylcholine receptor (nAChR) in a cooperative fashion, not seen for classical nicotinic agonists and antagonists. To examine receptor interactions of this structural family on ligand-gated ion channels, we employed HEK cells transfected with cDNAs encoding three requisite receptor subtypes: α7-nAChR, α4β2-nAChR, and a serotonin receptor (5-HT3AR), along with a fluorescent reporter. Initial screening of a series of over 50 newly characterized 2-aminopyrimidines with affinity for AChBP showed only two to be agonists on the α7-nAChR below 10 μM concentration. Their unique structural features were incorporated into design of a second subset of 2-aminopyrimidines yielding several congeners that elicited α7 activation with EC50 values of 70 nM and Kd values for AChBP in a similar range. Several compounds within this series exhibit specificity for the α7-nAChR, showing no activation or antagonism of α4β2-nAChR or 5-HT3AR at concentrations up to 10 μM, while others were weaker antagonists (or partial agonists) on these receptors. Analysis following cocrystallization of four ligand complexes with AChBP show binding at the subunit interface, but with an orientation or binding pose that differs from classical nicotinic agonists and antagonists and from the previously analyzed set of 2-aminopyrimidines that displayed distinct cooperative interactions with AChBP. Orientations of aromatic side chains of these complexes are distinctive, suggesting new modes of binding at the agonist-antagonist site and perhaps an allosteric action for heteromeric nAChRs.

  9. Differential Effects of Quercetin and Quercetin Glycosides on Human α7 Nicotinic Acetylcholine Receptor-Mediated Ion Currents

    PubMed Central

    Lee, Byung-Hwan; Choi, Sun-Hye; Kim, Hyeon-Joong; Jung, Seok-Won; Hwang, Sung-Hee; Pyo, Mi-Kyung; Rhim, Hyewhon; Kim, Hyoung-Chun; Kim, Ho-Kyoung; Lee, Sang-Mok; Nah, Seung-Yeol

    2016-01-01

    Quercetin is a flavonoid usually found in fruits and vegetables. Aside from its antioxidative effects, quercetin, like other flavonoids, has a various neuropharmacological actions. Quercetin-3-O-rhamnoside (Rham1), quercetin-3-O-rutinoside (Rutin), and quercetin-3-(2(G)-rhamnosylrutinoside (Rham2) are mono-, di-, and tri-glycosylated forms of quercetin, respectively. In a previous study, we showed that quercetin can enhance α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated ion currents. However, the role of the carbohydrates attached to quercetin in the regulation of α7 nAChR channel activity has not been determined. In the present study, we investigated the effects of quercetin glycosides on the acetylcholine induced peak inward current (IACh) in Xenopus oocytes expressing the α7 nAChR. IACh was measured with a two-electrode voltage clamp technique. In oocytes injected with α7 nAChR copy RNA, quercetin enhanced IACh, whereas quercetin glycosides inhibited IACh. Quercetin glycosides mediated an inhibition of IACh, which increased when they were pre-applied and the inhibitory effects were concentration dependent. The order of IACh inhibition by quercetin glycosides was Rutin≥Rham1>Rham2. Quercetin glycosides-mediated IACh enhancement was not affected by ACh concentration and appeared voltage-independent. Furthermore, quercetin-mediated IACh inhibition can be attenuated when quercetin is co-applied with Rham1 and Rutin, indicating that quercetin glycosides could interfere with quercetin-mediated α7 nAChR regulation and that the number of carbohydrates in the quercetin glycoside plays a key role in the interruption of quercetin action. These results show that quercetin and quercetin glycosides regulate the α7 nAChR in a differential manner. PMID:27098860

  10. Neural network technologies

    NASA Technical Reports Server (NTRS)

    Villarreal, James A.

    1991-01-01

    A whole new arena of computer technologies is now beginning to form. Still in its infancy, neural network technology is a biologically inspired methodology which draws on nature's own cognitive processes. The Software Technology Branch has provided a software tool, Neural Execution and Training System (NETS), to industry, government, and academia to facilitate and expedite the use of this technology. NETS is written in the C programming language and can be executed on a variety of machines. Once a network has been debugged, NETS can produce a C source code which implements the network. This code can then be incorporated into other software systems. Described here are various software projects currently under development with NETS and the anticipated future enhancements to NETS and the technology.

  11. Rabies virus interaction with various cell lines is independent of the acetylcholine receptor.

    PubMed

    Reagan, K J; Wunner, W H

    1985-01-01

    Rabies virus infects most cells in vitro. The presence of the nicotinic acetylcholine receptor on the plasma membrane of various cell lines is not an obligate factor for rabies virus susceptibility of those cells.

  12. Cyclic nucleotides of canine antral smooth muscle. Effects of acetylcholine, catecholamines and gastrin.

    PubMed

    Baur, S; Grant, B; Wooton, J

    1981-01-07

    1. The effects of acetylcholine, catecholamines and gastrin on the intracellular content of cyclic AMP and cyclic GMP in antral circular muscle have been determined. 2. Acetylcholine results in a significant but transient increase in intracellular cyclic GMP. 3. Isoproterenol and norepinephrine increase intracellular cyclic AMP. Based on half-maximal effective doses, isoproterenol is 2.7-times more effective than norepinephrine. The increase in intracellular cyclic AMP by both agents is inhibited by propranolol but not phentolamine, indicating that both agents act on the muscle cell by a beta-receptor-coupled mechanism. 4. Gastrin has no demonstrable effect on either cyclic AMP or cyclic GMP. This suggests that while gastrin and acetylcholine can produce a like myoelectric response in the muscle cell, the action of gastrin is mediated by a separate receptor, presumably on the muscle cell, and not by a release of acetylcholine.

  13. Nonenzymatic all-solid-state coated wire electrode for acetylcholine determination in vitro.

    PubMed

    He, Cheng; Wang, Zhan; Wang, You; Hu, Ruifen; Li, Guang

    2016-11-15

    A nonenzymatic all-solid-state coated wire acetylcholine electrode was investigated. Poly(3,4-ethylenedioxythiophene) doped with poly(styrenesulfonate) (PEDOT/PSS) as conducting polymer was coated on one end of a gold wire (0.5mm in diameter). The acetylcholine selective membrane containing heptakis(2,3,6-tri-Ο-methyl)-β-cyclodextrin as an ionophore covered the conducting polymer layer. The electrode could work stably in a pH range of 6.5-8.5 and a temperature range of 15-40°C. It covered an acetylcholine concentration range of 10(-5)-10(-1)M with a slope of 54.04±1.70mV/decade, while detection limit was 5.69±1.06µM. The selectivity, dynamic response, reproducibility and stability were evaluated. The electrode could work properly in the rat brain homogenate to detect different concentrations of acetylcholine.

  14. Notexin preferentially inhibits the release of newly synthesized acetylcholine from rat brain synaptosomal fractions

    SciTech Connect

    Gundersen, C.B.; Jenden, D.J.

    1981-01-01

    An investigation was made of the effects of the snake venom neurotoxin, notexin, on acetylcholine turnover in rat brain P2 fractions using a gas chromatographic mass spectrometric assay for acetylcholine and choline. In contrast to earlier reports, we found a stimulation of the uptake and acetylation of labeled choline by toxin-treated P2 fractions. More significantly, notexin inhibited the release of this newly synthesized transmitter. These effects were found to be dependent on the dose of the toxin and the time of exposure of the P2 fraction to notexin. Longer exposure to notexin or experiments involving resuspension of notexin-treated P2 fractions appeared to result in considerable lysis of the transmitter-containing particles. Thus, notexin may alter acetylcholine compartmentation in the nerve ending and thereby affect acetylcholine synthesis.

  15. Microtransplantation of acetylcholine receptors from normal or denervated rat skeletal muscles to frog oocytes

    PubMed Central

    Bernareggi, Annalisa; Reyes-Ruiz, Jorge Mauricio; Lorenzon, Paola; Ruzzier, Fabio; Miledi, Ricardo

    2011-01-01

    Cell membranes, carrying neurotransmitter receptors and ion channels, can be ‘microtransplanted’ into frog oocytes. This technique allows a direct functional characterization of the original membrane proteins, together with any associated molecules they may have, still embedded in their natural lipid environment. This approach has been previously demonstrated to be very useful to study neurotransmitter receptors and ion channels contained in cell membranes isolated from human brains. Here, we examined the possibility of using the microtransplantation method to study acetylcholine receptors from normal and denervated rat skeletal muscles. We found that the muscle membranes, carrying their fetal or adult acetylcholine receptor isoforms, could be efficiently microtransplanted to the oocyte membrane, making the oocytes become sensitive to acetylcholine. These results show that oocytes injected with skeletal muscle membranes efficiently incorporate functional acetylcholine receptors, thus making the microtransplantation approach a valuable tool to further investigate receptors and ion channels of human muscle diseases. PMID:21224230

  16. Role of calcium in the regulation of acetylcholine receptor synthese in cultured muscle cells*.

    PubMed

    Birnbaum, M; Reis, M A; Shainberg, A

    1980-05-01

    Embroyonic muscles differentiated in vitro were used to study the effects of intracellular Ca2+ ([Ca2+1]i) variations on the amount of acetylcholine receptors ([AChR]) in the cell membrane. 2. Increased Ca2+ concentration in the growth medium ([Ca2+]o) caused a marked elevation of AChR levels, apparently through de novo synthesis. 3. Agents known to increase [Ca2+]i and its accumulation in the sarcoplasmic reticulum (SR), such as ionophore A23187, sodium dantrolene (DaNa), or high [Mg2+]o all enhanced alpha-bungarotoxin (alpha-BGT) binding after 48 h of treatment. 4. Electrical stimulation or caffeine, both affectors of SR calcium release, brought about a decrease in [AChR] probably by suppressing its synthesis. 5. The effects of simultaneous treatment with two AChR-inducing agents, namely, high [Ca2+]o in the presence of tetrodotoxin (TTX) or high [Mg2+]o were not additive, thus suggesting action via a common saturable mediator. 6. Intermediate AChR levels obtained following simultaneous treatments with opposing effects, e.g., electrical stimulation in the presence of high [Ca2+]o or DaNa, suggest contradictory actions on a common mediator. 7. All these observations indicate a strong correlation between SR calcium levels and [AChR] on myotubes; while calcium accumulation in the Sr was followed by increased AChR synthesis, calcium release was accompanied by suppression of receptor synthesis.

  17. Dopamine modulates carotid nerve responses induced by acetylcholine on the cat petrosal ganglion in vitro.

    PubMed

    Alcayaga, J; Varas, R; Arroyo, J; Iturriaga, R; Zapata, P

    1999-06-12

    We have recently reported that application of acetylcholine (ACh) or nicotine to the petrosal ganglion-the sensory ganglion of the glossopharyngeal nerve-elicits a burst of discharges in the carotid nerve branch, innervating the carotid body and sinus, but not in the glossopharyngeal branch, innervating the tongue and pharynx. Thus, the perikarya of sensory neurons for the carotid bifurcation exhibit selective cholinosensitivity. Since dopamine (DA) modulates carotid nerve chemosensory activity, we searched for the presence of DA sensitivity at the perikarya of these neurons in the cat petrosal ganglion superfused in vitro. Applications of DA in doses of up to 5 mg to the ganglion did not modify the rate of spontaneous discharges in the carotid nerve. However, if DA was applied 30 s before ACh injections, ACh-evoked reactions were modified: low doses of DA enhanced the subsequent responses to ACh, while high doses of DA depressed the responses to ACh. This depressant effect of DA on ACh responses was partially antagonized by adding spiroperone to the superfusate. Our results show that the response to ACh of petrosal ganglion neurons projecting through the carotid nerve is modulated by DA acting on D(2) receptors located in the somata of these neurons. Thus, dopaminergic modulation of cholinosensitivity could be shared also by the membranes of peripheral endings and perikarya of primary sensory neurons involved in arterial chemoreception.

  18. Modelling and simulation of ion channels: applications to the nicotinic acetylcholine receptor.

    PubMed

    Sansom, M S; Adcock, C; Smith, G R

    1998-01-01

    Molecular dynamics simulations with experimentally derived restraints have been used to develop atomic models of M2 helix bundles forming the pore-lining domains of the nicotinic acetylcholine receptor and related ligand-gated ion channels. M2 helix bundles have been used in microscopic simulations of the dynamics and energetics of water and ions within an ion channel. Translational and rotational motion of water are restricted within the pore, and water dipoles are aligned relative to the pore axis by the surrounding helix dipoles. Potential energy profiles for translation of a Na+ ion along the pore suggest that the protein and water components of the interaction energy exert an opposing effect on the ion, resulting in a relatively flat profile which favors cation permeation. Empirical conductance calculations based on a pore radius profile suggest that the M2 helix model is consistent with a single channel conductance of ca. 50 pS. Continuum electrostatics calculations indicate that a ring of glutamate residues at the cytoplasmic mouth of the alpha 7 nicotinic receptor M2 helix bundle may not be fully ionized. A simplified model of the remainder of the channel protein when added to the M2 helix bundle plays a significant role in enhancing the ion selectivity of the channel.

  19. Antigenic role of single residues within the main immunogenic region of the nicotinic acetylcholine receptor.

    PubMed Central

    Papadouli, I; Potamianos, S; Hadjidakis, I; Bairaktari, E; Tsikaris, V; Sakarellos, C; Cung, M T; Marraud, M; Tzartos, S J

    1990-01-01

    The target of most of the autoantibodies against the acetylcholine receptor (AChR) in myasthenic sera is the main immunogenic region (MIR) on the extracellular side of the AChR alpha-subunit. Binding of anti-MIR monoclonal antibodies (mAbs) has been recently localized between residues alpha 67 and alpha 76 of Torpedo californica electric organ (WNPADYGGIK) and human muscle (WNPDDYGGVK) AChR. In order to evaluate the contribution of each residue to the antigenicity of the MIR, we synthesized peptides corresponding to residues alpha 67-76 from Torpedo and human AChRs, together with 13 peptide analogues. Nine of these analogues had one residue of the Torpedo decapeptide replaced by L-alanine, three had a structure which was intermediate between those of the Torpedo and human alpha 67-76 decapeptides, and one had D-alanine in position 73. Binding studies employing six anti-MIR mAbs and all 15 peptides revealed that some residues (Asn68 and Asp71) are indispensable for binding by all mAbs tested, whereas others are important only for binding by some mAbs. Antibody binding was mainly restricted to residues alpha 68-74, the most critical sequence being alpha 68-71. Fish electric organ and human MIR form two distinct groups of strongly overlapping epitopes. Some peptide analogues enhanced mAb binding compared with Torpedo and human peptides, suggesting that the construction of a very antigenic MIR is feasible. PMID:1695844

  20. BDNF up-regulates alpha7 nicotinic acetylcholine receptor levels on subpopulations of hippocampal interneurons.

    PubMed

    Massey, Kerri A; Zago, Wagner M; Berg, Darwin K

    2006-12-01

    In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing alpha7 subunits (alpha7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of alpha7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the effect. Blocking transmission through NMDA receptors with APV blocked the BDNF effect; increasing spontaneous excitatory activity with the GABA(A) receptor antagonist bicuculline replicated the BDNF effect. BDNF antibodies blocked the BDNF-mediated increase but not the bicuculline one, consistent with enhanced glutamatergic activity acting downstream from BDNF. Increased alpha7-nAChR clusters were most prominent on interneuron subtypes known to directly innervate excitatory neurons. The results suggest that BDNF, acting through glutamatergic transmission, can modulate hippocampal output in part by controlling alpha7-nAChR levels.

  1. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis†

    PubMed Central

    Leite, Maria Isabel; Jacob, Saiju; Viegas, Stuart; Cossins, Judy; Clover, Linda; Morgan, B. Paul; Beeson, David; Willcox, Nick

    2008-01-01

    Only around 80% of patients with generalized myasthenia gravis (MG) have serum antibodies to acetylcholine receptor [AChR; acetylcholine receptor antibody positive myasthenia gravis (AChR-MG)] by the radioimmunoprecipitation assay used worldwide. Antibodies to muscle specific kinase [MuSK; MuSK antibody positive myasthenia gravis (MuSK-MG)] make up a variable proportion of the remaining 20%. The patients with neither AChR nor MuSK antibodies are often called seronegative (seronegative MG, SNMG). There is accumulating evidence that SNMG patients are similar to AChR-MG in clinical features and thymic pathology. We hypothesized that SNMG patients have low-affinity antibodies to AChR that cannot be detected in solution phase assays, but would be detected by binding to the AChRs on the cell membrane, particularly if they were clustered at the high density that is found at the neuromuscular junction. We expressed recombinant AChR subunits with the clustering protein, rapsyn, in human embryonic kidney cells and tested for binding of antibodies by immunofluorescence. To identify AChRs, we tagged either AChR or rapsyn with enhanced green fluorescence protein, and visualized human antibodies with Alexa Fluor-labelled secondary or tertiary antibodies, or by fluorescence-activated cell sorter (FACS). We correlated the results with the thymic pathology where available. We detected AChR antibodies to rapsyn-clustered AChR in 66% (25/38) of sera previously negative for binding to AChR in solution and confirmed the results with FACS. The antibodies were mainly IgG1 subclass and showed ability to activate complement. In addition, there was a correlation between serum binding to clustered AChR and complement deposition on myoid cells in patients’ thymus tissue. A similar approach was used to demonstrate that MuSK antibodies, although mainly IgG4, were partially IgG1 subclass and capable of activating complement when bound to MuSK on the cell surface. These observations throw new

  2. A role for acetylcholine receptors in the fusion of chick myoblasts

    PubMed Central

    1988-01-01

    The role of acetylcholine receptors in the control of chick myoblast fusion in culture has been explored. Spontaneous fusion of myoblasts was inhibited by the nicotinic acetylcholine receptor antagonists alpha- bungarotoxin, Naja naja toxin and monoclonal antibody mcAb 5.5. The muscarinic antagonists QNB and n-methyl scopolamine were without effect. Atropine had no effect below 1 microM, where it blocks muscarinic receptors; at higher concentrations, when it blocks nicotinic receptors also, atropine inhibited myoblast fusion. The inhibitions imposed by acetylcholine receptor antagonists lasted for approximately 12 h; fusion stimulated by other endogenous substances then took over. The inhibition was limited to myoblast fusion. The increases in cell number, DNA content, the level of creatine phosphokinase activity (both total and muscle-specific isozyme) and the appearance of heavy chain myosin, which accompany muscle differentiation, followed a normal time course. Pre-fusion myoblasts, fusing myoblasts, and young myotubes specifically bound labeled alpha- bungarotoxin, indicating the presence of acetylcholine receptors. The nicotinic acetylcholine receptor agonist, carbachol, induced uptake of [14C]Guanidinium through the acetylcholine receptor. Myoblasts, aligned myoblasts and young myotubes expressed the synthetic enzyme Choline acetyltransferase and stained positively with antibodies against acetylcholine. The appearance of ChAT activity in myogenic cultures was prevented by treatment with BUDR; nonmyogenic cells in the cultures expressed ChAT at a level which was too low to account for the activity in myogenic cultures. We conclude that activation of the nicotinic acetylcholine receptor is part of the mechanism controlling spontaneous myoblast fusion and that myoblasts synthesize an endogenous, fusion- inducing agent that activates the nicotinic ACh receptor. PMID:3372592

  3. Role of dopamine receptor and muscarinic acetylcholine receptor blockade in the antiapomorphine action of neuroleptics

    SciTech Connect

    Zharkovskii, A.M.; Langel, Yu.L.; Chereshka, K.S.; Zharkovskaya, T.A.

    1987-08-01

    The authors analyze the role of dopamine and muscarinic acetylcholine receptor blocking components in the antistereotypic action of neuroleptics with different chemical structure. To determine dopamine-blocking activity in vitro, binding of /sup 3/H-spiperone with membranes of the rat striatum was measured. To study the blocking action of the substances on muscarinic acetylcholine receptors, binding of /sup 3/H-quinuclidinyl benzylate with brain membranes was chosen.

  4. Acetylcholine test in patients with angina pectoris and normal coronary angiography

    NASA Astrophysics Data System (ADS)

    Barbieri, Enrico; Destro, Gianni; Oliva, Massimo; Zardini, Piero

    1994-02-01

    Angina pectoris with normal coronary artery on the coronary angiography is an intriguing issue. Intracoronary infusion of acetylcholine has recently been used to test the integrity of endothelial cells. We studied 16 patients with this syndrome. A relationship has been found between the acetylcholine test and the exercise stress test in normotensive patients. The presence of hypertension makes the evaluation of the test more unpredictable, probably because of the damage on the endothelial cells related to systemic hypertension.

  5. Neural repair in the adult brain

    PubMed Central

    Jessberger, Sebastian

    2016-01-01

    Acute or chronic injury to the adult brain often results in substantial loss of neural tissue and subsequent permanent functional impairment. Over the last two decades, a number of approaches have been developed to harness the regenerative potential of neural stem cells and the existing fate plasticity of neural cells in the nervous system to prevent tissue loss or to enhance structural and functional regeneration upon injury. Here, we review recent advances of stem cell-associated neural repair in the adult brain, discuss current challenges and limitations, and suggest potential directions to foster the translation of experimental stem cell therapies into the clinic. PMID:26918167

  6. Electronic neural networks for global optimization

    NASA Technical Reports Server (NTRS)

    Thakoor, A. P.; Moopenn, A. W.; Eberhardt, S.

    1990-01-01

    An electronic neural network with feedback architecture, implemented in analog custom VLSI is described. Its application to problems of global optimization for dynamic assignment is discussed. The convergence properties of the neural network hardware are compared with computer simulation results. The neural network's ability to provide optimal or near optimal solutions within only a few neuron time constants, a speed enhancement of several orders of magnitude over conventional search methods, is demonstrated. The effect of noise on the circuit dynamics and the convergence behavior of the neural network hardware is also examined.

  7. The neural basis of non-verbal communication-enhanced processing of perceived give-me gestures in 9-month-old girls.

    PubMed

    Bakker, Marta; Kaduk, Katharina; Elsner, Claudia; Juvrud, Joshua; Gustaf Gredebäck

    2015-01-01

    This study investigated the neural basis of non-verbal communication. Event-related potentials were recorded while 29 nine-month-old infants were presented with a give-me gesture (experimental condition) and the same hand shape but rotated 90°, resulting in a non-communicative hand configuration (control condition). We found different responses in amplitude between the two conditions, captured in the P400 ERP component. Moreover, the size of this effect was modulated by participants' sex, with girls generally demonstrating a larger relative difference between the two conditions than boys.

  8. Neural Network Function Classifier

    DTIC Science & Technology

    2003-02-07

    neural network sets. Each of the neural networks in a particular set is trained to recognize a particular data set type. The best function representation of the data set is determined from the neural network output. The system comprises sets of trained neural networks having neural networks trained to identify different types of data. The number of neural networks within each neural network set will depend on the number of function types that are represented. The system further comprises

  9. Subpopulations of rat dorsal root ganglion neurons express active vesicular acetylcholine transporter.

    PubMed

    Tata, Ada Maria; De Stefano, M Egle; Tomassy, Giulio Srubek; Vilaró, M Teresa; Levey, Allan I; Biagioni, Stefano

    2004-01-15

    The vesicular acetylcholine transporter (VAChT) is a transmembrane protein required, in cholinergic neurons, for selective storage of acetylcholine into synaptic vesicles. Although dorsal root ganglion (DRG) neurons utilize neuropeptides and amino acids for neurotransmission, we have previously demonstrated the presence of a cholinergic system. To investigate whether, in sensory neurons, the vesicular accumulation of acetylcholine relies on the same mechanisms active in classical cholinergic neurons, we investigated VAChT presence, subcellular distribution, and activity. RT-PCR and Western blot analysis demonstrated the presence of VAChT mRNA and protein product in DRG neurons and in the striatum and cortex, used as positive controls. Moreover, in situ hybridization and immunocytochemistry showed VAChT staining located mainly in the medium/large-sized subpopulation of the sensory neurons. A few small neurons were also faintly labeled by immunocytochemistry. In the electron microscope, immunolabeling was associated with vesicle-like elements distributed in the neuronal cytoplasm and in both myelinated and unmyelinated intraganglionic nerve fibers. Finally, [(3)H]acetylcholine active transport, evaluated either in the presence or in the absence of ATP, also demonstrated that, as previously reported, the uptake of acetylcholine by VAChT is ATP dependent. This study suggests that DRG neurons not only are able to synthesize and degrade ACh and to convey cholinergic stimuli but also are capable of accumulating and, possibly, releasing acetylcholine by the same mechanism used by the better known cholinergic neurons.

  10. Detection of basal and potassium-evoked acetylcholine release from embryonic DRG explants.

    PubMed

    Bernardini, Nadia; Tomassy, Giulio Srubek; Tata, Ada Maria; Augusti-Tocco, Gabriella; Biagioni, Stefano

    2004-03-01

    Spontaneous and potassium-induced acetylcholine release from embryonic (E12 and E18) chick dorsal root ganglia explants at 3 and 7 days in culture was investigated using a chemiluminescent procedure. A basal release ranging from 2.4 to 13.8 pm/ganglion/5 min was detected. Potassium application always induced a significant increase over the basal release. The acetylcholine levels measured in E12 explants were 6.3 and 38.4 pm/ganglion/5 min at 3 and 7 days in culture, respectively, while in E18 explant cultures they were 10.7 and 15.5 pm/ganglion/5 min. In experiments performed in the absence of extracellular Ca2+ ions, acetylcholine release, both basal and potassium-induced, was abolished and it was reduced by cholinergic antagonists. A morphometric analysis of explant fibre length suggested that acetylcholine release was directly correlated to neurite extension. Moreover, treatment of E12 dorsal root ganglion-dissociated cell cultures with carbachol as cholinergic receptor agonist was shown to induce a higher neurite outgrowth compared with untreated cultures. The concomitant treatment with carbachol and the antagonists at muscarinic receptors atropine and at nicotinic receptors mecamylamine counteracted the increase in fibre outgrowth. Although the present data have not established whether acetylcholine is released by neurones or glial cells, these observations provide the first evidence of a regulated release of acetylcholine in dorsal root ganglia.

  11. Subunit profiling and functional characteristics of acetylcholine receptors in GT1-7 cells.

    PubMed

    Arai, Yuki; Ishii, Hirotaka; Kobayashi, Makito; Ozawa, Hitoshi

    2017-03-01

    GnRH neurons form a final common pathway for the central regulation of reproduction. Although the involvement of acetylcholine in GnRH secretion has been reported, direct effects of acetylcholine and expression profiles of acetylcholine receptors (AChRs) still remain to be studied. Using immortalized GnRH neurons (GT1-7 cells), we analyzed molecular expression and functionality of AChRs. Expression of the mRNAs were identified in the order α7 > β2 = β1 ≧ α4 ≧ α5 = β4 = δ > α3 for nicotinic acetylcholine receptor (nAChR) subunits and m4 > m2 for muscarinic acetylcholine receptor (mAChR) subtypes. Furthermore, this study revealed that α7 nAChRs contributed to Ca(2+) influx and GnRH release and that m2 and m4 mAChRs inhibited forskolin-induced cAMP production and isobutylmethylxanthine-induced GnRH secretion. These findings demonstrate the molecular profiles of AChRs, which directly contribute to GnRH secretion in GT1-7 cells, and provide one possible regulatory action of acetylcholine in GnRH neurons.

  12. High-affinity binding of (/sup 3/H)acetylcholine to muscarinic cholinergic receptors

    SciTech Connect

    Kellar, K.J.; Martino, A.M.; Hall, D.P. Jr.; Schwartz, R.D.; Taylor, R.L.

    1985-06-01

    High-affinity binding of (/sup 3/H)acetylcholine to muscarinic cholinergic sites in rat CNS and peripheral tissues was measured in the presence of cytisin, which occupies nicotinic cholinergic receptors. The muscarinic sites were characterized with regard to binding kinetics, pharmacology, anatomical distribution, and regulation by guanyl nucleotides. These binding sites have characteristics of high-affinity muscarinic cholinergic receptors with a Kd of approximately 30 nM. Most of the muscarinic agonist and antagonist drugs tested have high affinity for the (/sup 3/H)acetylcholine binding site, but pirenzepine, an antagonist which is selective for M-1 receptors, has relatively low affinity. The ratio of high-affinity (/sup 3/H)acetylcholine binding sites to total muscarinic binding sites labeled by (/sup 3/H)quinuclidinyl benzilate varies from 9 to 90% in different tissues, with the highest ratios in the pons, medulla, and heart atrium. In the presence of guanyl nucleotides, (/sup 3/H) acetylcholine binding is decreased, but the extent of decrease varies from 40 to 90% in different tissues, with the largest decreases being found in the pons, medulla, cerebellum, and heart atrium. The results indicate that (/sup 3/H)acetylcholine binds to high-affinity M-1 and M-2 muscarinic receptors, and they suggest that most M-2 sites have high affinity for acetylcholine but that only a small fraction of M-1 sites have such high affinity.

  13. Neural Networks

    NASA Astrophysics Data System (ADS)

    Schwindling, Jerome

    2010-04-01

    This course presents an overview of the concepts of the neural networks and their aplication in the framework of High energy physics analyses. After a brief introduction on the concept of neural networks, the concept is explained in the frame of neuro-biology, introducing the concept of multi-layer perceptron, learning and their use as data classifer. The concept is then presented in a second part using in more details the mathematical approach focussing on typical use cases faced in particle physics. Finally, the last part presents the best way to use such statistical tools in view of event classifers, putting the emphasis on the setup of the multi-layer perceptron. The full article (15 p.) corresponding to this lecture is written in french and is provided in the proceedings of the book SOS 2008.

  14. Mutational analysis of muscle nicotinic acetylcholine receptor subunit assembly

    PubMed Central

    1990-01-01

    The structural elements required for normal maturation and assembly of the nicotinic acetylcholine receptor alpha subunit were investigated by expression of mutated subunits in transfected fibroblasts. Normally, the wild-type alpha subunit acquires high affinity alpha bungarotoxin binding in a time-dependent manner; however, mutation of the 128 and/or 142 cysteines to either serine or alanine, as well as deletion of the entire 14 amino acids in this region abolished all detectable high affinity binding. Nonglycosylated subunits that had a serine to glycine mutation in the consensus sequence also did not efficiently attain high affinity binding to toxin. In contrast, mutation of the proline at position 136 to glycine or alanine, or a double mutation of the cysteines at position 192 and 193 to serines had no effect on the acquisition of high affinity toxin binding. These data suggest that a disulfide bridge between cysteines 128 and 142 and oligosaccharide addition at asparagine 141 are required for the normal maturation of alpha subunit as assayed by high affinity toxin binding. The unassembled wild-type alpha subunit expressed in fibroblasts is normally degraded with a t1/2 of 2 h; upon assembly with the delta subunit, the degradation rate slows significantly (t1/2 greater than 13 h). All mutated alpha subunits retained the capacity to assemble with a delta subunit coexpressed in fibroblasts; however, mutated alpha subunits that were not glycosylated or did not acquire high affinity toxin binding were rapidly degraded (t1/2 = 20 min to 2 h) regardless of whether or not they assembled with the delta subunit. Assembly and rapid degradation of nonglycosylated acetylcholine receptor (AChR) subunits and subunit complexes were also observed in tunicamycin- treated BC3H-1 cells, a mouse musclelike cell line that normally expresses functional AChR. Hence, rapid degradation may be one form of regulation assuring that only correctly processed and assembled subunits

  15. Chalcones as positive allosteric modulators of α7 nicotinic acetylcholine receptors: a new target for a privileged structure.

    PubMed

    Balsera, Beatriz; Mulet, José; Fernández-Carvajal, Asia; de la Torre-Martínez, Roberto; Ferrer-Montiel, Antonio; Hernández-Jiménez, José G; Estévez-Herrera, Judith; Borges, Ricardo; Freitas, Andiara E; López, Manuela G; García-López, M Teresa; González-Muñiz, Rosario; Pérez de Vega, María Jesús; Valor, Luis M; Svobodová, Lucie; Sala, Salvador; Sala, Francisco; Criado, Manuel

    2014-10-30

    The α7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new agents that target this receptor has great significance. Positive allosteric modulators might be advantageous, since they facilitate receptor responses without directly interacting with the agonist binding site. Here we report the search for and further design of new positive allosteric modulators having the relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chalcones substituted with hydroxyl groups at defined locations were identified as optimal and specific promoters of α7 nicotinic function. The most potent compound (2,4,2',5'-tetrahydroxychalcone, 111) was further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer, opening the way for future developments around the chalcone structure.

  16. Neural Engineering

    NASA Astrophysics Data System (ADS)

    He, Bin

    About the Series: Bioelectric Engineering presents state-of-the-art discussions on modern biomedical engineering with respect to applications of electrical engineering and information technology in biomedicine. This focus affirms Springer's commitment to publishing important reviews of the broadest interest to biomedical engineers, bioengineers, and their colleagues in affiliated disciplines. Recent volumes have covered modeling and imaging of bioelectric activity, neural engineering, biosignal processing, bionanotechnology, among other topics.

  17. Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression

    PubMed Central

    Obora, Kayoko; Onodera, Yuta; Takehara, Toshiyuki; Frampton, John; Hasei, Joe; Ozaki, Toshifumi; Teramura, Takeshi; Fukuda, Kanji

    2017-01-01

    Intracerebral inflammation resulting from injury or disease is implicated in disruption of neural regeneration and may lead to irreversible neuronal dysfunction. Analysis of inflammation-related microRNA profiles in various tissues, including the brain, has identified miR-155 among the most prominent miRNAs linked to inflammation. Here, we hypothesize that miR-155 mediates inflammation-induced suppression of neural stem cell (NSC) self-renewal. Using primary mouse NSCs and human NSCs derived from induced pluripotent stem (iPS) cells, we demonstrate that three important genes involved in NSC self-renewal (Msi1, Hes1 and Bmi1) are suppressed by miR-155. We also demonstrate that suppression of self-renewal genes is mediated by the common transcription factor C/EBPβ, which is a direct target of miR-155. Our study describes an axis linking inflammation and miR-155 to expression of genes related to NSC self-renewal, suggesting that regulation of miR-155 may hold potential as a novel therapeutic strategy for treating neuroinflammatory diseases. PMID:28240738

  18. Satellite image analysis using neural networks

    NASA Technical Reports Server (NTRS)

    Sheldon, Roger A.

    1990-01-01

    The tremendous backlog of unanalyzed satellite data necessitates the development of improved methods for data cataloging and analysis. Ford Aerospace has developed an image analysis system, SIANN (Satellite Image Analysis using Neural Networks) that integrates the technologies necessary to satisfy NASA's science data analysis requirements for the next generation of satellites. SIANN will enable scientists to train a neural network to recognize image data containing scenes of interest and then rapidly search data archives for all such images. The approach combines conventional image processing technology with recent advances in neural networks to provide improved classification capabilities. SIANN allows users to proceed through a four step process of image classification: filtering and enhancement, creation of neural network training data via application of feature extraction algorithms, configuring and training a neural network model, and classification of images by application of the trained neural network. A prototype experimentation testbed was completed and applied to climatological data.

  19. Looking below the surface of nicotinic acetylcholine receptors

    PubMed Central

    Stokes, Clare; Treinin, Millet; Papke, Roger L.

    2015-01-01

    The amino acid sequences of nicotinic acetylcholine receptors (nAChRs) from diverse species can be compared across extracellular, transmembrane, and intracellular domains. The intracellular domains are most divergent among subtypes, yet relatively consistent among species. The diversity indicates that each nAChR subtype possesses a unique language for communication with its host cell. The conservation across species also suggests that the intracellular domains may play defining functional roles for each subtype. Secondary structure prediction indicates two relatively conserved alpha helices within the intracellular domains of all nAChRs. Among all subtypes, the intracellular domain of α7 nAChR is one of the most-well conserved, and α7 nAChRs have effects in non-neuronal cells independent of generating ion currents, making it likely that the α7 intracellular domain directly mediates signal transduction. There are potential phosphorylation and protein binding sites in the α7 intracellular domain, which are conserved and may be the basis for α7-mediated signal transduction. PMID:26067101

  20. Vasoactive intestinal polypeptide provokes acetylcholine release from the myenteric plexus

    SciTech Connect

    Kusunoki, M.; Tsai, L.H.; Taniyama, K.; Tanaka, C.

    1986-07-01

    Effects of vasoactive intestinal polypeptide (VIP) on the release of acetylcholine (ACh) from longitudinal muscle strips with myenteric plexus (LM) preparations were examined in the guinea pig small intestine. VIP (10 to 10 W M) induced a concentration-dependent contraction of LM preparation. The VIP-induced contractions seem to be related to three components, the scopolamine-sensitive, the scopolamine-insensitive, the tetrodotoxin-sensitive, and the tetrodotoxin-insensitive contractions. VIP (10 to 10 W M) induced a concentration-dependent increase in the release of (TH)ACh from LM preparations preloaded with (TH)choline. The VIP-evoked (TH)ACh release was inhibited by removal of CaS from the perfusion medium and by treatment with tetrodotoxin but not by scopolamine and hexamethonium. The spontaneous and VIP-evoked (TH)ACh release was not affected by phentolamine, propranolol, methysergide, diphenhydramine, cimetidine, bicuculline, or (D-ProS, D-Trp/sup 7,9/)substance P. The result demonstrates that VIP induces contractions of longitudinal smooth muscle directly and indirectly by the stimulation of both cholinergic neurons and noncholinergic excitatory neurons.

  1. Regulation of hippocampal inhibitory circuits by nicotinic acetylcholine receptors

    PubMed Central

    Griguoli, Marilena; Cherubini, Enrico

    2012-01-01

    The hippocampal network comprises a large variety of locally connected GABAergic interneurons exerting a powerful control on network excitability and which are responsible for the oscillatory behaviour crucial for information processing. GABAergic interneurons receive an important cholinergic innervation from the medial septum-diagonal band complex of the basal forebrain and are endowed with a variety of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) that regulate their activity. Deficits in the cholinergic system lead to the impairment of high cognitive functions, which are particularly relevant in neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases as well as in schizophrenia. Here, we highlight some recent advances in the mechanisms by which cholinergic signalling via nAChRs regulates local inhibitory circuits in the hippocampus, early in postnatal life and in adulthood. We also discuss recent findings concerning the functional role of nAChRs in controlling short- and long-term modifications of synaptic efficacy. Insights into these processes may provide new targets for the therapeutic control of pathological conditions associated with cholinergic dysfunctions. PMID:22124144

  2. Discovery of new muscarinic acetylcholine receptor antagonists from Scopolia tangutica

    PubMed Central

    Du, Nana; Liu, Yanfang; Zhang, Xiuli; Wang, Jixia; Zhao, Jianqiang; He, Jian; Zhou, Han; Mei, Lijuan; Liang, Xinmiao

    2017-01-01

    Scopolia tangutica (S. tangutica) is a traditional Chinese medicinal plant used for antispasmodics, anesthesia, analgesia and sedation. Its pharmacological activities are mostly associated with the antagonistic activity at muscarinic acetylcholine receptors (mAchRs) of several known alkaloids such as atropine and scopolamine. With our recent identification of four hydroxycinnamic acid amides from S. tangutica, we hypothesized that this plant may contain previously unidentified alkaloids that may also contribute to its in vivo effect. Herein, we used a bioassay-guided multi-dimension separation strategy to discover novel mAchR antagonists from S. tangutica. The core of this approach is to use label-free cell phenotypic assay to first identify active fractions, and then to guide purification of active ligands. Besides four tropanes and six cinnamic acid amides that have been previously isolated from S. tangutica, we recently identified two new tropanes, one new cinnamic acid amide, and nine other compounds. Six tropane compounds purified from S. tangutica for the first time were confirmed to be competitive antagonists of muscarinic receptor 3 (M3), including the two new ones 8 and 12 with IC50 values of 1.97 μM and 4.47 μM, respectively. Furthermore, the cinnamic acid amide 17 displayed 15-fold selectivity for M1 over M3 receptors. These findings will be useful in designing lead compounds for mAchRs and elucidating mechanisms of action of S. tangutica. PMID:28387362

  3. Oseltamivir blocks human neuronal nicotinic acetylcholine receptor-mediated currents.

    PubMed

    Muraki, Katsuhiko; Hatano, Noriyuki; Suzuki, Hiroka; Muraki, Yukiko; Iwajima, Yui; Maeda, Yasuhiro; Ono, Hideki

    2015-02-01

    The effects of oseltamivir, a neuraminidase inhibitor, were tested on the function of neuronal nicotinic acetylcholine receptors (nAChRs) in a neuroblastoma cell line IMR32 derived from human peripheral neurons and on recombinant human α3β4 nAChRs expressed in HEK cells. IMR32 cells predominately express α3β4 nAChRs. Nicotine (nic, 30 μm)-evoked currents recorded at -90 mV in IMR32 cells using the whole-cell patch clamp technique were reversibly blocked by oseltamivir in a concentration-dependent manner. In contrast, an active metabolite of oseltamivir, oseltamivir carboxylate (OC) at 30 μm had little effect on the nic-evoked currents. Oseltamivir also blocked nic-evoked currents derived from HEK cells with recombinant α3β4 nAChRs. This blockade was voltage-dependent with 10, 30 and 100 μm oseltamivir inhibiting ~50% at -100, -60 and -40 mV, respectively. Non-inactivating currents in IMR32 cells and in HEK cells with α3β4 nAChRs, which were evoked by an endogenous nicotinic agonist, ACh (5 μm), were reversibly blocked by oseltamivir. These data demonstrate that oseltamivir blocks nAChRs, presumably via binding to a site in the channel pore.

  4. Muscarinic acetylcholine receptors: location of the ligand binding site

    SciTech Connect

    Hulme, E.; Wheatley, M.; Curtis, C.; Birdsall, N.

    1987-05-01

    The key to understanding the pharmacological specificity of muscarinic acetylcholine receptors (mAChR's) is the location within the receptor sequence of the amino acid residues responsible for ligand binding. To approach this problem, they have purified mAChR's from rat brain to homogeneity by sequential ion-exchange chromatography, affinity chromatography and molecular weight fractionation. Following labelling of the binding site with an alkylating affinity label, /sup 3/H-propylbenzilycholine mustard aziridinium ion (/sup 3/H-PrBCM), the mAChR was digested with a lysine-specific endoproteinase, and a ladder of peptides of increasing molecular weight, each containing the glycosylated N-terminus, isolated by chromatography on wheat-germ agglutinin sepharose. The pattern of labelling showed that a residue in the peptides containing transmembrane helices 2 and/or 3 of the mAChR was alkylated. The linkage was cleaved by 1 M hydroxylamine, showing that /sup 3/H-PrBCM was attached to an acidic residue, whose properties strongly suggested it to be embedded in a hydrophobic intramembrane region of the mAChR. Examination of the cloned sequence of the mAChR reveals several candidate residues, the most likely of which is homologous to an aspartic acid residue thought to protonate the retinal Schiff's base in the congeneric protein rhodopsin.

  5. Biochemical and immunological studies of the Muscarinic acetylcholine receptor

    SciTech Connect

    Gainer, M.W.

    1985-01-01

    Muscarinic acetylcholine receptors were solubilized from bovine brain membranes with 3(3-cholamidopropyl)dimethylammonio)propanesulfonate (CHAPS). A combination of 10 mM CHAPS and 1 M NaCl solubilized 15-40% of the specific receptor binding sites from these membranes. The solubilized receptors displayed high affinity binding of the muscarinic antagonist, (/sup 3/H)quinuclidinyl benzilate with a K/sub D/ = 300 pM. In addition, the solubilized and retained guanyl nucleotide regulation of agonist binding characteristic of membrane bound receptors. Gel filtration experiments showed that solubilized receptors from cortex and cerebellum had different elution profiles. Analysis by sucrose density gradient centrifugation showed that receptors in the lower molecular weight peak sedimented with a coefficient of 5S. Receptors in the larger molecular weight peak sedimented to the bottom of the gradient. Attempts to purify receptors by chromatography on propylbenzilycholine Sepharose were unsuccessful. The technique used to attach the ligand to the solid support, however, was used to synthesize a PrBCM-BSA conjugate and the conjugate used as an antigen in the production of anti-ligand antibodies. Two anti-PrBCM monoclonal antibodies were isolated that recognize muscarinic but not nicotinic cholinergic ligands. The abilities of the antibodies to recognize other muscarinic ligands indicated the antibodies recognized a portion of PrBCM involved in binding to the receptor. Construction of an antibody affinity resin resulted in the purification of this fragment a minimum of 170 fold.

  6. Molecular alteration of a muscarinic acetylcholine receptor system during synaptogenesis

    SciTech Connect

    Large, T.H.; Cho, N.J.; De Mello, F.G.; Klein, W.L.

    1985-07-25

    Biochemical properties of the muscarinic acetylcholine receptor system of the avian retina were found to change during the period when synapses form in ovo. Comparison of ligand binding to membranes obtained before and after synaptogenesis showed a significant increase in the affinity, but not proportion, of the high affinity agonist-binding state. There was no change in receptor sensitivity to antagonists during this period. Pirenzepine binding, which can discriminate muscarinic receptor subtypes, showed the presence of a single population of low affinity sites (M2) before and after synaptogenesis. The change in agonist binding was not due to the late development of receptor function. However, detergent-solubilization of membranes eliminated differences in agonist binding between receptors from embryos and hatched chicks, suggesting a developmental change in interactions of the receptor with functionally related membrane components. A possible basis for altered interactions was obtained from isoelectric point data showing that the muscarinic receptor population underwent a transition from a predominantly low pI form (4.25) in 13 day embryos to a predominantly high pI form (4.50) in newly hatched chicks. The possibility that biochemical changes in the muscarinic receptor play a role in differentiation of the system by controlling receptor position on the surface of nerve cells is discussed.

  7. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  8. Nicotinic Acetylcholine Receptors at the Single-Channel Level.

    PubMed

    Bouzat, Cecilia; Sine, Steven M

    2017-03-05

    Over the past four decades, the patch clamp technique and nicotinic acetylcholine (nACh) receptors have established an enduring partnership. Like all good partnerships, each partner has proven significant in its own right, while their union has spurred innumerable advances in life science research. A member and prototype of the superfamily of pentameric ligand-gated ion channels, the nACh receptor is a chemo-electric transducer, binding nerve-released ACh and rapidly opening its channel to cation flow to elicit cellular excitation. A subject of a Nobel Prize in Physiology or Medicine, the patch clamp technique provides unprecedented resolution of currents through single ion channels in their native cellular environments. Here, focusing on muscle and α7 nACh receptors, we describe the extraordinary contribution of the patch clamp technique toward understanding how they activate in response to neurotransmitter, how subtle structural and mechanistic differences among nACh receptor subtypes translate into significant physiological differences, and how nACh receptors are being exploited as therapeutic drug targets.

  9. Acetylcholine-induced current in perfused rat myoballs

    PubMed Central

    1980-01-01

    Spherical "myoballs" were grown under tissue culture conditions from striated muscle of neonatal rat thighs. The myoballs were examined electrophysiologically with a suction pipette which was used to pass current and perfuse internally. A microelectrode was used to record membrane potential. Experiments were performed with approximately symmetrical (intracellular and extracellular) sodium aspartate solutions. The resting potential, acetylcholine (ACh) reversal potential, and sodium channel reversal potential were all approximately 0 mV. ACh-induced currents were examined by use of both voltage jumps and voltage ramps in the presence of iontophoretically applied agonist. The voltage-jump relaxations had a single exponential time-course. The time constant, tau, was exponentially related to membrane potential, increasing e-fold for 81 mV hyperpolarization. The equilibrium current- voltage relationship was also approximately exponential, from -120 to +81 mV, increasing e-fold for 104 mV hyperpolarization. The data are consistent with a first-order gating process in which the channel opening rate constant is slightly voltage dependent. The instantaneous current-voltage relationship was sublinear in the hyperpolarizing direction. Several models are discussed which can account for the nonlinearity. Evidence is presented that the "selectivity filter" for the ACh channel is located near the intracellular membrane surface. PMID:7381423

  10. Revisiting the endocytosis of the m2 muscarinic acetylcholine receptor.

    PubMed

    Ockenga, Wymke; Tikkanen, Ritva

    2015-05-12

    The agonist-induced endocytosis of the muscarinic acetylcholine receptor M2 is different from that of the other members of the muscarinic receptor family. The uptake of the M2 receptor involves the adapter proteins of the β-arrestin family and the small GTPase ADP-ribosylation factor 6. However, it has remained inconclusive if M2 endocytosis is dependent on clathrin or the large GTPase dynamin. We here show by means of knocking down the clathrin heavy chain that M2 uptake upon agonist stimulation requires clathrin. The expression of various dominant-negative dynamin-2 mutants and the use of chemical inhibitors of dynamin function revealed that dynamin expression and membrane localization as such appear to be necessary for M2 endocytosis, whereas dynamin GTPase activity is not required for this process. Based on the data from the present and from previous studies, we propose that M2 endocytosis takes place by means of an atypical clathrin-mediated pathway that may involve a specific subset of clathrin-coated pits/vesicles.

  11. Acetylcholine-Atropine Interactions: Paradoxical Effects on Atrial Fibrillation Inducibility.

    PubMed

    Liu, Yu; Scherlag, Benjamin J; Fan, Youqi; Xia, Wenfang; Huang, He; Po, Sunny S

    2017-03-21

    Atropine (ATr) is well known as a cholinergic antagonist, however, at low concentrations ATr could paradoxically accentuate the parasympathetic actions of acetylcholine (ACh). In 22 pentobarbital anesthetized dogs, via a left and right thoracotomy, a leak proof barrier was attached to isolate the atrial appendages (AAs) from the rest of the atria. In Group 1(Ach+ATr+Ach), ACh, 100 mM, was placed on the AA followed by the application of ATr, 2mg/cc. The average AFdur was 17±7 minutes. After ATr was applied to the AA and ACh again tested, the AFdur was markedly attenuated (2±2 minutes, p<0.05). In Group 2 (ATr+Ach), ATr was initially applied to the AA followed by the application of ACh, 100 mM. There was no significant difference in AF duration (16±4 minutes vs 18±2 minutes, p=NS). The inhibitory effect of ATr on induced HR reduction (electrical stimulation of the anterior right ganglionated plexi and vagal nerves) was no difference between Groups 1 and 2. These observations suggest that when ATr is initially administered it attaches to the allosteric site of the muscarinic ACh receptor (M2 AChRs) leaving the orthosteric site free to be occupied by ACh. The M3 receptor that controls HR slowing does not show the same allosteric properties.

  12. Revisiting the Endocytosis of the M2 Muscarinic Acetylcholine Receptor

    PubMed Central

    Ockenga, Wymke; Tikkanen, Ritva

    2015-01-01

    The agonist-induced endocytosis of the muscarinic acetylcholine receptor M2 is different from that of the other members of the muscarinic receptor family. The uptake of the M2 receptor involves the adapter proteins of the β-arrestin family and the small GTPase ADP-ribosylation factor 6. However, it has remained inconclusive if M2 endocytosis is dependent on clathrin or the large GTPase dynamin. We here show by means of knocking down the clathrin heavy chain that M2 uptake upon agonist stimulation requires clathrin. The expression of various dominant-negative dynamin-2 mutants and the use of chemical inhibitors of dynamin function revealed that dynamin expression and membrane localization as such appear to be necessary for M2 endocytosis, whereas dynamin GTPase activity is not required for this process. Based on the data from the present and from previous studies, we propose that M2 endocytosis takes place by means of an atypical clathrin-mediated pathway that may involve a specific subset of clathrin-coated pits/vesicles. PMID:25985102

  13. Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake

    PubMed Central

    Shariff, Masroor; Quik, Maryka; Holgate, Joan; Morgan, Michael; Patkar, Omkar L.; Tam, Vincent; Belmer, Arnauld; Bartlett, Selena E.

    2016-01-01

    Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption. PMID:27028298

  14. Serotonergic modulation of muscle acetylcholine receptors of different subunit composition.

    PubMed Central

    García-Colunga, J; Miledi, R

    1996-01-01

    Modulation of muscle acetylcholine (AcCho) receptors (AcChoRs) by serotonin [5-hydroxytryptamine (5HT)] and other serotonergic compounds was studied in Xenopus laevis oocytes. Various combinations of alpha, beta, gamma, and delta subunit RNAs were injected into oocytes, and membrane currents elicited by AcCho were recorded under voltage clamp. Judging by the amplitudes of AcCho currents generated, the levels of functional receptor expression were: alpha beta gamma delta > alpha beta delta > alpha beta gamma > alpha gamma delta. The alpha beta gamma delta and alpha beta delta AcChoR Subtypes were strongly blocked by 5HT, whereas the alpha beta gamma receptor was blocked only slightly. The order of blocking potency of AcChoRs by 5HT was: alpha beta delta > alpha beta gamma delta > alpha beta gamma. 5HT receptor antagonists, such as methysergide and spiperone, were even more potent blockers of AcChoRs than 5HT but did not show much subunit selectivity. Blockage of alpha beta gamma delta and alpha beta delta receptors by 5HT was voltage-dependent, and the voltage dependence was abolished when the delta subunit was omitted. These findings may need to be taken into consideration when trying to elucidate the mode of action of many clinically important serotonergic compounds. Images Fig. 3 PMID:8633003

  15. Paroxysmal atrial fibrillation during intracoronary acetylcholine provocation test.

    PubMed

    Saito, Yuichi; Kitahara, Hideki; Shoji, Toshihiro; Tokimasa, Satoshi; Nakayama, Takashi; Sugimoto, Kazumasa; Fujimoto, Yoshihide; Kobayashi, Yoshio

    2016-12-22

    Intracoronary acetylcholine (ACh) provocation test is useful to diagnose vasospastic angina. However, paroxysmal atrial fibrillation (AF) often occurs during intracoronary ACh provocation test, leading to disabling symptoms. The aim of this study was to investigate the incidence and predictors of paroxysmal AF during the test. A total of 377 patients without persistent AF who underwent intracoronary ACh provocation test were included. Paroxysmal AF during ACh provocation test was defined as documented AF on electrocardiogram during the procedure. There were 31 patients (8%) with paroxysmal AF during the test. Of these, 11 (35%) required antiarrhythmic drugs, but none received electrical cardioversion. All of them recovered sinus rhythm within 48 h. At procedure, paroxysmal AF occurred mostly during provocation for the right coronary artery (RCA) rather than for the left coronary artery (LCA) (90 vs. 10%). Multivariate logistic regression analysis demonstrated that a history of paroxysmal AF (OR 4.38 CI 1.42-13.51, p = 0.01) and body mass index (OR 0.88 CI 0.78-0.99, p = 0.03) were independent predictors for occurrence of paroxysmal AF during intracoronary ACh provocation test. In conclusions, paroxysmal AF mostly occurs during ACh provocation test for the RCA, especially in patients with a history of paroxysmal AF and lower body mass index. It may be better to initially administer intracoronary ACh in the LCA when the provocation test is performed.

  16. Improvement of Acetylcholine-Induced Vasodilation by Acute Exercise in Ovariectomized Hypertensive Rats.

    PubMed

    Cheng, Tsung-Lin; Lin, Yi-Yuan; Su, Chia-Ting; Hu, Chun-Che; Yang, Ai-Lun

    2016-06-30

    Postmenopause is associated with the development of cardiovascular disease, such as hypertension. However, limited information is available regarding effects of exercise on cardiovascular responses and its underlying mechanisms in the simultaneous postmenopausal and hypertensive status. We aimed to investigate whether acute exercise could enhance vasodilation mediated by acetylcholine (ACh) and sodium nitroprusside (SNP) in ovariectomized hypertensive rats. The fifteen-week-old female spontaneously hypertensive rats (SHR) were bilaterally ovariectomized, at the age of twenty-four weeks, and randomly divided into sedentary (SHR-O) and acute exercise (SHR-OE) groups. Age-matched WKY rats were used as the normotensive control group. The SHR-OE group ran on a motor-driven treadmill at a speed of 24 m/min for one hour in a moderate-intensity program. Following a single bout of exercise, rat aortas were isolated for the evaluation of the endothelium-dependent (ACh-induced) and endothelium-independent (SNP-induced) vasodilation by the organ bath system. Also, the serum levels of oxidative stress and antioxidant activities, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase, were measured after acute exercise among the three groups. We found that acute exercise significantly enhanced the ACh-induced vasodilation, but not the SNP-induced vasodilation, in ovariectomized hypertensive rats. This increased vasodilation was eliminated after the inhibition of nitric oxide synthase (NOS). Also, the activities of SOD and catalase were significantly increased after acute exercise, whereas the level of MDA was comparable among the three groups. These results indicated that acute exercise improved the endothelium-dependent vasodilating response to ACh through the NOS-related pathway in ovariectomized hypertensive rats, which might be associated with increased serum antioxidant activities.

  17. Vesicular acetylcholine transporter knock down-mice are more susceptible to inflammation, c-Fos expression and sickness behavior induced by lipopolysaccharide.

    PubMed

    Leite, Hércules Ribeiro; Oliveira-Lima, Onésia Cristina de; Pereira, Luciana de Melo; Oliveira, Vinícius Elias de Moura; Prado, Vania Ferreira; Prado, Marco Antônio Máximo; Pereira, Grace Schenatto; Massensini, André Ricardo

    2016-10-01

    In addition to the well-known functions as a neurotransmitter, acetylcholine (ACh) can modulate of the immune system. Nonetheless, how endogenous ACh release inflammatory responses is still not clear. To address this question, we took advantage of an animal model with a decreased ACh release due a reduction (knockdown) in vesicular acetylcholine transporter (VAChT) expression (VAChT-KD(HOM)). These animals were challenged with lipopolysaccharide (LPS). Afterwards, we evaluated sickness behavior and quantified systemic and cerebral inflammation as well as neuronal activation in the dorsal vagal complex (DVC). VAChT-KD(HOM) mice that were injected with LPS (10mg/kg) showed increased mortality rate as compared to control mice. In line with this result, a low dose of LPS (0.1mg/kg) increased the levels of pro-inflammatory (TNF-α, IL-1β, and IL-6) and anti-inflammatory (IL-10) cytokines in the spleen and brain of VAChT-KD(HOM) mice in comparison with controls. Similarly, serum levels of TNF-α and IL-6 were increased in VAChT-KD(HOM) mice. This excessive cytokine production was completely prevented by administration of a nicotinic receptor agonist (0.4mg/kg) prior to the LPS injection. Three hours after the LPS injection, c-Fos expression increased in the DVC region of VAChT-KD(HOM) mice compared to controls. In addition, VAChT-KD(HOM) mice showed behavioral changes such as lowered locomotor and exploratory activity and reduced social interaction after the LPS challenge, when compared to control mice. Taken together, our results show that the decreased ability to release ACh exacerbates systemic and cerebral inflammation and promotes neural activation and behavioral changes induced by LPS. In conclusion, our findings support the notion that activity of cholinergic pathways, which can be modulated by VAChT expression, controls inflammatory and neural responses to LPS challenge.

  18. Enhancement of image quality and imaging depth with Airy light-sheet microscopy in cleared and non-cleared neural tissue

    PubMed Central

    Nylk, Jonathan; McCluskey, Kaley; Aggarwal, Sanya; Tello, Javier A.; Dholakia, Kishan

    2016-01-01

    We have investigated the effect of Airy illumination on the image quality and depth penetration of digitally scanned light-sheet microscopy in turbid neural tissue. We used Fourier analysis of images acquired using Gaussian and Airy light-sheets to assess their respective image quality versus penetration into the tissue. We observed a three-fold average improvement in image quality at 50 μm depth with the Airy light-sheet. We also used optical clearing to tune the scattering properties of the tissue and found that the improvement when using an Airy light-sheet is greater in the presence of stronger sample-induced aberrations. Finally, we used homogeneous resolution probes in these tissues to quantify absolute depth penetration in cleared samples with each beam type. The Airy light-sheet method extended depth penetration by 30% compared to a Gaussian light-sheet. PMID:27867712

  19. Enhanced Efficacy of Human Brain-Derived Neural Stem Cells by Transplantation of Cell Aggregates in a Rat Model of Parkinson's Disease

    PubMed Central

    Shin, Eun Sil; Hwang, Onyou; Hwang, Yu-Shik; Suh, Jun-Kyo Francis; Chun, Young Il

    2014-01-01

    Objective Neural tissue transplantation has been a promising strategy for the treatment of Parkinson's disease (PD). However, transplantation has the disadvantages of low-cell survival and/or development of dyskinesia. Transplantation of cell aggregates has the potential to overcome these problems, because the cells can extend their axons into the host brain and establish synaptic connections with host neurons. In this present study, aggregates of human brain-derived neural stem cells (HB-NSC) were transplanted into a PD animal model and compared to previous report on transplantation of single-cell suspensions. Methods Rats received an injection of 6-OHDA into the right medial forebrain bundle to generate the PD model and followed by injections of PBS only, or HB-NSC aggregates in PBS into the ipsilateral striatum. Behavioral tests, multitracer (2-deoxy-2-[18F]-fluoro-D-glucose ([18F]-FDG) and [18F]-N-(3-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([18F]-FP-CIT) microPET scans, as well as immunohistochemical (IHC) and immunofluorescent (IF) staining were conducted to evaluate the results. Results The stepping test showed significant improvement of contralateral forelimb control in the HB-NSC group from 6-10 weeks compared to the control group (p<0.05). [18F]-FP-CIT microPET at 10 weeks posttransplantation demonstrated a significant increase in uptake in the HB-NSC group compared to pretransplantation (p<0.05). In IHC and IF staining, tyrosine hydroxylase and human β2 microglobulin (a human cell marker) positive cells were visualized at the transplant site. Conclusion These results suggest that the HB-NSC aggregates can survive in the striatum and exert therapeutic effects in a PD model by secreting dopamine. PMID:25535514

  20. Inhibition of nicotinic acetylcholine receptors, a novel facet in the pleiotropic activities of snake venom phospholipases A2.

    PubMed

    Vulfius, Catherine A; Kasheverov, Igor E; Starkov, Vladislav G; Osipov, Alexey V; Andreeva, Tatyana V; Filkin, Sergey Yu; Gorbacheva, Elena V; Astashev, Maxim E; Tsetlin, Victor I; Utkin, Yuri N

    2014-01-01

    Phospholipases A2 represent the most abundant family of snake venom proteins. They manifest an array of biological activities, which is constantly expanding. We have recently shown that a protein bitanarin, isolated from the venom of the puff adder Bitis arietans and possessing high phospholipolytic activity, interacts with different types of nicotinic acetylcholine receptors and with the acetylcholine-binding protein. To check if this property is characteristic to all venom phospholipases A2, we have studied the capability of these enzymes from other snakes to block the responses of Lymnaea stagnalis neurons to acetylcholine or cytisine and to inhibit α-bungarotoxin binding to nicotinic acetylcholine receptors and acetylcholine-binding proteins. Here we present the evidence that phospholipases A2 from venoms of vipers Vipera ursinii and V. nikolskii, cobra Naja kaouthia, and krait Bungarus fasciatus from different snake families suppress the acetylcholine- or cytisine-elicited currents in L. stagnalis neurons and compete with α-bungarotoxin for binding to muscle- and neuronal α7-types of nicotinic acetylcholine receptor, as well as to acetylcholine-binding proteins. As the phospholipase A2 content in venoms is quite high, under some conditions the activity found may contribute to the deleterious venom effects. The results obtained suggest that the ability to interact with nicotinic acetylcholine receptors may be a general property of snake venom phospholipases A2, which add a new target to the numerous activities of these enzymes.

  1. Highly Selective and Sensitive Detection of Acetylcholine Using Receptor-Modified Single-Walled Carbon Nanotube Sensors

    NASA Astrophysics Data System (ADS)

    Xu, Shihong; Kim, Byeongju; Song, Hyun Seok; Jin, Hye Jun; Park, Eun Jin; Lee, Sang Hun; Lee, Byung Yang; Park, Tai Hyun; Hong, Seunghun

    2015-03-01

    Acetylcholine (ACh) is a neurotransmitter in a human central nervous system and is related to various neural functions such as memory, learning and muscle contractions. Dysfunctional ACh regulations in a brain can induce several neuropsychiatric diseases such as Alzheimer's disease, Parkinson's disease and myasthenia gravis. In researching such diseases, it is important to measure the concentration of ACh in the extracellular fluid of the brain. Herein, we developed a highly sensitive and selective ACh sensor based on single-walled carbon nanotube-field effect transistors (swCNT-FETs). In our work, M1 mAChR protein, an ACh receptor, was expressed in E.coli and coated on swCNT-FETs with lipid membranes. Here, the binding of ACh onto the receptors could be detected by monitoring the change of electrical currents in the underlying swCNT-FETs, allowing the real-time detection of ACh at a 100 pM concentration. Furthermore, our sensor could selectively detect ACh from other neurotransmitters. This is the first report of the real-time sensing of ACh utilizing specific binding between the ACh and M1 mAChR, and it may lead to breakthroughs in various biomedical applications such as drug screening and disease diagnosis.

  2. Mouse mutants for the nicotinic acetylcholine receptor ß2 subunit display changes in cell adhesion and neurodegeneration response genes.

    PubMed

    Rubin, Carol M; van der List, Deborah A; Ballesteros, Jose M; Goloshchapov, Andrey V; Chalupa, Leo M; Chapman, Barbara

    2011-04-25

    Mice lacking expression of the ß2 subunit of the neuronal nicotinic acetylcholine receptor (CHRNB2) display abnormal retinal waves and a dispersed projection of retinal ganglion cell (RGC) axons to their dorsal lateral geniculate nuclei (dLGNs). Transcriptomes of LGN tissue from two independently generated Chrnb2-/- mutants and from wildtype mice were obtained at postnatal day 4 (P4), during the normal period of segregation of eye-specific afferents to the LGN. Microarray analysis reveals reduced expression of genes located on the cell membrane or in extracellular space, and of genes active in cell adhesion and calcium signaling. In particular, mRNA for cadherin 1 (Cdh1), a known axon growth regulator, is reduced to nearly undetectable levels in the LGN of P4 mutant mice and Lypd2 mRNA is similarly suppressed. Similar analysis of retinal tissue shows increased expression of crumbs 1 (Crb1) and chemokine (C-C motif) ligand 21 (Ccl21) mRNAs in Chrnb2-/- mutant animals. Mutations in these genes are associated with retinal neuronal degeneration. The retinas of Chrnb2-/- mutants are normal in appearance, but the increased expression of these genes may also be involved in the abnormal projection patterns of RGC to the LGN. These data may provide the tools to distinguish the interplay between neural activity and molecular expression. Finally, comparison of the transcriptomes of the two different Chrnb2-/- mutant strains reveals the effects of genetic background upon gene expression.

  3. Docking of 6-chloropyridazin-3-yl derivatives active on nicotinic acetylcholine receptors into molluscan acetylcholine binding protein (AChBP).

    PubMed

    Artali, Roberto; Bombieri, Gabriella; Meneghetti, Fiorella

    2005-04-01

    The crystal structure of Acetylcholine Binding Protein (AChBP), homolog of the ligand binding domain of nAChR, has been used as model for computational investigations on the ligand-receptor interactions of derivatives of 6-chloropyridazine substituted at C3 with 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane and with piperazine and homopiperazine, substituted or not at N4. The ligand-receptor complexes have been analyzed by docking techniques using the binding site of HEPES complexed with AChBP as template. The good relationship between the observed binding affinity and the calculated docking energy confirms that this model provides a good starting point for understanding the binding domain of neuronal nicotinic receptors. An analysis of the possible factors significant for the ligand recognition has evidenced, besides the cation-pi interaction, the distance between the chlorine atom of the pyridazinyl group and the carbonylic oxygen of Leu B112 as an important parameter in the modulation of the binding energy.

  4. The prototoxin LYPD6B modulates heteromeric α3β4-containing nicotinic acetylcholine receptors, but not α7 homomers

    PubMed Central

    Ochoa, Vanessa; George, Andrew A.; Nishi, Rae; Whiteaker, Paul

    2015-01-01

    Prototoxins are a diverse family of membrane-tethered molecules expressed in the nervous system that modulate nicotinic cholinergic signaling, but their functions and specificity have yet to be completely explored. We tested the selectivity and efficacy of leukocyte antigen, PLAUR (plasminogen activator, urokinase receptor) domain-containing (LYPD)-6B on α3β4-, α3α5β4-, and α7-containing nicotinic acetylcholine receptors (nAChRs). To constrain stoichiometry, fusion proteins encoding concatemers of human α3, β4, and α5 (D and N variants) subunits were expressed in Xenopus laevis oocytes and tested with or without LYPD6B. We used the 2-electrode voltage-clamp method to quantify responses to acetylcholine (ACh): agonist sensitivity (EC50), maximal agonist-induced current (Imax), and time constant (τ) of desensitization. For β4–α3–α3–β4–α3 and β4–α3–β4–α3–α3, LYPD6B decreased EC50 from 631 to 79 μM, reduced Imax by at least 59%, and decreased τ. For β4–α3–α5D–β4–α3 and β4–α3–β4–α–α5D, LYPD6B decreased Imax by 63 and 32%, respectively. Thus, LYPD6B acted only on (α3)3(β4)2 and (α3)2(α5D)(β4)2 and did not affect the properties of (α3)2(β4)3, α7, or (α3)2(α5N)(β4)2 nAChRs. Therefore, LYPD6B acts as a mixed modulator that enhances the sensitivity of (α3)3(β4)2 nAChRs to ACh while reducing ACh-induced whole-cell currents. LYPD6B also negatively modulates α3β4 nAChRs that include the α5D common human variant, but not the N variant associated with nicotine dependence.—Ochoa, V., George, A. A., Nishi, R., Whiteaker, P. The prototoxin LYPD6B modulates heteromeric α3β4-containing nicotinic acetylcholine receptors, but not α7 homomers. PMID:26586467

  5. Immunohistochemical localization of monoclonal antibodies to the nicotinic acetylcholine receptor in chick midbrain.

    PubMed Central

    Swanson, L W; Lindstrom, J; Tzartos, S; Schmued, L C; O'Leary, D D; Cowan, W M

    1983-01-01

    We used the indirect immunofluorescence method to determine the crossreactivity of a library of 57 monoclonal antibodies (mAbs) against each of the subunits of the nicotinic acetylcholine receptor (nAcChoR) isolated from Torpedo and Electrophorus electric organs or from fetal calf and human muscle, with specific neural elements in the midbrain of the chick. Out of 17 mAbs that recognized motor end plates on chick muscle, 14 produced a similar pattern of labeling in the midbrain: the neuronal perikarya and dendrites in the lateral spiriform nucleus (SpL) were intensely labeled, and there was moderate labeling of fibers in certain of the deeper layers of the optic tectum, which disappeared after the SpL was destroyed electrolytically. Two lines of evidence suggest that the mAbs may be crossreacting with nAcChoRs in the midbrain. First, all of the mAbs that stained the SpL also stained neuromuscular junctions in skeletal muscle, whereas none of the 40 mAbs that failed to stain end plates crossreacted with the SpL; second, in vitro immunological studies and blocking experiments on tissue sections (in which unlabeled mAbs were used to block the staining of a directly fluorescein-treated mAb) indicated the presence of mAbs specific for unique antigenic determinants on all four of the subunits (alpha, beta, gamma, and delta) from Torpedo nAcChoR in chick midbrain and muscle. On the other hand, the distribution of mAb staining in the optic tectum does not closely parallel that of either acetylcholinesterase staining or of 125I-labeled alpha-bungarotoxin binding; no toxin binding has been observed autoradiographically in the SpL, but the nucleus does contain moderately dense acetylcholinesterase staining. Take together, our observations suggest that there may be a cholinergic input to the SpL and that the projection fibers from the SpL to the optic tectum (which are also stained with an antiserum to [Leu]enkephalin) may contain presynaptic nAcChoRs. It is clear, however

  6. Circulating antibodies against nicotinic acetylcholine receptors in chagasic patients

    PubMed Central

    GOIN, J C; VENERA, G; BONINO, M BISCOGLIO DE JIMÉNEZ; STERIN-BORDA, L

    1997-01-01

    Human and experimental Chagas' disease causes peripheral nervous system damage involving neuromuscular transmission alterations at the neuromuscular junction. Additionally, autoantibodies directed to peripheral nerves and sarcolemmal proteins of skeletal muscle have been described. In this work, we analyse the ability of serum immunoglobulin factors associated with human chagasic infection to bind the affinity-purified nicotinic acetylcholine receptor (nAChR) from electric organs of Discopyge tschudii and to identify the receptor subunits involved in the interaction. The frequency of serum anti-nAChR reactivity assayed by dot-blot was higher in seropositive chagasic patients than in uninfected subjects. Purified IgG obtained from chagasic patients immunoprecipitated a significantly higher fraction of the solubilized nAChR than normal IgG. Furthermore, immunoblotting assays indicated that α and β are the main subunits involved in the interaction. Chagasic IgG was able to inhibit the binding of α-bungarotoxin to the receptor in a concentration-dependent manner, confirming the contribution of the α-subunit in the autoantibody-receptor interaction. The presence of anti-nAChR antibodies was detected in 73% of chagasic patients with impairment of neuromuscular transmission in conventional electromyographical studies, indicating a strong association between seropositive reactivity against nAChR and electromyographical abnormalities in chagasic patients. The chronic binding of these autoantibodies to the nAChR could induce a decrease in the population of functional nAChRs at the neuromuscular junction and consequently contribute to the electrophysiological neuromuscular alterations described in the course of chronic Chagas' disease. PMID:9367405

  7. Cell-surface translational dynamics of nicotinic acetylcholine receptors

    PubMed Central

    Barrantes, Francisco J.

    2014-01-01

    Synapse efficacy heavily relies on the number of neurotransmitter receptors available at a given time. In addition to the equilibrium between the biosynthetic production, exocytic delivery and recycling of receptors on the one hand, and the endocytic internalization on the other, lateral diffusion and clustering of receptors at the cell membrane play key roles in determining the amount of active receptors at the synapse. Mobile receptors traffic between reservoir compartments and the synapse by thermally driven Brownian motion, and become immobilized at the peri-synaptic region or the synapse by: (a) clustering mediated by homotropic inter-molecular receptor–receptor associations; (b) heterotropic associations with non-receptor scaffolding proteins or the subjacent cytoskeletal meshwork, leading to diffusional “trapping,” and (c) protein-lipid interactions, particularly with the neutral lipid cholesterol. This review assesses the contribution of some of these mechanisms to the supramolecular organization and dynamics of the paradigm neurotransmitter receptor of muscle and neuronal cells -the nicotinic acetylcholine receptor (nAChR). Currently available information stemming from various complementary biophysical techniques commonly used to interrogate the dynamics of cell-surface components is critically discussed. The translational mobility of nAChRs at the cell surface differs between muscle and neuronal receptors in terms of diffusion coefficients and residence intervals at the synapse, which cover an ample range of time regimes. A peculiar feature of brain α7 nAChR is its ability to spend much of its time confined peri-synaptically, vicinal to glutamatergic (excitatory) and GABAergic (inhibitory) synapses. An important function of the α7 nAChR may thus be visiting the territories of other neurotransmitter receptors, differentially regulating the dynamic equilibrium between excitation and inhibition, depending on its residence time in each domain. PMID

  8. Acetylcholine Receptor Organization in Membrane Domains in Muscle Cells

    PubMed Central

    Piguet, Joachim; Schreiter, Christoph; Segura, Jean-Manuel; Vogel, Horst; Hovius, Ruud

    2011-01-01

    Nicotinic acetylcholine receptors (nAChR) in muscle fibers are densely packed in the postsynaptic region at the neuromuscular junction. Rapsyn plays a central role in directing and clustering nAChR during cellular differentiation and neuromuscular junction formation; however, it has not been demonstrated whether rapsyn is the only cause of receptor immobilization. Here, we used single-molecule tracking methods to investigate nAChR mobility in plasma membranes of myoblast cells during their differentiation to myotubes in the presence and absence of rapsyn. We found that in myoblasts the majority of nAChR were immobile and that ∼20% of the receptors showed restricted diffusion in small domains of ∼50 nm. In myoblasts devoid of rapsyn, the fraction of mobile nAChR was considerably increased, accompanied by a 3-fold decrease in the immobile population of nAChR with respect to rapsyn-expressing cells. Half of the mobile receptors were confined to domains of ∼120 nm. Measurements performed in heterologously transfected HEK cells confirmed the direct immobilization of nAChR by rapsyn. However, irrespective of the presence of rapsyn, about one-third of nAChR were confined in 300-nm domains. Our results show (i) that rapsyn efficiently immobilizes nAChR independently of other postsynaptic scaffold components; (ii) nAChR is constrained in confined membrane domains independently of rapsyn; and (iii) in the presence of rapsyn, the size of these domains is strongly reduced. PMID:20978122

  9. Cholinergic synaptic vesicle heterogeneity: evidence for regulation of acetylcholine transport

    SciTech Connect

    Gracz, L.M.; Wang, W.; Parsons, S.M.

    1988-07-12

    Crude cholinergic synaptic vesicles from a homogenate of the electric organ of Torpedo californica were centrifuged to equilibrium in an isosmotic sucrose density gradient. The classical VP/sub 1/ synaptic vesicles banding at 1.055 g/mL actively transported (/sup 3/H)acetylcholine (AcCh). An organelle banding at about 1.071 g/mL transported even more (/sup 3/H)AcCh. Transport by both organelles was inhibited by the known AcCh storage blockers trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol, formerly AH5183) and nigericin. Relative to VP/sub 1/ vesicles the denser organelle was slightly smaller as shown by size-exclusion chromatography. It is concluded that the denser organelle corresponds to the recycling VP/sub 2/ synaptic vesicle originally described in intact Torpedo marmorata electric organ. The properties of the receptor for vesamicol were studied by measuring binding of (/sup 3/H)vesamicol, and the amount of SV2 antigen characteristic of secretory vesicles was assayed with a monoclonal antibody directed against it. Relative to VP/sub 1/ vesicles the VP/sub 2/ vesicles had a ratio of (/sup 3/H)AcCh transport activity to vesamicol receptor concentration that typically was 4-7-fold higher, whereas the ratio of SV2 antigen concentration to vesamicol receptor concentration was about 2-fold higher. The Hill coefficients ..cap alpha../sub H/ and equilibrium dissociation constants K for vesamicol binding to VP/sub 1/ and VP/sub 2/ vesicles were essentially the same. The positive Hill coefficient suggests that the vesamicol receptor exists as a homotropic oligomeric complex. The results demonstrate that VP/sub 1/ and VP/sub 2/ synaptic vesicles exhibit functional differences in the AcCh transport system, presumably as a result of regulatory phenomena.

  10. Generation of choline for acetylcholine synthesis by phospholipase D isoforms

    PubMed Central

    Zhao, Di; Frohman, Michael A; Blusztajn, Jan Krzysztof

    2001-01-01

    Dedication This article is dedicated to the memory of Sue Kim Hanson, a graduate student in the department of Pathology and Laboratory Medicine at Boston University School of Medicine, who perished in the terrorist attacks of September 11, 2001. Abstract Background In cholinergic neurons, the hydrolysis of phosphatidylcholine (PC) by a phospholipase D (PLD)-type enzyme generates some of the precursor choline used for the synthesis of the neurotransmitter acetylcholine (ACh). We sought to determine the molecular identity of the relevant PLD using murine basal forebrain cholinergic SN56 cells in which the expression and activity of the two PLD isoforms, PLD1 and PLD2, were experimentally modified. ACh levels were examined in cells incubated in a choline-free medium, to ensure that their ACh was synthesized entirely from intracellular choline. Results PLD2, but not PLD1, mRNA and protein were detected in these cells and endogenous PLD activity and ACh synthesis were stimulated by phorbol 12-myristate 13-acetate (PMA). Introduction of a PLD2 antisense oligonucleotide into the cells reduced PLD2 mRNA and protein expression by approximately 30%. The PLD2 antisense oligomer similarly reduced basal- and PMA-stimulated PLD activity and ACh levels. Overexpression of mouse PLD2 by transient transfection increased basal- (by 74%) and PMA-stimulated (by 3.2-fold) PLD activity. Moreover, PLD2 transfection increased ACh levels by 26% in the absence of PMA and by 2.1-fold in the presence of PMA. Overexpression of human PLD1 by transient transfection increased PLD activity by 4.6-fold and ACh synthesis by 2.3-fold in the presence of PMA as compared to controls. Conclusions These data identify PLD2 as the endogenous enzyme that hydrolyzes PC to generate choline for ACh synthesis in cholinergic cells, and indicate that in a model system choline generated by PLD1 may also be used for this purpose. PMID:11734063

  11. Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons

    PubMed Central

    Azam, Layla; Chen, Yiling; Leslie, Frances M.

    2007-01-01

    We have combined anatomical and functional methodologies to provide a comprehensive analysis of the properties of nicotinic acetylcholine receptors (nAChRs) on developing dopamine (DA) neurons. Double-labeling in situ hybridization was used to examine the expression of nAChR subunit mRNAs within developing midbrain DA neurons. As brain maturation progressed there was a change in the pattern of subunit mRNA expression within DA neurons, such that α3 and α4 subunits declined and α6 mRNA increased. Although there were strong similarities in subunit mRNA expression in substantia nigra (SNc) and ventral tegmental area (VTA), there was higher expression of α4 mRNA in SNc than VTA at gestational day (G)15, and of α5, α6 and β3 mRNAs during postnatal development. Using a superfusion neurotransmitter release paradigm to functionally characterize nicotine-stimulated release of [3H]DA from striatal slices, the properties of the nAChRs on DA terminals were also found to change with age. Functional nAChRs were detected on striatal terminals at G18. There was a decrease in maximal release in the first postnatal week, followed by an increase in nicotine efficacy and potency during the second and third postnatal weeks. In the transition from adolescence (postnatal days (P) 30 and 40) to adulthood, there was a complex pattern of functional maturation of nAChRs in ventral, but not dorsal, striatum. In males, but not females, there were significant changes in both nicotine potency and efficacy during this developmental period. These findings suggest that nAChRs may play critical functional roles throughout DA neuronal maturation. PMID:17197101

  12. Inhibition of human α7 nicotinic acetylcholine receptors by cyclic monoterpene carveol.

    PubMed

    Lozon, Yosra; Sultan, Ahmed; Lansdell, Stuart J; Prytkova, Tatiana; Sadek, Bassem; Yang, Keun-Hang Susan; Howarth, Frank Christopher; Millar, Neil S; Oz, Murat

    2016-04-05

    Cyclic monoterpenes are a group of phytochemicals with antinociceptive, local anesthetic, and anti-inflammatory actions. Effects of cyclic monoterpenes including vanilin, pulegone, eugenole, carvone, carvacrol, carveol, thymol, thymoquinone, menthone, and limonene were investigated on the functional properties of the cloned α7 subunit of the human nicotinic acetylcholine receptor expressed in Xenopus oocytes. Monoterpenes inhibited the α7 nicotinic acetylcholine receptor in the order carveol>thymoquinone>carvacrol>menthone>thymol>limonene>eugenole>pulegone≥carvone≥vanilin. Among the monoterpenes, carveol showed the highest potency on acetylcholine-induced responses, with IC50 of 8.3µM. Carveol-induced inhibition was independent of the membrane potential and could not be reversed by increasing the concentration of acetylcholine. In line with functional experiments, docking studies indicated that cyclic monoterpenes such as carveol may interact with an allosteric site located in the α7 transmembrane domain. Our results indicate that cyclic monoterpenes inhibit the function of human α7 nicotinic acetylcholine receptors, with varying potencies.

  13. Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor

    PubMed Central

    Ockenga, Wymke; Kühne, Sina; Bocksberger, Simone; Banning, Antje; Tikkanen, Ritva

    2013-01-01

    Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2 receptor in human pathological conditions such as autoimmune diseases and cancer. PMID:24705159

  14. Purinergic component in the coronary vasodilatation to acetylcholine after ischemia-reperfusion in perfused rat hearts.

    PubMed

    García-Villalón, Ángel Luis; Granado, Miriam; Monge, Luis; Fernández, Nuria; Carreño-Tarragona, Gonzalo; Amor, Sara

    2014-01-01

    To determine the involvement of purinergic receptors in coronary endothelium-dependent relaxation, the response to acetylcholine (1 × 10(-8) to 3 × 10(-7)M) was recorded in isolated rat hearts perfused according to the Langendorff procedure before and after 30 min of ischemia and 15 min of reperfusion and after the inhibition of nitric oxide synthesis with L-NAME (10(-4)M), in the absence and presence of the antagonist of purinergic P2X receptors, PPADS (3 × 10(-6)M), and of the antagonist of purinergic P2Y receptors, Reactive Blue 2 (3 × 10(-7)M). In control conditions, the relaxation to acetylcholine was not altered by PPADS or Reactive Blue 2. The relaxation to acetylcholine was reduced after ischemia-reperfusion, and, in this condition, it was further reduced by treatment with PPADS or Reactive Blue 2. Likewise, the relaxation to acetylcholine was reduced by L-NAME, and reduced further by Reactive Blue 2 but not by PPADS. These results suggest that the relaxation to acetylcholine may be partly mediated by purinergic receptors after ischemia-reperfusion, due to the reduction of nitric oxide release in this condition.

  15. Enhancing dissolved oxygen control using an on-line hybrid fuzzy-neural soft-sensing model-based control system in an anaerobic/anoxic/oxic process.

    PubMed

    Huang, Mingzhi; Wan, Jinquan; Hu, Kang; Ma, Yongwen; Wang, Yan

    2013-12-01

    An on-line hybrid fuzzy-neural soft-sensing model-based control system was developed to optimize dissolved oxygen concentration in a bench-scale anaerobic/anoxic/oxic (A(2)/O) process. In order to improve the performance of the control system, a self-adapted fuzzy c-means clustering algorithm and adaptive network-based fuzzy inference system (ANFIS) models were employed. The proposed control system permits the on-line implementation of every operating strategy of the experimental system. A set of experiments involving variable hydraulic retention time (HRT), influent pH (pH), dissolved oxygen in the aerobic reactor (DO), and mixed-liquid return ratio (r) was carried out. Using the proposed system, the amount of COD in the effluent stabilized at the set-point and below. The improvement was achieved with optimum dissolved oxygen concentration because the performance of the treatment process was optimized using operating rules implemented in real time. The system allows various expert operational approaches to be deployed with the goal of minimizing organic substances in the outlet while using the minimum amount of energy.

  16. Modulation of the anti-acetylcholine receptor response and experimental autoimmune myasthenia gravis by recombinant fragments of the acetylcholine receptor.

    PubMed

    Barchan, D; Asher, O; Tzartos, S J; Fuchs, S; Souroujon, M C

    1998-02-01

    Myasthenia gravis (MG) is a neuromuscular disorder of man caused by a humoral response to the acetylcholine receptor (AChR). Most of the antibodies in MG and in experimental autoimmune myasthenia gravis (EAMG) are directed to the extracellular portion of the AChR alpha subunit, and within it, primarily to the main immunogenic region (MIR). We have cloned and expressed recombinant fragments, corresponding to the entire extracellular domain of the AChR alpha subunit (H alpha1-210), and to portions of it that encompass either the MIR (H alpha1-121) or the ligand binding site of AChR (H alpha122-210), and studied their ability to interfere with the immunopathological anti-AChR response in vitro and in vivo. All fragments were expressed as fusion proteins with glutathione S-transferase. Fragments H alpha1-121 and H alpha1-210 protected AChR in TE671 cells against accelerated degradation induced by the anti-MIR monoclonal antibody (mAb)198 in a dose-dependent manner. Moreover, these fragments had a similar effect on the antigenic modulation of AChR by other anti-MIR mAb and by polyclonal rat anti-AChR antibodies. Fragments H alpha1-121 and H alpha1-210 were also able to modulate in vivo muscle AChR loss and development of clinical symptoms of EAMG, passively transferred to rats by mAb 198. Fragment H alpha122-210 did not have such a protective activity. Our results suggest that the appropriate recombinant fragments of the human AChR may be employed in the future for antigen-specific therapy of myasthenia.

  17. The β2 nicotinic acetylcholine receptor subunit differentially influences ethanol behavioral effects in the mouse.

    PubMed

    Dawson, Anton; Miles, Micheal F; Damaj, M Imad

    2013-03-01

    The high co-morbidity between alcohol (ethanol) and nicotine abuse suggests that nicotinic acetylcholine receptors (nAChRs), thought to underlie nicotine dependence, may also be involved in alcohol dependence. The β2* nAChR subtype serves as a potential interface for these interactions since they are the principle mediators of nicotine dependence and have recently been shown to modulate some acute responses to ethanol. Therefore, the aim of this study was to more fully characterize the role of β2* nAChRs in ethanol-responsive behaviors in mice after acute exposure to the drug. We conducted a battery of tests in mice lacking the β2* coding gene (Chrnb2) or pretreated with a selective β2* nAChR antagonist for a range of ethanol-induced behaviors including locomotor depression, hypothermia, hypnosis, and anxiolysis. We also tested the effect of deletion on voluntary escalated ethanol consumption in an intermittent access two-bottle choice paradigm to determine the extent of these effects on drinking behavior. Our results showed that antagonism of β2* nAChRs modulated some acute behaviors, namely by reducing recovery time from hypnosis and enhancing the anxiolytic-like response produced by acute ethanol in mice. Chrnb2 deletion had no effect on ethanol drinking behavior, however. We provide further evidence that β2* nAChRs have a measurable role in mediating specific behavioral effects induced by acute ethanol exposure without affecting drinking behavior directly. We conclude that these receptors, along with being key components in nicotine dependence, may also present viable candidates in the discovery of the molecular underpinnings of alcohol dependence.

  18. Glutamatergic contributions to nicotinic acetylcholine receptor agonist-evoked cholinergic transients in the prefrontal cortex.

    PubMed

    Parikh, Vinay; Man, Kingson; Decker, Michael W; Sarter, Martin

    2008-04-02

    Because modulation of cortical cholinergic neurotransmission has been hypothesized to represent a necessary mechanism mediating the beneficial cognitive effects of nicotine and nicotinic acetylcholine receptor (nAChR) subtype-selective agonists, we used choline-sensitive microelectrodes for the real-time measurement of ACh release in vivo, to characterize cholinergic transients evoked by nicotine and the alpha4beta2*-selective nAChR partial agonist 2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride (ABT-089), a clinically effective cognition enhancer. In terms of cholinergic signal amplitudes, ABT-089 was significantly more potent than nicotine in evoking ACh cholinergic transients. Moreover, cholinergic signals evoked by ABT-089 were characterized by faster signal rise time and decay rate. The nAChR antagonist mecamylamine attenuated the cholinergic signals evoked by either compound. Cholinergic signals evoked by ABT-089 were more efficaciously attenuated by the relatively beta2*-selective nAChR antagonist dihydro-beta-erythroidine. The alpha7 antagonist methyllycaconitine did not affect choline signal amplitudes but partly attenuated the relatively slow decay rate of nicotine-evoked cholinergic signals. Furthermore, the AMPA receptor antagonist DNQX as well as the NMDA receptor antagonist APV more potently attenuated cholinergic signals evoked by ABT-089. Using glutamate-sensitive microelectrodes to measure glutamatergic transients, ABT-089 was more potent than nicotine in evoking glutamate release. Glutamatergic signals were highly sensitive to tetrodotoxin-induced blockade of voltage-regulated sodium channels. Together, the present evidence indicates that compared with nicotine, ABT-089 evokes more potent and sharper cholinergic transients in prefrontal cortex. Glutamatergic mechanisms necessarily mediate the cholinergic effects of nAChR agonists in the prefrontal cortex.

  19. High Throughput Random Mutagenesis and Single Molecule Real Time Sequencing of the Muscle Nicotinic Acetylcholine Receptor

    PubMed Central

    Groot-Kormelink, Paul J.; Ferrand, Sandrine; Kelley, Nicholas; Bill, Anke; Freuler, Felix; Imbert, Pierre-Eloi; Marelli, Anthony; Gerwin, Nicole; Sivilotti, Lucia G.; Miraglia, Loren; Orth, Anthony P.; Oakeley, Edward J.; Schopfer, Ulrich; Siehler, Sandra

    2016-01-01

    High throughput random mutagenesis is a powerful tool to identify which residues are important for the function of a protein, and gain insight into its structure-function relation. The human muscle nicotinic acetylcholine receptor was used to test whether this technique previously used for monomeric receptors can be applied to a pentameric ligand-gated ion channel. A mutant library for the α1 subunit of the channel was generated by error-prone PCR, and full length sequences of all 2816 mutants were retrieved using single molecule real time sequencing. Each α1 mutant was co-transfected with wildtype β1, δ, and ε subunits, and the channel function characterized by an ion flux assay. To test whether the strategy could map the structure-function relation of this receptor, we attempted to identify mutations that conferred resistance to competitive antagonists. Mutant hits were defined as receptors that responded to the nicotinic agonist epibatidine, but were not inhibited by either α-bungarotoxin or tubocurarine. Eight α1 subunit mutant hits were identified, six of which contained mutations at position Y233 or V275 in the transmembrane domain. Three single point mutations (Y233N, Y233H, and V275M) were studied further, and found to enhance the potencies of five channel agonists tested. This suggests that the mutations made the channel resistant to the antagonists, not by impairing antagonist binding, but rather by producing a gain-of-function phenotype, e.g. increased agonist sensitivity. Our data show that random high throughput mutagenesis is applicable to multimeric proteins to discover novel functional mutants, and outlines the benefits of using single molecule real time sequencing with regards to quality control of the mutant library as well as downstream mutant data interpretation. PMID:27649498

  20. Some properties of human neuronal alpha 7 nicotinic acetylcholine receptors fused to the green fluorescent protein.

    PubMed

    Palma, Eleonora; Mileo, Anna M; Martinez-Torres, Ataulfo; Eusebi, Fabrizio; Miledi, Ricardo

    2002-03-19

    The functional properties and cellular localization of the human neuronal alpha7 nicotinic acetylcholine (AcCho) receptor (alpha7 AcChoR) and its L248T mutated (mut) form were investigated by expressing them alone or as gene fusions with the enhanced version of the green fluorescent protein (GFP). Xenopus oocytes injected with wild-type (wt), mutalpha7, or the chimeric subunit cDNAs expressed receptors that gated membrane currents when exposed to AcCho. As already known, AcCho currents generated by wtalpha7 receptors decay much faster than those elicited by the mutalpha7 receptors. Unexpectedly, the fusion of GFP to the wt and mutated alpha7 receptors led to opposite results: the AcCho-current decay of the wt receptors became slower, whereas that of the mutated receptors was accelerated. Furthermore, repetitive applications of AcCho led to a considerable "run-down" of the AcCho currents generated by mutalpha7-GFP receptors, whereas those of the wtalpha7-GFP receptors remained stable or increased in amplitude. The AcCho-current run-down of mutalpha7-GFP oocytes was accompanied by a marked decrease of alpha-bungarotoxin binding activity. Fluorescence, caused by the chimeric receptors expressed, was seen over the whole oocyte surface but was more intense and abundant in the animal hemisphere, whereas it was much weaker in the vegetal hemisphere. We conclude that fusion of GFP to wtalpha7 and mutalpha7 receptors provides powerful tools to study the distribution and function of alpha7 receptors. We also conclude that fused genes do not necessarily recapitulate all of the properties of the original receptors. This fact must be borne close in mind whenever reporter genes are attached to proteins.

  1. Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology.

    PubMed

    Thomsen, Morten S; Hansen, Henrik H; Timmerman, Daniel B; Mikkelsen, Jens D

    2010-01-01

    Agonists and positive allosteric modulators of the alpha(7) nicotinic acetylcholine receptor (nAChR) are currently being developed for the treatment of cognitive disturbances in patients with schizophrenia or Alzheimer's disease. This review describes the neurobiological properties of the alpha nAChR and the cognitive effects of alpha(7) nAChR activation, focusing on the translational aspects in the development of these drugs. The functional properties and anatomical localization of the alpha(7) nAChR makes it well suited to modulate cognitive function. Accordingly, systemic administration of alpha(7) nAChR agonists improves learning, memory, and attentional function in variety of animal models, and pro-cognitive effects of alpha(7) nAChR agonists have recently been demonstrated in patients with schizophrenia or Alzheimer's disease. The alpha(7) nAChR desensitizes rapidly in vitro, and this has been a major concern in the development of alpha(7) nAChR agonists as putative drugs. Our review of the existing literature shows that development of tolerance to the behavioral effects of alpha(7) nAChR agonists does not occur in animal models or humans. However, the long-term memory-enhancing effects seen in animal models are not mimicked in healthy humans and schizophrenic patients, where attentional improvement predominates. This discrepancy may result from inherent differences in testing methods or from species differences in the level of expression of alpha(7) nAChRs in limbic brain regions, and may hamper preclinical evaluation of alpha(7) nAChR activation. It is therefore important to consider the translational power of the animal models used before entering into a clinical evaluation of the pro-cognitive effects of alpha(7) nAChR activation.

  2. Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.

    PubMed

    Marcus, Monica M; Björkholm, Carl; Malmerfelt, Anna; Möller, Annie; Påhlsson, Ninni; Konradsson-Geuken, Åsa; Feltmann, Kristin; Jardemark, Kent; Schilström, Björn; Svensson, Torgny H

    2016-09-01

    Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

  3. Some properties of human neuronal α7 nicotinic acetylcholine receptors fused to the green fluorescent protein

    PubMed Central

    Palma, Eleonora; Mileo, Anna M.; Martínez-Torres, Ataúlfo; Eusebi, Fabrizio; Miledi, Ricardo

    2002-01-01

    The functional properties and cellular localization of the human neuronal α7 nicotinic acetylcholine (AcCho) receptor (α7 AcChoR) and its L248T mutated (mut) form were investigated by expressing them alone or as gene fusions with the enhanced version of the green fluorescent protein (GFP). Xenopus oocytes injected with wild-type (wt), mutα7, or the chimeric subunit cDNAs expressed receptors that gated membrane currents when exposed to AcCho. As already known, AcCho currents generated by wtα7 receptors decay much faster than those elicited by the mutα7 receptors. Unexpectedly, the fusion of GFP to the wt and mutated α7 receptors led to opposite results: the AcCho-current decay of the wt receptors became slower, whereas that of the mutated receptors was accelerated. Furthermore, repetitive applications of AcCho led to a considerable “run-down” of the AcCho currents generated by mutα7-GFP receptors, whereas those of the wtα7-GFP receptors remained stable or increased in amplitude. The AcCho-current run-down of mutα7-GFP oocytes was accompanied by a marked decrease of α-bungarotoxin binding activity. Fluorescence, caused by the chimeric receptors expressed, was seen over the whole oocyte surface but was more intense and abundant in the animal hemisphere, whereas it was much weaker in the vegetal hemisphere. We conclude that fusion of GFP to wtα7 and mutα7 receptors provides powerful tools to study the distribution and function of α7 receptors. We also conclude that fused genes do not necessarily recapitulate all of the properties of the original receptors. This fact must be borne close in mind whenever reporter genes are attached to proteins. PMID:11891308

  4. Convergence of nicotine-induced and auditory-evoked neural activity activates ERK in auditory cortex.

    PubMed

    Kawai, Hideki D; La, Maggie; Kang, Ho-An; Hashimoto, Yusuke; Liang, Kevin; Lazar, Ronit; Metherate, Raju

    2013-08-01

    Enhancement of sound-evoked responses in auditory cortex (ACx) following administration of systemic nicotine is known to depend on activation of extracellular-signaling regulated kinase (ERK), but the nature of this enhancement is not clear. Here, we show that systemic nicotine increases the density of cells immunolabeled for phosphorylated (activated) ERK (P-ERK) in mouse primary ACx (A1). Cortical injection of dihydro-β-erythroidine reduced nicotine-induced P-ERK immunolabel, suggesting a role for nicotinic acetylcholine receptors located in A1 and containing α4 and β2 subunits. P-ERK expressing cells were distributed mainly in layers 2/3 and more sparsely in lower layers, with many cells exhibiting immunolabel within pyramidal-shaped somata and proximal apical dendrites. About one-third of P-ERK positive cells also expressed calbindin. In the thalamus, P-ERK immunopositive cells were found in the nonlemniscal medial geniculate (MG) and adjacent nuclei, but were absent in the lemniscal MG. Pairing broad spectrum acoustic stimulation (white noise) with systemic nicotine increased P-ERK immunopositive cell density in ACx as well as the total amount of P-ERK protein, particularly the phosphorylated form of ERK2. However, narrow spectrum (tone) stimulation paired with nicotine increased P-ERK immunolabel preferentially at a site within A1 where the paired frequency was characteristic frequency (CF), relative to a second site with a spectrally distant CF (two octaves above or below the paired frequency). Together, these results suggest that ERK is activated optimally where nicotinic signaling and sound-evoked neural activity converge.

  5. Prejunctional inhibition of norepinephrine release caused by acetylcholine in the human saphenous vein

    SciTech Connect

    Rorie, D.K.; Rusch, N.J.; Shepherd, J.T.; Vanhoutte, P.M.; Tyce, G.M.

    1981-08-01

    We performed experiments to determine whether or not acetylcholine exerts a prejunctional inhibitory effect on adrenergic neurotransmission in the human blood vessel wall. Rings of human greater saphenous veins were prepared 2 to 15 hours after death and mounted for isometric tension recording in organ chambers filled with Krebs-Ringer solution. Acetylcholine depressed contractile responses to electric activation of the sympathetic nerve endings significantly more than those to exogenous norepinephrine; the relaxations caused by the cholinergic transmitter were antagonized by atropine. Helical strips were incubated with (/sub 3/H)norepinephrine and mounted for superfusion. Electric stimulation augmented the fractional release of labeled norepinephrine. Acetylcholine caused a depression of the evoked /sub 3/H release which was antagonized by atropine but not by hexamethonium. These experiments demonstrate that, as in animal cutaneous veins, there are prejunctional inhibitory muscarinic receptors on the adrenergic nerve endings in the human saphenous vein. By contrast, the human vein also contains postjunctional inhibitory muscarinic receptors.

  6. Mechanisms underlying the basal forebrain enhancement of top-down and bottom-up attention.

    PubMed

    Avery, Michael C; Dutt, Nikil; Krichmar, Jeffrey L

    2014-03-01

    Both attentional signals from frontal cortex and neuromodulatory signals from basal forebrain (BF) have been shown to influence information processing in the primary visual cortex (V1). These two systems exert complementary effects on their targets, including increasing firing rates and decreasing interneuronal correlations. Interestingly, experimental research suggests that the cholinergic system is important for increasing V1's sensitivity to both sensory and attentional information. To see how the BF and top-down attention act together to modulate sensory input, we developed a spiking neural network model of V1 and thalamus that incorporated cholinergic neuromodulation and top-down attention. In our model, activation of the BF had a broad effect that decreases the efficacy of top-down projections and increased the reliance of bottom-up sensory input. In contrast, we demonstrated how local release of acetylcholine in the visual cortex, which was triggered through top-down gluatmatergic projections, could enhance top-down attention with high spatial specificity. Our model matched experimental data showing that the BF and top-down attention decrease interneuronal correlations and increase between-trial reliability. We found that decreases in correlations were primarily between excitatory-inhibitory pairs rather than excitatory-excitatory pairs and suggest that excitatory-inhibitory decorrelation is necessary for maintaining low levels of excitatory-excitatory correlations. Increased inhibitory drive via release of acetylcholine in V1 may then act as a buffer, absorbing increases in excitatory-excitatory correlations that occur with attention and BF stimulation. These findings will lead to a better understanding of the mechanisms underyling the BF's interactions with attention signals and influences on correlations.

  7. Neural Networks for Flight Control

    NASA Technical Reports Server (NTRS)

    Jorgensen, Charles C.

    1996-01-01

    Neural networks are being developed at NASA Ames Research Center to permit real-time adaptive control of time varying nonlinear systems, enhance the fault-tolerance of mission hardware, and permit online system reconfiguration. In general, the problem of controlling time varying nonlinear systems with unknown structures has not been solved. Adaptive neural control techniques show considerable promise and are being applied to technical challenges including automated docking of spacecraft, dynamic balancing of the space station centrifuge, online reconfiguration of damaged aircraft, and reducing cost of new air and spacecraft designs. Our experiences have shown that neural network algorithms solved certain problems that conventional control methods have been unable to effectively address. These include damage mitigation in nonlinear reconfiguration flight control, early performance estimation of new aircraft designs, compensation for damaged planetary mission hardware by using redundant manipulator capability, and space sensor platform stabilization. This presentation explored these developments in the context of neural network control theory. The discussion began with an overview of why neural control has proven attractive for NASA application domains. The more important issues in control system development were then discussed with references to significant technical advances in the literature. Examples of how these methods have been applied were given, followed by projections of emerging application needs and directions.

  8. Neural Network Studies

    DTIC Science & Technology

    1993-07-01

    basic useful theorems and general rules which apply to neural networks (in ’Overview of Neural Network Theory’), studies of training time as the...The Neural Network , Bayes- Gaussian, and k-Nearest Neighbor Classifiers’), an analysis of fuzzy logic and its relationship to neural network (in ’Fuzzy

  9. Computer modeling of the neurotoxin binding site of acetylcholine receptor spanning residues 185 through 196

    NASA Technical Reports Server (NTRS)

    Garduno-Juarez, R.; Shibata, M.; Zielinski, T. J.; Rein, R.

    1987-01-01

    A model of the complex between the acetylcholine receptor and the snake neurotoxin, cobratoxin, was built by molecular model building and energy optimization techniques. The experimentally identified functionally important residues of cobratoxin and the dodecapeptide corresponding to the residues 185-196 of acetylcholine receptor alpha subunit were used to build the model. Both cis and trans conformers of cyclic L-cystine portion of the dodecapeptide were examined. Binding residues independently identified on cobratoxin are shown to interact with the dodecapeptide AChR model.

  10. Subtype Differences in Pre-Coupling of Muscarinic Acetylcholine Receptors

    PubMed Central

    Jakubík, Jan; Janíčková, Helena; Randáková, Alena; El-Fakahany, Esam E.; Doležal, Vladimír

    2011-01-01

    Based on the kinetics of interaction between a receptor and G-protein, a myriad of possibilities may result. Two extreme cases are represented by: 1/Collision coupling, where an agonist binds to the free receptor and then the agonist-receptor complex “collides” with the free G-protein. 2/Pre-coupling, where stable receptor/G-protein complexes exist in the absence of agonist. Pre-coupling plays an important role in the kinetics of signal transduction. Odd-numbered muscarinic acetylcholine receptors preferentially couple to Gq/11, while even-numbered receptors prefer coupling to Gi/o. We analyzed the coupling status of the various subtypes of muscarinic receptors with preferential and non-preferential G-proteins. The magnitude of receptor-G-protein coupling was determined by the proportion of receptors existing in the agonist high-affinity binding conformation. Antibodies directed against the C-terminus of the α-subunits of the individual G-proteins were used to interfere with receptor-G-protein coupling. Effects of mutations and expression level on receptor-G-protein coupling were also investigated. Tested agonists displayed biphasic competition curves with the antagonist [3H]-N-methylscopolamine. Antibodies directed against the C-terminus of the α-subunits of the preferential G-protein decreased the proportion of high-affinity sites, and mutations at the receptor-G-protein interface abolished agonist high-affinity binding. In contrast, mutations that prevent receptor activation had no effect. Expression level of preferential G-proteins had no effect on pre-coupling to non-preferential G-proteins. Our data show that all subtypes of muscarinic receptors pre-couple with their preferential classes of G-proteins, but only M1 and M3 receptors also pre-couple with non-preferential Gi/o G-proteins. Pre-coupling is not dependent on agonist efficacy nor on receptor activation. The ultimate mode of coupling is therefore dictated by a combination of the receptor subtype

  11. The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

    PubMed Central

    Sors, Aurore; Krazem, Ali; Kehr, Jan; Yoshitake, Takashi; Dominguez, Gaelle; Henkous, Nadia; Letondor, Claire; Mocaer, Elisabeth; Béracochéa, Daniel J.

    2016-01-01

    Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.1 and 0.3 mg/kg) and S 38093 (at 0.1, 0.3, and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system. PMID:28066242

  12. Higher-Order Neural Networks Recognize Patterns

    NASA Technical Reports Server (NTRS)

    Reid, Max B.; Spirkovska, Lilly; Ochoa, Ellen

    1996-01-01

    Networks of higher order have enhanced capabilities to distinguish between different two-dimensional patterns and to recognize those patterns. Also enhanced capabilities to "learn" patterns to be recognized: "trained" with far fewer examples and, therefore, in less time than necessary to train comparable first-order neural networks.

  13. Electronic Neural Networks

    NASA Technical Reports Server (NTRS)

    Thakoor, Anil

    1990-01-01

    Viewgraphs on electronic neural networks for space station are presented. Topics covered include: electronic neural networks; electronic implementations; VLSI/thin film hybrid hardware for neurocomputing; computations with analog parallel processing; features of neuroprocessors; applications of neuroprocessors; neural network hardware for terrain trafficability determination; a dedicated processor for path planning; neural network system interface; neural network for robotic control; error backpropagation algorithm for learning; resource allocation matrix; global optimization neuroprocessor; and electrically programmable read only thin-film synaptic array.

  14. Temporal coherency between receptor expression, neural activity and AP-1-dependent transcription regulates Drosophila motoneuron dendrite development.

    PubMed

    Vonhoff, Fernando; Kuehn, Claudia; Blumenstock, Sonja; Sanyal, Subhabrata; Duch, Carsten

    2013-02-01

    Neural activity has profound effects on the development of dendritic structure. Mechanisms that link neural activity to nuclear gene expression include activity-regulated factors, such as CREB, Crest or Mef2, as well as activity-regulated immediate-early genes, such as fos and jun. This study investigates the role of the transcriptional regulator AP-1, a Fos-Jun heterodimer, in activity-dependent dendritic structure development. We combine genetic manipulation, imaging and quantitative dendritic architecture analysis in a Drosophila single neuron model, the individually identified motoneuron MN5. First, Dα7 nicotinic acetylcholine receptors (nAChRs) and AP-1 are required for normal MN5 dendritic growth. Second, AP-1 functions downstream of activity during MN5 dendritic growth. Third, using a newly engineered AP-1 reporter we demonstrate that AP-1 transcriptional activity is downstream of Dα7 nAChRs and Calcium/calmodulin-dependent protein kinase II (CaMKII) signaling. Fourth, AP-1 can have opposite effects on dendritic development, depending on the timing of activation. Enhancing excitability or AP-1 activity after MN5 cholinergic synapses and primary dendrites have formed causes dendritic branching, whereas premature AP-1 expression or induced activity prior to excitatory synapse formation disrupts dendritic growth. Finally, AP-1 transcriptional activity and dendritic growth are affected by MN5 firing only during development but not in the adult. Our results highlight the importance of timing in the growth and plasticity of neuronal dendrites by defining a developmental period of activity-dependent AP-1 induction that is temporally locked to cholinergic synapse formation and dendritic refinement, thus significantly refining prior models derived from chronic expression studies.

  15. Development of the electromotor system of Torpedo marmorata: distribution of extracellular matrix and cytoskeletal components during acetylcholine receptor focalization.

    PubMed

    Richardson, G P; Fiedler, W; Fox, G Q

    1987-03-01

    A combination of direct fluorescence and indirect immunofluorescence microscopy has been used to compare the distribution of the acetylcholine receptor with the distribution of major cytoskeletal and extracellular matrix components during electrocyte differentiation in the electric organs of Torpedo marmorata. Laminin, fibronectin and extracellular matrix proteoglycan are always more extensively distributed around the differentiating cell than the acetylcholine receptor-rich patch that forms on the ventral surface of the cell. The distribution of acetylcholinesterase within the ventral surface of the differentiating electrocyte closely resembles the distribution of the acetylcholine receptor. Areas of apparently high acetylcholine receptor density within the ventrally forming acetylcholine receptor-rich patch are always areas of apparently high extracellular matrix proteoglycan density but are not always areas of high laminin or fibronectin density. Desmin levels appear to increase at the onset of differentiation and desmin initially accumulates in the ventral pole of each myotube as it begins to form an electrocyte. During differentiation F-actin-positive filament bundles are observed that extend from the nuclei down to the ventrally forming acetylcholine receptor-rich patch. Most filament bundles terminate in the acetylcholine receptor-rich region of the cell membrane. Electron-microscopic autoradiography suggests that the filament bundles attach to the membrane at sites where small acetylcholine receptor clusters are found. The results of this study suggest that, out of the four extracellular matrix components studied, only the distribution of acetylcholinesterase (which may be both matrix- and membrane-bound at this stage) closely parallels that of the acetylcholine receptor, and that F-actin filament bundles terminate in a region of the cell that is becoming an area of high acetylcholine receptor density.

  16. Regulation of GABA release by nicotinic acetylcholine receptors in the neonatal rat hippocampus

    PubMed Central

    Maggi, Laura; Sher, Emanuele; Cherubini, Enrico

    2001-01-01

    The whole-cell configuration of the patch-clamp technique was used to study the modulation of giant depolarizing potentials (GDPs) by nicotinic acetylcholine receptors (nAChRs) in CA3 hippocampal neurons in slices from postnatal day (P) 2–6 rats.Bath application of nicotine increased GDP frequency in a concentration-dependent manner. For example, nicotine (0.5–1 μm) enhanced GDP frequency from 0.05 ± 0.04 to 0.17 ± 0.04 Hz. This effect was prevented by the broad-spectrum nicotinic receptor antagonist dihydro-β-erythtroidine (DHβE, 50 μm) and partially antagonized by methyllycaconitine (MLA, 50 nm) a competitive antagonist of α7 nAChRs. GDP frequency was also enhanced by AR-17779 (100 μm), a selective agonist of α7 nAChRs.The GABAA receptor antagonist bicuculline (10 μm) and the non-NMDA glutamate receptor antagonist DNQX (20 μm) blocked GDPs and prevented the effects of nicotine on GDPs. In the presence of DNQX, nicotine increased GABA-mediated synaptic noise, indicating that this drug may have a direct effect on GABAergic interneurons.Bath application of edrophonium (20 μm), a cholinesterase inhibitor, in the presence of atropine (1 μm), increased GDP frequency, indicating that nAChRs can be activated by ACh released from the septo-hippocampal fibres. This effect was prevented by DHβE (50 μm).In the majority of neurons tested, MLA (50 nm) and DHβE (50 μm) reduced the frequency of GDPs with different efficacy: a reduction of 98 ± 11 and 61 ± 29 % was observed with DHβE and MLA, respectively. In a subset of cells (40 % in the case of MLA and 17 % in the case of DHβE) these drugs induced a twofold increase in GDP frequency.It is suggested that, during development, nAChRs modulate the release of GABA, assessed as GDPs, through distinct nAChRs. The rise of intracellular calcium via nAChRs would further strengthen GABA-mediated oscillatory activity. This can be crucial for consolidation of synaptic contacts and for the fine-tuning of the

  17. Acetylcholine-induced neuronal differentiation: muscarinic receptor activation regulates EGR-1 and REST expression in neuroblastoma cells.

    PubMed

    Salani, Monica; Anelli, Tonino; Tocco, Gabriella Augusti; Lucarini, Elena; Mozzetta, Chiara; Poiana, Giancarlo; Tata, Ada Maria; Biagioni, Stefano

    2009-02-01

    Neurotransmitters are considered part of the signaling system active in nervous system development and we have previously reported that acetylcholine (ACh) is capable of enhancing neuronal differentiation in cultures of sensory neurons and N18TG2 neuroblastoma cells. To study the mechanism of ACh action, in this study, we demonstrate the ability of choline acetyltransferase-transfected N18TG2 clones (e.g. 2/4 clone) to release ACh. Analysis of muscarinic receptors showed the presence of M1-M4 subtypes and the activation of both IP(3) and cAMP signal transduction pathways. Muscarinic receptor activation increases early growth response factor-1 (EGR-1) levels and treatments with agonists, antagonists, and signal transduction enzyme inhibitors suggest a role for M3 subtype in EGR-1 induction. The role of EGR-1 in the enhancement of differentiation was investigated transfecting in N18TG2 cells a construct for EGR-1. EGR-1 clones show increased neurite extension and a decrease in Repressor Element-1 silencing transcription factor (REST) expression: both these features have also been observed for the 2/4 clone. Transfection of this latter with EGR zinc-finger domain, a dominant negative inhibitor of EGR-1 action, increases REST expression, and decreases fiber outgrowth. The data reported suggest that progression of the clone 2/4 in the developmental program is dependent on ACh release and the ensuing activation of muscarinic receptors, which in turn modulate the level of EGR-1 and REST transcription factors.

  18. A Subpopulation of Neuronal M4 Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors

    PubMed Central

    Jeon, Jongrye; Dencker, Ditte; Wortwein, Gitta; Woldbye, David P. D.; Cui, Yinghong; Davis, Albert A.; Levey, Allan I.; Schütz, Günther; Sager, Thomas; Mørk, Arne; Li, Cuiling; Deng, Chu-Xia; Fink-Jensen, Anders; Wess, Jürgen

    2010-01-01

    Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M1–M5 mAChRs). Like other mAChR subtypes, the M4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M4 mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M4 mAChRs only in D1 dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes wereaccompanied by a lack of muscarinic inhibition of D1 dopamine receptor-mediated camp stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M4 mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance. PMID:20147565

  19. Rabies virus binding to an acetylcholine receptor alpha-subunit peptide.

    PubMed

    Lentz, T L

    1990-04-01

    The binding of 125I-labeled rabies virus to a synthetic peptide comprising residues 173-204 of the alpha 1-subunit of the nicotinic acetylcholine receptor was investigated. Binding of rabies virus to the receptor peptide was dependent on pH, could be competed with by unlabeled homologous virus particles, and was saturable. Synthetic peptides of snake venom, curaremimetic neurotoxins and of the structurally similar segment of the rabies virus glycoprotein, were effective in competing with labeled virus binding to the receptor peptide at micromolar concentrations. Similarly, synthetic peptides of the binding domain on the acetylcholine receptor competed for binding. These findings suggest that both rabies virus and neurotoxins bind to residues 173-204 of the alpha 1-subunit of the acetylcholine receptor. Competition studies with shorter alpha-subunit peptides within this region indicate that the highest affinity virus binding determinants are located within residues 179-192. A rat nerve alpha 3-subunit peptide, that does not bind alpha-bungarotoxin, inhibited binding of virus to the alpha 1 peptide, suggesting that rabies binds to neuronal nicotinic acetylcholine receptors. These studies indicate that synthetic peptides of the glycoprotein binding domain and of the receptor binding domain may represent useful antiviral agents by targeting the recognition event between the viral attachment protein and the host cell receptor, and inhibiting attachment of virus to the receptor.

  20. Molecular forms and subunit structure of the acetylcholine receptor in the central nervous system of insects.

    PubMed

    Breer, H; Kleene, R; Hinz, G

    1985-12-01

    The nicotinic acetylcholine receptor as probed by alpha-bungarotoxin binding has been isolated from detergent-solubilized ganglionic membrane preparations from the insect, Locusta migratoria. The isolation and characterization of the receptor protein was achieved by preparation of membrane fragments, extraction by sodium deoxycholate, centrifugation on sucrose density gradient, affinity chromatography, gel electrophoresis, and immunoblotting. The purified receptor protein migrated as a single band on polyacrylamide when native (Mr = 250,000 to 300,000) but also under denaturing conditions (Mr = 65,000) and cross-reacted with some monoclonal antibodies against the Torpedo receptor. In immunohistochemical approaches using polyclonal antibodies the acetylcholine receptor antigenic sites could topochemically be identified at very distinct zones in the neuropil of locust ganglia. The results suggest that the acetylcholine receptor in the central nervous system of insects represents an oligomeric complex composed of four identical or very similar subunits and thus may represent a prototype of the recently proposed homo-oligomeric ancestral acetylcholine receptor.