The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Martin Sarter - One of the best experts on this subject based on the ideXlab platform.
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Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition
Neuropsychopharmacology, 2011Co-Authors: Michael E Hasselmo, Martin SarterAbstract:As indicated by the profound cognitive impairments caused by Cholinergic receptor antagonists, Cholinergic neurotransmission has a vital role in cognitive function, specifically attention and memory encoding. Abnormally regulated Cholinergic neurotransmission has been hypothesized to contribute to the cognitive symptoms of neuropsychiatric disorders. Loss of Cholinergic neurons enhances the severity of the symptoms of dementia. Cholinergic receptor agonists and acetylcholinesterase inhibitors have been investigated for the treatment of cognitive dysfunction. Evidence from experiments using new techniques for measuring rapid changes in Cholinergic neurotransmission provides a novel perspective on the Cholinergic regulation of cognitive processes. This evidence indicates that changes in Cholinergic modulation on a timescale of seconds is triggered by sensory input cues and serves to facilitate cue detection and attentional performance. Furthermore, the evidence indicates Cholinergic induction of evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input, and planned responses. Models have been developed to describe the neuronal mechanisms underlying the transient modulation of cortical target circuits by Cholinergic activity. These models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that Cholinergic neurotransmission is controlled in part by (cortical) target circuits. The available evidence and these models point to new principles governing the development of the next generation of Cholinergic treatments for cognitive disorders.
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glutamatergic contributions to nicotinic acetylcholine receptor agonist evoked Cholinergic transients in the prefrontal cortex
The Journal of Neuroscience, 2008Co-Authors: Vinay Parikh, Michael W. Decker, Martin SarterAbstract: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 α4β2*-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 β2*-selective nAChR antagonist dihydro-β-erythroidine. The α7 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.
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Cholinergic mediation of attention: contributions of phasic and tonic increases in prefrontal Cholinergic activity.
Annals of the New York Academy of Sciences, 2008Co-Authors: Vinay Parikh, Martin SarterAbstract:Contrary to the classic description of acetylcholine (ACh) as a slowly acting neuromodulator that influences arousal states, results from experiments that employed enzyme-selective microelectrodes for the real-time monitoring of ACh release in the cortex of attentional task-performing rats indicate that Cholinergic signals manifesting on multiple timescales (seconds, tens of seconds, and minutes) support, and are necessary for, the mediation of defined cognitive operations. Specifically, in the prefrontal cortex, second-based Cholinergic signals support the detection of behaviorally significant cues. In contrast to these prefrontal Cholinergic transients, performance-associated Cholinergic activity that manifested at lower temporal resolution also was observed elsewhere in the cortex. Although tonic Cholinergic signal levels were correlated with the amplitudes of cue-evoked Cholinergic transients, and the latter with response latencies, the interrelationships and interactions between the multiple Cholinergic signaling modes remains unclear. Hypotheses concerning the afferent circuitry contributing to the regulation of second- versus minute-based Cholinergic signals are discussed. The discovery of Cholinergic transients and their crucial role in cue detection and attentional performance form the basis for new hypotheses about the nature of Cholinergic dysfunction in cognitive disorders and offer new targets for the development of treatments for the cognitive symptoms of neuropsychiatric and neurodegenerative disorders.
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prefrontal acetylcholine release controls cue detection on multiple timescales
Neuron, 2007Co-Authors: Vinay Parikh, Rouba Kozak, Vicente Martinez, Martin SarterAbstract:Cholinergic neurons originating from the basal forebrain innervate the entire cortical mantle. Choline-sensitive microelectrodes were used to measure the synaptic release of cortical acetylcholine (ACh) at a subsecond resolution in rats performing a task involving the detection of cues. Cues that were detected, defined behaviorally, evoked transient increases in Cholinergic activity (at the scale of seconds) in the medial prefrontal cortex (mPFC), but not in a nonassociational control region (motor cortex). In trials involving missed cues, Cholinergic transients were not observed. Cholinergic deafferentation of the mPFC, but not motor cortex, impaired cue detection. Furthermore, decreases and increases in precue Cholinergic activity predicted subsequent cue detection or misses, respectively. Finally, cue-evoked Cholinergic transients were superimposed over slower (at the timescale of minutes) changes in Cholinergic activity. Cortical Cholinergic neurotransmission is regulated on multiple timescales to mediate the detection of behaviorally significant cues and to support cognitive performance.
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unraveling the attentional functions of cortical Cholinergic inputs interactions between signal driven and cognitive modulation of signal detection
Brain Research Reviews, 2005Co-Authors: Martin Sarter, Michael E Hasselmo, John P Bruno, Ben GivensAbstract:Neurophysiological studies demonstrated that increases in Cholinergic transmission in sensory areas enhance the cortical processing of thalamic inputs. Cholinergic activity also suppresses the retrieval of internal associations, thereby further promoting sensory input processing. Behavioral studies documented the role of cortical Cholinergic inputs in attentional functions and capacities by demonstrating, for example, that the integrity of the cortical Cholinergic input system is necessary for attentional performance, and that the activity of cortical Cholinergic inputs is selectively enhanced during attentional performance. This review aims at integrating the neurophysiological and behavioral evidence on the functions of cortical Cholinergic inputs and hypothesizes that the cortical Cholinergic input system generally acts to optimize the processing of signals in attention-demanding contexts. Such signals drecruitT, via activation of basal forebrain corticopetal Cholinergic projections, the cortical attention systems and thereby amplify the processing of attentiondemanding signals (termed dsignal-driven Cholinergic modulation of detectionT). The activity of corticopetal Cholinergic projections is also modulated by direct prefrontal projections to the basal forebrain and, indirectly, to Cholinergic terminals elsewhere in the cortex; thus, cortical Cholinergic inputs are also involved in the mediation of top-down effects, such as the knowledge-based augmentation of detection (see Footnote 1) of signals and the filtering of irrelevant information (termed dcognitive Cholinergic modulation of detectionT). Thus, depending on the quality of signals and task characteristics, cortical Cholinergic activity reflects the combined effects of signaldriven and cognitive modulation of detection. This hypothesis begins to explain signal intensity or duration-dependent performance in attention tasks, the distinct effects of cortex-wide versus prefrontal Cholinergic deafferentation on attention performance, and it generates specific predictions concerning cortical acetylcholine (ACh) release in attention task-performing animals. Finally, the consequences of abnormalities in the regulation of cortical Cholinergic inputs for the manifestation of the symptoms of major neuropsychiatric disorders are conceptualized in terms of dysregulation in the signal-driven and cognitive Cholinergic modulation of detection processes.
Francesco Amenta - One of the best experts on this subject based on the ideXlab platform.
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Effects of Cholinergic Enhancing Drugs on Cholinergic Transporters in the Brain and Peripheral Blood Lymphocytes of Spontaneously Hypertensive Rats
Current Alzheimer research, 2012Co-Authors: Daniele Tomassoni, Assia Catalani, C. Cinque, Maria Antonietta Di Tullio, Seyed Khosrow Tayebati, Angela Cadoni, Innocent Ejike Nwankwo, Enea Traini, Francesco AmentaAbstract:Cholinergic hypofunction is a trait of Alzheimers disease and vascular dementia and countering it is one of the main therapeutic strategies available for these disorders. Cholinergic transporters control cellular mechanisms of acetylcholine (ACh) synthesis and release at presynaptic terminals. This study has assessed the influence of 4 week treatment with two different Cholinergic enhancing drugs, the Cholinergic precursor choline alphoscerate (alpha-glyceryl-phosphorylcholine) or the acetylcholinesterase (AChE) inhibitor galantamine on high affinity choline uptake transporter (CHT) and vesicular ACh transporter (VAChT) expression in the brain of spontaneously hypertensive rats (SHR). SHR represent an animal model of cerebrovascular injury characterized by Cholinergic hypofunction. Analysis was performed by immunochemistry, ELISA and immunohistochemistry on frontal cortex, striatum and hippocampus. Immunochemical and ELISA analysis was extended to peripheral blood lymphocytes (PBL), used as a peripheral reference of changes of brain Cholinergic markers. An increased expression of VAChT and CHT was observed in brain areas investigated and in PBL of SHR. The similar trend for Cholinergic transporters observed in brain and PBL suggests these cells may represent a marker of brain Cholinergic transporters. Treatment with choline alphoscerate increased CHT and to a greater extent VAChT expression. Treatment with galantamine countered the increase of CHT and VAChT. The different activity of the Cholinergic precursor and of the AChE inhibitor on parameters investigated is likely related to their mechanism of action. Choline alphoscerate increases ACh synthesis and release. This requires an augmentation of systems regulating neurotransmitter uptake and storage. The effect of choline alphoscerate on CHT and VAChT observed in this study suggests an improved synaptic efficiency elicited by the compound. The AChE inhibitor slows-down ACh degradation in the synaptic cleft. A greater availability of neurotransmitter elicited by galantamine counters the enhanced activity of Cholinergic transporters compensating Cholinergic deficits. Differences in the activity of the Cholinergic precursor and AChE inhibitor investigated on CHT and VAChT suggests that association between choline alphoscerate and AChE/cholinesterase inhibitors may represent a strategy for potentiating deficient Cholinergic neurotransmission worthwhile of being investigated in clinical trials.
Yves Agid - One of the best experts on this subject based on the ideXlab platform.
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Does the enhancement of Cholinergic neurotransmission influence brain glucose kinetics and clinical symptomatology in progressive supranuclear palsy
Brain, 1995Co-Authors: Joël Blin, P. Mazetti, S. Ben Ayed, C. Malapani, S Rivaud, Bernard Mazoyer, Bernard Pillon, Yves AgidAbstract:Summary Chotinergic systems are markedly affected both in cortical and subcortical cerebral areas of patients with progressive supranuclear palsy(PSP). To determine whether it is possible to modify the clinical picture of PSP through the enhancement of brain Cholinergic neurotransmission, we studied the effects of physostigmine, an anticholinesterase reference drug, on symptoms and brain glucose metabolism using (18F)fluorodeoxyglucose (FDG) and PET. Patients were evaluated blind in a randomized order with both placebo and physostigmine infusions after an individual determination of maximal tolerated dose. Under steady-state physostigmine infusions, although glucose consumption was not significantly modified, the entry of glucose from blood to brain was regionally increased from 8 to 32% of placebo values suggesting an increase in cerebral blood flow (CBF) or an increase in the activity of brain glucose transporter. Following physostigmine administration in the same patients: the errors in antisaccades during ocular movement testing were significantly reduced, a significant reduction in errors or performance was found in four out of seven neuropsycho-logical tests, and motor disability was not significantly altered. Although the precise pathophysiology of these physostigmine-induced effects needs further investigations, our study suggests that part of the clinical symptomatology in PSP could be relieved by the enhancement of brain Cholinergic neurotransmission
Lorna W. Role - One of the best experts on this subject based on the ideXlab platform.
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Cholinergic circuits and signaling in the pathophysiology of schizophrenia.
International review of neurobiology, 2007Co-Authors: Joshua A. Berman, David A. Talmage, Lorna W. RoleAbstract:Central Cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central Cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central Cholinergic circuits are resistant to simplification—particularly when one tries to parse the contributions of various classes of Cholinergic receptors to disease related phenomena—the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of Cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of Cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.
Marsel M Mesulam - One of the best experts on this subject based on the ideXlab platform.
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revisiting the Cholinergic hypothesis in alzheimer s disease emerging evidence from translational and clinical research
The journal of prevention of Alzheimer's disease, 2019Co-Authors: Harald Hampel, Marsel M Mesulam, Martin R Farlow, Ezio Giacobini, Ara S Khachaturian, Andrea Vergallo, Peter J Snyder, A. C. Cuello, Z. S. KhachaturianAbstract:Scientific evidence collected over the past 4 decades suggests that a loss of Cholinergic innervation in the cerebral cortex of patients with Alzheimer’s disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the “Cholinergic Hypothesis of AD” and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the Cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the Cholinergic system and suggesting that Cholinergic therapy may slow brain atrophy. Other pathways that contribute to Cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the Cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.
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the Cholinergic system in the pathophysiology and treatment of alzheimer s disease
PMC, 2018Co-Authors: Harald Hampel, Marsel M Mesulam, Claudio A Cuello, Martin R Farlow, Ezio Giacobini, George T Grossberg, Ara S Khachaturian, Andrea Vergallo, Enrica Cavedo, Peter J SnyderAbstract:Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that Cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for Cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's Cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The Cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical Cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain Cholinergic neurons, giving rise to a widespread presynaptic Cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the Cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the Cholinergic system in cognition and an updated understanding of how Cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of Cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of Cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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withdrawn revisiting the Cholinergic hypothesis in alzheimer s disease emerging evidence from translational and clinical research
Alzheimers & Dementia, 2017Co-Authors: Harald Hampel, Marsel M Mesulam, Claudio A Cuello, Martin R Farlow, Ezio Giacobini, Ara S Khachaturian, Peter J Snyder, Z. S. KhachaturianAbstract:Abstract Scientific evidence collected over the past four decades suggests that a loss of Cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease (AD) is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the “Cholinergic hypothesis of AD” and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the Cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the Cholinergic system and suggesting that Cholinergic therapy may slow brain atrophy. Other pathways that contribute to Cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the Cholinergic system is one of several interacting systems failures that contribute to AD pathogenesis.
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Cholinergic innervation of the human striatum globus pallidus subthalamic nucleus substantia nigra and red nucleus
The Journal of Comparative Neurology, 1992Co-Authors: Marsel M Mesulam, Deborah C Mash, Louis Hersh, Mark Bothwell, Changiz GeulaAbstract:The anatomical organization of Cholinergic markers such as acetylcholinesterase, choline acetyltransferase, and nerve growth factor receptors was investigated in the basal ganglia of the human brain. The distribution of choline acetyltransferase-immunoreactive axons and varicosities and their relationship to regional perikarya showed that the caudate, putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra, red nucleus, and subthalamic nucleus of the human brain receive widespread Cholinergic innervation. Components of the striatum (i.e., the putamen, caudate, olfactory tubercle, and nucleus accumbens) displayed the highest density of Cholinergic varicosities. The next highest density of Cholinergic innervation was detected in the red nucleus and subthalamic nucleus. The level of Cholinergic innervation was of intermediate density in the globus pallidus and the ventral tegmental area and low in the pars compacta of the substantia nigra. Immunoreactivity for nerve growth factor receptors (NGFr) was confined to the Cholinergic neurons of the basal forebrain and their processes. Axonal immunoreactivity for NGFr was therefore used as a marker for Cholinergic projections originating from the basal forebrain (Woolf et al., '89: Neuroscience 30:143–152). Although the vast majority of striatal Cholinergic innervation was NGFr-negative and, therefore, intrinsic, the striatum also contained NGFr-positive axons, indicating the existence of an additional Cholinergic input from the basal forebrain. This basal forebrain Cholinergic innervation was more pronounced in the putamen than in the caudate. The distribution of NGFr-positive axons suggested that the basal forebrain may also project to the globus pallidus but probably not to the subthalamic nucleus, substantia nigra, or red nucleus. The great majority of Cholinergic innervation to these latter three structures and to parts of the globus pallidus appeared to come from Cholinergic neurons outside the basal forebrain, most of which are probably located in the upper brainstem. These observations indicate that Cholinergic neurotransmission originating from multiple sources is likely to play an important role in the diverse motor and behavioral affiliations that have been attributed to the human basal ganglia. © 1992 Wiley-Liss, Inc.
