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Scientific Reports Dec 2022Inhibitory control is a key executive function that limits unnecessary thoughts and actions, enabling an organism to appropriately execute goal-driven behaviors. The...
Inhibitory control is a key executive function that limits unnecessary thoughts and actions, enabling an organism to appropriately execute goal-driven behaviors. The efficiency of this inhibitory capacity declines with normal aging or in neurodegenerative dementias similar to memory or other cognitive functions. Acetylcholine signaling is crucial for executive function and also diminishes with aging. Acetylcholine's contribution to the aging- or dementia-related decline in inhibitory control, however, remains elusive. We addressed this in Drosophila using a Go/No-Go task that measures inhibition capacity. Here, we report that inhibition capacity declines with aging in wild-type flies, which is mitigated by lessening acetylcholine breakdown and augmented by reducing acetylcholine biosynthesis. We identified the mushroom body (MB) γ neurons as a chief neural site for acetylcholine's contribution to the aging-associated inhibitory control deficit. In addition, we found that the MB output neurons MBON-γ2α'1 having dendrites at the MB γ2 and α'1 lobes and axons projecting to the superior medial protocerebrum and the crepine is critical for sustained movement suppression per se. This study reveals, for the first time, the central role of acetylcholine in the aging-associated loss of inhibitory control and provides a framework for further mechanistic studies.
Topics: Animals; Acetylcholine; Synaptic Transmission; Aging; Causality; Cognition; Drosophila
PubMed: 36463374
DOI: 10.1038/s41598-022-25402-z -
International Review of Neurobiology 2015
Topics: Acetylcholine; Animals; Humans; Mental Disorders; Receptors, Nicotinic; Tobacco Use Disorder
PubMed: 26472534
DOI: 10.1016/S0074-7742(15)00107-5 -
Frontiers in Neural Circuits 2023Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and...
Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and basal forebrain, and hippocampal-projecting neurons of the medial septum. The co-release of the functionally antagonistic neurotransmitters GABA and acetylcholine (ACh) greatly expands the possible functional effects of cholinergic neurons and provides an additional exogenous source of inhibition to the cortex. Transgene expression suggests that nearly all forebrain cholinergic neurons in mice at some point in development express , which encodes the vesicular GABA transporter (VGAT). To determine the degree of co-expression of GABA and Ach handling proteins, we measured expression in adult mice of , and (which encode GAD67 and GAD65, respectively, the GABA synthetic enzymes) in cholinergic neurons using fluorescent hybridization. We found that only a subset of cholinergic neurons express the necessary machinery for GABA release at a single time in adult mice. This suggests that GABA co-release from cholinergic neurons is dynamic and potentially developmentally regulated. By measuring expression of , , and in the basal forebrain and medial septum in mice from post-natal day 0 to 28, we noted abundant yet variable expressions of GABAergic markers across early development, which are subsequently downregulated in adulthood. This is in contrast with the forebrain-projecting pedunculopontine nucleus, which showed no evidence of co-expression of GABAergic genes. These results suggest that expression of GABA signaling machinery in the cortically-projecting cholinergic system peaks during early development before settling at a non-zero level that is maintained through adulthood.
Topics: Mice; Animals; Acetylcholine; In Situ Hybridization, Fluorescence; gamma-Aminobutyric Acid; Cholinergic Neurons; Cerebral Cortex; Gene Expression; Choline O-Acetyltransferase
PubMed: 37035505
DOI: 10.3389/fncir.2023.1125071 -
Ceska a Slovenska Farmacie : Casopis... Dec 2015The cholinergic system of the heart can be either of neuronal or non-neuronal origin. The neuronal cholinergic system in the heart is represented by preganglionic... (Review)
Review
The cholinergic system of the heart can be either of neuronal or non-neuronal origin. The neuronal cholinergic system in the heart is represented by preganglionic parasympathetic pathways, intracardiac parasympathetic ganglia and postganglionic parasympathetic neurons projecting to the atria, SA node and AV node. The non-neuronal cholinergic system consists of cardiomyocytes that have complete equipment for synthesis and secretion of acetylcholine. Current knowledge suggests that the non-neuronal cholinergic system in the heart affects the regulation of the heart during sympathetic activation. The non-neuronal cholinergic system of the heart plays also a role in the energy metabolism of cardimyocites. Acetylcholine of both neuronal and non-neuronal origin acts in the heart through muscarinic and nicotinic receptors. The effect of acetylcholine in the heart is terminated by cholinesterases acetylcholinesterase and butyrylcholinesterase. Recently, papers suggest that the increased cholinergic tone in the heart by cholinesterase inhibitors has a positive effect on some cardiovascular disorders such as heart failure. For this reason, the cholinesterase inhibitors might be used in the treatment of certain cardiovascular disorders in the future.
Topics: Acetylcholine; Animals; Cardiovascular Diseases; Cholinesterase Inhibitors; Ganglia, Parasympathetic; Heart; Humans; Parasympathetic Nervous System
PubMed: 26841700
DOI: No ID Found -
Current Protocols Feb 2023The serine hydrolase acetylcholinesterase (AChE) is an important neuronal enzyme which catalyzes the hydrolysis of the neurotransmitter acetylcholine and other choline...
The serine hydrolase acetylcholinesterase (AChE) is an important neuronal enzyme which catalyzes the hydrolysis of the neurotransmitter acetylcholine and other choline esters. The breakdown of acetylcholine by AChE terminates synaptic transmission and regulates neuromuscular communication. AChE inhibition is a common mode of action of various insecticides, such as carbamates and organophosphorus pesticides. Freshwater planarians, especially the species Dugesia japonica, have been shown to possess AChE activity and to be a suitable alternative model for studying the effects of pesticides in vivo. AChE activity can be quantified in homogenates using the Ellman assay. However, this biochemical assay requires specialized equipment and large numbers of planarians. Here, we present a protocol for visualizing AChE activity in individual planarians. Activity staining can be completed in several hours and can be executed using standard laboratory equipment (a fume hood, nutator, and light microscope with imaging capability). We describe the steps for preparing the reagents, and the staining and imaging of the planarians. Planarians are treated with 10% acetic acid and fixed with 4% paraformaldehyde and then incubated in a staining solution containing the substrate acetylthiocholine. After incubation in the staining solution for 3.5 hr on a nutator at 4°C, or stationary on ice, planarians are washed and mounted for imaging. Using exposure to an organophosphorus pesticide as an example, we show how AChE inhibition leads to a loss of staining. Thus, this simple method can be used to qualitatively evaluate AChE inhibition due to chemical exposure or RNA interference, providing a new tool for mechanistic studies of effects on the cholinergic system. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Preparing the staining solution Basic Protocol 2: Fixing, staining, and imaging whole-mount planarian specimens for visualization of acetylcholinesterase activity.
Topics: Animals; Acetylcholinesterase; Planarians; Organophosphorus Compounds; Pesticides; Acetylcholine; Fresh Water
PubMed: 36799654
DOI: 10.1002/cpz1.674 -
Analytical Biochemistry Nov 2021Acetylcholine (ACh), the major neurotransmitter secreted by cholinergic neurons, is widely found in the peripheral and central nervous systems, and its main function is... (Review)
Review
Acetylcholine (ACh), the major neurotransmitter secreted by cholinergic neurons, is widely found in the peripheral and central nervous systems, and its main function is to complete the transmission of neural signals. When cholinergic neurons are impaired, the synthesis and decomposition of ACh are abnormal and the neural signalling transition is blocked. To some extent, the concentration changes of ACh reflects the occurrence and development of many kinds of nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Myasthenia gravis and so on. Thus, researches of the physiological and pathological roles and the tracking of the concentration changes of ACh in vivo are significant to the prevention and treatment of these diseases. In the paper, the pathophysiological functions and the comprehensive research progress on detection methods of ACh are summarized. Specifically, the latest research and related applications of the optical and electrochemical biosensors are described, and the future development directions and challenges are prospected, which provides a reference for the detection and applications of ACh.
Topics: Acetylcholine; Animals; Humans
PubMed: 34534543
DOI: 10.1016/j.ab.2021.114381 -
Proceedings of the National Academy of... Jul 2023The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural...
The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.
Topics: Cholinergic Agents; Acetylcholine; Prosencephalon; Cholinergic Neurons; gamma-Aminobutyric Acid; Logic
PubMed: 37399414
DOI: 10.1073/pnas.2218830120 -
Journal of Neuroscience Research Mar 2017Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and... (Review)
Review
Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc.
Topics: Acetylcholine; Animals; Extinction, Psychological; Fear; Humans; Learning; Prosencephalon
PubMed: 27704595
DOI: 10.1002/jnr.23840 -
Progress in Biophysics and Molecular... Jul 2021It is tacitly assumed that the biological role of acetylcholinesterase is termination of synaptic transmission at cholinergic synapses. However, together with its... (Review)
Review
It is tacitly assumed that the biological role of acetylcholinesterase is termination of synaptic transmission at cholinergic synapses. However, together with its structural homolog, butyrylcholinesterase, it is widely distributed both within and outside the nervous system, and, in many cases, the role of both enzymes remains obscure. The transient appearance of the cholinesterases in embryonic tissues is especially enigmatic. The two enzymes' extra-synaptic roles, which are known as 'non-classical' roles, are the topic of this review. Strong evidence has been presented that AChE and BChE play morphogenetic roles in a variety of eukaryotic systems, and they do so either by acting as adhesion proteins, or as trophic factors. As trophic factors, one mode of action is to directly regulate morphogenesis, such as neurite outgrowth, by poorly understood mechanisms. The other mode is by regulating levels of acetylcholine, which acts as the direct trophic factor. Alternate substrates have been sought for the cholinesterases. Quite recently, it was shown that levels of the aggression hormone, ghrelin, which also controls appetite, are regulated by butyrylcholinesterase. The rapid hydrolysis of acetylcholine by acetylcholinesterase generates high local proton concentrations. The possible biophysical and biological consequences of this effect are discussed. The biological significance of the acetylcholinesterases secreted by parasitic nematodes is reviewed, and, finally, the involvement of acetylcholinesterase in apoptosis is considered.
Topics: Acetylcholine; Acetylcholinesterase; Butyrylcholinesterase; Morphogenesis; Synapses
PubMed: 33307019
DOI: 10.1016/j.pbiomolbio.2020.12.001 -
Expert Review of Proteomics 2023Since the emergence of the cholinergic hypothesis of Alzheimer's disease (AD), acetylcholine has been viewed as a mediator of learning and memory. Donepezil improves... (Review)
Review
INTRODUCTION
Since the emergence of the cholinergic hypothesis of Alzheimer's disease (AD), acetylcholine has been viewed as a mediator of learning and memory. Donepezil improves AD-associated learning deficits and memory loss by recovering brain acetylcholine levels. However, it is associated with side effects due to global activation of acetylcholine receptors. Muscarinic acetylcholine receptor M1 (M1R), a key mediator of learning and memory, has been an alternative target. The importance of targeting a specific pathway downstream of M1R has recently been recognized. Elucidating signaling pathways beyond M1R that lead to learning and memory holds important clues for AD therapeutic strategies.
AREAS COVERED
This review first summarizes the role of acetylcholine in aversive learning, one of the outputs used for preliminary AD drug screening. It then describes the phosphoproteomic approach focused on identifying acetylcholine intracellular signaling pathways leading to aversive learning. Finally, the intracellular mechanism of donepezil and its effect on learning and memory is discussed.
EXPERT OPINION
The elucidation of signaling pathways beyond M1R by phosphoproteomic approach offers a platform for understanding the intracellular mechanism of AD drugs and for developing AD therapeutic strategies. Clarifying the molecular mechanism that links the identified acetylcholine signaling to AD pathophysiology will advance the development of AD therapeutic strategies.
Topics: Humans; Acetylcholine; Receptor, Muscarinic M1; Donepezil; Signal Transduction; Alzheimer Disease
PubMed: 37787112
DOI: 10.1080/14789450.2023.2265067