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Current Neuropharmacology 2016Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh... (Review)
Review
Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer's disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.
Topics: Acetylcholine; Alzheimer Disease; Animals; Cholinergic Agents; Cholinergic Neurons; Cholinesterase Inhibitors; Drug Delivery Systems; Humans; Receptors, Cholinergic
PubMed: 26813123
DOI: 10.2174/1570159x13666150716165726 -
Biomolecules Jun 2020It was a pleasure to receive a proposal to organize and be a guest editor of a Special Issue ofBiomolecules. This is the field in which I am working and personally know...
It was a pleasure to receive a proposal to organize and be a guest editor of a Special Issue ofBiomolecules. This is the field in which I am working and personally know some of the leadingscientists. My narrow field is the research on the peptide and protein neurotoxins from animalvenoms and their application as sophisticated tools for analysis of nicotinic acetylcholine receptors(nAChRs) [...].
Topics: Acetylcholine; Animals; Humans; Receptors, Cholinergic
PubMed: 32503306
DOI: 10.3390/biom10060852 -
Molecules (Basel, Switzerland) Mar 2022Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer's disease (AD), a... (Review)
Review
Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer's disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.
Topics: Acetylcholine; Alzheimer Disease; Cholinergic Agents; Humans; Neurodegenerative Diseases; Signal Transduction
PubMed: 35335180
DOI: 10.3390/molecules27061816 -
Science (New York, N.Y.) Mar 2022Information flow in neurons proceeds by integrating inputs in dendrites, generating action potentials near the soma, and releasing neurotransmitters from nerve terminals...
Information flow in neurons proceeds by integrating inputs in dendrites, generating action potentials near the soma, and releasing neurotransmitters from nerve terminals in the axon. We found that in the striatum, acetylcholine-releasing neurons induce action potential firing in distal dopamine axons. Spontaneous activity of cholinergic neurons produced dopamine release that extended beyond acetylcholine-signaling domains, and traveling action potentials were readily recorded from dopamine axons in response to cholinergic activation. In freely moving mice, dopamine and acetylcholine covaried with movement direction. Local inhibition of nicotinic acetylcholine receptors impaired dopamine dynamics and affected movement. Our findings uncover an endogenous mechanism for action potential initiation independent of somatodendritic integration and establish that this mechanism segregates the control of dopamine signaling between axons and somata.
Topics: Acetylcholine; Action Potentials; Animals; Axons; Cholinergic Neurons; Corpus Striatum; Dopamine; Mice; Receptors, Nicotinic; Synaptic Transmission
PubMed: 35324301
DOI: 10.1126/science.abn0532 -
Nature Neuroscience Nov 2015The mammalian basal forebrain (BF) has important roles in controlling sleep and wakefulness, but the underlying neural circuit remains poorly understood. We examined the...
The mammalian basal forebrain (BF) has important roles in controlling sleep and wakefulness, but the underlying neural circuit remains poorly understood. We examined the BF circuit by recording and optogenetically perturbing the activity of four genetically defined cell types across sleep-wake cycles and by comprehensively mapping their synaptic connections. Recordings from channelrhodopsin-2 (ChR2)-tagged neurons revealed that three BF cell types, cholinergic, glutamatergic and parvalbumin-positive (PV+) GABAergic neurons, were more active during wakefulness and rapid eye movement (REM) sleep (wake/REM active) than during non-REM (NREM) sleep, and activation of each cell type rapidly induced wakefulness. By contrast, activation of somatostatin-positive (SOM+) GABAergic neurons promoted NREM sleep, although only some of them were NREM active. Synaptically, the wake-promoting neurons were organized hierarchically by glutamatergic→cholinergic→PV+ neuron excitatory connections, and they all received inhibition from SOM+ neurons. Together, these findings reveal the basic organization of the BF circuit for sleep-wake control.
Topics: Acetylcholine; Animals; Basal Forebrain; Electroencephalography; GABAergic Neurons; Mice; Nerve Net; Parvalbumins; Sleep; Wakefulness
PubMed: 26457552
DOI: 10.1038/nn.4143 -
Cell Metabolism May 2023Autoreactive B cell responses are essential for the development of systemic lupus erythematosus (SLE). Fibroblastic reticular cells (FRCs) are known to construct...
Autoreactive B cell responses are essential for the development of systemic lupus erythematosus (SLE). Fibroblastic reticular cells (FRCs) are known to construct lymphoid compartments and regulate immune functions. Here, we identify spleen FRC-derived acetylcholine (ACh) as a key factor that controls autoreactive B cell responses in SLE. In SLE, CD36-mediated lipid uptake leads to enhanced mitochondrial oxidative phosphorylation in B cells. Accordingly, the inhibition of fatty acid oxidation results in reduced autoreactive B cell responses and ameliorated diseases in lupus mice. Ablation of CD36 in B cells impairs lipid uptake and differentiation of autoreactive B cells during autoimmune induction. Mechanistically, spleen FRC-derived ACh promotes lipid influx and generation of autoreactive B cells through CD36. Together, our data uncover a novel function of spleen FRCs in lipid metabolism and B cell differentiation, placing spleen FRC-derived ACh in a key position in promoting autoreactive B cells in SLE.
Topics: Mice; Animals; Spleen; Acetylcholine; Lipid Metabolism; Lupus Erythematosus, Systemic; Lipids
PubMed: 37019104
DOI: 10.1016/j.cmet.2023.03.010 -
Proceedings of the National Academy of... Mar 2021The alteration of the enteric nervous system (ENS) and its role in neuroimmune modulation remain obscure in the pathogenesis of inflammatory bowel diseases (IBDs). Here,...
The alteration of the enteric nervous system (ENS) and its role in neuroimmune modulation remain obscure in the pathogenesis of inflammatory bowel diseases (IBDs). Here, by using the xCell tool and the latest immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs technique, we found severe pathological damage of the entire ENS and decreased expression of choline acetyltransferase (ChAT) in IBD patients. As a result, acetylcholine (ACh), a major neurotransmitter of the nervous system synthesized by ChAT, was greatly reduced in colon tissues of both IBD patients and colitis mice. Importantly, administration of ACh via enema remarkably ameliorated colitis, which was proved to be directly dependent on monocytic myeloid-derived suppressor cells (M-MDSCs). Furthermore, ACh was demonstrated to promote interleukin-10 secretion of M-MDSCs and suppress the inflammation through activating the nAChR/ERK pathway. The present data reveal that the cholinergic signaling pathway in the ENS is impaired during colitis and uncover an ACh-MDSCs neuroimmune regulatory pathway, which may offer promising therapeutic strategies for IBDs.
Topics: Acetylcholine; Animals; Choline O-Acetyltransferase; Enteric Nervous System; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inflammatory Bowel Diseases; Interleukin-10; Mice; Mice, Inbred C57BL; Monocytes; Myeloid-Derived Suppressor Cells; Neurons; Receptors, Nicotinic
PubMed: 33836585
DOI: 10.1073/pnas.2017762118 -
The Journal of Neuroscience : the... Jun 2022Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not...
Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise on DA release using mice that were heterozygous for BDNF deletion (BDNF). In contrast to WT mice, evoked DA release did not differ between BDNF runners and controls. Complementary pharmacological studies using a tropomyosin receptor kinase B (TrkB) agonist in WT mouse slices showed that TrkB receptor activation also increased evoked DA release throughout striatum in an ACh-independent manner. Together, these data support a causal role for BDNF in exercise-enhanced striatal DA release and provide mechanistic insight into the beneficial effects of exercise in neuropsychiatric disorders, including Parkinson's, depression, and anxiety. Exercise has been shown to improve movement and cognition in humans and rodents. Here, we report that voluntary exercise for 30 d leads to an increase in evoked DA release throughout the striatum and an increase in BDNF in the dorsal (motor) striatum. The increase in DA release appears to require BDNF, indicated by the absence of DA release enhancement with running in BDNF mice. Activation of BDNF receptors using a pharmacological agonist was also shown to boost DA release. Together, these data support a necessary and sufficient role for BDNF in exercise-enhanced DA release and provide mechanistic insight into the reported benefits of exercise in individuals with dopamine-linked neuropsychiatric disorders, including Parkinson's disease and depression.
Topics: Acetylcholine; Animals; Brain-Derived Neurotrophic Factor; Corpus Striatum; Dopamine; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Parkinson Disease
PubMed: 35577554
DOI: 10.1523/JNEUROSCI.2273-21.2022 -
Neuropharmacology Jan 2016Neurons that produce acetylcholine (ACh) are positioned to broadly influence the brain, with axonal arborizations that extend throughout the cerebral cortex, striatum,... (Review)
Review
Neurons that produce acetylcholine (ACh) are positioned to broadly influence the brain, with axonal arborizations that extend throughout the cerebral cortex, striatum, and hippocampus. While the action of these neurons has typically been attributed entirely to ACh, neurons often release more than one primary neurotransmitter. Here, we review evidence for the cotransmission of the inhibitory neurotransmitter GABA from cholinergic neurons throughout the mammalian central nervous system. Functional cotransmission of ACh and GABA has been reported in the retina and cortex, and anatomical studies suggest that GABA cotransmission is a common feature of nearly all forebrain ACh-producing neurons. Further experiments are necessary to confirm the extent of GABA cotransmission from cholinergic neurons, and the contribution of GABA needs to be considered when studying the functional impact of activity in ACh-producing neurons. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
Topics: Acetylcholine; Animals; Brain; Cholinergic Neurons; Humans; Mice; Optogenetics; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 26220313
DOI: 10.1016/j.neuropharm.2015.07.031 -
Anesthesiology Apr 2021
Topics: Acetylcholine; Anesthesia; Animals; Consciousness; Isoflurane; Ketamine; Mice; Prosencephalon
PubMed: 33635939
DOI: 10.1097/ALN.0000000000003696