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The European Journal of Neuroscience May 2024
Topics: Humans; Animals; Signal Transduction; Acetylcholine; Cholinergic Neurons; Receptors, Cholinergic
PubMed: 38679811
DOI: 10.1111/ejn.16369 -
Journal of Internal Medicine Feb 2020Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known... (Review)
Review
Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non-neuronal cell types and even by some single-celled organisms. Within multicellular organisms, a non-neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL-21 signalling to the T cells. Furthermore, during infection this immune-derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh's role in the migration of T cells during infection and cancer.
Topics: Acetylcholine; Animals; Cell Movement; Humans; Immune System; Infections; Inflammation; Neoplasms; Signal Transduction
PubMed: 31710126
DOI: 10.1111/joim.13006 -
Clinical and Experimental Nephrology Sep 2021The autonomic nervous system plays an important role in maintaining homeostasis in organisms. Recent studies have shown that it also controls inflammation by directly... (Review)
Review
The autonomic nervous system plays an important role in maintaining homeostasis in organisms. Recent studies have shown that it also controls inflammation by directly altering the function of the immune system. The cholinergic anti-inflammatory pathway (CAP) is one of the neural circuits operating through the vagus nerve. Acetylcholine released from the terminal of the vagus nerve, which is a parasympathetic nerve, acts on the α7 nicotinic acetylcholine receptor of macrophages and reduces inflammation in the body. Previous animal studies demonstrated that vagus nerve stimulation reduced renal ischemia-reperfusion injury. Furthermore, restraint stress and pulsed ultrasound had similar protective effects against kidney injury, which were mainly thought to be mediated by the CAP. Using optogenetics, which can stimulate specific nerves, it was also revealed that activation of the CAP by restraint stress was mediated by C1 neurons in the medulla oblongata. Nevertheless, there still remain many unclear points regarding the role of the nervous and immune systems in controlling renal diseases, and further research is needed.
Topics: Acetylcholine; Acute Kidney Injury; Animals; Humans; Kidney; Neuroimmunomodulation; Neurons; Ultrasonic Waves; Vagus Nerve Stimulation
PubMed: 33877485
DOI: 10.1007/s10157-021-02062-3 -
Frontiers of Neurology and Neuroscience 2021Orexins have received a lot of attention as potent endogenous arousal-promoting peptides, and orexin receptor antagonists have shown clinical efficacy for the treatment... (Review)
Review
Orexins have received a lot of attention as potent endogenous arousal-promoting peptides, and orexin receptor antagonists have shown clinical efficacy for the treatment of insomnia. Orexin neurons are thought to act primarily on monoaminergic neurons to maintain arousal and vigilance. In this chapter, we discuss the functional interaction between monoaminergic systems, including noradrenaline, serotonin and histamine, and orexin neurons, as well as interactions between the acetylcholine system and the orexin neurons, focusing, in particular, on their function in the regulation of sleep-wakefulness states. Orexin also has close interactions with the dopaminergic system, and many studies have suggested roles of orexin signaling in the reward system and roles for orexins in drug addiction.
Topics: Acetylcholine; Animals; Biogenic Monoamines; Brain; Humans; Neurons; Orexin Receptors; Orexins
PubMed: 34052806
DOI: 10.1159/000514955 -
Ageing Research Reviews Jul 2023Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from... (Review)
Review
Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid β deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid β deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca influx into postsynaptic neurons generating slow excitotoxicity process leading to oxidative stress and finally impaired cognition and neuronal loss. Amyloid decreases acetylcholine release, synthesis and neuronal transport. The decreased levels of neurotransmitter acetylcholine, neuronal loss, tau aggregation, amyloid β plaques, increased oxidative stress, neuroinflammation, bio-metal dyshomeostasis, autophagy, cell cycle dysregulation, mitochondrial dysfunction, and endoplasmic reticulum dysfunction are the factors responsible for the pathogenesis of AD. Acetylcholinesterase, NMDA, Glutamate, BACE1, 5HT6, and RAGE (Receptors for Advanced Glycation End products) are receptors targeted in treatment of AD. The FDA approved acetylcholinesterase inhibitors Donepezil, Galantamine and Rivastigmine and N-methyl-D-aspartate antagonist Memantine provide symptomatic relief. Different therapies such as amyloid β therapies, tau-based therapies, neurotransmitter-based therapies, autophagy-based therapies, multi-target therapeutic strategies, and gene therapy modify the natural course of the disease. Herbal and food intake is also important as preventive strategy and recently focus has also been placed on herbal drugs for treatment. This review focuses on the molecular aspects, pathogenesis and recent studies that signifies the potential of medicinal plants and their extracts or chemical constituents for the treatment of degenerative symptoms related to AD.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Acetylcholine; Acetylcholinesterase; N-Methylaspartate; Aspartic Acid Endopeptidases
PubMed: 37224884
DOI: 10.1016/j.arr.2023.101960 -
Nature Reviews. Neuroscience Apr 2023Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have... (Review)
Review
Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have shown that the axons of basal forebrain cholinergic neurons innervate the pallium with far more topographical and functional organization than was historically appreciated. Together with the results of studies using new probes that allow release of acetylcholine to be detected with high spatial and temporal resolution, these findings have implicated cholinergic networks in 'binding' diverse behaviours that contribute to cognition. Here, we review recent findings on the developmental origins, connectivity and function of cholinergic neurons, and explore the participation of cholinergic signalling in the encoding of cognition-related behaviours.
Topics: Humans; Acetylcholine; Basal Forebrain; Cholinergic Agents; Cognition; Signal Transduction
PubMed: 36823458
DOI: 10.1038/s41583-023-00677-x -
The Journal of Pharmacology and... May 2019Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric...
Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but fewer endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO), have been identified. Acetylcholinesterase inhibitors, such as donepezil, can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets. We measured the effect of acetylcholine or analogs of acetylcholine on human platelet activation ex vivo. Acetylcholine and analogs of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and glycoprotein IIb IIIa conformational changes. Conversely, we found that antagonists of the acetylcholine receptor, such as pancuronium, enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase, such as donepezil, also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Our data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for antithrombotic therapies.
Topics: Acetylcholine; Blood Platelets; Humans; Nitric Oxide; Platelet Activation; Receptors, Cholinergic
PubMed: 30765424
DOI: 10.1124/jpet.118.253583 -
Neuroscience Mar 2017Cognitive flexibility, the ability to adjust behavior in response to new and unexpected conditions in the environment, is essential for adaptation to new challenges and... (Review)
Review
Cognitive flexibility, the ability to adjust behavior in response to new and unexpected conditions in the environment, is essential for adaptation to new challenges and survival. The cholinergic system is an important modulator of this complex behavior however, the exact cholinergic circuits involved in this modulation and the precise influence of acetylcholine (ACh) in the process is still not fully understood. Here we review the role of different cholinergic circuits in cognitive flexibility. Strong evidence indicates that cholinergic interneurons (CINs) from the dorsomedial striatum are essential for facilitating the establishment of a new selected strategy; an effect that seems to depend mainly on activation of muscarinic receptors. Cholinergic neurons from the nucleus basalis magnocellularis (nBM), which project to the prefrontal cortex, seem to modulate the initial inhibition of a previously learned strategy, however, this concept is still controversial. Additionally, some studies suggest that basal forebrain cholinergic neurons projecting to the hippocampus, basolateral amygdala, and posterior parietal cortex may also participate on the modulation of cognitive flexibility. We highlight the fact that when investigating effects of ACh on behavioral flexibility, or any other behavior, one has to keep in mind two important particularities of the cholinergic system: (1) Many cholinergic neurons in the brain co-release glutamate or GABA with ACh. Methodologies that rely on neuronal silencing or ablation lead to simultaneous elimination of both neurotransmitters, making interpretation of results complex. (2) The cholinergic gene locus has a unique organization, with the vesicular acetylcholine transporter (VAChT) gene present within the intron between the first and second exons of the choline acetyltransferase (ChAT) gene. Thus, behavioral studies using transgenic animals generated with ChAT bacterial artificial chromosome (BAC) clones should be considered carefully, taking into consideration that these mice may overexpress VAChT and therefore, present a hypercholinergic tone that can be a confounder in behavioral studies.
Topics: Acetylcholine; Animals; Brain; Cholinergic Neurons; Cognition; Executive Function; Neural Pathways
PubMed: 27641830
DOI: 10.1016/j.neuroscience.2016.09.013 -
ELife May 2020The neurotransmitter acetylcholine influences how male finches perform courtship songs by acting on a region of the premotor cortex called HVC.
The neurotransmitter acetylcholine influences how male finches perform courtship songs by acting on a region of the premotor cortex called HVC.
Topics: Acetylcholine; Animals; Finches; Male; Motor Cortex; Vocalization, Animal
PubMed: 32425156
DOI: 10.7554/eLife.57515 -
Molecules (Basel, Switzerland) Feb 2022The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the... (Review)
Review
The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the highest content of acetylcholine of almost any nucleus in the brain. The prevailing theory of striatal cholinergic interneuron signaling is that the numerous varicosities on the axon produce an extrasynaptic, volume-transmitted signal rather than mediating rapid point-to-point synaptic transmission. We review the evidence for this theory and use a mathematical model to integrate the measurements reported in the literature, from which we estimate the temporospatial distribution of acetylcholine after release from a synaptic vesicle and from multiple vesicles during tonic firing and pauses. Our calculations, together with recent data from genetically encoded sensors, indicate that the temporospatial distribution of acetylcholine is both short-range and short-lived, and dominated by diffusion. These considerations suggest that acetylcholine signaling by cholinergic interneurons is consistent with point-to-point transmission within a steep concentration gradient, marked by transient peaks of acetylcholine concentration adjacent to release sites, with potential for faithful transmission of spike timing, both bursts and pauses, to the postsynaptic cell. Release from multiple sites at greater distance contributes to the ambient concentration without interference with the short-range signaling. We indicate several missing pieces of evidence that are needed for a better understanding of the nature of synaptic transmission by the cholinergic interneurons of the striatum.
Topics: Acetylcholine; Animals; Corpus Striatum; Humans; Interneurons; Synaptic Transmission
PubMed: 35208986
DOI: 10.3390/molecules27041202