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Cholinergic neuron

Cholinergic neurons are specialized nerve cells in the nervous system that synthesize and release the neurotransmitter acetylcholine (ACh), a key chemical messenger essential for neurotransmission, synaptic plasticity, and modulation of various physiological processes.^[1] These neurons are defined by the expression of choline acetyltransferase (ChAT), the enzyme responsible for ACh production, and are found in both the central nervous system (CNS) and peripheral nervous system (PNS), where they facilitate communication between neurons, muscles, and glands.^[2] In the PNS, cholinergic neurons include preganglionic autonomic fibers, parasympathetic postganglionic neurons, and somatic motor neurons innervating skeletal muscles at neuromuscular junctions.^[1] In the CNS, cholinergic neurons are distributed across several key regions, including the basal forebrain (such as the medial septal nucleus, diagonal band nuclei, and nucleus basalis of Meynert), brainstem (pedunculopontine and laterodorsal tegmental nuclei), striatum (as interneurons), and other areas like the medial habenula and olfactory bulb.^[3] These neurons project widely to targets such as the cerebral cortex, hippocampus, thalamus, and basal ganglia, enabling diffuse modulation rather than point-to-point signaling.^[2] Functionally, they regulate critical processes including learning and memory formation, attention and arousal, motor control, sensory processing, and autonomic functions like heart rate and digestion.^[1] ACh released by these neurons acts on nicotinic and muscarinic receptors to influence synaptic transmission, neural oscillations (e.g., hippocampal theta rhythms), and behavioral flexibility.^[3] Dysfunction or degeneration of cholinergic neurons is implicated in numerous neurological and psychiatric disorders, underscoring their importance in brain health.^[2] For instance, loss of basal forebrain cholinergic projections contributes to cognitive deficits in Alzheimer's disease, while imbalances in striatal cholinergic interneurons are linked to Parkinson's disease motor symptoms and psychiatric conditions like schizophrenia.^[3] Ongoing research highlights the diversity of cholinergic neuron subtypes based on genetics, morphology, and connectivity, revealing their specialized roles in fine-tuning excitation-inhibition balance and adaptive behaviors.^[2]

Anatomy and Distribution

Central Nervous System Locations

Cholinergic neurons in the central nervous system are predominantly clustered in two major regions: the basal forebrain and the brainstem, with additional intrinsic populations in select areas. In the basal forebrain, these neurons are organized into distinct groups based on anatomical location, including the medial septal nucleus (Ch1 group), the vertical limb of the diagonal band of Broca (Ch2 group), the horizontal limb of the diagonal band of Broca (Ch3 group), and the substantia innominata/nucleus basalis of Meynert (Ch4 group).^[4] These populations constitute a minority of basal forebrain neurons, comprising approximately 10-20% of the total cellular content depending on the subregion.^[5] The neurons exhibit characteristic morphology as large, multipolar cells with expansive dendritic fields spanning up to several millimeters and highly branched axons that extend over wide cortical territories.^[6] From the basal forebrain, cholinergic neurons send diffuse, long-range projections that broadly innervate the cerebral cortex, hippocampus, and amygdala, forming key modulatory pathways such as the septohippocampal pathway originating from the Ch1 and Ch2 groups to target hippocampal formation.^[7] Individual axons from these neurons can measure over 100 meters in total length in humans, enabling widespread distribution of acetylcholine across target areas.^[8] In the brainstem, cholinergic neurons are primarily located within the pedunculopontine tegmental nucleus (PPT, Ch5 group) and the laterodorsal tegmental nucleus (LDT, Ch6 group), situated in the mesopontine tegmentum.^[9] These nuclei house cholinergic neurons intermingled with glutamatergic and GABAergic populations, with cholinergic cells accounting for about 22-25% of the total neuronal population in each structure based on stereological estimates in rodents.^[9] Morphologically, brainstem cholinergic neurons are also multipolar with varicose axons that form diffuse projections to thalamic relay nuclei, pontine structures, and select forebrain targets, contributing to ascending cholinergic pathways.^[10] Intrinsic cholinergic interneurons are found in several CNS regions, including the striatum (caudate-putamen and nucleus accumbens), where they comprise 1-2% of neurons but play key modulatory roles; the olfactory bulb, particularly in the glomerular layer; and the medial habenula, which projects to the interpeduncular nucleus.^[4]^[11]

Peripheral Nervous System Locations

Cholinergic neurons play a central role in the peripheral nervous system (PNS), particularly within the autonomic and somatic divisions, where they utilize acetylcholine as their primary neurotransmitter. In the autonomic nervous system, all preganglionic neurons are cholinergic. Sympathetic preganglionic neurons originate from the intermediolateral cell column in the thoracic and upper lumbar spinal cord segments (T1–L2), sending long myelinated axons that synapse in paravertebral chain ganglia or prevertebral ganglia.^[12] In the parasympathetic branch, preganglionic neurons originate from nuclei in the brainstem (via cranial nerves III, VII, IX, and X) and the sacral spinal cord (segments S2–S4), sending long myelinated axons that synapse in peripheral parasympathetic ganglia located near or within target organs. These preganglionic neurons are typically small to medium-sized, fusiform or multipolar in shape, with relatively scant cytoplasm. Postganglionic neurons, also cholinergic, reside in these ganglia and extend short unmyelinated axons to innervate visceral effectors such as smooth muscles and glands.^[13]^[14] Key parasympathetic ganglia include the ciliary ganglion, associated with the oculomotor nerve (CN III), which supplies the eye's sphincter pupillae and ciliary muscle; the pterygopalatine and submandibular ganglia, linked to the facial nerve (CN VII), innervating lacrimal, nasal, and salivary glands; the otic ganglion, connected to the glossopharyngeal nerve (CN IX), targeting the parotid gland; and various intramural ganglia along the vagus nerve (CN X) pathway, which distribute to thoracic and abdominal viscera. In the sacral region, pelvic splanchnic nerves from S2–S4 terminate in pelvic and intramural ganglia, providing cholinergic innervation to pelvic organs like the bladder and distal colon. This near-target positioning of parasympathetic ganglia contrasts with the more centralized sympathetic chain, facilitating precise, localized control.^[15]^[1] In the somatic nervous system, cholinergic alpha motor neurons, located in the ventral horn of the spinal cord, extend axons through peripheral nerves to form neuromuscular junctions with skeletal muscle fibers, enabling voluntary motor control. These large multipolar neurons release acetylcholine at the synaptic cleft to activate nicotinic receptors on muscle endplates, triggering contraction. Although their cell bodies are central, their extensive axonal projections constitute a major cholinergic component of the PNS.^[16]^[17] The sympathetic division features limited cholinergic elements in the PNS beyond preganglionics, primarily postganglionic neurons that innervate sweat glands via cholinergic transmission, diverging from the typical noradrenergic sympathetic postganglionics. These neurons originate from paravertebral and prevertebral ganglia but specifically target eccrine sweat glands in the skin, promoting thermoregulation through localized sweating. This exception highlights the selective cholinergic role in sympathetic sudomotor function.^[12]

Physiology and Biochemistry

Acetylcholine Synthesis and Release

Cholinergic neurons synthesize acetylcholine (ACh) primarily in the cytoplasm of their presynaptic terminals, where the process relies on the availability of choline and acetyl-coenzyme A (acetyl-CoA). Choline is taken up from the extracellular space through the high-affinity choline transporter 1 (CHT1), a sodium- and chloride-dependent plasma membrane protein that serves as the rate-limiting step for ACh production by efficiently recycling choline derived from prior hydrolysis.^[18] Once internalized, choline reacts with acetyl-CoA in a reaction catalyzed by the enzyme choline acetyltransferase (ChAT), a characteristic marker of cholinergic neurons that transfers the acetyl group to form ACh.^[19] This biosynthetic pathway can be represented by the equation:

\text{Choline} + \text{Acetyl-CoA} \xrightarrow{\text{ChAT}} \text{Acetylcholine} + \text{CoA}

The resulting ACh is then actively transported into synaptic vesicles by the vesicular acetylcholine transporter (VAChT), a proton antiporter that exchanges cytoplasmic ACh for protons in the acidic vesicle lumen, concentrating the neurotransmitter for storage.^[20] Release of ACh occurs via calcium-dependent exocytosis, triggered when an action potential depolarizes the presynaptic terminal, opening voltage-gated calcium channels and allowing Ca²⁺ influx that promotes fusion of synaptic vesicles with the plasma membrane.^[1] This mechanism ensures rapid, regulated secretion into the synaptic cleft. At the neuromuscular junction, ACh is released in discrete quanta, each corresponding to the contents of a single vesicle and containing approximately 5,000 to 10,000 ACh molecules, which collectively generate the end-plate potential.^[21] To maintain cholinergic signaling efficiency, released ACh is swiftly hydrolyzed in the synaptic cleft by the enzyme acetylcholinesterase (AChE), which cleaves it into choline and acetate, thereby terminating neurotransmission and preventing receptor overstimulation.^[1] The released choline is subsequently reuptaken by presynaptic CHT1, closing the recycling loop that supports sustained ACh synthesis and release during neuronal activity.^[18]

Receptors and Synaptic Transmission

Cholinergic neurons primarily mediate synaptic transmission through acetylcholine (ACh), which binds to two distinct classes of postsynaptic receptors: nicotinic and muscarinic. Nicotinic receptors are ionotropic, functioning as ligand-gated ion channels that permit rapid influx of cations such as sodium and calcium upon ACh binding, leading to fast excitatory postsynaptic potentials. These receptors are pentameric assemblies composed of various subunits, with prominent subtypes including the muscle-type (α1β1δε) at neuromuscular junctions and neuronal subtypes like α7 homomers in the central nervous system (CNS).^[22]^[23] In contrast, muscarinic receptors are metabotropic, G-protein-coupled receptors that activate intracellular signaling cascades, resulting in slower and more prolonged modulatory effects. There are five subtypes (M1 through M5), each coupled to different G-proteins: M1, M3, and M5 link to Gq for phospholipase C activation, while M2 and M4 couple to Gi/o for inhibition of adenylyl cyclase. For instance, M1 receptors in the CNS facilitate arousal and attention by modulating neuronal excitability via second messengers like IP3 and DAG.^[22]^[24] The transmission process at cholinergic synapses varies by receptor type and location. At peripheral neuromuscular junctions, ACh release triggers rapid nicotinic receptor activation, causing millisecond-scale depolarization and muscle contraction for swift motor responses. In the CNS, muscarinic receptors predominate for modulatory roles, such as M1-mediated enhancement of cortical excitability that supports sustained signaling over seconds to minutes, distinct from the presynaptic ACh release mechanism. This dichotomy enables both phasic, point-to-point signaling via nicotinic pathways and tonic, volume transmission via muscarinic ones.^[1]^[25] Key kinetic differences underscore these roles: nicotinic receptors exhibit fast activation and desensitization within milliseconds, ideal for precise, transient excitation, whereas muscarinic responses unfold over seconds to minutes due to G-protein kinetics and downstream effectors.^[26]^[22] Cholinergic synapses also display short-term plasticity, including paired-pulse facilitation and depression, which adjust neurotransmitter release probability based on prior activity. Facilitation occurs at low initial release probabilities, enhancing subsequent responses, while depression arises from vesicle depletion during high-frequency stimulation. Additionally, α7 nicotinic receptors contribute to long-term potentiation (LTP) in hippocampal circuits by boosting calcium influx and NMDA receptor function, thereby strengthening synaptic efficacy over extended periods.^[27]^[28]^[29]

Development and Lifespan Changes

Embryonic and Postnatal Development

Cholinergic neurons originate from progenitor cells within the neural tube during embryonic development. In the spinal cord, they arise from the ventral progenitor domains, where transcription factors such as Isl1 and Lhx3 play crucial roles in specifying motor neuron identity and cholinergic fate. The interaction between Isl1 and Lhx3, often mediated by competition with Ldb1, directs the differentiation of postmitotic precursors into cholinergic motor neurons.^[30]^[31] In the basal forebrain, cholinergic neurons derive from the ventral telencephalon, particularly the Nkx2.1-expressing regions like the medial ganglionic eminence and preoptic area, with Isl1 expression marking commitment to the cholinergic lineage as early as embryonic day 10.5 in mice.^[31] The onset of choline acetyltransferase (ChAT) expression, a hallmark of cholinergic identity, begins around embryonic day 11.5-E12 in mice for spinal motor neurons and E13-E15 for basal forebrain populations, enabling initial acetylcholine synthesis.^[31]^[30]^[32] Postnatally, cholinergic neurons undergo maturation characterized by axonal outgrowth and synapse formation. In the peripheral nervous system, spinal motor neurons extend axons to form neuromuscular junctions, guided by signaling molecules such as agrin, which clusters acetylcholine receptors on target muscle cells, and neuregulin, which promotes postsynaptic differentiation. Central cholinergic neurons, particularly in the basal forebrain, exhibit extensive axonal branching along specific pathways to innervate cortical and hippocampal targets, with trophic factors like nerve growth factor (NGF) supporting survival and refinement.^[30] This process peaks during the first two postnatal weeks in rodents, a critical period for establishing functional connectivity. During these early postnatal stages, the cholinergic system experiences refinement through synaptic pruning and apoptosis, ensuring precise wiring and eliminating excess connections. In mice, programmed cell death peaks around postnatal day 14, sculpting the neuronal population to match target demands. While development is accelerated in rodents, with major milestones achieved by weaning, human cholinergic maturation is more protracted, extending through adolescence to fully establish adult distributions in regions like the basal forebrain and spinal cord.^[30] Cholinergic interneurons in the striatum arise from progenitors in the lateral ganglionic eminence around embryonic day 12 in mice, with ChAT expression initiating by E12.5 and maturation continuing postnatally. Brainstem cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei originate from progenitor cells in rhombomeres 5-7, expressing ChAT from mid-gestation (around E11-E13), and refine their ascending projections to the thalamus and cortex during postnatal development.^[30]

Normal Aging Processes

During normal aging, cholinergic neurons in the basal forebrain undergo a gradual reduction in number, with postmortem studies indicating a 20-30% loss of these cells by the ninth decade of life compared to younger adults.^[33] This decline is accompanied by decreased activity of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis, particularly in cortical regions.^[34] Consequently, ACh release in the cortex diminishes, contributing to subtle alterations in neuronal signaling without overt pathology.^[34] Morphological changes in these neurons include dendritic shrinkage and a reduction in synaptic density, leading to decreased connectivity in projection areas such as the cortex and hippocampus.^[34] In rodent models of aging, cholinergic neuron somata exhibit significant atrophy and reduced neurite length by advanced age. These alterations result in functional impacts such as mild cognitive slowing, particularly in attention and memory tasks, while motor functions remain largely preserved.^[34] The cholinergic decline correlates with hippocampal volume loss and reduced synaptic connections in this region, influencing spatial processing without severely impairing overall cognition.^[34] Protective factors like regular physical exercise and enriched environments can mitigate this decline; for instance, chronic treadmill running in aged rodents increases cholinergic neuron numbers in the medial septum and diagonal band, enhances ACh levels in the hippocampus, and attenuates fiber loss.^[35] Longitudinal studies in animal models through the 2020s demonstrate that such interventions, including voluntary wheel running, preserve cholinergic inputs and support cognitive resilience during aging.^[35]

Functional Roles

Autonomic and Motor Functions

Cholinergic neurons play a central role in the parasympathetic division of the autonomic nervous system, where postganglionic fibers release acetylcholine to modulate visceral functions. In the cardiovascular system, vagus nerve postganglionic cholinergic neurons innervate the heart, stimulating muscarinic M2 receptors on sinoatrial and atrioventricular nodes to reduce heart rate and conduction velocity, thereby promoting bradycardia during rest or digestion.^[36] This parasympathetic tone counterbalances sympathetic activity to maintain hemodynamic stability. Similarly, these neurons control glandular secretions; for instance, vagal postganglionics activate M3 receptors in salivary glands to increase water, electrolyte, and enzyme release, facilitating lubrication and initial digestion.^[36] In gastrointestinal regulation, cholinergic innervation via the vagus nerve enhances digestive processes by stimulating smooth muscle contraction and glandular activity. Postganglionic fibers target M3 receptors in the stomach and intestines, promoting peristalsis, sphincter relaxation, and secretion of gastric acid, mucus, and pancreatic enzymes such as amylase and lipase, which are essential for nutrient breakdown and absorption.^[37] This innervation originates from preganglionic neurons in the dorsal motor nucleus and nucleus ambiguus, synapsing in intramural ganglia of the enteric nervous system.^[36] Normal variability in heart rate, known as vagal tone, reflects this cholinergic influence and is quantified through respiratory sinus arrhythmia (RSA), where inspiration inhibits vagal activity to accelerate heart rate, while expiration enhances it to slow the rate, with R-R interval variations exceeding 0.12 seconds indicating robust parasympathetic function.^[38] Cholinergic neurons also drive motor functions in the somatic nervous system by facilitating voluntary and reflexive movements. At the neuromuscular junction, alpha motor neurons in the spinal cord release acetylcholine from their terminals onto nicotinic receptors on skeletal muscle endplates, depolarizing the membrane from approximately -90 mV to -40 mV and generating an endplate potential that propagates as an action potential to trigger calcium release and muscle contraction.^[17] This mechanism underpins excitation of skeletal muscles during locomotion and reflexes, such as the knee-jerk response, ensuring precise and rapid force generation without fatigue under normal conditions, as acetylcholine is swiftly hydrolyzed by acetylcholinesterase.^[17] An exception in the sympathetic nervous system involves cholinergic postganglionic neurons innervating eccrine sweat glands for thermoregulation. These fibers, originating from thoracolumbar preganglionic neurons, release acetylcholine onto muscarinic receptors to stimulate sweat production, enabling evaporative cooling of the skin and core body temperature in response to hypothalamic signals, with daily sweat output ranging from 500 to 750 mL.^[39] This cholinergic sympathetic pathway contrasts with the typical noradrenergic sympathetic innervation of other targets.

Cognitive and Sensory Functions

Cholinergic neurons in the basal forebrain project diffusely to the cerebral cortex, where they release acetylcholine to enhance cortical excitability and promote states of arousal and attention.^[40] Tonic acetylcholine release from these neurons modulates global cortical activity, facilitating sustained vigilance and responsiveness to environmental stimuli.^[41] In the hippocampus, septohippocampal cholinergic projections synchronize theta rhythms (4-8 Hz oscillations), which are essential for maintaining attentional focus during exploratory behaviors.^[42] These cholinergic inputs play a pivotal role in memory encoding, particularly working memory, by enabling the selective strengthening of neural representations. Lesion studies in rodents demonstrate that damage to septohippocampal cholinergic neurons impairs working memory performance, as evidenced by deficits in spatial navigation tasks where animals fail to update and retain location information.^[43] Acetylcholine from these neurons reduces interference between overlapping memory traces, achieving this through adaptive timing that separates encoding from consolidation phases during learning.^[44] In sensory processing, cholinergic modulation refines perceptual discrimination across modalities. In the olfactory bulb, basal forebrain-derived acetylcholine enhances odor discrimination by increasing the signal-to-noise ratio in mitral cell responses, allowing for finer differentiation of similar scents in awake, behaving animals.^[45] For visual attention, cholinergic projections to the pulvinar nucleus of the thalamus gate thalamo-cortical pathways, sharpening contrast sensitivity and directing focus to behaviorally relevant stimuli while suppressing irrelevant ones.^[46] Cholinergic signaling integrates these functions by acting as a gatekeeper for sensory inputs, preventing perceptual overload during selective attention tasks. This gating mechanism amplifies task-relevant signals in cortical circuits, as shown in models where acetylcholine promotes winner-take-all dynamics in primary visual cortex, thereby optimizing resource allocation for decision-making.^[47] Such modulation ensures that cognitive processes remain efficient amid competing sensory demands.

Interactions with Circadian System

Firing Patterns and Rhythms

Cholinergic neurons in the basal forebrain typically exhibit tonic firing rates ranging from 1 to 5 Hz during baseline conditions, reflecting their role in maintaining steady neuromodulation across cortical and hippocampal targets.^[48] This regular, low-frequency discharge pattern supports sustained acetylcholine release essential for arousal and attention states. During periods of heightened behavioral engagement, these neurons transition to phasic bursting activity, particularly in the theta frequency range (4-8 Hz), which occurs prominently during active wakefulness.^[49] Such bursts synchronize with hippocampal theta oscillations, enhancing signal processing in downstream circuits. Circadian modulation influences cholinergic neuron activity, with peak firing and acetylcholine release observed during the active phase in nocturnal rodents, aligning with periods of high arousal and exploration.^[50] The suprachiasmatic nucleus (SCN), the master circadian pacemaker, exerts indirect control over these patterns through arousal-promoting projections that interact with basal forebrain circuits, though direct glutamatergic inputs remain less characterized.^[51] Electrophysiological recordings reveal strong theta-band (4-8 Hz) coupling between basal forebrain cholinergic neurons and hippocampal activity, where neuronal spikes phase-lock to theta troughs, facilitating coordinated network rhythms during wakefulness.^[52] Optogenetic studies in ChAT-Cre mice confirm this rhythmicity; selective stimulation of these neurons enhances theta power while suppressing competing oscillations like sharp-wave ripples, underscoring their causal role in generating and maintaining theta entrainment.^[53] At the molecular level, cholinergic nuclei in the basal forebrain express core clock genes such as Per, which exhibit diurnal variations that influence firing patterns and acetylcholine dynamics.^[54] These genes form part of the transcriptional-translational feedback loop that entrains neuronal excitability to circadian cycles, with elevated Per expression during the rest phase potentially dampening activity to prevent overstimulation.^[55] This intrinsic clock mechanism ensures that cholinergic modulation adapts to daily behavioral demands, contributing to the temporal organization of arousal states.^[50]

Time Perception and Memory

Cholinergic modulation plays a key role in interval timing, particularly through striatal circuits that process durations spanning seconds to minutes. Striatal tonically active neurons (TANs), which are primarily cholinergic interneurons, exhibit brief firing depressions in response to timing cues, acting as a potential start signal for interval timing and integrating temporal information with reward prediction.^[56] Lesions of these cholinergic interneurons in the dorsal striatum specifically delay the acquisition of new duration memories without impairing the ability to adjust behavior to altered durations, thereby reducing timing accuracy for novel intervals.^[57] This modulation ensures precise behavioral responses to timed events, such as anticipating rewards, by embedding cholinergic signaling within striatal dopamine interactions.^[56] In the hippocampus, acetylcholine release contributes to timestamping events for episodic memory by tagging their temporal context. High levels of acetylcholine during active states enhance encoding through suppression of recurrent excitatory transmission in CA3, preventing interference from prior memories and allowing distinct time-specific representations.^[58] This process supports the activity of "time cells," which sequentially fire to represent moments within experiences, coordinated by acetylcholine-driven theta oscillations that align neural dynamics across hippocampal regions.^[59]^[60] Disruptions in cholinergic signaling, such as through antagonists, alter the precise spike timing of these cells, impairing the temporal organization essential for recalling event sequences.^[61] Cholinergic neurons facilitate entrainment of sleep-wake cycles and circadian behaviors via projections to the suprachiasmatic nucleus (SCN), where acetylcholine exhibits diurnal rhythms with peaks during the active phase to promote wakefulness.^[62] This innervation modulates SCN neuron excitability through muscarinic receptors, aiding synchronization of internal clocks to environmental cycles and supporting rhythmic acetylcholine release that reinforces daily arousal patterns.^[62] Olfactory cues contribute to circadian phase setting by leveraging cholinergic modulation in the olfactory bulb, where acetylcholine enhances sensory processing and signaling to basal forebrain circuits that influence SCN activity for adaptive behavioral timing.^[63]^[64]

Associations with Neurological Disorders

Alzheimer's Disease Mechanisms

In Alzheimer's disease (AD), cholinergic neurons exhibit selective vulnerability, particularly those in the nucleus basalis of Meynert (nbM), where degeneration can reach up to 80%, reducing neuron counts from approximately 500,000 in healthy adults to fewer than 100,000 in affected individuals.^[65] This profound loss correlates strongly with the severity of cognitive decline, as the extent of nbM neuron depletion aligns with impairments in memory and attention observed in AD patients.^[66] Such degeneration exceeds the gradual cholinergic decline seen in normal aging, accelerating pathological processes in the basal forebrain.^[67] Pathological mechanisms linking amyloid-beta (Aβ) to cholinergic dysfunction involve direct toxicity, where Aβ peptides impair acetylcholine (ACh) synthesis and release in cholinergic neurons without necessarily causing immediate cell death.^[68] For instance, nontoxic concentrations of Aβ1-42 suppress choline acetyltransferase (ChAT) activity, reducing ACh production in neuronal models.^[69] Additionally, tau hyperphosphorylation disrupts axonal transport in cholinergic projections, contributing to synaptic loss and impaired signaling in the basal forebrain and cortex.^[70] These changes exacerbate the cholinergic deficit, as hyperphosphorylated tau aggregates destabilize microtubules essential for neurotransmitter delivery.^[71] Histologically, AD brains show neurofibrillary tangle (NFT) accumulation preferentially in basal forebrain cholinergic neurons, rendering them highly susceptible to degeneration compared to other neuronal populations.^[72] This is accompanied by reduced ChAT immunoreactivity in surviving neurons and their projections, indicating diminished ACh synthetic capacity and contributing to the overall hypocholinergic state.^[73] Autopsy studies confirm that ChAT levels drop markedly in the basal forebrain, correlating with NFT burden and cognitive symptoms.^[74] The cholinergic hypothesis, first formulated in the mid-1970s and prominently articulated by Bartus et al. in 1982, posits that central cholinergic deficits underlie memory dysfunction in AD, based on observations of reduced ChAT activity and nbM loss.^[75] Recent updates in the 2020s integrate neuroinflammation into this framework, highlighting how chronic microglial activation and cytokine release exacerbate cholinergic neuron vulnerability, further impairing ACh signaling and promoting degeneration.^[76] These models emphasize interactions between inflammation, Aβ, and tau pathologies in driving selective cholinergic loss.^[66] In Parkinson's disease, degeneration of cholinergic neurons in the brainstem, particularly within the pedunculopontine nucleus (PPN), contributes significantly to gait disturbances and postural instability.^[77] These neurons modulate locomotor control and balance through projections to spinal and basal ganglia circuits, and their loss leads to progressive freezing of gait and falls, independent of dopaminergic deficits.^[78] Additionally, L-DOPA therapy, while alleviating motor symptoms, paradoxically enhances striatal cholinergic interneuron activity, promoting burst-pause firing patterns that exacerbate levodopa-induced dyskinesias via altered acetylcholine release and downstream signaling in medium spiny neurons.^[79] Schizophrenia involves cholinergic dysregulation, characterized by reduced expression of nicotinic and muscarinic receptors in cortical regions, contributing to cognitive impairments such as deficits in attention and sensory gating by impairing prefrontal network dynamics.^[80] This hypocholinergic state may contribute to negative and cognitive symptoms by impairing signal-to-noise ratios in cortical processing.^[81] Therapeutic strategies targeting α7 nicotinic acetylcholine receptors (nAChRs), such as selective agonists, aim to normalize these deficits; clinical trials have shown improvements in cognitive performance, including verbal learning and executive function, with compounds like encenicline demonstrating pro-cognitive effects in early-phase studies.^[82] Myasthenia gravis is an autoimmune disorder characterized by antibodies targeting nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction, leading to receptor blockade, degradation, and complement-mediated destruction that impairs synaptic transmission and causes muscle weakness.^[83] These autoantibodies, primarily IgG1 and IgG3 subclasses, bind postsynaptic AChRs, reducing their density by up to 70-90% and eliciting fatigable weakness in ocular, bulbar, and limb muscles.^[84] Recent research from the 2020s highlights cholinergic deficits in Lewy body dementia, where degeneration of basal forebrain cholinergic neurons parallels or exceeds that in Alzheimer's disease, correlating with rapid cognitive decline, visual hallucinations, and attentional impairments.^[85] In depression, emerging evidence points to hyperactivity of M1 muscarinic receptors in limbic circuits, promoting negative bias in emotional processing and anhedonia; selective M1 antagonists like scopolamine have shown rapid antidepressant effects in clinical trials, suggesting cholinergic modulation as a novel therapeutic avenue.^[86]

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https://doi.org/10.1016/j.ydbio.2016.11.007
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Ageing and the brain - PMC - PubMed Central - NIH
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Physiology, Gastrointestinal Nervous Control - StatPearls - NCBI - NIH
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Sinus Arrhythmia - StatPearls - NCBI Bookshelf - NIH
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Anatomy, Skin Sweat Glands - StatPearls - NCBI Bookshelf
Eccrine sweat glands receive sympathetic innervation via cholinergic fibers that send impulses in response to changes in core body temperature. The ...
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A functional topography within the cholinergic basal forebrain ... - eLife
Nov 25, 2021 · Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning.
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Basal forebrain cholinergic input mediates adaptive attention ... - PMC
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Synergy of Direct and Indirect Cholinergic Septo-Hippocampal ...
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https://www.nature.com/articles/1301116
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Cholinergic Modulation Promotes Attentional Modulation in Primary ...
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Activity Profiles of Cholinergic and Intermingled GABAergic and ...
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Cholinergic Basal Forebrain Neurons Burst with Theta during ...
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The cholinergic system, circadian rhythmicity, and time memory
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The cholinergic forebrain arousal system acts directly on the ... - PNAS
We demonstrate that cholinergic input from the basal forebrain is both necessary and sufficient for eliciting this arousal-induced resetting of the circadian ...
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Distinct synchronization, cortical coupling and behavioral function of ...
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Optogenetic activation of septal cholinergic neurons suppresses ...
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Transcriptional Profiling of Cholinergic Neurons From Basal ...
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The Molecular Genetic Interaction Between Circadian Rhythms and ...
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Insights into the interaction between time and reward prediction on ...
Sep 8, 2024 · We conclude that the role of the striatal cholinergic TAN system in time processing is embedded in predicting rewarding outcomes during timing behavior.
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[PDF] 1 Cholinergic interneurons in the dorsal striatum play an important ...
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[PDF] Role of Cholinergic and GABAergic Modulation in the Hippocampus
ABSTRACT: This research focuses on linking episodic memory function to the cellular physiology of hippocampal neurons, with a particular.<|control11|><|separator|>
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Acetylcholine modulates the temporal dynamics of human theta ...
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Review article Time as the fourth dimension in the hippocampus
The hippocampus plays a central role in temporal processing, including timing, sequence learning, and memory, using 'time cells' to track time.
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Episodic Memories: How do the Hippocampus and the Entorhinal ...
Hippocampal “time cells” bridge the gap in memory ... Precise spike timing dynamics of hippocampal place cell activity sensitive to cholinergic disruption.Missing: acetylcholine timestamping
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The cholinergic system, circadian rhythmicity, and time memory
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Paying attention to smell: cholinergic signaling in the olfactory bulb
In addition to modulating odor detection and discrimination (Chaudhury et al., 2009), nAChRs are also involved in olfactory working memory. Mice that lacked the ...
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Social information as an entrainment cue for the circadian clock - PMC
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Alzheimer's Disease: Targeting the Cholinergic System - PMC
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Revisiting the Cholinergic Hypothesis in Alzheimer's Disease
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Alzheimer's Disease and Senile Dementia: Loss of Neurons in the ...
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Nontoxic Amyloid β Peptide1-42 Suppresses Acetylcholine Synthesis
We report here that Aβ 1-42 freshly solubilized in water impairs ACh synthesis in cholinergic neurons without affecting neuronal survival.
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Progression of Tau Pathology in Cholinergic Basal Forebrain ...
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[68]
Role of Cholinergic Signaling in Alzheimer's Disease - PMC
The abnormal cholinergic system regulates and promotes changes in amyloid precursor protein (APP) metabolism and tau phosphorylation, leading to neurotoxicity, ...
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cholinergic system in the pathophysiology and treatment of ...
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Cholinergic system during the progression of Alzheimer's disease
The loss of cholinergic markers within vulnerable neurons and their respective projection sites has been a major tenet in AD research for over 30 years.
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Chemical genetic activation of the cholinergic basal forebrain ...
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The cholinergic hypothesis of geriatric memory dysfunction - PubMed
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Pharmacological enhancement of cholinergic neurotransmission ...
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Cholinergic mesencephalic neurons are involved in gait and ... - PMC
Our data therefore reveal that the cholinergic neurons of the PPN play a central role in controlling gait and posture and represent a possible target for ...
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Overview of the Cholinergic Contribution to Gait, Balance and Falls ...
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Enhanced striatal cholinergic neuronal activity mediates l-DOPA ...
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Neuromodulation by Acetylcholine: Examples from Schizophrenia ...
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Cholinergic system in schizophrenia: A systematic review and meta ...
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Proof-of-Concept Trial of an α7 Nicotinic Agonist in Schizophrenia
Conclusions An α7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the ...
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Myasthenia gravis | Nature Reviews Disease Primers
May 2, 2019 · Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase ...
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Muscle autoantibodies in myasthenia gravis: beyond diagnosis? - NIH
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction ... blocking antibodies against acetylcholine receptors with changes in disease severity ...
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Cholinergic changes in Lewy body disease - PubMed
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Cholinergic Regulation of Mood: From Basic and Clinical Studies to ...
On the other hand, activating M1-AChRs increases depression-like behaviors in humans and animals. Stimulation of presynaptic M2-AChRs and M4-AChRs decreases ...Missing: 2020s | Show results with:2020s