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A cholinergic neuron is a
nerve cell A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...
which mainly uses the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
(ACh) to send its messages. Many neurological systems are
cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...
. Cholinergic neurons provide the primary source of acetylcholine to the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
, and promote cortical activation during both wakefulness and
rapid eye movement sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
. The cholinergic system of neurons has been a main focus of research in aging and neural degradation, specifically as it relates to
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. The dysfunction and loss of
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons and their cortical projections are among the earliest pathological events in Alzheimer's disease.


Anatomy

Most research involving cholinergic neurons involves the
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons. However, cholinergic neurons only represent about 5% of the total basal forebrain cell population. Most of these neurons originate in different areas of the basal forebrain and have extensive projections into almost all layers of the cortex. Basal forebrain cholinergic neurons are homologous within a particular basal forebrain region but vary across different regions. In the brainstem acetylcholine originates from the pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the meso-pontine tegmental area or pontomesencephalotegmental complex.


Normal aging

Normal
aging Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
is described as aging unaccompanied by the behavioral or
cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
dysfunctions associated with the cholinergic basal forebrain system. In normal aging, there are beadlike swellings within the cholinergic fibers with enlarged or thickened
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
s, often in grape-like clusters. This fiber swelling can be induced in a laboratory setting by damaging the cell body of the cholinergic neuron, which implies there is a slow cell and fiber degeneration of affected neurons and their projecting axons.


Neuroprotective effects

Nerve growth factor Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was ...
protects cholinergic neurons. The small non-toxic molecule
urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...
has no neuroprotective effect on cholinergic neurons by itself, but when experimental brain slices were treated with nerve growth factor and urea, the number of cholinergic neurons in the brain slices was significantly enhanced when compared to slices treated with nerve growth factor only. The enhancing effect of urea may be due to inhibition of the
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
-system within the cholinergic neuron.


Relationship to mammalian circadian system

Cholinergic neurons, along with non-cholinergic neurons, have sleep/wake regulatory functions in the
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
that can be categorized based on their firing patterns in different regions. The cholinergic system allows the circadian system to have the cycle of one day. The cholinergic neuron may also play a role in time memory, and the ability of an individual to form a memory around a certain time of day, which is known as "time stamping". The cholinergic system is characterized by high
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
release during the active phase of an individual’s circadian rhythm.


Firing patterns and the circadian system

In the medial septum-diagonal band of
Broca's area Broca's area, or the Broca area (, also , ), is a region in the frontal lobe of the dominant Cerebral hemisphere, hemisphere, usually the left, of the Human brain, brain with functions linked to speech production. Language processing in the brai ...
of the brain, cholinergic neurons have very low firing rates during both wake and non-REM sleep, and show no rhythmic bursts during
hippocampal The hippocampus (: hippocampi; via Latin from Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum ar ...
(
theta Theta (, ) uppercase Θ or ; lowercase θ or ; ''thē̂ta'' ; Modern: ''thī́ta'' ) is the eighth letter of the Greek alphabet, derived from the Phoenician letter Teth 𐤈. In the system of Greek numerals, it has a value of 9. Gree ...
)
Electroencephalography Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignal, bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in ...
activity. However, cholinergic neurons in the magnocellular preoptic nucleus and Substantia innominata have increased firing rates with fast cortical (
gamma Gamma (; uppercase , lowercase ; ) is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. In Ancient Greek, the letter gamma represented a voiced velar stop . In Modern Greek, this letter normally repr ...
) Electroencephalography activity during wake and
rapid eye movement sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
. This indicates that cholinergic neurons may be activated through α1-receptors by
noradrenaline Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" (from ...
, which were released by
locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...
neurons during wake cycles. In a basic summary, cholinergic neurons are always active during wake or rapid eye movement sleep cycles, and are more likely to activate the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
to induce the
gamma wave A gamma wave or gamma rhythm is a pattern of neural oscillation in humans with a frequency between 30 and 100  Hz, the 40 Hz point being of particular interest. Gamma waves with frequencies between 30 and 70 hertz may be classified as low ...
and Theta rhythm activities while behaviorally promoting the states of wakefulness and rapid eye movement sleep.


Time memory and time stamping

The
suprachiasmatic nucleus The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for regulating sleep cycles in animals. Reception of light inputs from photosensitive r ...
functions as the hypothalamic master clock, controlling the body's
Circadian rhythm A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
. The suprachiasmatic nucleus of mice, hamsters, and rats have a small amount of cholinergic innervation. A "time memory" is the memory at a specific time of day for which an individual made an association with a certain event or location. "Time stamping" is the process by which the specific time-of-day is encoded to support the formation of a time memory. The situation must be important and specific, without unnecessary prolonging, for a time stamp to occur. Acetylcholine excites cells in the suprachiasmatic nucleus, so cholinergic transmission of more Acetylcholine into the suprachiasmatic nucleus should support the formation of a time memory. The number of free and available
muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...
s (mAChRs) is highest when acetylcholine release is at the lowest levels. When a memorable event occurs, there is a massive release of acetylcholine that will attach to mAChRs. Once too many are involved, the mAChRs will reduce or block further cholinergic input, which protects these cells and the networks from additional cholinergic input that could disrupt the signal. This allows the suprachiasmatic nucleus to perform time stamping and produce a time memory of what has just occurred to the individual. If correct, this would explain the cholinergic neuron’s role in memory.


Circadian system and Alzheimer's disease

The circadian system is one of the first systems to be damaged in
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. Alzheimer's patients often complain of disrupted sleep, shortened
rapid eye movement sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
, and increased night time awakening. These disruptions steadily worsen as the disease progresses. It is normal in aging for circadian rhythms to deteriorate as choline acetyltransferase (ChAT) fluctuations change in pattern and acetylcholine levels fluctuate more often. As Alzheimer's disease drastically changes cholinergic function, the circadian system naturally follows the changed levels. Circadian rhythmicity in acetylcholine release is critical for optimal memory processing, and a loss of this rhythmicity contributes to
cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
problems in Alzheimer's disease.


Olfactory behavior

Circadian modulation of cholinergic neuronal could be important for mediating sexual behaviors in mice. Modifications of basal forebrain cholinergic neuronal activity disrupted odor discrimination of simple odors, and the investigation of social odors.


Neurological disorders

Degeneration of the cholinergic neurons in the
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
has been linked to progressing memory deficits related to aging, which eventually results in decreased cholinergic function. The dysfunction and loss of
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons has been observed in many dementias, especially Alzheimer's. Recent findings imply that aging-related cognitive deficits are due to impairments of cholinergic function rather than cholinergic cell loss. This suggests that it will be possible to reverse cognitive declines, as the cells are not dead, but deteriorating.


Alzheimer's disease

Alzheimer's disease is the most common form of
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, and the sixth leading cause of death in the United States. The proportion of deaths associated with Alzheimer's continues to grow rapidly, increasing by 66% from 2000 to 2008. Alzheimer's typically involves a decline in the activity of choline acetyltransferase and
acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...
, as well as a decline in acetylcholine release. Cholinergic system research may provide the key to treating and reversing this devastating disease.


Histological hallmarks

Although degeneration of
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic cells has been observed in many other dementias, Alzheimer's has two distinctive histological hallmarks: Beta amyloid plaques and
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
s. The Beta amyloid plaques are high-molecular weight
fibril Fibrils () are structural biological materials found in nearly all living organisms. Not to be confused with fibers or protein filament, filaments, fibrils tend to have diameters ranging from 10 to 100 nanometers (whereas fibers are micro to ...
s and are major components of the senile Alzheimer's disease brain. There appears to be a vast, intrinsic microvascular pathology of the brain in these cases, which suggests a link between Beta amyloid production, impairments in cerebrovascular function, and
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic deficits in AD. It appears that Beta amyloid (1-42) mediates its
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...
action by affecting key proteins that play a role in
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
induction. There is also evidence that shows beta amyloid proteins actually bind to cholinergic neurons and physically inhibit ChAT activity in cultures treated with oligomers of beta amyloid. The other histological hallmarks,
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
s, are the intracellular inclusions formed by aggregates of hyperphosphorylated tau protein. This is found only in select populations of patients with Alzheimer's. This tau protein has specific pathology, and has been found both in patients with
mild cognitive impairment Mild cognitive impairment (MCI) is a diagnosis that reflects an intermediate stage of cognitive impairment that is often, but not always, a transitional phase from cognitive changes in normal aging to those typically found in dementia, especially ...
(a forerunner of Alzheimer's) and Alzheimer's itself. The neurofibrillary tangles seem to increase within the
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic complex with old age and at a more accelerated pace in patients with Alzheimer's.


Probable cause for vulnerable cholinergic neurons

The "cholinergic hypothesis" is a well-established pathology of the involvement of cholinergic neurons on Alzheimer's disease due to their role in memory. Research in 2007 determined why cholinergic neurons were becoming more vulnerable to Beta amyloid plaque formation. A pathway exists for both the maturation and degradation of
Nerve Growth Factor Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was ...
, which causes cholinergic neurons to become vulnerable.
Basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons are highly dependent on the constant internal supply of Nerve Growth Factor throughout life. If the supply of Nerve Growth Factor is interrupted, cholinergic atrophy could begin to occur in these neurons and change their
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
. This supply could be interrupted if there is a failure in the protease cascade and the precursor cannot be converted to Nerve Growth Factor. This is caused by a rise in
matrix metalloproteinase Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...
-9 activity, which increases the degradation of Nerve Growth Factor and reduces its production. This double failure of Nerve Growth Factor stimulation leads to the progressive atrophy of
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons, which in turn contributes to Alzheimer's-related learning and memory declines.


Disease model

Most studies of Alzheimer's have used mice or rat brains with Beta amyloid plaque buildup as the disease model. In 2013, Dr. Su-Chun Zhang and his research team derived cholinergic neurons from neuroepithelial stem cells in a laboratory setting, making it easier to test potential treatments without the use of live animals.


Potential treatments

Potential treatments for Alzheimer's include the use of memantine, a moderate affinity uncompetitive
NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...
that preferentially blocks excessive
N-methyl-D-aspartate ''N''-methyl--aspartic acid, or ''N''-methyl--aspartate (NMDA), is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unl ...
(NMDA) receptor activity without disrupting normal activity. This treatment is based on the theory that degenerative neural disorders have excitotoxic processes due to the inappropriate overstimulation of the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
. In a rat model, memantine treatment given preventatively to certain rats pre-β-amyloid (1-42) lesion significantly reduced the loss of cholinergic fibers. Memantine treatment reversed attention and learning deficits in Beta amyloid (1-42) affected rats. This data indicates the ability of memantine to rescue
neocortical The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sense, sensory perception, cognition, generation of motor cortex ...
cholinergic fibers (originating from
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons) from the neurotoxic effects of Beta amyloid (1-42)
oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
s. It should also be noted that memantine is able to inhibit the truncation of glycogen synthase kinase-3 (triggered by activated calpain), which is believed to play a key role in the pathogenesis of Alzheimer's, affecting
tau Tau (; uppercase Τ, lowercase τ or \boldsymbol\tau; ) is the nineteenth letter of the Greek alphabet, representing the voiceless alveolar plosive, voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300 ...
phosphorylation (the second histological hallmark). Another treatment involves the use of exogenous choline acetyltransferase as supplementation in cholinergic neurons. Cholinergic neurons have significantly reduced choline acetyltransferase and acetylcholine activity, which is correlated to the severity of the dementia or cognitive impairments. The problem with this therapy is that choline acetyltransferase is largely blocked by the blood-brain barrier. PTD-ChAT is a fusion protein made up of both protein transduction domain and choline acetyltransferase; it can pass through the blood-brain barrier and cell membranes. It regulates acetylcholine levels in the brain, curing mice treated with PTD-ChAT from their memory and cognitive deficits.


Other potential diseases

Cholinergic neurons have an effect on other neurodegenerative diseases such as
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
,
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...
and Down syndrome. As with Alzheimer's, the degeneration of
basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal ba ...
cholinergic neurons and the decrease in the neurotransmitter acetylcholine have a drastic effect on behavioral and cognitive function.


References

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