Molecular neuroscience is a branch of
neuroscience
Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, developme ...
that observes concepts in
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
applied to the
nervous systems of animals. The scope of this subject covers topics such as molecular
neuroanatomy
Neuroanatomy is the study of the structure and organization of the nervous system. In contrast to animals with radial symmetry, whose nervous system consists of a distributed network of cells, animals with bilateral symmetry have segregated, defi ...
, mechanisms of
molecular signaling in the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
, the effects of
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
and
epigenetics
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
on neuronal development, and the molecular basis for
neuroplasticity
Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it p ...
and
neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
s.
As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.
Locating neurotransmitters
In
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, communication between neurons typically occurs by chemical transmission across gaps between the cells called
synapses. The transmitted chemicals, known as
neurotransmitters
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurot ...
, regulate a significant fraction of vital body functions.
It is possible to anatomically locate neurotransmitters by labeling techniques. It is possible to chemically identify certain neurotransmitters such as
catecholamines by
fixing
Fixing may refer to:
* The present participle of the verb "to fix", an action meaning maintenance, repair, and operations
* "fixing someone up" in the context of arranging or finding a social date for someone
* "Fixing", craving an addictive drug, ...
neural
tissue sections with
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
. This can give rise to formaldehyde-induced fluorescence when exposed to
ultraviolet light
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
.
Dopamine, a catecholamine, was identified in the
nematode ''
C. elegans'' by using this technique.
Immunocytochemistry, which involves raising antibodies against targeted chemical or biological entities, includes a few other techniques of interest. A targeted neurotransmitter could be specifically tagged by
primary and secondary antibodies
Primary and secondary antibodies are two groups of antibodies that are classified based on whether they bind to ''antigens or proteins'' directly or target another (primary) antibody that, in turn, is bound to an ''antigen or protein''.
Primary
A ...
with radioactive labeling in order to identify the neurotransmitter by
autoradiography. The presence of neurotransmitters (though not necessarily the location) can be observed in enzyme-linked immunocytochemistry or
enzyme-linked immunosorbent assays (ELISA) in which substrate-binding in the enzymatic assays can induce
precipitate
In an aqueous solution, precipitation is the process of transforming a dissolved substance into an insoluble solid from a super-saturated solution. The solid formed is called the precipitate. In case of an inorganic chemical reaction leading ...
s,
fluorophores, or
chemiluminescence. In the event that neurotransmitters cannot be histochemically identified, an alternative method is to locate them by their neural uptake mechanisms.
Voltage-gated ion channels
Excitable cells in living organisms have
voltage-gated ion channels. These can be observed throughout the nervous system in neurons. The first ion channels to be characterized were the sodium and potassium ion channels by
A.L. Hodgkin and
A.F. Huxley in the 1950s upon studying the giant axon of the squid genus ''
Loligo
''Loligo'' is a genus of squid and one of the most representative and widely distributed groups of myopsid squid.
The genus was first described by Jean Baptiste Lamarck in 1798. However, the name had been used earlier than Lamarck (Schneider, ...
''. Their research demonstrated the selective permeability of cellular membranes, dependent on physiological conditions, and the electrical effects that result from these permeabilities to produce
action potentials
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...
.
Sodium ion channels
Sodium channels were the first voltage-gated ion channels to be isolated in 1984 from the eel ''
Electrophorus electricus
''Electrophorus electricus'' is the best-known species of electric eel. It is a South American electric fish. Until the discovery of two additional species in 2019, the genus was classified as the monotypic, with this species the only one in the ...
'' by
Shosaku Numa. The
pufferfish toxin
tetrodotoxin (TTX), a sodium channel blocker, was used to isolate the sodium channel protein by binding it using the
column chromatography
Column chromatography in chemistry is a chromatography method used to isolate a single chemical compound from a mixture. Chromatography is able to separate substances based on differential adsorption of compounds to the adsorbent; compounds move th ...
technique for chemical separation. The
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
sequence of the protein was analyzed by
Edman degradation
Edman degradation, developed by Pehr Edman, is a method of sequencing amino acids in a peptide. In this method, the amino-terminal residue is labeled and cleaved from the peptide without disrupting the peptide bonds between other amino acid residu ...
and then used to construct a
cDNA library which could be used to clone the channel protein. Cloning the channel itself allowed for applications such as identifying the same channels in other animals.
Sodium channels are known for working in concert with potassium channels during the development of graded potentials and action potentials. Sodium channels allow an influx of Na
+ ions into a neuron, resulting in a
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...
from the
resting membrane potential A relatively static membrane potential which is usually referred to as the ground value for trans-membrane voltage.
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as oppo ...
of a neuron to lead to a graded potential or action potential, depending on the degree of depolarization.
Potassium ion channels
Potassium channels
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
come in a variety of forms, are present in most
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells, and typically tend to stabilize the cell membrane at the potassium
equilibrium potential In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are pe ...
. As with sodium ions, graded potentials and action potentials are also dependent on potassium channels. While influx of Na
+ ions into a neuron induce cellular depolarization, efflux of K
+ ions out of a neuron causes a cell to repolarize to resting membrane potential. The activation of potassium ion channels themselves are dependent on the depolarization resulting from Na
+ influx during an action potential.
As with sodium channels, the potassium channels have their own toxins that block channel protein action. An example of such a toxin is the large cation,
tetraethylammonium (TEA), but it is notable that the toxin does not have the same mechanism of action on all potassium channels, given the variety of channel types across species. The presence of potassium channels was first identified in ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'' mutant flies that shook uncontrollably upon anesthesia due to problems in cellular repolarization that led to abnormal neuron and muscle electrophysiology. Potassium channels were first identified by manipulating molecular genetics (of the flies) instead of performing channel protein purification because there were no known high-affinity ligands for potassium channels (such as TEA) at the time of discovery.
Calcium ion channels
Calcium channels are important for certain cell-signaling cascades as well as neurotransmitter release at
axon terminals
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
. A variety of different types of calcium ion channels are found in excitable cells. As with sodium ion channels, calcium ion channels have been isolated and cloned by chromatographic purification techniques. It is notable, as with the case of neurotransmitter release, that calcium channels can interact with intracellular proteins and plays a strong role in signaling, especially in locations such as the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are ke ...
of muscle cells.
Receptors
Various types of receptors can be used for cell signaling and communication and can include ionotropic receptors and metabotropic receptors. These cell surface receptor types are differentiated by the mechanism and duration of action with ionotropic receptors being associated with fast signal transmission and metabotropic receptors being associated with slow signal transmission. Metabotropic receptors happen to cover a wide variety of cell-surface receptors with notably different
signaling cascades.
Ionotropic receptors
Ionotropic receptors, otherwise known as
ligand-gated ion channels, are fast acting receptors that mediate neural and physiological function by ion channel flow with ligand-binding. Nicotinic, GABA, and Glutamate receptors are among some of the
cell surface receptors regulated by ligand-gated ion channel flow.
GABA is the brain's main inhibitory neurotransmitter and glutamate is the brain's main excitatory neurotransmitter.
GABA receptors
GABA
A and GABA
C receptors are known to be ionotropic, while the GABA
B receptor is metabotropic. GABA
A receptors mediate fast inhibitory responses in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS) and are found on neurons,
glial cells
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
, and
adrenal medulla cells. It is responsible for inducing Cl
− ion influx into cells, thereby reducing the probability that membrane depolarization will occur upon the arrival of a graded potential or an action potential. GABA receptors can also interact with non-endogenous ligands to influence activity. For example, the compound
diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
(marketed as Valium) is an
allosteric agonist which increases the affinity of the receptor for GABA. The increased physiological inhibitory effects resulting from increased GABA binding make diazepam a useful
tranquilizer
A tranquilizer is a drug that is designed for the treatment of anxiety, fear, tension, agitation, and disturbances of the mind, specifically to reduce states of anxiety and tension.
Etymology
Tranquilizer, as a term, was first used by F.F. Yonk ...
or
anticonvulsant (antiepileptic drugs). On the other hand, GABA receptors can also be targeted by decreasing Cl
− cellular influx with the effect of convulsants like
picrotoxin
Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Gree ...
. The antagonistic mechanism of action for this compound is not directly on the GABA receptor, but there are other compounds that are capable of allosteric inactivation, including T-butylbicyclophorothionate (TBPS) and pentylenetetrazole (PZT).
Compared with GABA
A, GABA
C receptors have a higher affinity for GABA, they are likely to be longer-lasting in activity, and their responses are likely to be generated by lower GABA concentrations.
Glutamate receptors
Ionotropic
glutamate receptors
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous syste ...
can include
NMDA
''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. Unlike ...
,
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
There are several types of glutamatergic ...
, and
kainate receptors
Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a dru ...
. These receptors are named after agonists that facilitate glutamate activity. NMDA receptors are notable for their excitatory mechanisms to affect neuronal plasticity in learning and memory, as well as neuropathologies such as stroke and epilepsy. NDMA receptors have multiple binding sites just like ionotropic GABA receptors and can be influenced by co-agonists such the
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
neurotransmitter or
phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percept ...
(PCP). The NMDA receptors carry a current by Ca
2+ ions and can be blocked by extracellular Mg
2+ ions depending on voltage and membrane potential. This Ca
2+ influx is increased by
excitatory postsynaptic potentials (EPSPs) produced by NMDA receptors, activating Ca
2+-based signaling cascades (such as neurotransmitter release). AMPA generate shorter and larger excitatory postsynaptic currents than other ionotropic glutamate receptors.
Nicotinic ACh receptors
Nicotinic receptors
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...
bind the
acetylcholine (ACh) neurotransmitter to produce non-selective cation channel flow that generates excitatory postsynaptic responses. Receptor activity, which can be influenced by nicotine consumption, produces feelings of euphoria, relaxation, and inevitably addiction in high levels.
Metabotropic receptors
Metabotropic receptors, are slow response receptors in postsynaptic cells. Typically these slow responses are characterized by more elaborate intracellular changes in biochemistry. Responses of neurotransmitter uptake by
metabotropic receptors can result in the activation of intracellualar enzymes and cascades involving second messengers, as is the case with
G protein-linked receptors. Various metabotropic receptors can include certain glutamate receptors, muscarinic ACh receptors, GABA
B receptors, and
receptor tyrosine kinases
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
.
G protein-linked receptors
The
G protein-linked signaling cascade can significantly amplify the signal of a particular neurotransmitter to produce hundreds to thousands of second messengers in a cell. The mechanism of action by which
G protein-linked receptors cause a signaling cascade is as follows:
# Neurotransmitter binds to the receptor
# The receptor undergoes a conformational change to allow
G-protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
complex binding
#
GDP
Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is ofte ...
is exchanged with
GTP upon G protein complex binding to the receptor
# The α-subunit of the G protein complex is bound to GTP and separates to bind with a target protein such as
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
# The binding to the target protein either increases or decreases the rate of second messenger (such as
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...
) production
#
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
hydrolyzes the α-subunit so that is bound to GDP and the α-subunit returns to the G protein complex inactive
Neurotransmitter release
Neurotransmitters are released in discrete packets known as quanta from the
axon terminal of one neuron to the
dendrites
Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the ...
of another across a
synapse. These quanta have been identified by
electron microscopy as
synaptic vesicles
In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulse ...
. Two types of vesicles are small synaptic vessicles (SSVs), which are about 40-60
nm in diameter, and large dense-core vesicles (LDCVs), electron-dense vesicles approximately 120-200
nm in diameter.
The former is derived from
endosomes and houses neurotransmitters such as
acetylcholine,
glutamate,
GABA, and
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
. The latter is derived from the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ...
and houses larger neurotransmitters such as
catecholamines and other
peptide neurotransmitters.
Neurotransmitters are released from an axon terminal and bind to postsynaptic dendrites in the following procession:
# Mobilization/recruitment of synaptic vesicle from
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
# Docking of vesicle (binding) to presynaptic membrane
# Priming of vesicle by
ATP (relatively slow step)
# Fusion of primed vesicle with presynaptic membrane and
exocytosis of the housed neurotransmitter
# Uptake of neurotransmitters in receptors of a postsynaptic cell
# Initiation or inhibition of action potential in postsynaptic cell depending on whether the neurotransmitters are excitatory or inhibitory (excitatory will result in depolarization of the postsynaptic membrane)
Neurotransmitter release is calcium-dependent
Neurotransmitter release is dependent on an external supply of Ca
2+ ions which enter axon terminals via voltage-gated
calcium channels. Vesicular fusion with the terminal membrane and release of the neurotransmitter is caused by the generation of Ca
2+ gradients induced by incoming
action potentials
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...
. The Ca
2+ ions cause the mobilization of newly synthesized vesicles from a reserve pool to undergo this membrane fusion. This mechanism of action was discovered in squid giant axons.
Lowering intracellular Ca
2+ ions provides a direct inhibitory effect on neurotransmitter release.
After release of the neurotransmitter occurs, vesicular membranes are recycled to their origins of production. Calcium ion channels can vary depending on the location of incidence. For example, the channels at an axon terminal differ from the typical calcium channels of a cell body (whether
neural or not). Even at axon terminals, calcium ion channel types can vary, as is the case with P-type calcium channels located at the
neuromuscular junction.
Neuronal gene expression
Sex differences
Differences in sex determination are controlled by
sex chromosomes
A sex chromosome (also referred to as an allosome, heterotypical chromosome, gonosome, heterochromosome, or idiochromosome) is a chromosome that differs from an ordinary autosome in form, size, and behavior. The human sex chromosomes, a typical ...
. Sex hormonal releases have a significant effect on
sexual dimorphisms
Sexual dimorphism is the condition where the sexes of the same animal and/or plant species exhibit different morphological characteristics, particularly characteristics not directly involved in reproduction. The condition occurs in most ani ...
(phenotypic differentiation of sexual characteristics) of the brain. Recent studies seem to suggest that regulating these dimorphisms has implications for understanding normal and abnormal brain function. Sexual dimorphisms may be significantly influenced by sex-based brain gene expression which varies from species to species.
Animal models such as rodents, ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'', and ''
Caenorhabditis elegans'', have been used to observe the origins and/or extent of sex bias in the brain versus the hormone-producing gonads of an animal. With the rodents, studies on genetic manipulation of sex chromosomes resulted in an effect on one sex that was completely opposite of the effect in the other sex. For example, a
knockout of a particular gene only resulted in anxiety-like effects in males. With studies on ''D. menlanogaster'' it was found that a large brain sex bias of expression occurred even after the gonads were removed, suggesting that sex bias could be independent of hormonal control in certain aspects.
Observing sex-biased genes has the potential for clinical significance in observing brain physiology and the potential for related (whether directly or indirectly) neurological disorders. Examples of
diseases with sex biases in development include
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
,
cerebral ischemia
Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke. ...
, and
Alzheimer's disease.
Epigenetics of the brain
Many brain functions can be influenced at the cellular and molecular level by variations and changes in gene expression, without altering the sequence of DNA in an organism. This is otherwise known as
epigenetic regulation. Examples of epigenetic mechanisms include
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
modifications and
DNA methylation. Such changes have been found to be strongly influential in the incidence of brain disease, mental illness, and addiction.
Epigenetic control has been shown to be involved in high levels of plasticity in early development, thereby defining its importance in the
critical period
In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...
of an organism.
Examples of how epigenetic changes can affect the human brain are as follows:
* Higher methylation levels in rRNA genes in the
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
of the brain results in a lower production of proteins and thus limited hippocampal function can result in learning and memory impairment and resultant suicidal tendencies.
* In a study comparing genetic differences between healthy people and psychiatric patients 60 different epigenetic markers associated with brain cell signaling were found.
* Environmental factors such as child abuse appears to cause the expression of an epigenetic tag on
glucocorticoid receptor
The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind.
The GR is expressed in almost every cell in the body and regulates ...
s (associated with stress responses) that was not found in suicide victims.
This is an example of experience-dependent plasticity.
*Environmental enrichment in individuals is associated with increased hippocampal gene histone acetylation and thus improved memory consolidation (notably
spatial memory).
Molecular mechanisms of neurodegenerative diseases
Excitotoxicity and glutamate receptors
Excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
is phenomenon in which glutamate receptors are inappropriately activated. It can be caused by prolonged excitatory synaptic transmission in which high levels of
glutamate neurotransmitter cause excessive activation in a postsynaptic neuron that can result in the death of the postsynaptic neuron. Following brain injury (such as from
ischemia), it has been found that excitotoxicity is a significant cause of neuronal damage. This can be understandable in the case where sudden perfusion of blood after reduced blood flow to the brain can result in excessive synaptic activity caused by the presence of increased
glutamate and
aspartate during the period of ischemia.
Alzheimer's disease
Alzheimer's disease is the most common neurodegenerative disease and is the most common form of
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
in the elderly. The disorder is characterized by progressive loss of memory and various cognitive functions. It is
hypothesized that the deposition of
amyloid-β peptide (40-42 amino acid residues) in the brain is integral in the incidence of Alzheimer's disease. Accumulation is purported to block
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
. It is also possible that a receptor for amyloid-β oligomers could be a
prion protein.
Parkinson's disease
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
is the second most common neurodegenerative disease after Alzheimer's disease. It is a hypokinetic movement
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
disease caused by the loss of dopaminergic neurons in the
substantia nigra of the human brain. The inhibitory outflow of the basal ganglia is thus not decreased, and so
upper motor neurons, mediated by the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
, are not activated in a timely manner. Specific symptoms include rigidity, postural problems, slow movements, and tremors. Blocking
GABA receptor input from
medium spiny neurons to
reticulata cells, causes inhibition of upper motor neurons similar to the inhibition that occurs in Parkinson's disease.
Huntington's disease
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
is a hyperkinetic movement
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
disease caused by lack of normal inhibitory inputs from
medium spiny neurons of the basal ganglia. This poses the opposite effects of those associated with Parkinson's disease, including inappropriate activation of
upper motor neurons. As with the GABAergic mechanisms observed in relation to Parkinson's disease, a GABA agonist injected into the
substantia nigra pars reticulata
The pars reticulata (SNpr) is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons (i.e., these neurons release GABA, which is ...
decreases inhibition of upper motor neurons, resulting in ballistic involuntary motor movements, similar to symptoms of Huntington's disease.
References
{{DEFAULTSORT:Molecular Neuroscience