Neuromodulation
Encyclopedia
In Neuromodulation several classes of neurotransmitters regulate diverse populations of central nervous system neurons (one neuron uses different neurotransmitters to connect to several neurons). This is in contrast to direct synaptic transmission
, in which one presynaptic neuron directly influences a postsynaptic partner (one neuron
reaching one other neuron
), neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons. Examples of neuromodulators include dopamine
, serotonin
, acetylcholine
, histamine
and others.
A neuromodulator is a relatively new concept. It can be conceptualized as a neurotransmitter
that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite
. Such neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid
), influencing (or modulating) the overall activity level of the brain
. For this reason, some neurotransmitters are also considered as neuromodulators, such as serotonin
and acetylcholine
.
Neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the transmitter acts on local postsynaptic receptors, but in neuromodulation the receptors are typically 7-membrane spanning G-protein coupled receptors while in the latter case they are ligand-gated ion channels. The former type of synaptic transmission often involves effects on voltage-gated ion channels, and is quite slow. The latter type is much faster. A related distinction is also sometimes drawn between modulator and driver synaptic inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus causing that spiking.
s). However, modeling work suggests that this alone is insufficient, because the neuromuscular transformation from neural input to muscular output may be tuned for particular ranges of input. Stern et al. (2007) suggest that neuromodulators must act not only on the input system but must change the transformation itself to produce the proper contractions of muscles as output.
The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine
system, the serotonin
system and the cholinergic
system. Drugs targeting the neurotransmitter of such systems affects the whole system, and explains the mode of action of many drugs.
Most other neurotransmitters, on the other hand, e.g. glutamate, GABA
and glycine
, are used very generally throughout the central nervous system.
The noradrenaline system consists of just 1500 neurons on each side of the brain, primarily in the locus coeruleus. This is diminutive compared to the more than 100 billion neurons in the brain. As with dopaminergic neurons in the substantia nigra, neurons in the locus caeruleus tend to be melanin
-pigmented. In spite of their small number, when activated, the system plays major roles in the brain, as seen in table above. Noradrenaline is released from the neurons, and acts on adrenergic receptors.
The dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum
or substantia nigra
as examples. It acts on dopamine receptors.
Parkinson's disease
is at least in part related to dropping out of dopaminergic cells in deep-brain nuclei, primarily the melanin-pigmented neurons in the substantia nigra
but secondarily the noradrenergic neurons of the locus ceruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
The serotonin system in the CNS contains only 1% of total body serotonin, the rest being found as transmitters in the peripheral nervous system
. It travels around the brain along the medial forebrain bundle
and acts on serotonin receptors. In the peripheral nervous system
(such as in the gut wall) serotonin regulates vascular tone.
(GABA) system is more generally distributed throughout the brain. Nevertheless, it has an overall inhibitory effect.
s (SCS) (surgically implanted) or transcutaneous electrical nerve stimulation
devices (externally placed).
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, in which one presynaptic neuron directly influences a postsynaptic partner (one neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
reaching one other neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
), neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons. Examples of neuromodulators include dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
and others.
A neuromodulator is a relatively new concept. It can be conceptualized as a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
. Such neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
), influencing (or modulating) the overall activity level of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. For this reason, some neurotransmitters are also considered as neuromodulators, such as serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
.
Neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the transmitter acts on local postsynaptic receptors, but in neuromodulation the receptors are typically 7-membrane spanning G-protein coupled receptors while in the latter case they are ligand-gated ion channels. The former type of synaptic transmission often involves effects on voltage-gated ion channels, and is quite slow. The latter type is much faster. A related distinction is also sometimes drawn between modulator and driver synaptic inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus causing that spiking.
Neuromuscular systems
Neuromodulators may alter the output of a physiological system by acting on the associated inputs (for instance, central pattern generatorCentral pattern generator
Central pattern generators are neural networks that produce rhythmic patterned outputs without sensory feedback. CPGs have been shown to produce rhythmic outputs resembling normal "rhythmic motor pattern production" even in isolation from motor and sensory feedback from limbs and other muscle...
s). However, modeling work suggests that this alone is insufficient, because the neuromuscular transformation from neural input to muscular output may be tuned for particular ranges of input. Stern et al. (2007) suggest that neuromodulators must act not only on the input system but must change the transformation itself to produce the proper contractions of muscles as output.
Diffuse modulatory neurotransmitter systems
Neurotransmitter systems are systems of neurons in the brain expressing certain types of neurotransmitters, and thus form distinct systems. Activation of the system causes effects in large volumes of the brain, called volume transmission.The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
system, the serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
system and the cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
system. Drugs targeting the neurotransmitter of such systems affects the whole system, and explains the mode of action of many drugs.
Most other neurotransmitters, on the other hand, e.g. glutamate, GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
, are used very generally throughout the central nervous system.
Comparison
| System | Origin | Targets | Effects |
|---|---|---|---|
| Noradrenaline system | Locus coeruleus | adrenergic receptors in:
|
Reward system In neuroscience, the reward system is a collection of brain structures which attempts to regulate and control behavior by inducing pleasurable effects... |
| Lateral tegmental field |
Hypothalamus The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions... |
||
| Dopamine system | dopamine Dopamine Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their... pathways Neural pathway A neural pathway, neural tract, or neural face, connects one part of the nervous system with another and usually consists of bundles of elongated, myelin-insulated neurons, known collectively as white matter... : Mesocortical pathway The mesocortical pathway is a neural pathway that connects the ventral tegmentum to the cerebral cortex, particularly the frontal lobes. It is one of the four major dopamine pathways in the brain... Mesolimbic pathway The mesolimbic pathway is one of the dopaminergic pathways in the brain. The pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus as well as to the medial prefrontal cortex... Nigrostriatal pathway The nigrostriatal pathway is a neural pathway that connects the substantia nigra with the striatum. It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement, as part of a system called the basal ganglia motor loop.Loss of dopamine... Tuberoinfundibular pathway The tuberoinfundibular pathway refers to a population of dopamine neurons in the arcuate nucleus of the mediobasal hypothalamus that project to the median eminence . It is one of the four major dopamine pathways in the brain... |
Dopamine receptor Dopamine receptor Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.... s at pathway terminations. |
motor system Motor system The motor system is the part of the central nervous system that is involved with movement. It consists of the pyramidal and extrapyramidal system.... , reward system Reward system In neuroscience, the reward system is a collection of brain structures which attempts to regulate and control behavior by inducing pleasurable effects... , cognition Cognition In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science... , endocrine, nausea Nausea Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting... |
| Serotonin system | caudal dorsal raphe nucleus |
Deep cerebellar nuclei The Cerebellum has four deep cerebellar nuclei embedded in the white matter in its center.-Inputs:These nuclei receive inhibitory inputs from Purkinje cells in the cerebellar cortex and excitatory inputs from mossy fiber and climbing fiber pathways. Most output fibers of the cerebellum originate... Spinal cord The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system... >rowspan=2| Increase (introversion Extraversion and introversion The trait of extraversion-introversion is a central dimension of human personality theories.Extraverts tend to be gregarious, assertive, and interested in seeking out external stimulus. Introverts, in contrast, tend to be introspective, quiet and less sociable. They are not necessarily loners but... ), mood Mood (psychology) A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event.... , satiety, body temperature and sleep Sleep Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than... , while decreasing nociception. |
|
| rostral dorsal raphe nucleus | Serotonin receptors in:
|
||
| Cholinergic system | Pedunculopontine nucleus Pedunculopontine nucleus The pedunculopontine nucleus is located in the brainstem, caudal to the substantia nigra and adjacent to the superior cerebellar peduncle. It has two divisions, one containing cholinergic neurons, the pars compacta, and one containing mostly glutamatergic neurons, the pars dissipata... and dorsolateral tegmental nuclei (pontomesencephalotegmental complex) |
(mainly) M1 receptors in:
Pontine nuclei The pontine nuclei are a part of the pons involved in motor activity. Corticopontine fibres carry information from the primary motor cortex to the ipsilateral pontine nucleus in the ventral pons, and the pontocerebellar projection then carries that information to the contralateral cerebellum via... Locus ceruleus The locus coeruleus , is a nucleus in the brainstem involved with physiological responses to stress and panic. It was discovered in the 18th century by Félix Vicq-d'Azyr.... Lateral reticular nucleus The lateral reticular nucleus, of the funiculus, can be divided into three subnuclei, the parvocellular, magnocellular and the subtrigeminal. As is typical of the reticular formation, none of these are very distinct subnuclei, but rather blurred distinctions between cell types and location...
|
Learning Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning... |
| basal optic nucleus of Meynert | (mainly) M1 receptors in:
Neocortex The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI... |
||
| medial septal nucleus | (mainly) M1 receptors in:
Hippocampus The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in... Neocortex The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI... |
Noradrenaline system
Further reading: Norepinephrine#Norepinephrine systemThe noradrenaline system consists of just 1500 neurons on each side of the brain, primarily in the locus coeruleus. This is diminutive compared to the more than 100 billion neurons in the brain. As with dopaminergic neurons in the substantia nigra, neurons in the locus caeruleus tend to be melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
-pigmented. In spite of their small number, when activated, the system plays major roles in the brain, as seen in table above. Noradrenaline is released from the neurons, and acts on adrenergic receptors.
Dopamine system
Further reading: Dopamine#Functions in the brainThe dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum
Ventral tegmentum
The ventral tegmentum , better known as the ventral tegmental area , is a group of neurons located close to the midline on the floor of the midbrain...
or substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
as examples. It acts on dopamine receptors.
Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
is at least in part related to dropping out of dopaminergic cells in deep-brain nuclei, primarily the melanin-pigmented neurons in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
but secondarily the noradrenergic neurons of the locus ceruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
Pharmacology
- CocaineCocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, for example, blocks the reuptake of dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, leaving these neurotransmitters in the synaptic gapSynapseIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
longer. - AMPTAMPTAlpha-methyl-p-tyrosine is a tyrosine hydroxylase enzyme inhibitor. It has been used in the treatment of pheochromocytoma. It has been demonstrated to inhibit the production of melanin.-Side-effects:...
prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpineReserpineReserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...
prevents dopamine storage within vesiclesSynaptic vesicleIn a neuron, synaptic 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 impulses between neurons and are constantly recreated by the cell...
; and deprenyl inhibits monoamine oxidaseMonoamine oxidaseL-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
(MAO)-B and thus increases dopamine levels.
Serotonin system
Further reading: Serotonin#Gross anatomyThe serotonin system in the CNS contains only 1% of total body serotonin, the rest being found as transmitters in the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
. It travels around the brain along the medial forebrain bundle
Medial forebrain bundle
The Medial forebrain bundle , is a complex bundle of axons coming from the basal olfactory regions, the periamygdaloid region, and the septal nuclei.-Anatomy:...
and acts on serotonin receptors. In the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(such as in the gut wall) serotonin regulates vascular tone.
Pharmacology
- Prozac is a selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin.
Others
The gamma-aminobutyric acidGamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(GABA) system is more generally distributed throughout the brain. Nevertheless, it has an overall inhibitory effect.
- Opioid peptides - these substances block nerve impulse generation in the secondary afferent pain neurons. These peptides are called opioid peptides because they have opium-like activity. The types of opioid peptides are:
- Endorphins
- Enkephalins
- Dynorphins
- Substance PSubstance PIn the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
- OctopamineOctopamineOctopamine is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic and dopaminergic systems. It is also found naturally in numerous plants, including bitter orange. Biosynthesis of the D--enantiomer of octopamine is by β-hydroxylation of...
Other uses
Neuromodulation also refers to a medical procedure used to alter nervous system function for relief of pain. It consists primarily of electrical stimulation, lesioning of specific regions of the nervous system, or infusion of substances into the cerebrospinal fluid. Electrical stimulation are devices such as Spinal Cord StimulatorSpinal Cord Stimulator
A spinal cord stimulator is a device used to exert pulsed electrical signals to the spinal cord to control chronic pain. Spinal cord stimulation , in the simplest form, consists of stimulating electrodes, implanted in the epidural space, an electrical pulse generator, implanted in the lower...
s (SCS) (surgically implanted) or transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes...
devices (externally placed).
External links
- North American Neuromodulation SocietyNorth American Neuromodulation SocietyNorth American Neuromodulation Society is a scientific organization that serves to promote and advance neuromodulation as a treatment for various diseases.-History:NANS was founded in 1994 as the American Neuromodulation Society...
- Neuromodulation and Neural Plasticity
- International Neuromodulation Society
- Scolarpedia article on neuromodulation