Neuromodulation

This article is about the natural physiological process in the nervous system. For the therapeutic electromagnetic or chemical stimulation of nerve cells, see Neuromodulation (medicine).

Neuromodulation is the physiological process by which a given neuron uses one or more neurotransmitters to regulate diverse populations of neurons. This is in contrast to classical synaptic transmission, in which one presynaptic neuron directly influences a single postsynaptic partner. Neuromodulators secreted by a small group of neurons diffuse through large areas of the nervous system, affecting multiple neurons. Major neuromodulators in the central nervous system include dopamine, serotonin, acetylcholine, histamine, and norepinephrine.

Neuromodulation 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 cerebrospinal fluid (CSF), influencing (or "modulating") the activity of several other neurons in the brain. For this reason, some neurotransmitters are also considered to be 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 G-protein coupled receptors while in classical chemical neurotransmission, they are ligand-gated ion channels. Neurotransmission that involves metabotropic receptors (like G-protein linked receptors) often also involves voltage-gated ion channels, and is relatively slow. Conversely, neurotransmission that involves exclusively ligand-gated ion channels 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 generators). 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.

Volume transmission

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. Volume transmission is the diffusion through the brain extracellular fluid of neurotransmitters released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors, and with a longer time course than for transmission at a single synapse.

The major neurotransmitter systems

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.

Comparison

Neuromodulator systems

System	Origin	Targets	Effects
Noradrenaline system	Locus coeruleus	adrenergic receptors in: spinal cord thalamus hypothalamus striatum neocortex cingulate gyrus cingulum hippocampus amygdala	arousal (Arousal is a physiological and psychological state of being awake or reactive to stimuli) reward system
	Lateral tegmental field	hypothalamus
Dopamine system	dopamine pathways: mesocortical pathway mesolimbic pathway nigrostriatal pathway tuberoinfundibular pathway	Dopamine receptors at pathway terminations.	motor system, reward system, cognition, endocrine, nausea
Serotonin system	caudal dorsal raphe nucleus	Serotonin receptors in: deep cerebellar nuclei cerebellar cortex spinal cord	Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception.
	rostral dorsal raphe nucleus	Serotonin receptors in: thalamus striatum hypothalamus nucleus accumbens neocortex cingulate gyrus cingulum hippocampus amygdala
Cholinergic system	Pedunculopontine nucleus and dorsolateral tegmental nuclei (pontomesencephalotegmental complex)	(mainly) M1 receptors in: brainstem deep cerebellar nuclei pontine nuclei locus ceruleus raphe nucleus lateral reticular nucleus inferior olive thalamus tectum basal ganglia basal forebrain	muscle and motor control system learning short-term memory arousal reward
	basal optic nucleus of Meynert	(mainly) M1 receptors in: neocortex
	medial septal nucleus	(mainly) M1 receptors in: hippocampus neocortex

Noradrenaline system

Further reading: Norepinephrine#Norepinephrine 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.

Dopamine system

Further reading: Dopamine#Functions in the brain

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 coeruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.

Dopamine pharmacology

• Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer.
• AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.

Serotonin system

Further reading: Serotonin#Gross anatomy

The serotonin created by the brain comprises around 10% of total body serotonin. The majority (80-90%) is found in the gastrointestinal (GI) tract. 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.

Serotonin pharmacology

• Prozac or fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a widely used antidepressant that blocks the reuptake of serotonin. Although changes in neurochemistry are found immediately after taking an antidepressant, symptoms will not begin to improve until 4 to 6 weeks after administration.
• Monoamine oxidase inhibitors are thought to change the rate of oxidation of biogenic amines within the brain. A lack of oxidation means that more neurotransmitters (specifically monoamines such as dopamine or serotonin) are available for release into synapses. MOAIs take several weeks to alleviate the symptoms of depression.
• Tricyclic antidepressants block the reuptake of biogenic amines from the synapse, back into the neuron. They typically take 4 to 6 weeks to alleviate any symptoms of depression. They are considered to have immediate and long-term effects.

GABA

Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity.

Neuropeptides

• Opioid peptides - a large family of endogenous neuropeptides that are widely distributed throughout the central and peripheral nervous system. Opiate drugs such as heroin and morphine act at the receptors of these neurotransmitters.

1. Endorphins
2. Enkephalins
3. Dynorphins

• Substance P

Other uses

Neuromodulation also refers to an emerging class of medical therapies that target the nervous system for restoration of function (such as in cochlear implants), relief of pain, or control of symptoms, such as tremor seen in movement disorders like Parkinson's disease. The therapies consist primarily of targeted electrical stimulation, or infusion of medications into the cerebrospinal fluid using intrathecal drug delivery, such as baclofen for spasticity. Electrical stimulation devices include deep brain stimulation systems (DBS), colloquially referred to as "brain pacemakers", spinal cord stimulators (SCS), which are implanted using minimally invasive procedures, or transcutaneous electrical nerve stimulation devices, which are fully external, among others.

See also

• 5-HT2c receptor agonist

External links

• North American Neuromodulation Society
• Neuromodulation and Neural Plasticity
• International Neuromodulation Society
• Scolarpedia article on neuromodulation