In neuroscience, neuromodulation is the process in which several classes of neurotransmitters in the nervous system regulate diverse populations of neurons. As opposed to direct synaptic transmission in which one presynaptic neuron directly influences a postsynaptic partner, 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 in the field and 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) and influencing (or modulating) the overall activity level of the brain. For this reason, some neurotransmitters are also considered as neuromodulators. Examples of neuromodulators in this category are serotonin and acetylcholine
Additional recommended knowledge
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[1], 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.[1]
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 system, the serotonin system and the cholinergic system. Drugs targetting 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
Neurotransmitter systems
| System | Origin [2] | Targets[2] | Effects[2]
|
| Noradrenaline system
| locus coeruleus | adrenergic receptors in:
- spinal cord
- thalamus
- hypothalamus
- striatum
- neocortex
- cingulate gyrus
- cingulum
- hippocampus
- amygdala
|
|
| Lateral tegmental field |
|
| 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 (introverson), 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
| pontomesencephalotegmental complex | (mainly) M1 receptors in:
|
- learning
- short-term memory
- arousal
- reward
|
| basal optic nucleus of Meynert | (mainly) M1 receptors in:
|
| medial septal nucleus | (mainly) M1 receptors in:
|
Noradrenaline system
Further reading: Norepinephrine#Norepinephrine_system
The noradrenaline system consists of just 1500 neurons on each side of the brain, which is diminutive compared to the total amount of more than 100 billion neurons in the brain. Nevertheless, 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 system consists of several pathways, originating from e.g. the substantia nigra. It acts on dopamine receptors.
Parkinson's disease is at least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
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 system system 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.
Pharmacology
Cholinergic system
Further reading: Acetylcholine#in CNS
The cholinergic system works primary by M1 receptors, but M2-, M3-, M4- and M5 receptors are also found in the CNS.
Others
The gamma-aminobutyric acid (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:
- Substance P
- Octopamine
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 Stimulators (SCS) (surgically implanted) or Transcutaneous Electrical Nerve Stimulators (TENS) (external device).
References
- ^ a b Stern, E; Fort TJ, Millier MW, Peskin CS, Brezina V (2007). "Decoding modulation of the neuromuscular transform". Neurocomputing (6954). doi:10.1016/j.neucom.2006.10.117. Retrieved on 2007-04-7.
- ^ a b c Unless else specified in boxes, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone, page 474 for noradrenaline system, page 476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system.. ISBN 0-443-07145-4.
| Nervous system |
|---|
| Central nervous system (Brain, Spinal cord) • Peripheral nervous system • Somatic nervous system • Autonomic nervous system (Sympathetic, Parasympathetic) • Enteric nervous system • Sensory system |
| Brain: telencephalon (cerebrum, cerebral cortex, cerebral hemispheres) |
|---|
| Primary sulci/fissures | Medial longitudinal, Lateral, Central, Parietoöccipital, Calcarine, Cingulate, Callosal Collateral fissure |
|---|
| Frontal lobe | Precentral gyrus (Primary motor cortex, 4), Precentral sulcus, Superior frontal gyrus/Frontal eye fields (6, 8, 9), Middle frontal gyrus (46), Inferior frontal gyrus (44-Pars opercularis, 45-Pars triangularis), Orbitofrontal cortex (10, 11, 12, 47) |
|---|
| Parietal lobe | Somatosensory cortex (Primary (1, 2, 3, 43), Secondary (5)), Precuneus (7m), Parietal lobules (Arcuate fasciculus/Superior (7l), Inferior (40)), Angular gyrus (39), Intraparietal sulcus, Marginal sulcus |
|---|
| Occipital lobe | Primary visual cortex (17), Cuneus, Lingual gyrus, 18, 19 - Lateral occipital sulcus |
|---|
| Temporal lobe | Primary auditory cortex (41, 42), Superior temporal gyrus (38, 22), Middle temporal gyrus (21), Inferior temporal gyrus (20), Fusiform gyrus (37) Medial temporal lobe (Amygdala, Hippocampus, Parahippocampal gyrus (27, 28, 34, 35, 36) |
|---|
| Cingulate cortex/gyrus | Subgenual area (25), anterior cingulate (24, 32, 33), Posterior cingulate (23, 31), Retrosplenial cortex (26, 29, 30), Supracallosal gyrus |
|---|
| white matter tracts | Corpus callosum (Splenium, Genu, Rostrum, Tapetum), Septum pellucidum, Internal capsule, Corona radiata, External capsule, Olfactory tract, Fornix (Commissure of fornix), Anterior commissure, Posterior commissure Terminal stria Superior and Inferior longitudinal fasciculus, uncinate fasciculus, cingulum, Inferior occipitofrontal fasciculus |
|---|
| Basal ganglia | Striatum (Putamen,Caudate nucleus, Nucleus accumbens), Globus pallidus, Claustrum, Subthalamic nucleus, Substantia nigra |
|---|
| Other | Insular cortex Olfactory bulb, Anterior olfactory nucleus Septal nuclei Basal optic nucleus of Meynert |
|---|
| Some categorizations are approximations, and some Brodmann areas span gyri. |
| Brain: diencephalon |
|---|
| Epithalamus | Pineal body • Habenula (Habenular nuclei) |
|---|
| Hypothalamus |
anterior: Anterior hypothalamic nucleus • Paraventricular nucleus • Preoptic area • Supraoptic nucleus • Suprachiasmatic nucleus
intermediate/middle/tuberal/pituitary: infundibulum • median eminence • arcuate nucleus • Ventromedial nucleus • Dorsomedial hypothalamic nucleus • Tuber cinereum, Pituitary gland (Anterior pituitary, Posterior pituitary)
posterior/lateral: posterior nucleus • Mammillary body • Lateral nucleus
other: Medial forebrain bundle
|
|---|
| Subthalamus | Subthalamic nucleus • Zona incerta • Thalamic fasciculus • Lenticular fasciculus |
|---|
| Thalamus/nuclei | Ventral nuclear group (VA/VL, VP/VPM/VPL) • MD • AN • LNG (Pulvinar) • Intralaminar nucleus (Centromedian nucleus) • Midline nuclear group • Thalamic reticular nucleus • Metathalamus (MG, LG) • Interthalamic adhesion |
|---|
| Third ventricle | recesses: (Optic recess, Infundibular recess, Suprapineal recess, Pineal recess) • Hypothalamic sulcus |
|---|
| Other | Interventricular foramina • Optic chiasm • Subfornical organ • Mammillothalamic tract |
|---|
| Brain: mesencephalon (midbrain) |
|---|
| Tectum | Corpora quadrigemina (Inferior colliculi, Superior colliculi) • Subcommissural organ • Pretectum |
|---|
| Peduncle tegmentum | Periaqueductal gray (Cerebral aqueduct, Dorsal raphe nucleus) • Ventral tegmentum • Pedunculopontine nucleus • Red nucleus • MLF (riMLF) • lemnisci (Medial, Lateral) • cranial nuclei (III: Oculomotor nucleus, III: Edinger-Westphal nucleus, IV: Trochlear nucleus, V: Mesencephalic) |
|---|
| Peduncle base | Substantia nigra • Cerebral crus (Corticospinal tract, Corticobulbar tract, Corticopontine tract/Frontopontine fibers/Temporopontine fibers) |
|---|
| Brain: rhombencephalon (hindbrain) |
|---|
| Myelencephalon/medulla |
anterior/ventral: Arcuate nucleus of medulla • Pyramid (Decussation) • Olivary body • Inferior olivary nucleus • Anterior median fissure • Ventral respiratory group
posterior/dorsal: VII,IX,X: Solitary/tract • XII, X: Dorsal • IX,X,XI: Ambiguus • IX: Inferior salivatory nucleus • Gracile nucleus/Cuneate nucleus/Accessory cuneate nucleus • Area postrema • Posterior median sulcus • Dorsal respiratory group
raphe/reticular: Sensory decussation • Reticular formation (Gigantocellular nucleus, Parvocellular reticular nucleus, Ventral reticular nucleus, Lateral reticular nucleus, Paramedian reticular nucleus) • Raphe nuclei (Obscurus, Magnus, Pallidus)
tracts: Corticospinal tract (Lateral, Anterior) • Inferior cerebellar peduncle • Olivocerebellar tract • Spinocerebellar (Dorsal, Ventral) • Spinothalamic tract • PCML (Posterior external arcuate fibers, Internal arcuate fibers, Medial lemniscus) • Extrapyramidal (Rubrospinal tract, Vestibulospinal tract, Tectospinal tract)
|
|---|
| Metencephalon/pons |
anterior/ventral: Superior olivary nucleus • Basis pontis (Pontine nuclei, Middle cerebellar peduncles)
posterior/dorsal: Pontine tegmentum (Trapezoid body, Superior medullary velum, Locus ceruleus, MLF, Vestibulocerebellar tract, V Principal Spinal & Motor, VI, VII, VII: Superior salivary nucleus) • VIII-c (Dorsal, Anterior)/VIII-v (Lateral, Superior, Medial, Inferior)
raphe/reticular: Reticular formation (Caudal pontine reticular nucleus, Oral pontine reticular nucleus, Tegmental pontine reticular nucleus, Paramedian pontine reticular formation) • Median raphe nucleus
Apneustic center • Pneumotaxic center
|
|---|
| Metencephalon/cerebellum | Vermis • Flocculus • Arbor vitae • Cerebellar tonsil • Inferior medullary velum
Molecular layer (Stellate cell, Basket cell, Parallel fiber) • Purkinje cell layer (Purkinje cell) • Granule cell layer (Golgi cell) • Mossy fibers • Climbing fiber
Deep cerebellar nuclei (Dentate, Emboliform, Globose, Fastigial) |
|---|
| Fourth ventricle | apertures (Median, Lateral) • Rhomboid fossa (Vagal trigone, Hypoglossal trigone, Obex, Sulcus limitans, Facial colliculus, Medial eminence) • Lateral recess |
|---|
|
