Neuromodulation

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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 chemicals 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.[1]

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[edit]

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,[2] 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.[2]

Volume transmission[edit]

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 of neurotransmitters through the brain extracellular fluid 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.[3]

Neurotransmitter systems[edit]

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[edit]

Neuromodulator systems
System Origin[4] Targets[4] Effects[4]
Noradrenaline system Locus coeruleus adrenergic receptors in:
  • arousal (Arousal is a physiological and psychological state of being awake or reactive to stimuli)
  • reward system
Lateral tegmental field
Dopamine system dopamine pathways: Dopamine receptors at pathway terminations. motor system, reward system, cognition, endocrine, nausea
Serotonin system caudal dorsal raphe nucleus Serotonin receptors in: Increase (introversion)[clarification needed], mood, satiety, body temperature and sleep, while decreasing nociception.
rostral dorsal raphe nucleus Serotonin receptors in:
Cholinergic system Pedunculopontine nucleus and dorsolateral tegmental nuclei (pontomesencephalotegmental complex) (mainly) M1 receptors in:
basal optic nucleus of Meynert (mainly) M1 receptors in:
medial septal nucleus (mainly) M1 receptors in:

Noradrenaline system[edit]

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. Noradrenaline is released from the neurons, and acts on adrenergic receptors. Noradrenaline is often released steadily so that it can prepare the supporting glial cells for calibrated responses. Despite containing a relatively small number of neurons, when activated, the noradrenaline system plays major roles in the brain including involvement in suppression of the neuroinflammatory response, stimulation of neuronal plasticity through LTP, regulation of glutamate uptake by astrocytes and LTD, and consolidation of memory.[7]

Dopamine system[edit]

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[edit]

Serotonin system[edit]

Further information: 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.[8][9] 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[edit]

Although changes in neurochemistry are found immediately after taking these antidepressants, symptoms may not begin to improve until several weeks after administration. Increased transmitter levels in the synapse alone does not relieve the depression or anxiety.[10][12][15]

Cholinergic System[edit]

The cholinergic system consists of projection neurons from the pedunculopontine nucleus, laterodorsal tegmental nucleus, and basal forebrain and interneurons from the striatum and nucleus accumbens. It is not yet clear whether acetylcholine as a neuromodulator acts through volume transmission or classical synaptic transmission, as there is evidence to support both theories. Acetylcholine binds to both metabotropic muscarinic receptors (mAChR) and the ionotropic nicotinic receptors (nAChR). The cholinergic system has been found to be involved in responding to cues related to the reward pathway, enhancing signal detection and sensory attention, regulating homeostasis, mediating the stress response, and encoding the formation of memories.[16][17]

GABA[edit]

Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity.[10]

Neuropeptides[edit]

  • 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.[10][18]
  1. Endorphins
  2. Enkephalins
  3. Dynorphins

Other uses[edit]

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) and vagus nerve stimulators (VNS), which are implanted using minimally invasive procedures, or transcutaneous electrical nerve stimulation devices, which are fully external, among others.[19]

See also[edit]

References[edit]

  1. ^ Conlay, L. A.; Sabounjian, L. A.; Wurtman, R. J. (1992). "Exercise and neuromodulators: Choline and acetylcholine in marathon runners". International Journal of Sports Medicine. 13 Suppl 1: S141–2. doi:10.1055/s-2007-1024619. PMID 1483754. 
  2. ^ a b Stern, E; Fort TJ; Millier MW; Peskin CS; Brezina V (2007). "Decoding modulation of the neuromuscular transform". Neurocomputing. 70 (6954): 1753–1758. doi:10.1016/j.neucom.2006.10.117. PMC 2745187Freely accessible. PMID 19763188. 
  3. ^ Castaneda-Hernandez, Gilberto C.; Bach-y-Rita, Paul (2003). "Volume Transmission and Pain Perception". The Scientific World JOURNAL. 3: 677–683. doi:10.1100/tsw.2003.53. 
  4. ^ a b c Unless else specified in boxes, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. pp. 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. 
  5. ^ a b c d e f g Woolf NJ, Butcher LL (1989). "Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum". Brain Res Bull. 23 (6): 519–40. doi:10.1016/0361-9230(89)90197-4. PMID 2611694. 
  6. ^ a b c d Woolf NJ, Butcher LL (1986). "Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain". Brain Res Bull. 16 (5): 603–37. doi:10.1016/0361-9230(86)90134-6. PMID 3742247. 
  7. ^ O'Donnell, John; Zeppenfeld, Douglas; McConnell, Evan; Pena, Salvador; Nedergaard, Maiken (2012). "Norepinephrine: A Neuromodulator That Boosts the Function of Multiple Cell Types to Optimize CNS Performance". Neurochemical Research. 37 (11): 2496–2512. 
  8. ^ McIntosh, James. "What is serotonin? What does serotonin do?". Medical News Today. Medical News Today. Retrieved 12 April 2015. 
  9. ^ Berger, Miles (2009). "The Expanded Biology of Serotonin". Annual Review of Medicine. 60: 355–66. doi:10.1146/annurev.med.60.042307.110802. PMID 19630576. 
  10. ^ a b c d e f Kandel, Eric R (1991). Principles of Neural Science. East Norwalk, Connecticut: Appleton & Lang. pp. 872–873. ISBN 0-8385-8034-3. 
  11. ^ "Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepressants, TCAs, Antidepressants, MAO Inhibitors, Augmenting Agents, Serotonin-Dopamine Activity Modulators, Antidepressants, Other, Stimulants, Thyroid Products, Neurology & Psychiatry, Herbals". emedicine.medscape.com. Retrieved 7 November 2016. 
  12. ^ a b c d Coryell, William (2016). "Drug Treatment of Depression". In Porter, Robert S. The Merck Manual (19 ed.). Whitehouse Station, N.J.: Merck. ISBN 978-0-911910-19-3. 
  13. ^ "Drug Treatment of Depression". Merck Manuals Professional Edition. Retrieved 7 November 2016. 
  14. ^ Bender, KJ; Walker, SE (8 October 2012). "Irreversible Monoamine Oxidase Inhibitors Revisited". Psychiatric Times. Retrieved 7 November 2016. 
  15. ^ a b Wimbiscus, Molly; Kostenko, Olga; Malone, Donald (1 December 2010). "MAO inhibitors: risks, benefits, and lore". Cleveland Clinic Journal of Medicine. 77 (12): 859–882. doi:10.3949/ccjm.77a.09103. ISSN 1939-2869. PMID 21147941. 
  16. ^ Picciotto, Marina; Higley, Michael; Mineur, Yann (2012). "Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior". Neuron. 76 (1): 116–129. 
  17. ^ Hasselmo, Michael; Sarter, Martin (2011). "Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition" (PDF). Neuropsychopharmocology. 36: 52–73. 
  18. ^ Froehlich, J. C. (1 January 1997). "Opioid peptides" (PDF). Alcohol Health and Research World. 21 (2): 132–136. ISSN 0090-838X. PMID 15704349. 
  19. ^ Krames, Elliot S.; Peckham, P. Hunter; Rezai, Ali R., eds. (2009). Neuromodulation, Vol. 1-2. Academic Press. pp. 1–1200. ISBN 978-0-12-374248-3. Retrieved 6 September 2012. 

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