Editing Neurotransmitter (section)

==Neurotransmitter systems {{anchor|table}}==
Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called [[volume transmission]]. Major neurotransmitter systems include the [[noradrenaline]] (norepinephrine) system, the [[dopamine]] system, the [[serotonin]] system, and the [[cholinergic]] system, among others. [[Trace amine]]s have a modulatory effect on neurotransmission in [[monoamine]] pathways (i.e., dopamine, norepinephrine, and serotonin pathways) throughout the brain via signaling through [[TAAR1|trace amine-associated receptor&nbsp;1]].<ref name="Miller">{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–76 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref><ref name="E Weihe">{{cite journal | vauthors = Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Annals of the New York Academy of Sciences | volume = 1216 | issue = 1 | pages = 86–98 | date = January 2011 | pmid = 21272013 | pmc = 4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | quote = VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)&nbsp;... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). | bibcode = 2011NYASA1216...86E }}</ref> A brief comparison of these systems follows:
<!--"Neurotransmitter system" and other articles redirect to the anchor in the wikitable title-->
{| class="wikitable" style="width:92%"
|+Neurotransmitter systems in the brain
|-
! System !! Pathway origin and projections !! Regulated cognitive processes and behaviors
|-
!id=Noradrenaline|Noradrenaline system<br /><ref name="VTA inputs">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 155 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote= Different subregions of the VTA receive glutamatergic inputs from the prefrontal cortex, orexinergic inputs from the lateral hypothalamus, cholinergic and also glutamatergic and GABAergic inputs from the laterodorsal tegmental nucleus and pedunculopontine nucleus, noradrenergic inputs from the locus ceruleus, serotonergic inputs from the raphe nuclei, and GABAergic inputs from the nucleus accumbens and ventral pallidum.}}</ref><ref name="Noradrenergic pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 145, 156–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote=Descending NE fibers modulate afferent pain signals.&nbsp;... The locus ceruleus (LC), which is located on the floor of the fourth ventricle in the rostral pons, contains more than 50% of all noradrenergic neurons in the brain; it innervates both the forebrain (eg, it provides virtually all the NE to the cerebral cortex) and regions of the brainstem and spinal cord.&nbsp;... The other noradrenergic neurons in the brain occur in loose collections of cells in the brainstem, including the lateral tegmental regions.  These neurons project largely within the brainstem and spinal cord. NE, along with 5HT, ACh, histamine, and orexin, is a critical regulator of the sleep-wake cycle and of levels of arousal.&nbsp;... LC firing may also increase anxiety&nbsp;...Stimulation of β-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion&nbsp;... Epinephrine occurs in only a small number of central neurons, all located in the medulla. Epinephrine is involved in visceral functions, such as control of respiration.<!--Note: the noradrenergic pathways are based upon a projection diagram that can't be quoted.-->}}</ref><ref name=Rang>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= 474 for noradrenaline system, page 476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system |isbn=978-0-443-07145-4 }}</ref><ref name="ARAS" /><ref name="NHM - ascending reticular activating system" /><ref name=Rinaman>{{cite journal | vauthors = Rinaman L | title = Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 300 | issue = 2 | pages = R222-35 | date = February 2011 | pmid = 20962208 | pmc = 3043801 | doi = 10.1152/ajpregu.00556.2010 }}</ref>
| '''Noradrenergic pathways''':
* [[Locus coeruleus]] (LC) projections
:* LC → [[Amygdala]] and [[Hippocampus]]
:* LC → [[Brain stem]] and [[Spinal cord]]
:* LC → [[Cerebellum]]
:* LC → [[Cerebral cortex]]
:* LC → [[Hypothalamus]]
:* LC → [[Tectum]]
:* LC → [[Thalamus]]
:* LC → [[Ventral tegmental area]]
* [[Lateral tegmental field]] (LTF) projections
:* LTF → [[Brain stem]] and [[Spinal cord]]
:* LTF → [[Olfactory bulb]]
|
* anxiety
* [[arousal]] (wakefulness)
* [[circadian rhythm]]
* [[cognitive control]] and [[working memory]] (co-regulated by dopamine)
* feeding and [[energy homeostasis]]
* [[medullary respiratory center|medullary control of respiration]]
* negative emotional memory
* [[nociception]] (perception of pain)
* [[reward system|reward]] (minor role)
|-
!id=Dopamine|Dopamine system<br /><ref name=Rang /><ref name="ARAS" /><ref name="NHM - ascending reticular activating system" /><ref name="Malenka pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147–148, 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote=Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs.  Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory.&nbsp;... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum).&nbsp;... DA has multiple actions in the prefrontal cortex.  It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals.  Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions.&nbsp;... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control.&nbsp;...}}</ref><ref name="Reward and aversion MSNs">{{cite journal | vauthors = Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Peña CJ, Walker DM, Pirpinias ST, Guise KG, Ramakrishnan C, Deisseroth K, Nestler EJ | display-authors = 6 | title = In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 10 | pages = 2726–31 | date = March 2016 | pmid = 26831103 | pmc = 4791010 | doi = 10.1073/pnas.1521238113 | quote = Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. | doi-access = free | bibcode = 2016PNAS..113.2726C }}</ref><ref name="Dopaminergic pathways and reward system review">{{cite journal | vauthors = Ikemoto S | title = Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory | journal = Neuroscience and Biobehavioral Reviews | volume = 35 | issue = 2 | pages = 129–50 | date = November 2010 | pmid = 20149820 | pmc = 2894302 | doi = 10.1016/j.neubiorev.2010.02.001 | quote = Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle.&nbsp;... In the 1970s it was recognized that the olfactory tubercle contains a striatal component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus accumbens }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894302/figure/F3/ Figure 3: The ventral striatum and self-administration of amphetamine]</ref>
| '''[[Dopaminergic pathways]]''':
* [[Ventral tegmental area]] (VTA) projections
:* VTA → [[Amygdala]]
:* VTA → [[Cingulate cortex]]
:* VTA → [[Hippocampus]]
:* VTA → [[Ventral striatum]] ([[Mesolimbic pathway]])
:* VTA → [[Olfactory bulb]]
:* VTA → [[Prefrontal cortex]] ([[Mesocortical pathway]])
* [[Nigrostriatal pathway]]
:* [[Substantia nigra pars compacta]] → [[Dorsal striatum]]
* [[Tuberoinfundibular pathway]]
:* [[Arcuate nucleus]] → [[Median eminence]]
* Hypothalamospinal projection
:* [[Hypothalamus]] → [[Spinal cord]]
* [[Incertohypothalamic pathway]]
:* [[Zona incerta]] → Hypothalamus
|
* [[arousal]] (wakefulness)
* aversion
* [[cognitive control]] and [[working memory]] (co-regulated by norepinephrine)
* emotion and [[mood (psychology)|mood]]
* motivation ([[motivational salience]])
* [[motor system|motor function]] and control
* [[positive reinforcement]]
* [[reward system|reward]] (primary mediator)
* [[sexual arousal]], [[orgasm]], and [[sexual refractory period|refractory period]] (via neuroendocrine regulation)
|-
!id=Histamine|Histamine system<br /><ref name="ARAS">{{cite journal | vauthors = Iwańczuk W, Guźniczak P | title = Neurophysiological foundations of sleep, arousal, awareness and consciousness phenomena. Part 1 | journal = Anaesthesiology Intensive Therapy | volume = 47 | issue = 2 | pages = 162–7 | date = 2015 | pmid = 25940332 | doi = 10.5603/AIT.2015.0015 | quote = The ascending reticular activating system (ARAS) is responsible for a sustained wakefulness state.&nbsp;... The thalamic projection is dominated by cholinergic neurons originating from the pedunculopontine tegmental nucleus of pons and midbrain (PPT) and laterodorsal tegmental nucleus of pons and midbrain (LDT) nuclei [17, 18]. The hypothalamic projection involves noradrenergic neurons of the locus coeruleus (LC) and serotoninergic neurons of the dorsal and median raphe nuclei (DR), which pass through the lateral hypothalamus and reach axons of the histaminergic tubero-mamillary nucleus (TMN), together forming a pathway extending into the forebrain, cortex and hippocampus. Cortical arousal also takes advantage of dopaminergic neurons of the substantia nigra (SN), ventral tegmenti area (VTA) and the periaqueductal grey area (PAG). Fewer cholinergic neurons of the pons and midbrain send projections to the forebrain along the ventral pathway, bypassing the thalamus [19, 20]. | doi-access = free }}</ref><ref name="NHM - ascending reticular activating system">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 295 | edition = 2nd | chapter = Chapter 12: Sleep and Arousal | quote = The ARAS is a complex structure consisting of several different circuits including the four monoaminergic pathways&nbsp;... The norepinephrine pathway originates from the locus ceruleus (LC) and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the brainstem as well; the dopaminergic neurons originate in ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brain stem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.}}</ref><ref name="Histamine pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 175–176 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote = Within the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary nucleus (TMN) that lies within the posterior hypothalamus. There are approximately 64000 histaminergic neurons per side in humans. These cells project throughout the brain and spinal cord. Areas that receive especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and hypothalamus. &nbsp;... While the best characterized function of the histamine system in the brain is regulation of sleep and arousal, histamine is also involved in learning and memory&nbsp;...It also appears that histamine is involved in the regulation of feeding and energy balance.}}</ref>
|'''Histaminergic pathways''':
* [[Tuberomammillary nucleus]] (TMN) projections
:* TMN → [[Cerebral cortex]]
:* TMN → [[Hippocampus]]
:* TMN → [[Neostriatum]]
:* TMN → [[Nucleus accumbens]]
:* TMN → [[Amygdala]]
:* TMN → [[Hypothalamus]]
|
* [[arousal]] (wakefulness)
* feeding and [[energy homeostasis]]
* learning
* memory
|-
!id=Serotonin|Serotonin system<br /><ref name="VTA inputs" /><ref name=Rang /><ref name="ARAS" /><ref name="NHM - ascending reticular activating system" /><ref name="Serotonergic pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 158–160 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote= [The] dorsal raphe preferentially innervates the cerebral cortex, thalamus, striatal regions (caudate-putamen and nucleus accumbens), and dopaminergic nuclei of the midbrain (eg, the substantia nigra and ventral tegmental area), while the median raphe innervates the hippocampus, septum, and other structures of the limbic forebrain.&nbsp;... it is clear that 5HT influences sleep, arousal, attention, processing of sensory information in the cerebral cortex, and important aspects of emotion (likely including aggression) and mood regulation.&nbsp;...The rostral nuclei, which include the nucleus linearis, dorsal raphe, medial raphe, and raphe pontis, innervate most of the brain, including the cerebellum.  The caudal nuclei, which comprise the raphe magnus, raphe pallidus, and raphe obscuris, have more limited projections that terminate in the cerebellum, brainstem, and spinal cord.}}</ref><ref>{{cite web| vauthors = Nestler EJ |title= Brain Reward Pathways |url= http://neuroscience.mssm.edu/nestler/brainRewardpathways.html|website=Icahn School of Medicine at Mount Sinai|publisher=Nestler Lab|access-date=16 August 2014|quote=The dorsal raphe is the primary site of serotonergic neurons in the brain, which, like noradrenergic neurons, pervasively modulate brain function to regulate the state of activation and mood of the organism.}}</ref><ref name="pmid21216242">{{cite journal | vauthors = Marston OJ, Garfield AS, Heisler LK | title = Role of central serotonin and melanocortin systems in the control of energy balance | journal = European Journal of Pharmacology | volume = 660 | issue = 1 | pages = 70–9 | date = June 2011 | pmid = 21216242 | doi = 10.1016/j.ejphar.2010.12.024 }}</ref>
|'''[[Serotonergic pathways]]''':
[[Caudal nuclei]] (CN):<br />
[[Raphe magnus]], [[raphe pallidus]], and [[raphe obscurus]]
* Caudal projections
:* CN → [[Cerebral cortex]]
:* CN → [[Thalamus]]
:* CN → [[Caudate nucleus|Caudate]]-[[putamen]] and [[nucleus accumbens]]
:* CN → [[Substantia nigra]] and [[ventral tegmental area]]
:* CN → [[Cerebellum]]
:* CN → [[Spinal cord]]
[[Rostral nuclei]] (RN):<br />
[[Nucleus linearis]], [[dorsal raphe]], [[medial raphe]], and [[raphe pontis]]
* Rostral projections
:* RN → [[Amygdala]]
:* RN → [[Cingulate cortex]]
:* RN → [[Hippocampus]]
:* RN → [[Hypothalamus]]
:* RN → [[Neocortex]]
:* RN → [[Septum]]
:* RN → [[Thalamus]]
:* RN → [[Ventral tegmental area]]
|
* [[arousal]] (wakefulness)
* [[body temperature]] regulation
* emotion and [[mood (psychology)|mood]], potentially including aggression
* feeding and [[energy homeostasis]]
* [[reward system|reward]] (minor role)
* sensory perception
|-
!id=Acetylcholine|Acetylcholine system<br /><ref name="VTA inputs" /><ref name=Rang /><ref name="ARAS" /><ref name="NHM - ascending reticular activating system" /><ref name="Cholinergic pathways">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 167–175 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote= The basal forebrain cholinergic nuclei are comprised the medial septal nucleus (Ch1), the vertical nucleus of the diagonal band (Ch2), the horizontal limb of the diagonal band (Ch3), and the nucleus basalis of Meynert (Ch4).  Brainstem cholinergic nuclei include the pedunculopontine nucleus (Ch5), the laterodorsal tegmental nucleus (Ch6), the medial habenula (Ch7), and the parabigeminal nucleus (Ch8).}}</ref>
|'''Cholinergic pathways''':
Forebrain cholinergic nuclei (FCN):<br />
[[Nucleus basalis of Meynert]], [[medial septal nucleus]], and [[nucleus of diagonal band|diagonal band]]
* Forebrain nuclei projections
:*FCN → [[Hippocampus]]
:*FCN → [[Cerebral cortex]]
:*FCN → [[Limbic cortex]] and [[sensory cortex]]
Striatal tonically active cholinergic neurons (TAN)
:*TAN → [[Medium spiny neuron]]

Brainstem cholinergic nuclei (BCN):<br />
[[Pedunculopontine nucleus]], [[laterodorsal tegmental nucleus|laterodorsal tegmentum]], [[medial habenula]], and<br />[[parabigeminal nucleus]]
* Brainstem nuclei projections
:*BCN → [[Ventral tegmental area]]
:*BCN → [[Thalamus]]

|
* [[arousal]] (wakefulness)
* emotion and [[mood (psychology)|mood]]
* learning
* [[motor system|motor function]]
* motivation ([[motivational salience]])
* [[Memory#Short-term|short-term memory]]
* [[reward system|reward]] (minor role)
|-
!id=Adrenaline|Adrenaline system<br /><ref>{{cite journal | vauthors = Guyenet PG, Stornetta RL, Bochorishvili G, Depuy SD, Burke PG, Abbott SB | title = C1 neurons: the body's EMTs | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 305 | issue = 3 | pages = R187-204 | date = August 2013 | pmid = 23697799 | doi = 10.1152/ajpregu.00054.2013 | pmc = 3743001 }}</ref><ref>{{cite journal | vauthors = Stornetta RL, Guyenet PG | title = C1 neurons: a nodal point for stress? | journal = Experimental Physiology | volume = 103 | issue = 3 | pages = 332–336 | date = March 2018 | pmid = 29080216 | doi = 10.1113/EP086435 | pmc = 5832554 }}</ref>
| '''Adrenergic pathways''':
* [[Rostral ventrolateral medulla]] (RVLM) projections
:* RVLM → [[Spinal cord]]
:* RVLM → [[Brain stem]]
:* RVLM → [[Hypothalamus]]
|
* [[medullary respiratory center|medullary control of respiration]]
* [[sympathetic nervous system]]
* feeding and [[energy homeostasis]]
* [[arousal]]
* [[Stress (biology)|stress]]
|}

{{further|Neural pathway|Neuromodulation|List of regions in the human brain}}