Editing Ventral tegmental area (section)

== Structure ==
Neurobiologists have often had great difficulty distinguishing the VTA in humans and other primate brains from the [[substantia nigra]] (SN) and surrounding nuclei. Originally, the ventral tegmental area was designated as a ‘nucleus’, but over time ‘area’ became the more appropriate term used because of the heterogeneous [[Cytoarchitectonics|cytoarchitectonic]] features of the region and the lack of clear borders that separate it from adjacent regions.<ref>{{Cite journal| doi = 10.1016/j.neuroimage.2019.01.062| issn = 1053-8119| volume = 191| pages = 258–268| last1 = Trutti| first1 = Anne C.| last2 = Mulder| first2 = Martijn J.| last3 = Hommel| first3 = Bernhard| last4 = Forstmann| first4 = Birte U.| title = Functional neuroanatomical review of the ventral tegmental area| journal = NeuroImage| date = 2019| pmid = 30710678| hdl = 1887/72460| s2cid = 72333763| url = https://dare.uva.nl/personal/pure/en/publications/functional-neuroanatomical-review-of-the-ventral-tegmental-area(751fe3c1-b9ab-4e95-842d-929af69887ed).html| hdl-access = free}}</ref>  Because of the selective [[limbic system|limbic-related]] [[afferent nerve fiber|afferents]] to the VTA,  the cells of the VTA are given the designation [[Dopaminergic cell group A10|A10]] to differentiate them from surrounding cells.<ref>{{Cite journal| doi = 10.1016/j.tins.2007.03.006| issn = 0166-2236| volume = 30| issue = 5| pages = 194–202| last1 = Björklund| first1 = Anders| last2 = Dunnett| first2 = Stephen B.| title = Dopamine neuron systems in the brain: an update| journal = Trends in Neurosciences| date = May 2007| pmid = 17408759| s2cid = 14239716}}</ref>

===Location===
The ventral tegmental area is in the midbrain between several other major areas, some of which are described here. The [[mammillary bodies]] and the posterior [[hypothalamus]], both included in the [[diencephalon]], extend rostrally from the VTA. The [[red nucleus]] is situated laterally and oculomotor fibers are situated ventromedially to the VTA.<ref>{{Cite journal| title = Intramesencephalic course of the oculomotor nerve fibers: microanatomy and possible clinical significance {{!}} SpringerLink| year = 2013| doi = 10.1007/s12565-012-0166-6| pmid = 23242853| last1 = Vitošević| first1 = Z.| last2 = Marinković| first2 = S.| last3 = Cetković| first3 = M.| last4 = Stimec| first4 = B.| last5 = Todorović| first5 = V.| last6 = Kanjuh| first6 = V.| last7 = Milisavljević| first7 = M.| journal = Anatomical Science International| volume = 88| issue = 2| pages = 70–82| s2cid = 25783211}}</ref> The [[pons]] and the [[hindbrain]] lie caudally to the VTA. Finally, the substantia nigra is located laterally to the VTA.<ref>{{Cite journal| doi = 10.1016/j.nicl.2018.03.019| issn = 2213-1582| volume = 18| pages = 770–783| last1 = Coenen| first1 = Volker Arnd| last2 = Schumacher| first2 = Lena Valerie| last3 = Kaller| first3 = Christoph| last4 = Schlaepfer| first4 = Thomas Eduard| last5 = Reinacher| first5 = Peter Christoph| last6 = Egger| first6 = Karl| last7 = Urbach| first7 = Horst| last8 = Reisert| first8 = Marco| title = The anatomy of the human medial forebrain bundle: Ventral tegmental area connections to reward-associated subcortical and frontal lobe regions| journal = NeuroImage: Clinical| date = 2018-01-01| pmid = 29845013| pmc = 5964495| url = }}</ref>

=== Subdivisions ===
In 1987, Oades identified four primary nuclei in the [[Dopaminergic cell group A10|VTA A10 group of cells]]: the nucleus paranigralis (Npn), the nucleus parabrachialis pigmentosus (Npbp), the nucleus interfascicularis (Nif), and the nucleus linearis (Nln) caudalis and rostralis. Presently, scientists divide the VTA up into four similar zones that are called the paranigral nucleus (PN), the parabrachial pigmented area (PBP), the parafasciculus retroflexus area (PFR), and the [[rostromedial tegmental nucleus]] (RMTg), which approximately adhere to the previous divisions. Some definitions of the VTA also include the midline nuclei (i.e. the interfascicular nucleus, rostral linear nucleus, and central linear nucleus).

The PN and PBP are rich in dopaminergic cells, whereas the other two regions have low densities of these neurons. The PFR and RMTg contain a low density of [[tyrosine hydroxylase]] (TH)-positive cell bodies that are small in size and lightly stain; the RMTg is composed mostly of GABAergic cells. On the other hand, the PN and PBP consist mainly of medium to large sized TH-positive cell bodies that stain moderately.

=== Inputs ===
Almost all areas receiving projections from the VTA project back to it. Thus, the ventral tegmental area is reciprocally connected with a wide range of structures throughout the brain suggesting that it has a role in the control of function in the [[phylogenetically]] newer and highly developed [[neocortex]], as well as that of the phylogenetically older limbic areas.{{citation needed|date=January 2018}}

The VTA is a heterogeneous region consisting of a variety of neurons that are characterized by different neurochemical and neurophysiological properties. Therefore, glutamatergic and GABAergic inputs are not exclusively excitatory nor inhibitory.<ref name="ReferenceB">{{Cite journal| doi = 10.1038/nrn.2016.165| issn = 1471-0048| volume = 18| issue = 2| pages = 73–85| last1 = Morales| first1 = Marisela| last2 = Margolis| first2 = Elyssa B.| title = Ventral tegmental area: cellular heterogeneity, connectivity and behaviour| journal = Nature Reviews Neuroscience| date = 2017-02-01| pmid = 28053327| s2cid = 10311562}}</ref>  The VTA receives glutamatergic afferents from the [[prefrontal cortex]], [[pedunculopontine nucleus|pedunculopontine tegmental nucleus]] (PPTg), [[laterodorsal tegmental nucleus]], [[subthalamic nucleus]], [[bed nucleus of the stria terminalis]], [[superior colliculus]], [[periaqueductal gray]], [[lateral habenula]], [[dorsal raphe nucleus]], and [[lateral hypothalamus|lateral hypothalamic]] and [[preoptic area]]s.<ref>{{cite journal | vauthors = Morikawa H, Paladini CA | title = Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms | journal = Neuroscience | volume = 198 | pages = 95–111 | date = December 2011 | pmid = 21872647 | pmc = 3221882 | doi = 10.1016/j.neuroscience.2011.08.023 }}</ref><ref name="ReferenceB"/> These glutamatergic afferents play a key role in regulating VTA cell firing. When the glutamatergic neurons are activated, the firing rates of the dopamine neurons increase in the VTA and induce burst firing. Studies have shown that these glutamatergic actions in the VTA are critical to the effects of drugs of abuse.  In contrast, the [[tail of the ventral tegmental area]] (tVTA, {{aka}} the RMTg) projects to the VTA with GABAergic afferents, functioning as a "master brake" for the VTA dopamine pathways.<ref name="VTA tail">{{cite journal | vauthors = Bourdy R, Barrot M | title = A new control center for dopaminergic systems: pulling the VTA by the tail | journal = Trends in Neurosciences | volume = 35 | issue = 11 | pages = 681–90 | date = November 2012 | pmid = 22824232 | doi = 10.1016/j.tins.2012.06.007 | s2cid = 43434322 | quote = In light of the crucial role of the tVTA in the opiate control of dopamine activity&nbsp;...<br />In the context of addiction, the tVTA is a target for psychostimulant-induced plasticity [1,6,23] and is also essential for morphine action on dopamine neurons [19]. This latter finding suggests that the classical disinhibition model may need to be revisited in light of the GABAergic control that the tVTA exerts on dopamine systems.&nbsp;...<br />The tVTA is rich in inhibitory GABA neurons expressing μ-opioid receptors and sends extensive projections toward midbrain dopamine cells. It is proposed as a major brake for dopamine systems.&nbsp;...<br />The tVTA was initially described in rats as a bilateral cluster of GABA neurons within the posterior VTA, dorsolateral to the interpeduncular nucleus, and expressing FosB/ΔFosB after psychostimulant administration [1]. However, the Fos staining showed that this group of cells extends caudally beyond the defined borders of the VTA [1], shifting dorsally to become embedded within the superior cerebellar peduncle [2]. Around the same time as the tVTA was described, a region caudal to the rat VTA and lateral to the median raphe was proposed to influence passive aversive responses [24]. This region belongs to the reticular formation and was later designated as RMTg [3]. The RMTg extends rostrally, shifting ventrally to become embedded within the posterior VTA. A similar region has also been observed in primates [18] and in mice [25]. There is now agreement that the tVTA and RMTg are two faces of the same structure. }}</ref><ref name="Brake">{{cite journal | vauthors = Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC | title = Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions | journal = The Journal of Neuroscience | volume = 32 | issue = 41 | pages = 14094–101 | date = October 2012 | pmid = 23055478 | pmc = 3513755 | doi = 10.1523/JNEUROSCI.3370-12.2012 | quote = The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons.&nbsp;... <br />Indeed, tVTA/RMTg cells express high levels of mu-opioid receptors (Jhou et al., 2009a, 2012; Jalabert et al., 2011), and in vivo, ex vivo and optogenetic electrophysiological approaches demonstrated that morphine excites dopamine neurons by targeting receptors localized to tVTA/RMTg cell bodies as well as its terminals within the VTA (Jalabert et al., 2011; Lecca et al., 2011; Matsui and Williams, 2011; Lecca et al., 2012).&nbsp;... Recent research on the tVTA/RMTg started from observations related to psychostimulant induction of FosB/ΔFosB (Perrotti et al., 2005) and to the control of aversive responses (Jhou, 2005). The rat tVTA/RMTg showed a neuroanatomically delimited increase in the expression of Fos-related proteins following exposure to psychostimulants (Scammel et al., 2000; Perrotti et al., 2005; Geisler et al., 2008; Jhou et al., 2009a; Kaufling et al., 2009, 2010a, 2010b; Rottlant et al., 2010; Zahm et al., 2010; Cornish et al., 2012). This induction was observed with both acute and chronic exposure to psychostimulants, and with both self-administration and non-contingent administration. There is a strong selectivity of this molecular response, as the Fos-related induction was never observed with non-psychostimulant drugs (Perrotti et al., 2005; Kaufling et al., 2010b). }}</ref>

GABAergic inputs to the VTA also include the [[nucleus accumbens]], [[ventral pallidum]], [[dorsal raphe nucleus]], [[lateral hypothalamus]], [[periaqueductal gray]], [[bed nucleus of the stria terminalis]], and [[rostromedial tegmental nucleus]] (RMTg).<ref name="ReferenceB"/>  The [[lateral habenula]] can also exert an inhibitory effect on dopaminergic neurons in the VTA by exciting RMTg GABAergic neurons, which is thought to play an important role in reward prediction errors.<ref>{{cite journal | vauthors = Watabe-Uchida M, Eshel N, Uchida N | title = Neural Circuitry of Reward Prediction Error | journal = Annual Review of Neuroscience | volume = 40 | pages = 373–394 | date = July 2017 | pmid = 28441114 | pmc = 6721851 | doi = 10.1146/annurev-neuro-072116-031109 | author-link3 = Naoshige Uchida }}</ref> Subpallidal afferents into the VTA are mainly [[GABAergic]] and, thus, inhibitory.<ref name="ReferenceB"/><ref name="Subpallidal">{{Cite journal| doi = 10.1016/S0006-8993(96)00859-1| issn = 0006-8993| volume = 740| issue = 1| pages = 151–161| last1 = Wu| first1 = Michael| last2 = Hrycyshyn| first2 = Alan W.| last3 = Brudzynski| first3 = Stefan M.| title = Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies| journal = Brain Research| access-date = 2020-10-04| date = 1996-11-18| pmid = 8973809| s2cid = 44512008| url = http://www.sciencedirect.com/science/article/pii/S0006899396008591| url-access = subscription}}</ref> There is a substantial pathway from the subpallidal area to the VTA.<ref name="Subpallidal"/> When this pathway is disinhibited, an increase in the dopamine release in the [[mesolimbic pathway]] [[hyperlocomotion|amplifies locomotor activity]].{{medical citation needed|date=January 2018}}

There are also cholinergic inputs to the VTA, although less studied than the glutamatergic and GABAergic inputs. Optogenetic studies in mice looking at cholinergic inputs from the [[pedunculopontine nucleus|pedunculopontine tegmental nucleus]] (PPTg) and the [[laterodorsal tegmental nucleus]] demonstrate that these circuits reinforce the discharge properties of VTA neurons, suggesting a modulatory influence on reward circuits.<ref>{{Cite journal| doi = 10.1038/nn.4335| issn = 1546-1726| volume = 19| issue = 8| pages = 1025–1033| last1 = Dautan| first1 = Daniel| last2 = Souza| first2 = Albert S.| last3 = Huerta-Ocampo| first3 = Icnelia| last4 = Valencia| first4 = Miguel| last5 = Assous| first5 = Maxime| last6 = Witten| first6 = Ilana B.| last7 = Deisseroth| first7 = Karl| last8 = Tepper| first8 = James M.| last9 = Bolam| first9 = J. Paul| last10 = Gerdjikov| first10 = Todor V.| last11 = Mena-Segovia| first11 = Juan| title = Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits| journal = Nature Neuroscience| date = 2016| pmid = 27348215| pmc = 5086413}}</ref>

=== Outputs ===

The two primary efferent fiber projections of the VTA are the [[mesocortical pathway|mesocortical]] and the [[mesolimbic pathway]]s, which correspond to the [[prefrontal cortex]] and [[nucleus accumbens]] respectively.<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="Mesolimbic pathway source">{{cite journal | vauthors = Nechifor M | title = Magnesium in drug dependences | journal = Magnesium Research | volume = 21 | issue = 1 | pages = 5–15 | date = March 2008 | pmid = 18557129 | doi = 10.1684/mrh.2008.0124 | doi-broken-date = 1 November 2024 }}</ref> In addition, experiments in rodents have identified a mesohabenular pathway consisting of VTA neurons that do not release [[dopamine]], but [[glutamate]] and [[GABA]].<ref>{{Cite journal| doi = 10.1016/j.neuron.2013.08.023| issn = 0896-6273| volume = 80| issue = 4| pages = 1039–1053| last1 = Stamatakis| first1 = Alice M.| last2 = Jennings| first2 = Joshua H.| last3 = Ung |first3 = Randall L.| last4 = Blair| first4 = Grace A.| last5 = Weinberg| first5 = Richard J.| last6 = Neve| first6 = Rachael L.| last7 = Boyce| first7 = Frederick| last8 = Mattis| first8 = Joanna| last9 = Ramakrishnan| first9 = Charu| last10 = Deisseroth| first10 = Karl| last11 = Stuber| first11 = Garret D.| title = A Unique Population of Ventral Tegmental Area Neurons Inhibits the Lateral Habenula to Promote Reward| journal = Neuron| date = 2013-11-20| pmid = 24267654| pmc = 3873746| url = }}</ref><ref>{{Cite journal| doi = 10.1038/nn.3823| issn = 1546-1726| volume = 17| issue = 11| pages = 1543–1551| last1 = Root| first1 = David H.| last2 = Mejias-Aponte| first2 = Carlos A.| last3 = Zhang| first3 = Shiliang| last4 = Wang| first4 = Hui-Ling| last5 = Hoffman| first5 = Alexander F.| last6 = Lupica| first6 = Carl R.| last7 = Morales| first7 = Marisela| title = Single rodent mesohabenular axons release glutamate and GABA| journal = Nature Neuroscience| date = November 2014| pmid = 25242304| pmc = 4843828}}</ref> Other VTA projections, which utilize [[dopamine]] as their primary [[neurotransmitter]], are listed below.<ref name="Malenka pathways" />
* Ventral tegmental area (VTA) projections<ref name="Malenka pathways" />

:* VTA → [[Amygdala]]<ref>{{cite journal | vauthors = Mingote S, Chuhma N, Kusnoor SV, Field B, Deutch AY, Rayport S | title = Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions | journal = The Journal of Neuroscience | volume = 35 | issue = 49 | pages = 16259–71 | date = December 2015 | pmid = 26658874 | pmc = 4682788 | doi = 10.1523/JNEUROSCI.1674-15.2015 }}</ref><ref name=":0">{{cite journal | vauthors = Tang W, Kochubey O, Kintscher M, Schneggenburger R | title = A VTA to basal amygdala dopamine projection contributes to signal salient somatosensory events during fear learning | journal = The Journal of Neuroscience | pages = JN–RM–1796-19 | date = April 2020 | volume = 40 | issue = 20 | pmid = 32277045 | doi = 10.1523/JNEUROSCI.1796-19.2020 | pmc = 7219297 }}</ref>
:*VTA → [[Entorhinal cortex]]
:* VTA → [[Cingulate gyrus]]
:* VTA → [[Hippocampus]]
:* VTA → [[Nucleus accumbens]]
:* VTA → [[Olfactory bulb]]
:* VTA → [[Prefrontal cortex]]

=== Development ===
Because they develop from common embryonic tissue and partly overlap in their projection fields, [[Dopaminergic]] cell groups lack clear anatomical boundaries. During the development of the mammalian brain, both substantia nigra (SN) and VTA neurons initially project to the dorsolateral and ventromedial [[striatum]].   However, at birth the SN dopaminergic neurons project exclusively into the dorsolateral striatum, and the VTA dopaminergic neurons project solely into the ventromedial striatum. This pruning of connections occurs through the elimination of the unnecessary collaterals.{{citation needed|date=August 2020}}