Editing Ventral tegmental area (section)

== Function ==
As stated above, the VTA, in particular the VTA dopamine neurons, serve several functions in the [[reward system]], [[motivation]], [[cognition]], and drug [[Substance dependence|addiction]], and may be the focus of several [[psychiatric disorders]]. The VTA has also been shown to process various types of [[emotion]] output from the [[amygdala]], where it may also play a role in avoidance and fear-conditioning.<ref name=":0" /><ref>{{cite journal | vauthors = Fadok JP, Dickerson TM, Palmiter RD | title = Dopamine is necessary for cue-dependent fear conditioning | journal = The Journal of Neuroscience | volume = 29 | issue = 36 | pages = 11089–97 | date = September 2009 | pmid = 19741115 | pmc = 2759996 | doi = 10.1523/JNEUROSCI.1616-09.2009 }}</ref> Electrophysiological recordings have demonstrated that VTA neurons respond to novel stimuli, unexpected rewards, and reward-predictive sensory cues. The firing pattern of these cells is consistent with the encoding of a reward expectancy error.

In 2006, MRI studies by [[Helen Fisher (anthropologist)|Helen Fisher]] and her research team found and documented various emotional states relating to intense love correlated with activity in the VTA, which may help explain obsessive behaviors of rejected partners, since this is shared by the reward system.  Nest sharing behavior is associated with increased V1aR expression in the VTA of newly paired zebra finches.<ref name="ReferenceA">{{cite journal | vauthors = Tomaszycki ML, Richardson KK, Mann KJ | title = Sex and pairing status explain variations in the activation of nonapeptide receptors in song and motivation regions | journal = Behavioral Neuroscience | volume = 130 | issue = 5 | pages = 479–89 | date = October 2016 | pmid = 27504854 | doi = 10.1037/bne0000159 }}</ref>  However, V1aR expression was not related to female directed song rates, which may indicate a selective role of vasotocin in the VTA on pair maintenance versus courtship behavior.<ref name="ReferenceA"/>

=== Presence of gap junctions ===
The VTA has been shown to have a large network of [[gamma-Aminobutyric acid|GABAergic]] neurons that are interconnected via [[gap junctions]]. This network allows for electrical conduction, which is considerably faster than the chemical conduction of signals between synapses, though less spatially flexible.<ref>{{cite book | last1 = Urry |last2=Cain|last3= Wasserman|last4=Minorsky| title = Biology In Focus | edition = 3 | pages = 794 | date = 2019}}</ref><ref>{{cite journal | author1 = Allison DW|author2=Ohran AJ|author3=Stobbs SH|author4=Mameli M|author5=Valenzuela CFA|author6=Sudweeks SN|author7=Ray AP|author8=Henriksen SJ|author9=Steffensen SC | display-authors = 5 | title = Connexin-36 gap junctions mediate electrical coupling between ventral tegmental area GABA neurons | journal = Synapse | volume = 60 | issue = 1 | pages = 20–31 | date = July 2006 | pmid = 16575850 | doi = 10.1002/syn.20272 | s2cid = 4576603 }}</ref>

=== Neural composition ===
The VTA, like the [[substantia nigra]], is populated with [[melanin]]-pigmented [[dopamine]]rgic neurons.<ref>{{cite web|url=http://cogprints.org/1390/2/vta-rev-87.pdf |title=Info |publisher=cogprints.org |access-date=2019-12-24}}</ref> Recent studies have suggested that dopaminergic neurons comprise 50-60% of all neurons in the VTA,<ref>{{cite journal | vauthors = Margolis EB, Lock H, Hjelmstad GO, Fields HL | title = The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons? | journal = The Journal of Physiology | volume = 577 | issue = Pt 3 | pages = 907–24 | date = December 2006 | pmid = 16959856 | pmc = 1890372 | doi = 10.1113/jphysiol.2006.117069 }}</ref> which is contrary to previous evidence that noted 77% of neurons within the VTA to be dopaminergic.<ref name="Johnson 1992">{{cite journal | vauthors = Johnson SW, North RA | title = Two types of neurone in the rat ventral tegmental area and their synaptic inputs | journal = The Journal of Physiology | volume = 450 | pages = 455–68 | date = May 1992 | pmid = 1331427 | pmc = 1176131 | doi = 10.1113/jphysiol.1992.sp019136 }}</ref> In addition, there is a sizable population of GABAergic neurons in the [[rostromedial tegmental nucleus]] (RMTg), a functionally distinct brain structure.<ref name="VTA tail" /><ref name="Brake" /> These GABAergic neurons regulate the firing of their dopaminergic counterparts that send projections throughout the brain to, but not limited to, the following regions: the [[prefrontal cortex]], the [[nucleus accumbens]], and the [[locus coeruleus]]. The VTA also contains a small percentage of excitatory [[glutamatergic]] neurons.

=== Limbic loop ===
The “limbic loop” is very similar to the direct pathway motor loop of the [[basal ganglia]]. In both systems, there are major excitatory inputs from the cortex to the striatum (accumbens nucleus), the midbrain projects neuromodulatory dopamine neurons to the striatum, the striatum makes internuclear connections to the pallidum, and the pallidum has outputs to the thalamus, which projects to the cortex, thus completing the loop. The limbic loop is distinguished from the motor loop by the source and nature of the cortical input, the division of the striatum and pallidum that process the input, the source of the dopaminergic neurons from the midbrain, and the thalamic target of the pallidal output.
The ''limbic loop'' controls [[cognitive]] and [[affective]] functioning and the motor loop controls movement.

=== CA3 loop ===
Linking context to reward is important for reward seeking. In 2011, a group of researchers documented a [[Hippocampus proper|CA3]]-VTA connection that uses the [[septal area|lateral septum]] as an intermediary. They used a [[Pseudorabies#Applications in Neuroscience|pseudo-rabies virus]] (PRV) as a transsynaptic tracer, and injected it into the VTA. They found that unilateral injection into the VTA resulted in bilateral PRV labeling in CA3 beginning 48&nbsp;hours after injection. Lesions of the caudodorsal lateral septum (cd-LS) before VTA PRV injection resulted in significantly less PRV labeled neurons in CA3. [[theta rhythm#Hippocampal|Theta wave]] stimulation of CA3 resulted in increased firing rates for dopamine cells in the VTA, and decreased firing rates for GABA neurons in the VTA. The identity of VTA neurons was confirmed by neurobiotin labeling of the recording neuron, and then histological staining for [[tyrosine hydroxylase]] (TH). Temporary inactivation of CA3 via GABA agonists prevented context induced reinstatement of lever pressing for intravenous [[cocaine]].<ref name=Luo>{{cite journal | vauthors = Luo AH, Tahsili-Fahadan P, Wise RA, Lupica CR, Aston-Jones G | title = Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area | journal = Science | volume = 333 | issue = 6040 | pages = 353–7 | date = July 2011 | pmid = 21764750 | pmc = 3150711 | doi = 10.1126/science.1204622 | bibcode = 2011Sci...333..353L }}</ref>

The authors propose a functional circuit loop where activation of glutamatergic cells in CA3 causes activation of GABAergic cells in cd-LS, which inhibits GABA interneurons in the VTA, releasing the dopamine cells from the tonic inhibition, and leading to an increased firing rate for the dopamine cells.<ref name=Luo />

=== Reward system ===

The dopamine reward circuitry in the human brain involves two projection systems from the ventral midbrain to the nucleus accumbens-[[olfactory tubercle]] complex.  First, the posteromedial VTA and central linear raphe cells selectively project to the [[ventral striatum|ventromedial striatum]], which includes the medial olfactory tubercle and the medial [[nucleus accumbens shell|NAC shell]].  Second, the lateral VTA projects largely to the ventrolateral striatum, which includes the [[nucleus accumbens core|NAC core]], the medial NAC shell, and the lateral olfactory tubercle. These pathways are called the meso-ventromedial and the meso-ventrolateral striatal dopamine systems, respectively. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed behavior than the lateral projection system. Unlike the lateral part, the medial one is activated not by rewarding but by noxious stimuli.<ref name="pmid17574681">{{cite journal | vauthors = Ikemoto S | title = Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex | journal = Brain Research Reviews | volume = 56 | issue = 1 | pages = 27–78 | date = November 2007 | pmid = 17574681 | pmc = 2134972 | doi = 10.1016/j.brainresrev.2007.05.004 }}</ref><ref name="pmid19261850">{{cite journal | vauthors = Brischoux F, Chakraborty S, Brierley DI, Ungless MA | title = Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 12 | pages = 4894–9 | date = March 2009 | pmid = 19261850 | pmc = 2660746 | doi = 10.1073/pnas.0811507106 | bibcode = 2009PNAS..106.4894B | doi-access = free }}</ref> Therefore, the NAC shell and the posterior VTA are the primary areas involved in the reward system.{{citation needed|date=April 2015}}