Ventral tegmental area
Ventral tegmental area | |
---|---|
Details | |
Part of | Midbrain |
Identifiers | |
Latin | area tegmentalis ventralis |
Acronym(s) | VTA |
MeSH | D017557 |
NeuroNames | 521 |
NeuroLex ID | birnlex_1415 |
Anatomical terms of neuroanatomy |
The ventral tegmental area (VTA) (tegmentum is Latin for covering), also known as the ventral tegmental area of Tsai,
Structure
Neurobiologists have often had great difficulty distinguishing the VTA in humans and other primate brains from the
Location
The ventral tegmental area is in the midbrain between several other major areas, some of which are described here. The
Subdivisions
In 1987, Oades identified four primary nuclei in the
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
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 inhibitory nor exclusively excitatory.
GABAergic inputs to the VTA also include the
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 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.[13]
Outputs
The two primary efferent fiber projections of the VTA are the
- Ventral tegmental area (VTA) projections[14]
- VTA → Amygdala[18][19]
- 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]
Function
As stated above, the VTA, in particular the VTA dopamine neurons, serve several functions in the
In 2006, MRI studies by 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.[21] 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.[21]
Presence of gap junctions
The VTA has been shown to have a large network of
Neural composition
The VTA, like the substantia nigra, is populated with melanin-pigmented dopaminergic neurons.[23] Recent studies have suggested that dopaminergic neurons comprise 50-60% of all neurons in the VTA,[24] which is contrary to previous evidence that noted 77% of neurons within the VTA to be dopaminergic.[25] In addition, there is a sizable population of GABAergic neurons in the rostromedial tegmental nucleus (RMTg), a functionally distinct brain structure.[9][10] 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
CA3 loop
Linking context to reward is important for reward seeking. In 2011, a group of researchers documented a
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.[26]
Reward system
The dopamine reward circuitry in the human brain involves two projection systems from the ventral midbrain to the nucleus accumbens-
Clinical significance
Disorders
The dopaminergic neurons of the substantia nigra and the ventral tegmental area of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. The close proximity of these two pathways causes them to be grouped together under dopaminergic projections. Several disorders result from the disruption of these two pathways: schizophrenia, Parkinson's disease, and attention deficit hyperactivity disorder (ADHD). Current research is examining the subtle difference between the neurons that are involved in these conditions and trying to find a way to selectively treat a specific dopamine projection.
Drug addiction
The nucleus accumbens and the ventral tegmental area are the primary sites where
Experiments in rats have shown that they learn to press a lever for the administration of stimulant drugs into the posterior VTA more readily than into the anterior VTA. Other studies have shown that microinjections of dopaminergic drugs into the nucleus accumbens shell increase locomotor activity and exploratory behaviors, conditioned approach responses, and anticipatory sexual behaviors.
The withdrawal phenomenon occurs because the deficit in reward functioning initiates a distress cycle wherein the drugs become necessary to restore the normal homeostatic state. Recent research has shown that even after the final stages of withdrawal have been passed, drug-seeking behavior can be restored if exposed to the drug or drug-related stimuli.[31][32][33]
Comparative anatomy and evolution
All studies since 1964 have emphasized the impressive general similarity between the VTA of all mammals from rodents to humans. These studies have focused their efforts on rats, rabbits, dogs, cats, opossum, non-human primates, and humans. There have been slight differences noted, such as changes in the dorsal extent of the A10 cells. To be specific, the dorsal peak of A10 cells is more extensive in primates when compared to other mammals. Furthermore, the number of dopaminergic cells in the VTA increases with phylogenetic progression; for instance, the VTA of the mouse contains approximately 25,000 neurons, while the VTA of a 33-year-old man contains around 450,000 cell bodies.[34]
See also
- Phenylalanine
- List of regions in the human brain
References
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In light of the crucial role of the tVTA in the opiate control of dopamine activity ...
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. ...
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. ...
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. - ^ PMID 23055478.
The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. ...
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). ... 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). - PMID 28441114.
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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. ... 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). ... 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. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. ...
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Further reading
- Alcaro A, Huber R, Panksepp J (December 2007). "Behavioral functions of the mesolimbic dopaminergic system: an affective neuroethological perspective". Brain Research Reviews. 56 (2): 283–321. PMID 17905440.
- Geisler S, Derst C, Veh RW, Zahm DS (May 2007). "Glutamatergic afferents of the ventral tegmental area in the rat". The Journal of Neuroscience. 27 (21): 5730–43. PMID 17522317.
- Hikosaka O, Bromberg-Martin E, Hong S, Matsumoto M (April 2008). "New insights on the subcortical representation of reward". Current Opinion in Neurobiology. 18 (2): 203–8. PMID 18674617.
- Hu Z, Cooper M, Crockett DP, Zhou R (August 2004). "Differentiation of the midbrain dopaminergic pathways during mouse development". The Journal of Comparative Neurology. 476 (3): 301–11. S2CID 20737056.
- Ikemoto S (November 2007). "Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex". Brain Research Reviews. 56 (1): 27–78. PMID 17574681.
- Lammel S, Hetzel A, Häckel O, Jones I, Liss B, Roeper J (March 2008). "Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system". Neuron. 57 (5): 760–73. S2CID 12452120.
- Lu XY, Ghasemzadeh MB, Kalivas PW (February 1998). "Expression of D1 receptor, D2 receptor, substance P and enkephalin messenger RNAs in the neurons projecting from the nucleus accumbens". Neuroscience. 82 (3): 767–80. S2CID 26963758.
- Margolis EB, Lock H, Hjelmstad GO, Fields HL (December 2006). "The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?". The Journal of Physiology. 577 (Pt 3): 907–24. PMID 16959856.
- Olson VG, Nestler EJ (February 2007). "Topographical organization of GABAergic neurons within the ventral tegmental area of the rat". Synapse. 61 (2): 87–95. S2CID 39917231.
- Sziráki I, Sershen H, Hashim A, Lajtha A (March 2002). "Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens". Neurochemical Research. 27 (3): 253–61. S2CID 843088.
- van Furth WR, van Ree JM (August 1996). "Sexual motivation: involvement of endogenous opioids in the ventral tegmental area". Brain Research. 729 (1): 20–8. PMID 8874873.
- Wu M, Hrycyshyn AW, Brudzynski SM (November 1996). "Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies". Brain Research. 740 (1–2): 151–61. S2CID 44512008.