The ventral tegmental area (VTA) (tegmentum is Latin for covering), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition (motivational salience, associative learning, and positively-valenced emotions) and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.
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 cytoarchitectonic features of the region and the lack of clear borders that separate it from adjacent regions. Because of the selective limbic-related afferents to the VTA, the cells of the VTA are given the designation A10 to differentiate them from surrounding cells.
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. The pons and the hindbrain lie caudally to the VTA. Finally, the substantia nigra is located laterally to the VTA.
Subdivisions In 1987, Oades identified four primary nuclei in the 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. 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. The VTA receives glutamatergic afferents from the prefrontal cortex, 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 hypothalamic and preoptic areas. 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, a.k.a. the RMTg) projects to the VTA with GABAergic afferents, functioning as a "master brake" for the VTA dopamine pathways. 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). 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. Subpallidal afferents into the VTA are mainly GABAergic and, thus, inhibitory. There is a substantial pathway from the subpallidal area to the VTA. When this pathway is disinhibited, an increase in the dopamine release in the mesolimbic pathway amplifies locomotor activity. 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.
Outputs The two primary efferent fiber projections of the VTA are the mesocortical and the mesolimbic pathways, which correspond to the prefrontal cortex and nucleus accumbens respectively. In addition, experiments in rodents have identified a mesohabenular pathway consisting of VTA neurons that do not release dopamine, but glutamate and GABA. Other VTA projections, which utilize dopamine as their primary neurotransmitter, are listed below.
Ventral tegmental area (VTA) projections VTA → Amygdala VTA → Entorhinal cortex VTA → Cingulate gyrus VTA → Hippocampus VTA → Nucleus accumbens VTA → Olfactory bulb VTA → Prefrontal cortex
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