Ventral tegmental area

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.

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). Subpallidal afferents into the VTA are mainly GABAergic and, thus, inhibitory. There is a substantial pathway from the subpallidal area to the VTA.

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.

:*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.

Function

As stated above, the VTA, in particular the VTA dopamine neurons, serve several functions in the reward system, motivation, cognition, and drug 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. 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 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. 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.

Neural composition

The VTA, like the substantia nigra, is populated with melanin-pigmented dopaminergic neurons. Recent studies have suggested that dopaminergic neurons comprise 50-60% of all neurons in the VTA, which is contrary to previous evidence that noted 77% of neurons within the VTA to be dopaminergic. In addition, there is a sizable population of GABAergic neurons in the rostromedial tegmental nucleus (RMTg), a functionally distinct brain structure.

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. Therefore, the NAC shell and the posterior VTA are the primary areas involved in the reward system.

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 addictive drugs act. The following are commonly considered to be addictive: cocaine, alcohol, opioids, nicotine, cannabinoids, and amphetamine and its analogs. These drugs alter the neuromodulatory influence of dopamine on the processing of reinforcement signals by prolonging the action of dopamine in the nucleus accumbens or by stimulating the activation of neurons there and also in the VTA. The most common drugs of abuse stimulate the release of dopamine, which creates both their rewarding and the psychomotor effects. Compulsive drug-taking behaviors are a result of the long-lasting or permanent functional changes in the mesolimbic dopamine system arising from repetitive dopamine stimulation. Molecular and cellular adaptations are responsible for a sensitized dopamine activity in the VTA and along the mesolimbic dopamine projection in response to drug abuse. In the VTA of addicted individuals, the activity of the dopamine-synthesizing enzyme tyrosine hydroxylase increases, as does the ability of these neurons to respond to excitatory inputs. The latter effect is secondary to increases in the activity of the transcription factor CREB and the up regulation of GluR1, an important subunit of AMPA receptors for glutamate. These alterations in neural processing could account for the waning influence of adaptive emotional signals in the operation of decision making faculties as drug-seeking and drug-taking behaviors become habitual and compulsive.

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.

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.