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 is widely implicated in the drug and natural reward circuitry of the brain.

The ventral tegmental area is important in cognition, motivation, orgasm, drug addiction, intense emotions relating to love, and several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, from the prefrontal cortex to the caudal brainstem and several regions in between.

Anatomy

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 tegmentum 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.

Structure

Anatomical location of VTA

Anatomical location of VTA in humans. Credit: NIDA – NIDA Research Report Series

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.

Ventral Tegmental Area Function

As stated above, the ventral tegmental area, in particular the VTA dopamine neurons, serve several functions in the reward system, motivation, cognition, drug addiction, and may be the focus of several psychiatric disorders. It 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 ventral tegmental area 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.

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 ventral tegmental area dopaminergic neurons project solely into the ventromedial striatum. This pruning of connections occurs through the elimination of the unnecessary collaterals.

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. 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 ventral tegmental area 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 project 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 form the midbrain, and the thalamic target of the pallidal output.

CA3 Loop

Linking context to reward is important for reward seeking.

In 2011, a group of researchers documented a VTA-CA3 loop that uses the lateral septum as an intermediary. They used a 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 hours after injection. Lesions of the caudodorsal lateral septum (cd-LS) prior to VTA PRV injection resulted in significantly less PRV labeled neurons in CA3.

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.

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 ventral tegmental area, releasing the dopamine cells from the tonic inhibition, and leading to an increased firing rate for the dopamine cells.

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 ventromedial striatum, which includes the medial olfactory tubercle and the medial NAC shell. Second, the lateral VTA projects largely to the ventrolateral striatum, which includes the 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.

Normally, the dopaminergic neurons are only phasically active. When they are excited, they fire a barrage of action potentials and dopamine is released in the NAC.

The medium spiny neurons of the NAC are much more responsive to this increase in dopamine if there is coincident excitatory input from the telencephalic structures such as the amygdala and orbital-medial prefrontal cortex.

The activated striatal neurons (NAC neurons) then project to the ventral pallidum, where they inhibit the inhibitory GABA neurons. This inhibition in the pallidum disinhibits the thalamic target of the limbic loop, which is the mediodorsal nucleus.

The thalamus then innervates the cortical division of the limbic forebrain. This final connection is reinforced by activity in direct cortical projections from the dopaminergic neurons of the ventral tegmental area.

Ventral Tegmental Area Clinical Relevance

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 tegmentum are the primary sites where addictive drugs act.

The following are commonly considered to be addictive: heroin, cocaine, alcohol, opiates, nicotine, amphetamine, and their synthetic 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 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 ventral tegmental area 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 ventral tegmental area more readily than into the anterior ventral tegmental area. 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.

Top Image: Henry Vandyke Carter – Henry Gray (1918) Gray’s Anatomy, Plate 712

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