Ventral tegmental area

The ventral tegmentum (tegmentum is Latin for covering), better known as the ventral tegmental area (VTA), is a group of neurons located close to the midline on the floor of the midbrain (mesencephalon). 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. It is important in cognition, motivation, drug addiction, intense emotions relating to love, and several psychiatric disorders. The VTA contains neurons that project to numerous areas of the brain, from the prefrontal cortex (PFC) 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. 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 VTA is in the midbrain between several other major areas, some of which are described here. The mammilary bodies and the posterior hypothalamus, both included in the diencephalon, extend rostrally from the VTA. The nucleus ruber (red nucleus) and oculomotor fibers are situated dorsolateral to the VTA. The pons and the hindbrain (rhombencephalon) lie caudally to the VTA. Finally, the substantia nigra is located laterally to the VTA.

Structure
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 ventral tegmental tail (VTT), 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 VTT contain a low density of tyrosine hydroxylase (TH)-positive cell bodies that are small in size and lightly stain. On the other hand, the PN and PBP consist mainly of medium to large sized TH-positive cell bodies that stain moderately.

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

Presence of gap junctions
The VTA has been shown to have a large network of 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.

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 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.

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 which noted 77% of neurons within the VTA to be dopaminergic. Additionally, there is a sizable population of GABAergic neurons in the VTA. These GABAergic neurons regulate the firing of their dopaminergic counterparts and 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.

Comparative anatomy
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. More specifically, 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.

Outputs
The two primary efferent fiber projections of the VTA are the mesocortical and the mesolimbic pathways. Three less important pathways also exists: the mesostriatal, the mesodiencephalic, and the mesorhombencephalic pathways. Below is a brief summary of where each pathway originates and terminates:


 * Mesostriatal: originates in the SN and VTA; innervates the anteromedial striatum
 * Mesocortical: originates in the VTA; innervates the prefrontal and insular corticies
 * Mesolimbic: originates in the VTA; innervates the limbic cortices, septo-hippocampal complex, nucleus accumbens (NAC), and amygdala
 * Mesodiencephalic: originates in the SN and VTA; innervates several thalamic nuclei and several hypothalamic nuclei
 * Mesorhombencephalic: originates in the SN and VTA; innervates the monoaminergic nuclei, superior colliculus, reticular formation, and periaqueductal gray

The large mesolimbic pathway projects primarily to the NAC and the olfactory tubercle. The projection is so named to contrast it with the nigro-striatal dopamine system that runs parallel to it but connects the substantia nigra to the dorsal striatum. Other projections of the VTA dopamine neurons include the limbic-related regions (i.e. septum, hippocampus, amygdala, and prefrontal cortex). The mesocortical pathway projects to sensory, motor, limbic, and polysensory association cortices. The prefrontal, orbitofrontal, and cingulate cortices receive the majority of innervation from the VTA. Most of these connections are unilateral, but some project to one or more area.

Inputs
Almost all areas receiving projections from the VTA project back to it. Thus, the ventral tegmentum 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 new and highly developed neocortex, as well as that of the phylogenetically older limbic areas.

There are excitatory glutamatergic afferents that arise from almost every structure that projects into the VTA, except the NAC and the lateral septum. 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.

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.

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. Recently 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 transsnyaptic 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 biotin 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 VTA, 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. Secondly, the lateral VTA largely projects to the ventrolateral striatum, which includes the NAC core, the medial NAC shell, and the lateral olfactory tubercle. These pathways are respectively called the meso-ventromedial and the meso-ventrolateral striatal dopamine systems. 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. Therefore, the NAC shell and the posterior VTA are the primary areas involved in the reward system.

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 form 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 VTA.

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 diseases and trying to find a way to selectively treat a specific dopamine projection.

Drug addiction
The NAC and the VTA are the primary sites where drugs of abuse act. The following are commonly considered abused drugs: heroin, cocaine, alcohol, opiates, marijuana, nicotine, amphetamine and their synthetic analogs.(Where is it said that marijuana is a dopaminergic drug?) 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 potentiating the activation of neurons in the VTA and NAC. 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 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, and 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 animals learn to press a lever for the administration of drugs such as nicotine, carbachol, opiates, cocaine, and ethanol into the posterior VTA more readily than into the anterior VTA. Other studies have shown that microinjections of dopaminergic drugs into the NAC shell increase locomotor activity and exploratory behaviors, conditioned approach responses, and anticipatory sexual behaviors.

The withdrawal phenomenon occurs because the deficit in reward functioning causes the organism to enter a distress cycle where 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, an organism will reinstate the drug-seeking behavior if exposed to the drug or drug-related stimuli.