| Ventral tegmental area | |
|---|---|
Transverse section of mid-brain at level of superior colliculi. (Tegmentum labeled at center right.)
| |
| Details | |
| Part of | Midbrain |
| Identifiers | |
| Latin | Area tegmentalis ventralis |
| Acronym(s) | VTA |
| MeSH | D017557 |
| NeuroNames | 521 |
| NeuroLex ID | birnlex_1415 |
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 cognition, motivation, orgasm, and intense emotions relating to love, 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
Anatomical location of VTA in humans
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 not a homogenous region, as it consists of a variety
of neurons that are characterized by different neurochemical and
neurophysiological properties. Therefore, glutaminergic and GABAergic
inputs are not exclusively inhibitory nor exclusively excitatory. The
VTA receives glutaminergic afferents from the prefrontal cortex, pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus, subthalamic nucleus, bed nucleus of the stria terminalis, superior colliculus, and lateral hypothalamic and preoptic areas.
GABAergic inputs to the VTA include the nucleus accumbens, ventral pallidum, and rostromedial tegmental nucleus (RMTg). The lateral habenula
exerts an inhibitory effect on dopaminergic neurons in the VTA via
exciting RMTg GABAergic neurons, which is thought to play an important
role in reward prediction errors.
There are excitatory glutamatergic afferents that arise from most
structures that project into the VTA. 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.
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.
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. The full set of projections, all of which utilize dopamine as their primary neurotransmitter, is listed below.
- Ventral tegmental area (VTA) projections
- VTA → Amygdala
- 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. 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 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.
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.
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 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 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) before 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 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. 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. 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: heroin, cocaine, alcohol, opioids, nicotine, cannabinoids, amphetamine,
and their 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 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.
