Ventral tegmental area

Summary

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.

Official source

https://en.wikipedia.org/wiki/Ventral_tegmental_area

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The dopaminergic VTA - basal amygdala projection contributes to signal aversive state in fear memory

Wei Tang

Dopamine released from midbrain neurons is an important neuromodulatory signal during associative learning in many forebrain circuits. One model of associative learning is auditory cued fear learning, during which an innocuous sensory percept like a tone (called conditioned stimulus, CS), acquires an aversive meaning after pairing with an aversive event, like a mild footshock (called unconditioned stimulus, US). The amygdala plays an important role in fear learning in mammals. Nevertheless, our knowledge of the synaptic- or neuromodulatory input(s) which carry information about the US to the amygdala is still limited. Here, I have investigated the hypothesis that dopamine, released from midbrain dopaminergic neurons in the ventral tegmental area (VTA) of mice, might signal aversive sensory events to the amygdala during fear learning. Using viral anterograde tracing approaches in transgenic mice expressing Cre-recombinase under the control of the dopamine transporter promoter (DAT-Cre), we found a dopaminergic projection from VTA to the basal amygdala (BA) and to the central amygdala (CeA). In addition, retrograde tracing approaches showed that tyrosine hydroxylase positive (TH+) dopamine neurons targeting these two areas might be differentially distributed in the VTA. To investigate a role of these projections during fear learning, we silenced the electrical activity of VTA dopamine neurons, or else their projection fibers to the BA or the CeA, by using Cre-dependent expression of a light-driven proton pump Archaerhodopsin (Arch). Silencing VTA neurons specifically during the footshock presentation (US) led to a moderate reduction of fear memory tested one day following the initial US - CS pairing. Silencing the dopaminergic fibers bilaterally in the BA (but not in the CeA) during footshock presentation had a somewhat larger effect on fear memory retrieval, and similarly reduced contextual fear memory. Furthermore, we made recordings of the spiking activity of DAT+ - as well as of non-identified VTA neurons in-vivo in behaving mice using optrodes. We found that about half of all units strongly respond to footshock stimulation (US), and show increasing responses to tones (CS) during the US - CS pairing. To investigate the possible cellular functions of dopamine in the BA during fear learning, we performed in-vitro recordings of genetically identified parvalbumin (PV)-positive interneurons and BA principal neurons that project to the CeA. This showed that bath application of dopamine or of a D1- receptor agonist enhances the evoked firing rate of CeA projectors in the BA. Finally, bath application of dopamine reduces afferent excitatory inputs onto PV-positive interneurons in the BA and in the LA. Taken together, by using complementary optogenetic, electrophysiological and anatomical approaches, this PhD thesis suggests that VTA dopamine neurons facilitate associative learning in the BA by providing a neuromodulatory signal to the BA during the time of the footshock. Furthermore, the VTA might also provide dopamine to the amygdala during fear memory retrieval. Thus, this work contributes to an understanding of the functional role of the dopaminergic VTA to BA projection in auditory-cued fear learning.

EPFL2018

Social hierarchies are established across a range of different taxa in the animal kingdom. Given that hierarchy inequalities are highly present in nowadays society and the health problems that low rank individuals suffer from this, it is surprising that not much is known about the underlying neurobiological mechanisms that predispose an individual to become dominant or submissive. We aimed to have a better understanding of personality-related factors (such as anxiety and reward-seeking behaviors) and underlying brain mechanisms that predispose rats to become dominant. We aimed to study the neurobiological mechanisms involved in the modulation of dominance by anxiety. Peripheral injection of anxiolytic drugs has been shown to modulate the dopaminergic mesolimbic system by acting in the GABAergic neurons on the ventral tegmental area (VTA). Our studies specifically targeted GABAergic receptors within the VTA modulating both anxiety and dominance. However, the activation of GABAergic receptors in the nucleus accumbens (NAc) affected dominance but had no effect on anxiety. Furthermore, we found that the NAc is required for the effects of the anxiolytic diazepam on the establishment of social dominance. We assessed potential differences on the accumbal dopaminergic system in relation to anxiety. To this end, we assessed catecholamines levels by high performance liquid chromatography (HPLC) and confirmed the existence of differences in accumbal dopamine content between high and low anxious rats. Subsequently, we showed that pharmacological activation of D1 receptors within the NAc enhanced social dominance. In addition, activation of GABAergic receptors in the VTA, in addition to enhancing social dominance, enhanced the accumbal dopaminergic system. These findings lead us to hypothesize a critical role on the observed behavioral effects for the firing of the VTA dopaminergic neurons that project to the NAc. Subsequently, we investigated the consequences of phasically activating VTA dopaminergic neurons projecting to the NAc in a social competition test. To specifically modulate firing properties of dopaminergic neurons within the VTA of behaving animals, we performed optogenetic activation in TH::Cre rats infused with Cre-dependent virus expressing channelrhodopsin-2 (ChR2). Our results showed that phasic activation of the VTA dopaminergic neurons during the social competition test for palatable rewards was not sufficient to modify the output of the encounters. Winners of the social competition tests were found to have a trend for higher reward-seeking phenotype (lower latencies to get rewards on their last day of individual training) which leads us to subsequently study the role of reward-seeking trait on the rank attained in a social hierarchy. Our data indicates a role for reward-seeking behaviors during last day of individual training (on social competition for palatable rewards test) on the output of several social competition tests. Interestingly, the combination of phasic optical activation of VTA dopaminergic neurons during the last two days of training and during social competition increased dominance. Altogether, our studies have elucidated the effects of anxiety and reward-seeking traits on rat's hierarchy establishment. Furthermore, we were able to modulate the output of a social competition test by optical activations of the mesolimbic dopaminergic system.

EPFL2015

GABA A receptors in the ventral tegmental area control the outcome of a social competition in rats

Maria del Carmen Sandi Perez, Michael van der Kooij, Ioannis Zalachoras

Social dominance can be attained through social competitions. Recent work in both humans and rodents has identified trait anxiety as a crucial predictor of social competitiveness. In addition, the anxiolytic GABAA positive modulator, diazepam, injected either systemically or into the ventral tegmental area (VTA) was shown to increase social dominance. Here, we investigated the impact of pharmacologically targeting GABAA receptors in the VTA for the outcome of a social competition between two unfamiliar male rats, one of them infused with vehicle and the other one with the drug under study. We show that infusion of the GABAA receptor agonist, muscimol, reduced anxiety-like behaviors and enhanced social competition, the GABAA receptor antagonist, bicuculline had the opposite effects. Importantly, intra-VTA muscimol administration also counteracted the disadvantage of high anxious rats to win a social competition against low anxious rats. Furthermore, we assessed the effectiveness of targeting specific GABAA receptor subunits by infusing zolpidem (α1-subunit agonist) or TCS1105 (a benzodiazepine ligand with α2-subunit agonistic and α1-subunit antagonistic effects) into the VTA. While zolpidem infusion did not affect the outcome of the social competition, TCS1105 enhanced social dominance. Our data highlight GABAergic mechanisms involving the engagement of α2-subunit containing GABAA receptors in the VTA in the attainment of dominance rank. The involvement of α2-subunit containing GABAA receptors in the VTA in the regulation of social competitiveness supports the potential therapeutic relevance of targeting these receptors to ameliorate anxiety-related social dysfunctions.

2018

The dopaminergic VTA - basal amygdala projection contributes to signal aversive state in fear memory

Wei Tang

EPFL2018

EPFL2015