Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning

Abstract

The ventral tegmental area (VTA) and nucleus accumbens (NAc) are essential for learning about environmental stimuli associated with motivationally relevant outcomes. The task of signalling such events, both rewarding and aversive, from the VTA to the NAc has largely been ascribed to dopamine neurons. The VTA also contains GABA (γ-aminobutyric acid)-releasing neurons, which provide local inhibition and also project to the NAc. However, the cellular targets and functional importance of this long-range inhibitory projection have not been ascertained. Here we show that GABA-releasing neurons of the VTA that project to the NAc (VTA GABA projection neurons) inhibit accumbal cholinergic interneurons (CINs) to enhance stimulus-outcome learning. Combining optogenetics with structural imaging and electrophysiology, we found that VTA GABA projection neurons selectively target NAc CINs, forming multiple symmetrical synaptic contacts that generated inhibitory postsynaptic currents. This is remarkable considering that CINs represent a very small population of all accumbal neurons, and provide the primary source of cholinergic tone in the NAc. Brief activation of this projection was sufficient to halt the spontaneous activity of NAc CINs, resembling the pause recorded in animals learning stimulus-outcome associations. Indeed, we found that forcing CINs to pause in behaving mice enhanced discrimination of a motivationally important stimulus that had been associated with an aversive outcome. Our results demonstrate that VTA GABA projection neurons, through their selective targeting of accumbal CINs, provide a novel route through which the VTA communicates saliency to the NAc. VTA GABA projection neurons thus emerge as orchestrators of dopaminergic and cholinergic modulation in the NAc.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

“…However, the NAc core, but not the NAc shell, was blocked by a-conotoxins, suggesting that nicotine's effects are mediated by a6*-nAChRs. Although it was previously determined that cholinergic interneurons excite presynaptic nAChRs on DA terminals (Jones et al, 2001;Yang et al, 2009b;Zhang et al, 2009;Brown et al, 2012), we demonstrate here that short-term nicotine administration causes a decrease in evoked DA release in the NAc, as reported previously by others (Zhang et al, 2009;Perez et al, 2013). Under the previous model, direct activation of the nAChR on the DA terminal would induce increased DA release, as a cationic influx into the presynaptic terminal would induce a higher magnitude of vesicular release.…”

“…One population of GABA neurons in the VTA has projections to the NAc (Brown et al, 2012;van Zessen et al, 2012). It has recently been theorized that because of the high percentage of codependence with these drugs, both ethanol and nicotine may act on similar targets in the brain, specifically nicotinic acetylcholine receptors (nAChRs) on presynaptic GABAergic neurons or DAergic terminals (Hendrickson et al, 2013;Taylor et al, 2013b).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Another major source of GABA to the NAcore originates from the VTA (Taylor et al, 2014). Although this projection has not been studied extensively in the context of addiction, recent work shows that VTA GABA-mediated inhibition of NAc cholinergic interneurons facilitates associative learning processes (Brown et al, 2012), suggesting that these GABA afferents may play an important role in drug memories and related plasticity. Finally, the NAcore receives GABAergic inputs from the lateral septum (Brog et al, 1993) and a minor GABAergic input from medial prefrontal parvalbumin projection neurons , but these have yet to be investigated in drug-related behaviors.…”

“…Furthermore, silencing accumbens ACh neurons decreased The Nucleus Accumbens: Mechanisms of Addiction cocaine CPP, whereas activating these cells was not sufficient to drive or potentiate a place preference (Witten et al, 2010). Additional optogentic studies have shown that the inputs from the VTA to the ACh interneurons in the accumbens are selectively GABAergic, and activating GABAergic inputs (and thereby inhibiting ACh interneuron firing) enhanced outcome learning only to aversive stimuli (Brown et al, 2012).…”

Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei

“…GABAergic SNpr is the main output source of the basal ganglia and projects to brain regions important for activation of voluntary movements. Furthermore, some VTA GABAergic and glutamatergic neurons project to the forebrain and regulate pathways involved in associative learning (Fields et al, 2007;Brown et al, 2012;Kabanova et al, 2015).…”