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

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Published in Nature. 2012, vol. 492, no. 7429, p. 452-6
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.
Keywords AnimalsAxons/metabolismCholinergic Neurons/metabolismDopamine/metabolismGABAergic Neurons/physiologyInhibitory Postsynaptic PotentialsInterneurons/metabolismLearning/physiologyMiceNucleus Accumbens/cytology/physiologyOptogeneticsPatch-Clamp TechniquesSynapses/metabolismVentral Tegmental Area/physiologyGamma-Aminobutyric Acid/metabolism/secretion
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PMID: 23178810
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Article (Published version) (2 MB) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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BROWN, Matthew et al. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. In: Nature, 2012, vol. 492, n° 7429, p. 452-6. https://archive-ouverte.unige.ch/unige:26981

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Deposited on : 2013-03-25

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