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


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 neurons1,2,3. The VTA also contains GABA (γ-aminobutyric acid)-releasing neurons, which provide local inhibition4,5 and also project to the NAc6,7. 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 associations8,9,10,11,12. 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.

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Figure 1: Long-range GABA projections from the VTA form synaptic contacts selectively with CINs in the NAc.
Figure 2: Inhibitory currents can be selectively elicited in CINs by activating VTA GABA axons in the NAc.
Figure 3: Pausing NAc CINs through selective VTA GABA projection neuron activation.
Figure 4: Activation of VTA GPN axons in the NAc enhances stimulus–outcome learning in an aversive paradigm.


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We thank the members of the Lüscher laboratory for discussion and comments on the manuscript. This work was funded by a grant of the Swiss National Science Foundation to C.L. and the National Center of Competence in Research (NCCR) ‘SYNAPSY – The Synaptic Bases of Mental Diseases’ of the Swiss National Science Foundation. fTomPVALBcre mice were provided by A. Holtmaat.

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M.T.C.B., K.R.T. and E.C.O’C. performed the in vitro electrophysiological recordings. M.T.C.B. and K.R.T. performed the in vivo electrophysiological recordings. M.T.C.B. performed the fluorescence immunohistochemical experiments and confocal microscopy. I.N. and D.M. conceived and performed the light and electron microscopic experiments. E.C.O’C. performed the behavioural experiments. C.L., M.T.C.B., K.R.T. and E.C.O’C. designed the study, and C.L. wrote the manuscript with the help of M.T.C.B., K.R.T. and E.C.O’C.

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Correspondence to Christian Lüscher.

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The authors declare no competing financial interests.

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Brown, M., Tan, K., O’Connor, E. et al. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 492, 452–456 (2012).

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