Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-D-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.

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.

Feeding satisfies metabolic need but is also controlled by external stimuli, like palatability or predator threat. Nucleus accumbens shell (NAcSh) projections to the lateral hypothalamus (LH) are implicated in mediating such feeding control, but the neurons involved and their mechanism of action remain elusive. We show that dopamine D1R-expressing NAcSh neurons (D1R-MSNs) provide the dominant source of accumbal inhibition to LH and provide rapid control over feeding via LH GABA neurons. In freely feeding mice, D1R-MSN activity reduced during consumption, while their optogenetic inhibition prolonged feeding, even in the face of distracting stimuli. Conversely, activation of D1R-MSN terminals in LH was sufficient to abruptly stop ongoing consumption, even during hunger. Direct inhibition of LH GABA neurons, which received input from D1R-MSNs, fully recapitulated these findings. Together, our study resolves a feeding circuit that overrides immediate metabolic need to allow rapid consumption control in response to changing external stimuli. VIDEO ABSTRACT.

SummaryHaploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of Autism Spectrum Disorder (ASD). How SHANK3 insufficiency affects specific neural circuits and this is related to specific ASD symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the Ventral Tegmental Area (VTA) of mice. We identified dopamine (DA) and GABA cell-type specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) during the first postnatal week restored DA neuron excitatory synapse transmission and rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired VTA function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.

The effects of varenicline on nicotine-induced reinstatement of drug-seeking are consistent with the demonstrated clinical efficacy of varenicline for smoking cessation.