Nucleus Accumbens Subnuclei Regulate Motivated Behavior via Direct Inhibition and Disinhibition of VTA Dopamine Subpopulations

Abstract

SUMMARY Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent inputs, little is known about the circuits in which they are embedded. Using retrograde tracing, electrophysiology, optogenetics and behavioral assays we identify principles of afferent-specific control in the mesolimbic DA system. Neurons in the medial shell subdivision of the nucleus accumbens (NAc) exert direct inhibitory control over two separate populations of mesolimbic DA neurons by activating different GABA receptor subtypes. In contrast, NAc lateral shell neurons mainly synapse onto ventral tegmental area (VTA) GABA neurons, resulting in disinhibition of DA neurons that project back to the NAc lateral shell. Lastly, we establish a critical role for NAc subregion-specific input to the VTA underlying motivated behavior. Collectively, our results suggest a distinction in the incorporation of inhibitory inputs between different subtypes of mesolimbic DA neurons.

Regulatory system of mGluR group II in the nucleus accumbens for methamphetamine‐induced dopamine increase by the medial prefrontal cortex

“…In accordance with previous reports, our experiments showed that NAc shell projects to VTA (Figure A). Optogenetic studies showed that MSN neurons from the NAc targeted VTA interneurons .…”

“…Next, we injected AAV‐GFP vector into the NAc shell and checked the expression of GFP protein in the VTA (Figure A). In concert with previous reports, NAc shell projects to VTA …”

The nucleus accumbens shell in reinstatement and extinction of drug seeking

“…There are important functional differences across these AcbSh sub-divisions. In the mediolateral plane, D1 expressing SPNs in ventrolateral AcbSh have different long-range connectivity and function in reward to SPNs in the medial AcbSh (Yang et al, 2018). These two regions target different VTA sub-regions and whereas optical stimulation of ventrolateral AcbSh neurons projecting to VTA is positively reinforcing, such stimulation of medial AcbSh neurons is not (Yang et al, 2018).…”

“…There is a rich and diverse pattern of connectivity between AcbSh and VTA (Xia et al, 2011;Brown et al, 2012;Watabe-Uchida et al, 2012;Bocklisch et al, 2013;Lammel et al, 2013;Beier et al, 2015;Nieh et al, 2015;Faget et al, 2016). AcbSh projections to VTA emerge predominantly from D1 expressing SPNs and provide direct inhibitory GABAergic inputs to both VTA dopamine and GABAergic neurons (Bocklisch et al, 2013;O'Connor et al, 2015;Yang et al, 2018). This targeting of different VTA cell types yields diverse effects, including direct and indirect effects of AcbSh inputs on VTA dopamine vs. GABA neurons achieved via different GABA receptors (Edwards et al, 2017) and effects on VTA GABAergic neurons that vary across the medial to lateral VTA (Edwards et al, 2017;Yang et al, 2018).…”

“…AcbSh projections to VTA emerge predominantly from D1 expressing SPNs and provide direct inhibitory GABAergic inputs to both VTA dopamine and GABAergic neurons (Bocklisch et al, 2013;O'Connor et al, 2015;Yang et al, 2018). This targeting of different VTA cell types yields diverse effects, including direct and indirect effects of AcbSh inputs on VTA dopamine vs. GABA neurons achieved via different GABA receptors (Edwards et al, 2017) and effects on VTA GABAergic neurons that vary across the medial to lateral VTA (Edwards et al, 2017;Yang et al, 2018). It is likely that AcbSh inhibition of VTA GABAergic neurons contributes to context-induced reinstatement because reinstatement of alcohol-seeking was also prevented by chemogenetic excitation of VTA Gad1 neurons (Gibson et al, 2018).…”