# VTA-NAc GABAergic communication underlying stress-induced reward deficits > **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2022 · $540,520 ## Abstract Millions of Americans suffer from deficits in reward-seeking, in the context of psychiatric disorders, such as major depressive disorder, schizophrenia, and substance use disorders. Stress can both exacerbate these disorders and directly cause reward-seeking deficits. Mice subjected to chronic stress also develop reward-seeking deficits. However, it remains unclear how stress disrupts reward-seeking. Reward-seeking is a complex process that includes anticipatory motivation to obtain rewards, an assessment of the hedonic value of rewards, and learning to associate reward-predicting cues with rewarding outcomes. Communication between the ventral tegmental area (VTA) and the nucleus accumbens (NAc) plays a central role in these processes. Dopamine (DA) released from the VTA to the NAc supports components of reward-seeking, including anticipation and learning. Yet efforts to show that VTA-NAc DA deficits underlie stress-induced reward-seeking deficits have yielded mixed results. Recently, researchers have identified that inhibitory VTA GABA neurons are also key for setting expectations that both guide reward anticipation and associative learning. We have found that during acute stress, these VTA GABA neurons induce rhythmic NAc activity and that this activity predicts subsequent transient reductions in reward-seeking. Moreover, rhythmically stimulating NAc projecting VTA GABA neurons suffices to recapitulate both stress-induced NAc rhythmic activity and subsequent reward-seeking deficits. These data raise the possibility that chronic stress causes reward-seeking deficits via VTA-NAc GABA activity. Since VTA GABA neurons have known roles in anticipation and learning, these data also suggest that chronic stress might disrupt encoding of specific aspects of reward-seeking. This proposal tests these ideas and directly links chronic stress- induced VTA-NAc GABAergic activity to subsequent deficits in the encoding of reward-seeking. Specific Aim 1 will test whether two chronic stress disrupts specific aspects of reward-seeking using tasks that assess associative learning, anticipatory motivation and hedonic valuation and consider mice along the susceptible- resilient spectrum. Specific Aim 2 will use optogenetics and chronic in vivo multi-site electrophysiology in awake, behaving mice to test whether VTA-NAc GABAergic activity causes chronic stress-induced reward-seeking deficits by recording the in vivo firing activity of VTA-NAc GABA projections during chronic stress and subsequent reward-seeking. We will also determine whether chronic optogenetic stimulation of this pathways suffices to induce persistent reward-seeking deficits. Finally, Specific Aim 3 will use pathway-specific chemogenetic blockade to test whether blocking VTA-NAc GABAergic activity can prevent chronic stress-induced reward- seeking deficits. We will also use Cal-Light (calcium and light-activated gene expression) to express an inhibitory opsin in stress-activated VTA neurons. This tec... ## Key facts - **NIH application ID:** 10426273 - **Project number:** 5R01MH124998-02 - **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC - **Principal Investigator:** Alexander Harris - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $540,520 - **Award type:** 5 - **Project period:** 2021-06-10 → 2026-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10426273 ## Citation > US National Institutes of Health, RePORTER application 10426273, VTA-NAc GABAergic communication underlying stress-induced reward deficits (5R01MH124998-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10426273. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*