Paraventricular Nucleus of the Thalamus and Nucleus Accumbens Neurons in Aversion-Resistant Alcohol Drinking - Project Summary/Abstract This project proposes to investigate the underlying neural mechanisms within the nucleus accumbens (NAc) driving cue-elicited reward seeking during aversion-resistant alcohol drinking (ARD), defined as drinking despite negative consequences or “compulsive alcohol drinking”, using optogenetics and simultaneous in-vivo electrophysiology and optogenetics in male and female Long-Evans rats. Environmental reward predicting cues provide a source of motivation for reward-seeking which may be heightened following extended alcohol use, resulting in maladaptive, ARD, a defining feature of alcohol use disorder (AUD). Despite the well- established role of the NAc in mediating cue-elicited reward seeking, motivation, and ARD, the neural signature within the NAc during cue and alcohol access in ARD is not known, which greatly limits prevention and treatment of AUD. The NAc is innervated by glutamatergic projections from the paraventricular nucleus of the thalamus (PVT). This projection is thought to be relevant for processing motivational conflict and preventing unproductive reward seeking, while sparing normal affective behavior. However, the PVT-to-NAc pathway’s role in modulating NAc encoding during ARD or how the activity of PVT-to-NAc neurons alter ARD is not known. Thus, the central hypotheses of this project are 1) the NAc encodes cue and outcome information related to ARD. Specifically, neural activity in the NAc responds to reward (alcohol access) predictive cues and to alcohol rewards in a discriminative stimulus task and that over continued alcohol use, this activity increases in correlation with the development of ARD and 2) the neuronal activity in the NAc is causally related to an excitatory projection from the PVT that acts to prevent ARD initially, but erodes over time resulting in ARD. This project will assess the neural mechanisms of cue-elicited reward seeking and ARD during a discriminative stimulus task using both optogenetic circuit manipulations and simultaneous optogenetics and awake-and- behaving electrophysiology recordings. The training plan for this project is curated in an ideal research environment in the Department of Neuroscience at the University of Minnesota which will provide training in cutting edge neuroscience techniques, professional development, and research ethics that will amass an ideal training experience to facilitate my career as an independent alcohol research scientist. The specific research hypotheses are 1) Optogenetic inhibition of PVT-to-NAc neurons at cue presentation and alcohol reward will cause ARD in otherwise aversion-sensitive rats. 2) Optogenetic excitation of PVT-to-NAc at cue presentation and alcohol reward will reduce ARD, causing aversion-sensitivity, in otherwise ARD rats. 3) Ensembles of neurons within the NAc encode cue and alcohol rewards during ARD. This encoding is facilitated by the PVT- to-NAc projection whereby PVT-to-NAc inhibition will increase NAc encoding of cues and alcohol rewards and PVT-to-NAc excitation will reduce this encoding within the NAc. Completion of the proposed work will elucidate understanding of the neural mechanisms of ARD and will aid in the prevention and treatment of AUD.
