Assessing the contributions of the ventral subiculum to the nucleus accumbens shell projection in a novel ethanol self-administration choice paradigm

PROJECT SUMMARY The progression of recreational drinking to alcohol use disorder (AUD) is characterized by increased seeking behavior and loss of intake control, with individuals continuing to use alcohol despite experiencing negative consequences. While one operant paradigm has been developed to assess operant alcohol self-administration in a manner that can procedurally separate the appetitive (seeking) vs. consummatory facets of behavior, no studies have yet leveraged this model to investigate these independent aspects of alcohol self-administration in the presence of an alternative reinforcer, an astonishing gap in the literature given that six of the eleven diagnostic criteria of AUD are related to the individual allocating behavior towards alcohol compared to alternative reinforcers. The paucity of translational models of operant alcohol choice self-administration may contribute to the continued mystery of the circuitry underlying maladaptive alcohol seeking, precluding the discovery of therapeutic targets. The present study proposes a novel operant self-administration choice paradigm which will be used to assess the role that the ventral subiculum of the hippocampus to the nucleus accumbens shell projection (vSub-NAc) has on alcohol seeking. Preliminary findings from our lab demonstrate that chemogenetic inhibition of the vSub-NAc produces a uniform reduction in alcohol seeking with minimal effects on consumption without altering seeking or intake of a sucrose solution in a separate cohort of animals. Both our lab and others have additionally shown that chronic intermittent ethanol (CIE) not only produces heightened excitability in vSub, but also results in escalation of seeking and intake. Despite these advances, it remains unknown how the vSub-NAc projection modulates operant choice behavior when a subject can respond for ethanol and an alternative reinforcer, whether the behavioral outcome of vSub-NAc inhibition would differ between CIE-exposed subjects vs. AIR controls, and how sex as a biological variable might mediate these synaptic and behavioral consequences. Therefore, the overarching goal of this proposal is to implement a multidisciplinary approach to test the hypotheses that CIE results in reallocation of behavior towards alcohol and away from an alternative reinforcer via hyperexcitation of the vSub-NAc projection, suggesting that inhibition of this projection will redirect operant choice behavior towards an alternative reinforcer. Aim 1 will employ optogenetic techniques to selectively activate or inhibit the vSub-NAc during alcohol vs. sucrose operant choice self-administration. In Aim 2, we will use CIE as a model of alcohol dependence coupled with optogenetic circuit manipulations to determine if this circuit has unique behavioral effects when assessed in alcohol dependent vs. non-dependent subjects. These studies may identify a novel behavioral mechanism through which the vSub-NAc exerts control over alcohol self-administration, with the potential to provide further evidence that targeting this circuit may have therapeutic value in treating AUD.