Role of prelimbic input to the rostromedial tegmental nucleus in encoding sensitivity to the aversive properties of ethanol

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PROJECT SUMMARY An individual’s subjective response to alcohol’s rewarding and aversive properties contribute to their risk for developing alcohol use disorder (AUD). For example, individuals who are less sensitive to the aversive properties of alcohol, which typically limit drinking, are more likely to drink heavily and develop AUD. Conditioned taste aversion (CTA) is an assay that allows preclinical researchers to probe sensitivity to the aversive properties of drugs. Using this assay, our preliminary data reveal the presence of significant individual differences in sensitivity to the aversive properties of ethanol similar to that which is observed in clinical populations. Specifically, some individuals exhibit strong ethanol-induced CTA (CTA-sensitive), whereas others exhibit minimal CTA to ethanol (CTA-resistant). Despite strong evidence for a relationship between subjective response to ethanol and risk for AUD, the neurobiological substrates that encode sensitivity to ethanol’s aversive properties are poorly understood. Recent work from our lab suggests that the rostromedial tegmental nucleus (RMTg) signals the aversive properties of ethanol. The neural circuits driving engagement of the RMTg to signal ethanol aversion are unknown, but data from our lab point toward the prelimbic (PL) subdivision of the medial prefrontal cortex as a potential source. The PL and RMTg are both implicated in the behavioral response to aversive stimuli, and we have discovered that the PL sends dense projections to the RMTg. We also found that this projection is activated during exposure to aversive stimuli, and that stimulation of this circuit drives avoidance. Together, this leads us to hypothesize that RMTg-projecting PL neurons encode sensitivity to the aversive properties of ethanol and that differences in circuit activity contribute to individual differences in subjective response to ethanol. We will test this hypothesis across three specific aims. In Aim 1, we will combine CTA with in vivo fiber photometry to compare PL-RMTg activity in CTA-sensitive and -resistant individuals. In Aim 2, we will use whole-cell patch-clamp electrophysiology to examine differences in the physiology of RMTg-projecting PL neurons across CTA phenotypes. In Aim 3, we will conduct whole-genome RNA-sequencing in RMTg-projecting PL neurons to assess translational differences in CTA-sensitive and -resistant individuals. Together, these experiments will provide new mechanistic insight into the neurobiology underlying sensitivity to ethanol’s aversive properties, while also providing the applicant with new training in conceptually innovative and cutting-edge approaches in neuroscience research.