Sex-dependent effects of adolescent alcohol on neural regulation of Poly I:C-induced fever - PROJECT SUMMARY/ABSTRACT The prevalence of binge-drinking across the lifespan is highest during adolescence, a critical period of neurodevelopment during which alcohol consumption is especially problematic. Adolescent binge-drinking produces long-lasting changes in neuroimmune function that have the potential to compromise many centrally regulated processes, including changes in thermoregulation. In rodent models, binge-like ethanol exposure permanently alters neuroimmune function and these alterations appear to be sex-dependent. Specifically, our lab recently found that male rats exposed to an adolescent intermittent ethanol (AIE) paradigm exhibited sensitized fever responses when challenged with polyinosine:polycytidylic acid (Poly I:C; a synthetic double- stranded RNA that mimics viral infection) in adulthood, but this was not seen in AIE females. Interestingly, this abnormal immune response appears to be pathogen specific as AIE males did not show a sensitized fever when challenged with the bacterial endotoxin, Lipopolysaccharide, in adulthood. Thus, the goal of this study is to investigate these lasting, sex-dependent effects of AIE on Poly I:C-induced fever with immunofluorescence, transcriptomic analysis, and pharmacological interventions. Experiments will focus on the vagal-mediated fever pathway as alcohol use is known to damage the vagus nerve and cause autonomic neuropathy, but alcohol’s effects on its thermoregulatory actions have not been widely studied. More specifically, I will investigate the nucleus tractus solitarius (NTS) and anterior hypothalamus-preoptic area (POA) which are two sexually dimorphic brain regions within this fever circuitry that are developmentally altered by ethanol exposure. Accordingly, the overarching hypothesis of this proposal is that AIE permanently alters NTS and POA thermoregulatory responses to Poly I:C in a sex-dependent manner. Experiments will use immunofluorescence and RNA sequencing to determine if the sensitized fever of AIE males is due to decreased activity of anti-inflammatory NTSàPOA circuitry. Additionally, this proposal will pharmacologically manipulate this circuit to further elucidate its role in the sensitized Poly I:C-induced fever of AIE males. Completion of these studies may identify adolescent alcohol use as a previously unconsidered risk factor for increased severity of viral infections and provide important insight into emerging sex-differences in viral immunity. This proposal will also generate necessary preliminary data that will lay the foundation for a future K99/R00 application further dissecting this vagal-mediated thermoregulatory circuit. Finally, the strong mentorship team that will guide this project provides ample opportunities to diversify my technical skillset and strengthen my professional development to shape me into a productive, independent researcher.
