Project Summary
Traumatic stress can lead to alcohol misuse and alcohol use disorder (AUD). In particular, avoidance coping
after stress (i.e., persistent mental and/or physical avoidance of stress-related stimuli) is associated with higher
rates of alcohol misuse. Using an animal model, we have shown that exposure to predator odor stress produces
persistent avoidance of predator odor-paired stimuli in a subset of rats, termed ‘Avoiders’. Importantly, Avoider
rats show long-lasting increases in alcohol self-administration after stress, similar to findings in humans. The
neurobiology underlying this phenomenon remains an open area of investigation. This K99/R00 award includes
a comprehensive career development and research plan based on Dr. Marcus Weera’s preliminary data showing
that Avoider rats exhibit increased tolerance to the aversive effects of alcohol, which is hypothesized to facilitate
increased alcohol self-administration in these rats. Our preliminary data also show that Avoider rats exhibit
blunted activation of lateral habenula (LHb)-projecting lateral hypothalamus (LHA) neurons by aversive doses of
alcohol. The scientific goal of this K99/R00 award is to test the central hypothesis that LHA-LHb neurons mediate
stress-induced tolerance to alcohol aversion and stress-induced escalation of alcohol self-administration in
Avoider rats via three aims. In Aim 1, we predict that Avoider rats show blunted activation of LHA-LHb and LHb
neurons in response to an aversive dose of alcohol, as measured by Fos immunohistochemistry and in vivo fiber
photometry. In Aim 2, we predict that in vivo chemogenetic stimulation of LHA-LHb neurons rescues stress-
induced blunting of LHb activity and stress-induced tolerance to alcohol aversion in Avoider rats, as measured
by in vivo fiber photometry and alcohol conditioned place aversion, respectively. In Aim 3, we predict that in vivo
chemogenetic stimulation of LHA-LHb neurons rescues stress-induced blunting of LHb activity and stress-
induced escalation of alcohol responding in Avoider rats, as measured by in vivo fiber photometry and operant
alcohol self-administration, respectively. Results from these studies will improve our understanding of the neural
circuits underlying stress-induced changes in sensitivity to alcohol’s aversive effects and in alcohol self-
administration. The career development goal of this K99/R00 award is to provide the principal investigator, Dr.
Marcus Weera, with additional technical training and professional development, and to help him establish an
independently-funded research program. During the K99 portion of the award, under the guidance of an expert
team of mentors, Dr. Weera will expand his technical and analytical repertoire to include in vivo fiber photometry
and computational analysis of photometry data. He will also search for and secure a tenure-track faculty position.
During the R00 portion of the award at his new institution, Dr. Weera will use his acquired skills to build upon
these studies, gathering rigorous data for submission of an R01 application. The work and training supported by
this award will be critical for the PI’s successful transition to an independent research career studying the
neurobiology underlying individual differences in stress and alcohol responsiveness.
