PROJECT SUMMARY (See instructions):
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 repertoire to include in vivo fiber photometry. 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.
