Identifying how alcohol-evoked changes in neural firing affect systems level computations during decision-making

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Project Summary Administrative Supplement Summary: The purpose of this administrative supplement is to provide additional financial support in order to allow for more time to complete the original goals of the parent K99/R00 award. This additional time is necessary due to the impacts of the Covid-19 pandemic (please see Introduction to the Supplement document for full justification). The scientific and career development goals of the supplement are identical to the original project. During this supplemental time period, Dr. Timme will conduct crucial experiments outlined in the original proposal (specifically, pilot head-fixed electrophysiological recordings) and continue to pursue faculty appointments. Original Project Summary: The primary training objective of the K99 phase of this K99/R00 application is to provide the candidate with training in state-of-the-art electrophysiology techniques in preparation for a career as an independent investigator in the field of alcohol research. The overarching hypothesis of this proposal is that decision-making malfunctions in alcohol use disorder (AUD) are caused by concurring neural activity changes in multiple key brain regions that serve to route the decision-making process through different circuits. To address this hypothesis, this award will use high-density neural probes to record the electrical activity of hundreds of neurons across many brain regions in head-fixed mice during the decision to drink. The candidate will obtain the necessary training in the use of these neural probes to generate large neural recording data sets that can be used to directly observe changes in the neural circuits underlying malfunctioning decision-making in AUD. To obtain this necessary training, the candidate will work with leading researchers already using these tools in the International Brain Laboratory collaboration and attend a training workshop. The candidate’s career development will also be furthered by publishing results in high-impact journals, attending conferences, and attending relevant on-campus seminars. The proposed mentoring team includes Dr. Christopher Lapish, Dr. Woody Hopf, Dr. Susan Sangha, Dr. Kenneth Harris, and Dr. David Kareken. These individuals are experts in systems and computational neuroscience, the neural circuitry of fear and reward, alcohol research, head-fixed mouse studies, and sex as a biological variable. The long-standing collaborative research environment at IUPUI will provide the candidate with the necessary resources to complete the aims as outlined in this proposal. During the end of the K99 phase of the award, the candidate will seek out a faculty position as an independent investigator to begin at the start of the R00 phase of the award. In this new position, the studies will expand to include the neural correlates of aversive stimuli in order to better understand the decision to continue drinking alcohol in the face of negative consequences. This work will lead to R01 grant applications by the candidate related to further recordings and interventions in neural circuits to treat malfunctioning decision-making. By identifying changes in the neural circuits underlying malfunctioning decision-making, this research will guide future studies that seek to develop novel treatments for those people suffering from or at risk for AUD. This award will lay the foundation for an independent career in alcohol research which has the potential to greatly improve the lives of people impacted by this disease.