Exploring the Ethanol Engram: From Initiation to Excessive Ethanol Drinking

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7. SUMMARY/ABSTRACT Excessive alcohol (ethanol) consumption is a hallmark characteristic of individuals with alcohol use disorder (AUD) and a risk factor for developing ethanol dependence. Currently, there is a substantial gap in our understanding of the neural mechanisms and circuits that drive initiation of excessive drinking. Gaining insight into the neurobiological factors that facilitate the transition from moderate to excessive ethanol intake may lead to the development of new treatment strategies for reducing relapse rates. The prefrontal cortex (PFC) is a crucial neural substrate for executive cognitive function and appetitive responding, and its ability to impose inhibitory control over reward-motivated behaviors is disrupted following excessive drinking. While the heterogeneous architecture and function of principal PFC neurons has limited the understanding of drinking-induced adaptations in behaving animals, there are newly developed and powerful tools that allow for genetic access to unique subpopulations of neurons that drive behaviors. The Targeted Recombination in Active Populations (TRAP) mouse line (FosTRAP) is one such technology that allows for identification, measurement, and manipulation of neural ensembles activated in response to ethanol drinking behavior. Using this novel technology, our preliminary results show that intermittent access to ethanol activated (or `TRAPed') subpopulations of neurons in subregions of the PFC, including the infralimbic (IL), orbitofrontal, insular, and anterior cingulate cortices. Importantly, the TRAPed pyramidal neurons in the IL-PFC of ethanol drinking mice fired more evoked action potentials in comparison with adjacent non-activated neurons, suggesting that enhanced intrinsic excitability in activated IL-PFC neurons is a functional signature of ethanol consumption. Thus, the overarching hypothesis of the present proposal is that TRAPed neurons that are activated by initial ethanol drinking display functional plasticity and control future excessive drinking. To test this hypothesis, studies in Aim 1 will use electrophysiological, immunofluorescent, and single-cell calcium imaging approaches in ethanol-drinking FosTRAP double transgenic mice. In Aim 2, we will combine FosTRAP technology with chemogenetics to test the hypothesis that neurons activated by initial drinking drive subsequent excessive consumption of ethanol. With the emergence of novel techniques, we can now study the function of a subpopulation of cortical neurons and control their activity during development of excessive drinking in the behaving mouse. The findings from these studies using a combination of newly developed technology will identify stable and specific subsets of neural populations that are activated by the initiation of ethanol consumption that drive subsequent drinking behaviors. Collectively, the proposed research will characterize the functional adaptations in PFC engrams that contribute to excessive ethanol intake.