3/8: INIA Stress and Chronic Alcohol Interactions: Norepinephrine and corticostriatal circuit regulation of cognitive effort after chronic alcohol and stress

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PROJECT SUMMARY/ABSTRACT Chronic alcohol use disrupts a number of cognitive functions, including attention, memory, flexibility, and other aspects of executive control. This is exacerbated by both exogenous stress and stress associated with alcohol use and withdrawal. We hypothesize that a key factor relating widespread cognitive dysfunction to problematic alcohol use is cognitive effort, which is needed to sustain diverse cognitive functions, particularly under conditions of heavy demand. In particular, we hypothesize that a history of chronic alcohol and stress disrupts the willingness and ability to exert cognitive effort, and conversely, that pre-alcohol limitations in cognitive effort predict future problematic alcohol use. There is strong interest in the neural basis of cognitive effort, but to our knowledge, no studies have examined the relationship between cognitive effort and alcohol at either a behavioral or neural level. Here we will investigate a neural circuit critical for cognitive effort and impacted by stress and alcohol use. This circuit is formed by the locus coeruleus norepinephrine (LC-NE) system, its strong projections to the anterior cingulate cortex (ACC), and ACC projections to the dorsomedial striatum (DMS). Unique to this proposal is 1) the integration of these systems into a unified circuit and 2) the investigation of this circuit in the integrated framework of cognitive effort, alcohol, and stress. We will measure the impact of chronic intermittent ethanol (CIE) and/or forced swim stress (FSS) on willingness and ability to perform two cognitively-demanding tasks (extradimensional set shifting and cognitive effort discounting in a sustained attention task) in mice. We will identify CIE/FSS associated changes in ACC noradrenergic regulation using RNAscope and probe them with CRISPR-mediated NE receptor knockdown (Aim 1). We will record neural dynamics in this network during cognitive performance after CIE/FSS (Aim 2), and manipulate the activity of this circuit using optogenetics to reversibly disrupt or rescue cognitive effort (Aim 3). Finally, we will collaborate with INIA Neuroimmune investigators to identify the impact of the phosphodiesterase inhibitor apremilast on cognitive function after CIE/FSS and characterize its effect in this circuit (Aim 4). Studies will integrate individual and sex differences to capitalize on heterogeneity in behavior and its relationship to underlying neural function. Cognitive effort is a novel and powerful framework for investigating the impact of alcohol and stress on cognition. Our studies have the potential to unite diverse findings related to the cognition and AUD. By identifying changes in neural circuitry underlying CIE/FSS-induced changes in cognitive effort, there is significant potential for identifying broadly-influential treatments for AUD that strengthen cognitive abilities to serve as a bulwark against the combined influences of alcohol and stress.