4/8: INIA Stress and Chronic Alcohol Interactions: Role of corticotropin-releasing factor in cortico- and thalamo-striatal pathways in regulating alcohol-stress interactions

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PROJECT SUMMARY Alcohol use disorder (AUD) is a devastating neuropsychiatric condition that is characterized by chronic and relapsing episodes of excessive, uncontrolled alcohol consumption. AUD is also associated with significant disruption of brain function and behavior, frequently presenting with cognitive deficits and comorbid negative affective disorders (e.g., anxiety and depression). These negative affective and cognitive disturbances that are present during abstinence from alcohol drinking can drive relapse-like behaviors in both humans and rodent models and are often exacerbated by stress. Thus, alcohol and stress may be working synergistically to cause more profound cognitive deficits that lead to decreased cognitive control over alcohol consumption, but the molecular and cellular adaptations and the neurocircuitry underlying these concerted changes are not well understood. The ventral striatum, specifically the nucleus accumbens (NAc), mediates aspects of alcohol taking and seeking, negative affect, and is one of the primary outputs of both the medial prefrontal cortex (mPFC) and the anterior paraventricular thalamus (aPVT). These circuits mediate appetitive and reward-motivated behaviors, are sensitive to stress and alcohol, and are involved decision making and choice behaviors particularly during motivational conflict. Additionally, in both the mPFC and aPVT, pro-stress molecules, like corticotropin-releasing factor (CRF), are recruited and have been implicated in regulating responses to stress and/or alcohol. Thus, this component of the INIAstress Consortium seeks to understand the mechanisms and circuitry involved in the complex interaction between stress and alcohol exposure that engender such high rates of alcohol consumption, cognitive impairments, and negative affective states. We provide evidence that the chronic intermittent ethanol (CIE) exposure model and repeated forced swim stress (FSS) alter reward-choice behaviors under conditions of motivational conflict. We also show that mPFC CRF knockout blocks the escalation of alcohol drinking in the CIE-FSS model. The overarching hypothesis is that CIE-FSS hyper-recruits CRF in the mPFC and aPVT to promote excessive drinking, cognitive deficits, and anxiety-like phenotypes. In Aim 1, we will identify chronic alcohol- and stress-induced changes in synaptic and functional plasticity that occur in a CRF-dependent and independent manner in mPFC®NAc and aPVT®NAc circuitry. Studies in Aim 2 will focus on understanding the influence of CRF on mPFC function and circuitry using high-density silicon Neuropixels probes and fiber photometry. Finally, Aim 3 will identify the role of CRF in the aPVT and its influence on aPVT®NAc projections in the CIE-FSS model. The focus of this new INIAstress Consortium component is to understand the broader implications of CRF modulation of neurocircuitry regulating reward-guided behaviors in chronically stressed, alcohol dependent mice, which is critical to our understanding of the complex interaction between alcohol and stress, and aid in identifying promising therapeutic targets.