Anterior Insula Projections for Alcohol Drinking/Anxiety Interactions in Female and Male Rats

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Abstract Alcohol Use Disorder (AUD) extracts substantial medical, social, and economic costs, and compulsion-like alcohol drinking (CLAD), where intake persists despite negative consequences, can be a particular obstacle to treatment. Also concerning is that problem drinking in women has risen dramatically, and women can have greater alcohol problems. However, mechanisms underlying sex differences remain poorly understood, although anxiety-like states can strongly contribute to alcohol drinking, and women have greater prevalence of mood disorders and AUD/anxiety comorbidity. Also, our rat studies suggest that females have greater persistence in responding for alcohol, as well as greater anxiety-like responding. Thus, to help develop better, personalized therapies, it is essential to understand sex differences and similarities in mechanisms underlying excessive drinking and comorbidity with anxiety. Alcohol intake is likely driven by its salient motivational properties, and anterior insula (aINS) is a critical regulator of responding to important situations and regulating accompanying emotional states. We find that specific aINS projections (including aINS-Nucleus Accumbens, NAcb) promote male CLAD, with little impact on alcohol-only drinking (AOD); in agreement, compulsion-like responding for alcohol in women and men with AUD activates a similar aINS circuit. However, very little is known about specific aINS mechanisms for alcohol drinking in females, or overcoming higher challenge more generally. Also, global aINS inhibition reduces AOD, but the underlying aINS projection(s) remain completely undiscovered. Here, we address the overarching hypothesis that different aINS circuits drive CLAD vs AOD, and, especially, that particular aINS circuits mediate both CLAD and anxiety-like behavior (ALB) in higher-anxiety individuals, which is especially cogent in females. Aim 1 uses projection-specific optogenetic inhibition to examine particular aINS projections for AOD and CLAD: aINS-NAcb and aINS- amygdala for CLAD, and aINS-posterior insula (pINS) for AOD. aINS-pINS projection is large, and pINS inhibition decreases drinking, but aINS-pINS is nearly unstudied in rodent. Also, to best understand how aINS outputs regulate behavior, it is critical to identify actual activity patterns within specific aINS projections. Thus, Aim 2 uses cutting edge in vivo electrophysiology recording methods with “opto-tagging” to identify firing patterns within specific aINS projections, especially predicted higher activity in females that underlies greater persistence for alcohol. Finally, Aim 3 examines potential sex differences in the relation between ALB and alcohol drinking, aINS encoding of these behaviors, and the impact of optogenetic inhibition of specific aINS projections on both ALB and drinking. We predict that higher ALB rats will have greater aINS encoding of both ALB and drinking, and greater optogenetic inhibition of ALB and intake, particularly in females. If successful, we will discover key aINS projection mechanisms that drive AOD, CLAD, ALB, and their interrelations, including important sex differences, which may open novel, sex-specific AUD treatments.