Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

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Although individuals with anxiety disorders are more likely to develop alcohol use disorder (AUD) than healthy controls, the neural substrates responsible for this heightened risk are poorly understood. These dual diagnoses are also associated with greater symptom severity of both disorders and poor treatment outcomes. The central goal of this project is to employ neurobiological and behavioral approaches in rodent models to identify neural circuit adaptations that play a causal role in promoting increased risk of developing AUD and anxiety disorders. To that end, we have established a rodent adolescent social isolation model (aSI) that engenders many behaviors associated with greater risk of developing AUD and anxiety disorders. Relative to rats reared in groups throughout adolescence (aGH), aSI rats exhibit increases in anxiety-like behaviors, novelty responding, impulsivity, and aggression in adulthood. aSI rats also display impaired fear extinction and long-lasting increases in voluntary ethanol drinking. Neurobiological studies revealed that aSI promotes increases in the excitability of glutamatergic projection neurons in the basolateral amygdala (BLA), a brain region integral to anxiety-like and motivated behaviors, as well as increased synaptic activity in areas that receive dense innervation from the BLA. It has also recently been discovered that BLA projection neurons are not homogenous. Rather, these cells are distributed into two distinct clusters along the anterior- posterior axis and form largely non-overlapping circuits in downstream brain regions. Activation of anterior BLA (aBLA) circuits promotes aversion/anxiogenesis whereas activation of posterior BLA (pBLA) circuits elicits rewarding/anxiolytic behaviors. Based on these findings, this project will test the hypothesis that aSI shifts the excitatory/inhibitory balance between these opposing amygdala circuits, leading to excessive excitability within aBLA pathways, and that these maladaptive changes play a causal role in the “addiction vulnerable” phenotypes promoted by aSI. A secondary hypothesis to be investigated is that aSI promotes similar adaptations in male and female rats but that the behavioral phenotypes that emerge are sexually dimorphic. Additional studies will also seek to identify novel pharmacological approaches to restore normal aBLA/pBLA excitability. Collectively, this project will provide critical new insight into the circuitry underlying vulnerability to AUD and anxiety disorders and potentially lead to the identification of novel and much needed treatments for individuals suffering from these frequently co-occurring diseases. RELEVANCE (See instructions): These studies will employ a rodent model that promotes an “addiction vulnerable” phenotype to identify circuit-specific neural adaptations responsible for these behaviors. Studies will also seek to identify novel interventions to reverse these maladaptive changes. Collectively, these studies will help to identify specific neural pathways associated with AUD and comorbid anxiety disorders and potentially identify novel treatments for individuals afflicted with these diseases.