Insula-amygdala circuits in alcohol abuse

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PROJECT SUMMARY Alcohol use disorder (AUD) may result from profound dysregulations of affective valence processing in brain circuits. Repeated episodes of binge drinking can alter positive and negative valence processing and result in enhanced appetitive drives to seek and drink alcohol and the emergence of aversive symptoms, respectively. This research proposal aims to understand how repeated binge drinking alters neural coding and plasticity correlated with behavioral changes in the basolateral amygdala (BLA), a well-known brain area for valence coding, and its afferents from the anterior insular cortex (aIC), a core area for interoception. These aims will be empirically pursued using a combination of an alcohol operant self- administration paradigm, behavioral assays for anxiety measurement, and a “drinking-in-the-dark” procedure. Here, experiments will functionally and molecularly identify neuronal populations within the aIC- BLA circuits that participate in alcohol drinking and determine how repeated binge drinking affects these neurons and leads to maladaptive affective behavior, such as enhanced alcohol seeking and anxiety-like behavior. Supported by preliminary data, our central hypothesis is that repeated binge drinking differentially alters the activity of valence coding amygdala neurons (Thy1+), in part, through the synaptic plasticity of aIC-amygdala projections, resulting in alcohol-related enhanced appetitive and aversive behavior. Aim one will use in vivo calcium imaging and optogenetic approaches to determine the role of BLA valence coding in repeated binge drinking-induced behavioral plasticity. In the second aim, we plan to investigate synaptic plasticity in the aIC afferents to the BLA valance coding neurons that contribute to the persistent motivation for alcohol intake after repeated episodes of binge alcohol drinking. This work will uncover changes in overlapping, intersecting or parallel valence coding systems in the aIC-BLA circuits that are critical for the development of maladaptive affective behaviors by repeated excessive alcohol drinking. The proposed experimental work portrays a neural circuit-oriented and highly translational investigation of AUD-associated symptoms.