Mechanisms underlying sex differences in stress-induced alcohol seeking

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Project Summary/Abstract Historically, alcohol abuse and alcohol use disorders (AUDs) have been more common in men than women. However, recent epidemiological data in younger cohorts of women suggest that this gender gap is closing. Rates of risky/binge drinking in women are going up at a much faster rate than in men, women show a faster transition from social use to dependence, and women suffer greater alcohol-related health problems. Thus, identifying sex-specific neurobiological factors that underlie the development of problem drinking could lead to improved treatment approaches. In particular, women have been shown to have increased craving in response to alcohol-related cues and stressors relative to men, and neuroimaging studies show that this effect is associated with differential activation of brain circuits including the amygdala. We have found that female rats also show a greater relapse-like response to alcohol-associated cues, particularly when combined with an acute stressor, similar to the human studies. Moreover, we also have evidence for increased glutamatergic signaling in the basolateral amygdala (BLA) of female rats, raising the possibility that alcohol-associated memories may be more readily encoded in the BLA of females relative to males, and/or that the neurons encoding alcohol memories are more responsive to acute stress and able to drive activity in circuits controlling craving and relapse. Importantly, we have previously shown that differences in circulating gonadal hormones do not mediate the sex difference in behavior, suggesting that fundamental differences at the synaptic or circuit level underlie differential relapse-like behavior. For example, we have found that glutamatergic synapses from sensory thalamus to the BLA are critical for the encoding and extinction of cocaine-associated memories, and that depotentiating these synapses is sufficient to reduce cocaine relapse-like behavior. However, no one has previously investigated whether alcohol-cue memories are similarly encoded or if there are differences between males and females in the neural mechanisms mediating alcohol memory formation. Thus, in Aim 1 we will compare plasticity related mechanisms in the BLA regulating alcohol memory formation and extinction in males and females. In Aim 2, we will use genetically-encoded calcium indicators and miniature microendoscopes to image neural activity (calcium signals) in males and females when alcohol-cues are presented in the presence or absence of acute stressors. Finally, in Aim 3 we will use comprehensive cFos mapping to determine if males and females engage similar or different circuits during stress+/-alcohol-cue- induced relapse-like behavior. These results will inform if sex differences are due to altered circuit engagement that would point to sex specific neural targets for treatment. All together, these studies will provide a comprehensive analysis of how alcohol-cue memories are formed, modulated by stress, what other circuits are engaged, and if there are sex differences in any of these neurobiological factors that could explain the increasing vulnerability of females to alcohol-related disorders.