Amygdala circuit mechanisms underlying alcohol seeking

Alcohol seeking during abstinence is mediated in part by strong associations between the pharmacological effects of alcohol and the environment within which alcohol is administered. The amygdala, particularly the basolateral amygdala (BLA), is a key neural substrate of environmental cue and reward associations since it is involved in associative learning and memory recall. However, we still lack a clear understanding of how the activity of molecularly distinct BLA neurons is affected by alcohol and encodes information that drives environmental cue-dependent, alcohol-related behaviors. We previously demonstrated that a subset of BLA neurons which express the CaMKII and Thy1 markers project preferentially to the nucleus accumbens (NAcc), rather than the central amygdala; and these neurons mediate fear inhibition rather than fear acquisition or expression, suggesting a specific role in positive valence processing. We now demonstrate that Pavlovian conditioning with alcohol administration increases the activity of these Thy1-expressing (Thy1+) excitatory neurons in mouse BLA, which is necessary for the conditioned appetitive response. In vivo calcium imaging indicates that the temporal activity profile of these neurons is also correlated with alcohol seeking behavior in response to environmental cues. Optogenetic inhibition of BLA Thy1+ neuronal activity disrupts both the formation and recall of alcohol conditioned place preference. Furthermore, selective axonal inhibition of BLA-Thy1+ neurons reveals that the activity of their NAcc and prefrontal cortex (PFC) projections are differentially necessary for alcohol cue association vs. recall, respectively. Together, these findings provide insights into a molecularly distinct subset of BLA neurons that regulates environmental cue-reward associations and drives alcohol seeking behaviors in a projection-specific manner. DisclosuresKJR has received consulting income from Acer, Bionomics, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, the Brain and Behavior Research Foundation, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. None of this work is directly related to the work presented here.