Projection-specific roles of basolateral amygdala Thy1 neurons in alcohol-induced place preference

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 alcohol affects the activity of BLA neurons, which may encode information that drives environmental cue-dependent, alcohol-related behaviors. We previously demonstrated that a subset of BLA neurons which express the calcium/calmodulin-dependent protein kinase II (CaMKII) and thymus cell antigen 1 (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-induced motivated behavior in response to environmental cues. Optogenetic inhibition of BLA Thy1+ neuronal activity at cell body disrupts both the formation and expression of alcohol-induced conditioned place preference. Furthermore, selective axonal inhibition of BLA-Thy1+ efferents 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-induced motivated behaviors in a projection-specific manner.