Mesolimbic Neural Response Dynamics Predict Future Individual Alcohol Drinking in Mice

Background Individual variability in response to rewarding stimuli is a striking but understudied phenomenon. The mesolimbic dopamine system is critical in encoding the reinforcing properties of both natural reward and alcohol; however, how innate or baseline differences in the response dynamics of this circuit define individual behavior and shape future vulnerability to alcohol remain unknown. Methods Using naturalistic behavioral assays, a voluntary alcohol drinking paradigm, in vivo fiber photometry, in vivo electrophysiology, and chemogenetics, we investigated how differences in mesolimbic neural circuit activity contribute to the individual variability seen in reward processing and, by proxy, alcohol drinking. Results We first characterized heterogeneous behavioral and neural responses to natural reward and defined how these baseline responses predicted future individual alcohol-drinking phenotypes in male mice. We then determined spontaneous ventral tegmental area dopamine neuron firing profiles associated with responses to natural reward that predicted alcohol drinking. Using a dual chemogenetic approach, we mimicked specific mesolimbic dopamine neuron firing activity before or during voluntary alcohol drinking to link unique neurophysiological profiles to individual phenotype. We show that hyperdopaminergic individuals exhibit a lower neuronal response to both natural reward and alcohol that predicts lower levels of alcohol consumption in the future. Conclusions These findings reveal unique, circuit-specific neural signatures that predict future individual vulnerability or resistance to alcohol and expand the current knowledge base on how some individuals are able to titrate their alcohol consumption whereas others go on to engage in unhealthy alcohol-drinking behaviors.