The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice

Abstract

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNST^CRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNST^CRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNST^CRF neurons, and this polysynaptic PVT^VGLUT2-BNST^CRF circuit is more robust in females than males. Chemogenetic inhibition of the PVT^BNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNST^CRF excitatory synapse without altering the function of PVT^BNST neurons per se. Our data describe a complex, feedforward inhibitory PVT^VGLUT2-BNST^CRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.