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

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.