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

Olivia B. Levine, Mary Jane Skelly, John D. Miller, Jean K. Rivera-Irizarry, Sydney A. Rowson, Jeffrey F. DiBerto, Jennifer A. Rinker, Todd E. Thiele, Thomas L. Kash and Kristen E. Pleil ()
Additional contact information
Olivia B. Levine: Cornell University
Mary Jane Skelly: Cornell University
John D. Miller: Cornell University
Jean K. Rivera-Irizarry: Cornell University
Sydney A. Rowson: Cornell University
Jeffrey F. DiBerto: University of North Carolina-Chapel Hill School of Medicine
Jennifer A. Rinker: Medical University of South Carolina
Todd E. Thiele: University of North Carolina
Thomas L. Kash: University of North Carolina-Chapel Hill School of Medicine
Kristen E. Pleil: Cornell University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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 BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST 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-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

Date: 2021
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DOI: 10.1038/s41467-021-25368-y

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