Olivia B. Levine,1 Mary Jane Skelly,2,9 John D. Miller,2 Jean K. Rivera-Irizarry,1 Sydney A. Rowson,2 Jeffrey F. DiBerto,3,4 Jennifer A. Rinker,5,6,7 Todd E. Thiele,8 Thomas L. Kash,3,4 and Kristen E. Pleilcorresponding author1,2
1Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY USA
2Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY USA
3Department of Pharmacology, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC USA
4Bowles Center for Alcohol Studies, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC USA
5Department of Neuroscience, Medical University of South Carolina, Charleston, SC USA
6Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC USA
7Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC USA
8Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC USA
9Present Address: Psychology Department, Iona College, New Rochelle, NY USA
Kristen E. Pleil, Email: [email protected]
Calcium Imaging, Neuroscience
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.
GCaMP6s was excited with 35% 470 nm LED (CoolLED) at a frequency of 1 Hz for 10 s every min to minimize photobleaching, and videos were acquired at a frame rate of 10 Hz with an optiMOS monochrome camera (QImaging, Surrey, British Columbia, Canada) and MicroManager 1.4 software, across the entire experiment including a five min baseline, 10 min bath application of CNO (10 μM), and 10 min washout period.
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