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.
Highlights
Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety
Using whole-cell patch-clamp slice electrophysiological recordings in BNSTCRF neurons (Fig. 1b), we found that the proportion of BNSTCRF neurons active in their basal state was more than twice as high in females compared to males (60% in females vs. 24% in males; Fig. 1c)
By comprehensively analyzing the effects of sex and agonist dose in a broader dataset from a mixed-sex cohort of mice we previously published[18], we found that females with the hM4D Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) in BNSTCRF neurons required a higher dose of CNO (10 mg/kg) to attenuate binge drinking than their male counterparts (3 mg/kg; Supplementary Fig. 2)
Summary
Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Human neuroimaging studies have demonstrated a functional connection between the thalamus and BNST that is denser in females than males[7,8] and decreased thalamic projection strength in young individuals with alcohol abuse[15]. These converging lines of evidence suggest that the PVT-BNST projection might contribute to sex-dependent behavior via modulation of BNSTCRF neurons. We systematically examined in both sexes the anatomical and functional architecture of the PVTBNSTCRF circuit and its role in binge alcohol drinking and anxiety behaviors, as well as alcohol-induced plasticity
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