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

TitleThe paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice
Publication TypeJournal Article
Year of Publication2021
AuthorsLevine OB, Skelly MJane, Miller JD, Rivera-Irizarry JK, Rowson SA, DiBerto JF, Rinker JA, Thiele TE, Kash TL, Pleil KE
JournalNat Commun
Volume12
Issue1
Pagination5080
Date Published2021 Aug 23
ISSN2041-1723
KeywordsAlcohol Drinking, Animals, Anxiety, Avoidance Learning, Behavior, Animal, Corticotropin-Releasing Hormone, Excitatory Postsynaptic Potentials, Female, Glutamic Acid, Inhibitory Postsynaptic Potentials, Integrases, Limbic System, Male, Mice, Mice, Inbred C57BL, Neurons, Phenotype, Septal Nuclei, Sex Characteristics, Synapses, Thalamus
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.

DOI10.1038/s41467-021-25368-y
Alternate JournalNat Commun
PubMed ID34426574
PubMed Central IDPMC8382748
Grant ListU01 AA020911 / AA / NIAAA NIH HHS / United States
P60 AA011605 / AA / NIAAA NIH HHS / United States
R37 AA013573 / AA / NIAAA NIH HHS / United States
T32 DA039080 / DA / NIDA NIH HHS / United States
K99 AA023559 / AA / NIAAA NIH HHS / United States
R01 AA019454 / AA / NIAAA NIH HHS / United States
R00 AA023559 / AA / NIAAA NIH HHS / United States
R01 AA027645 / AA / NIAAA NIH HHS / United States
F32 AA025530 / AA / NIAAA NIH HHS / United States