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BDNF in ventrolateral orbitofrontal cortex to dorsolateral striatum circuit moderates alcohol consumption, seeking and relapse

Sowmya Gunasekaran,J. J. Moffat,Joshua D. Epstein,Khanhky Phamluong,Yann Ehinger,D. Ron

Published 2025 in Neuropsychopharmacology

ABSTRACT

BDNF plays a crucial role in shaping the structure and function of neurons. In rodents, BDNF signaling in the dorsolateral striatum (DLS) is part of an endogenous pathway that protects against the development of phenotypes associated with alcohol use. Dysregulation of BDNF levels in the cortex or dysfunction of BDNF/TrkB signaling in the DLS of rodents results in the escalation of alcohol drinking and compulsive alcohol intake. The major source of BDNF in the striatum is the prefrontal cortex. We identified a small ensemble of BDNF-positive neurons in the mouse ventrolateral orbitofrontal cortex (vlOFC), a region implicated in alcohol use disorder (AUD), that extend axonal projections to the DLS, which is associated with alcohol drinking behaviors. We speculated that BDNF in vlOFC-to-DLS circuit may play a role in limiting alcohol drinking and that heavy alcohol intake disrupts this protective pathway. We found that BDNF expression is reduced in the vlOFC of male but not female mice after long-term cycles of binge alcohol drinking and withdrawal. We further discovered that overexpression of BDNF in vlOFC-to-DLS but not in vlOFC-to-dorsomedial striatum (DMS) or M2 motor cortex-to-DLS circuit reduces alcohol but not sucrose intake and preference. We further showed that BDNF in vlOFC-to DLS reduces alcohol self-administration, alcohol seeking, and relapse. Finally, we found that systemic administration of BDNF receptor TrkB agonist, LM22A-4, dampens habitual alcohol seeking. Together, our data suggest that BDNF in a small ensemble of vlOFC-to-DLS neurons may gate alcohol drinking behaviors by attenuating habitual alcohol seeking.

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