BDNF in Ventrolateral Orbitofrontal Cortex to Dorsolateral Striatum Circuit Moderates Alcohol Consumption and Gates Alcohol Habit

Abstract BDNF plays a crucial role in shaping the structure and function of neurons. BDNF signaling in the dorsolateral striatum (DLS) is part of an endogenous pathway that protects against the development of alcohol use disorder (AUD). Dysregulation of BDNF levels in the cortex or dysfunction of BDNF/TrkB signaling in the DLS results in the escalation of alcohol drinking and compulsive alcohol use. The major source of BDNF in the striatum is the prefrontal cortex. We identified a small ensemble of BDNF-positive neurons in the ventrolateral orbitofrontal cortex (vlOFC), a region involved in AUD, that extend axonal projections to the DLS. We speculated that BDNF in vlOFC-to-DLS circuit may play a role in limiting alcohol drinking and that heavy alcohol use 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 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. The DLS plays a major role in habitual behaviors. We hypothesized that BDNF in vlOFC-to-DLS circuitry controls alcohol intake by gating habitual alcohol seeking. We found that BDNF over-expression in vlOFC-to-DLS circuit and systemic administration of BDNF receptor TrkB agonist, LM22A-4, biases habitually trained mice towards goal-directed alcohol seeking. Together, our data suggest that BDNF in a small ensemble of vlOFC-to-DLS neurons gates alcohol intake by attenuating habitual alcohol seeking.