Reduced Prefrontal PRDM2 Increases Stress-Induced Reinstatement Across Sexes via a dmPFC-Nucleus Accumbens Pathway

Stress is a major trigger of relapse in alcohol use disorder (AUD), and dysfunction of prefrontal cortex (PFC) circuits has been implicated in this process. Epigenetic regulators may contribute to relapse by shaping transcriptional programs within these circuits. Here, we investigated the role of the histone methyltransferase PRDM2 in stress-induced alcohol seeking. Analysis of postmortem human tissue showed that PRDM2 expression in the PFC was reduced in both men and women with AUD compared with control individuals. To examine the functional significance of this reduction, we used viral-mediated knockdown of Prdm2 in the dorsomedial prefrontal cortex (dmPFC) of male and female rats. Prdm2 knockdown enhanced stress-induced reinstatement of alcohol seeking in both sexes, particularly at intermediate shock intensity, without altering pain sensitivity or being influenced by estrous cycle stage. To determine whether this effect was mediated through specific prefrontal output pathways, we selectively reduced Prdm2 expression in dmPFC neurons projecting to the nucleus accumbens (NAc). Projection-specific knockdown also increased stress-induced reinstatement of alcohol seeking in male and female rats in an intensity-dependent manner. Together, these findings suggest that reduced PRDM2 expression in the PFC may contribute to stress-induced relapse-like behavior and identify the dmPFC-NAc projection as a circuit through which PRDM2 can influence alcohol seeking.