Reduced Prefrontal PRDM2 Promotes Stress-Induced Alcohol Reinstatement Across Sexes through a dmPFC-Nucleus Accumbens Pathway

Abstract

Stress is a major driver of relapse in alcohol use disorder (AUD), partly through stress-induced dysregulation of prefrontal cortex (PFC) circuits that govern executive control, craving regulation, and adaptive behavioral responses. Such dysfunction may be partly driven by epigenetic regulation of transcriptional programs that shape PFC responses to stress. Here, we investigated the role of the histone methyltransferase PRDM2 in stress-induced relapse to 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 in alcohol-related behaviors, we used viral-mediated knockdown of Prdm2 in the dorsomedial prefrontal cortex (dmPFC) of male and female rats. Prdm2 knockdown increased vulnerability to stress-induced reinstatement of alcohol seeking in both sexes, 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 a shock intensity-dependent manner. Together, these findings suggest that reduced PRDM2 expression in the PFC contribute to stress-induced relapse-like behavior and identify the dmPFC-NAc projection as a circuit through which PRDM2 influences alcohol seeking.