Stress resilience is associated with transcriptional remodeling in the VTA

Individual responses to chronic stress vary, with some individuals remaining resilient while others exhibit susceptibility. Here, we use single-nucleus RNA sequencing to understand molecular adaptations in the ventral tegmental area (VTA) and lateral habenula (LHb) that mediate susceptibility vs. resilience to social stress. While we find minimal gene expression changes in the LHb after stress, the VTA exhibits prominent transcriptional remodeling associated with resilience that is not found with susceptibility. Across VTA cell types, resilience is associated with upregulation of genes involved in intercellular signaling and neural communication, with maintenance of receptor-ligand interaction strength. Within glutamatergic and dopaminergic neuron clusters that exhibit the most prominent changes, multivariate analyses show that resilient neurons diverge more from control than susceptible neurons but along a similar trajectory, supporting a model in which resilience reflects greater stress-related adaptations. Together, these findings highlight the VTA as a key site of active molecular plasticity in stress resilience.