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. The ventral tegmental area (VTA), a region involved in reward learning, and the lateral habenula (LHb), a region involved in aversive learning, have been implicated in the pathophysiology of stress-related mood disorders. Here, we seek to understand the molecular adaptations in these regions at the level of single cells that mediate susceptibility versus resilience. In particular, it remains unclear whether, at the level of gene expression, different cell types within different brain regions mediate stress susceptibility versus resilience, or if these phenotypes are mediated by distinct trajectories within the same cell types. To address this gap, we performed single-nucleus RNA-sequencing of LHb and VTA of mice subjected to chronic social defeat stress. While we found minimal gene expression changes in the LHb after stress, the VTA exhibited widespread, cell type-specific transcriptional remodeling in resilient individuals and few gene expression changes in susceptible individuals. Across VTA cell types, resilience was associated with the coordinated upregulation of genes involved in intercellular signaling and neural communication, with maintenance of receptor-ligand interaction strength in resilience that was not present in susceptibility. Within VTA neurons, gene expression changes were most prominent in glutamatergic and dopaminergic clusters. Multivariate analyses of dopamine and glutamate subclusters showed that resilient neurons diverged more from control than susceptible neurons, but along a similar trajectory, supporting a model in which resilience reflects greater stress-related adaptations in these cell types. Together, these findings highlight the VTA as a key site of molecular plasticity in stress resilience and therefore a potential therapeutic target.