Transcriptomic analysis of chronic social instability stress during adolescence reveals major shifts in the extracellular matrix.

Adolescence represents a sensitive window of neural plasticity, when social experiences exert enduring influences on emotional and cognitive development. Adverse social conditions, such as social instability stress (SIS), disrupt peer relationships and lead to long-term changes in social and affective behaviour. Here, we used RNA sequencing to characterize the immediate (P46) and enduring (P70) molecular consequences of adolescent SIS in male and female rats in two stress-sensitive regions: the dorsal hippocampus (dHPC) and basolateral amygdala (BLA). SIS produced region- and sex-specific transcriptional profiles. In males, SIS upregulated extracellular matrix (ECM) and perineuronal net (PNN)-related genes in the hippocampus, whereas females exhibited broad suppression of ECM-related genes in the amygdala. The opposing ECM trajectories between hippocampus and amygdala suggest that SIS drives premature structural stabilization in the male hippocampus and maintains heightened plasticity in the female amygdala. In both sexes, synaptic signaling pathways were consistently downregulated, whereas mitochondrial and metabolic programs were enhanced. Additionally, we observed sex and region-specific changes in neuroendocrine and hormonal gene expression, including oxytocin (Oxt), vasopressin (Avp), and testosterone signaling components. These transcriptional programs were largely distinct from normative age-dependent gene expression changes between adolescence and adulthood. Together, these findings identify adolescent SIS as a potent regulator of ECM and synaptic gene networks, revealing molecular pathways through which social stress may sculpt circuit maturation in a sex- and region-specific manner.