POST-STRESS ENVIRONMENTAL ENRICHMENT AS A RESCUE STRATEGY AGAINST LONG-TERM EFFECTS OF ADOLESCENT STRESS

Adolescent stress (AS) increases vulnerability to neuropsychiatric disorders in adulthood by inducing long-lasting alterations in brain function. In contrast, Enriched Environment (EE) promotes cognitive performance, resilience, and antidepressant-like effects. Beneficial actions of EE have been linked to increased levels of activin A, a neuroactive member of the TGF-β family. This study investigates how AS induces persistent hippocampal dysfunction and whether post-stress EE can reverse these alterations, with a particular focus on activin signaling.
Using an oral corticosterone-based model of AS in mice (PND 30-45), we applied a multidisciplinary approach combining ex vivo hippocampal electrophysiology and molecular profiling to assess synaptic plasticity and mitochondrial function in adulthood (PND 90-120). Experiments were conducted in wild-type mice and transgenic mice with forebrain-specific disruption of activin receptor signaling. AS induced persistent deficits in short- and long-term synaptic plasticity in the dentate gyrus. Disruption of activin signaling further exacerbated these deficits and caused a shift in excitatory-inhibitory (E-I) balance, indicating that activin limits neuronal dysfunction after stress. Mitochondrial alterations persisted in adulthood and were characterized by increased spare respiratory capacity, suggestive of maladaptive metabolic compensation.
Following AS or control treatment, animals were exposed to EE for three weeks (PND 46-67). EE modified AS-induced E-I disbalance in an activin-dependent manner and partially restored mitochondrial function, suggesting its capability to reverse AS-induced long-term deficits.
Our findings suggest adolescence as a critical window for stress-induced brain vulnerability and EE- and activin-dependent mechanisms as potential targets to enhance resilience and mitigate long-term stress-related brain malfunction.