Enriched environment mitigates anxiety and depression-like behaviors induced by SNI via restoration of AMPA and NMDA receptors function in mice.

Background: Chronic pain is well-known for inducing anxiety and depression in humans. Enriched environment (EE) has shown promising effects in alleviating mood disorders; however, the precise mechanisms remain poorly understood. The medial prefrontal cortex (mPFC), a pivotal brain region associated with emotion regulation, particularly through excitatory synaptic transmission, is implicated in the processing of pain-related mood disorders.

Methods: First, adult male C57BL/6 mice 6 weeks after spared nerve injury surgery, were subjected to the behavioral tests and dendritic spine morphology staining. Then, 2 weeks after spared nerve injury (SNI), mice were housed in enriched environment, to establish model EE. Behavioral outcomes, dendritic spine maturation, and AMPA and NMDA receptors expression were assessed up to 4 weeks after EE treatment using behavioral tests, Golgi staining, Western blot, and pharmacological experiments.

Results: Our results showed that SNI mice exhibit anxiety and depression-like behaviors. Further analysis revealed that SNI mice displayed a significant reduction in mature dendritic spines in the mPFC. After 4 weeks of housekeeping in EE, dendritic complexity, spine maturity, and the expression of AMPAR and NMDAR of SNI mice were restored, leading to a rescue of anxiety and depression-like behaviors. Moreover, pharmacological antagonism of AMPAR or NMDAR, by intraperitoneal injection of AP-5 or CNQX, effectively abolished the alleviating effect of EE on anxiety and depression-like behaviors in SNI mice.

Conclusions: Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism of EE in mitigates anxiety and depression-like behaviors in SNI mice via restoration of mPFC excitatory synaptic transmission.