Enriched environment prevented glutamate receptor loss in the prefrontal cortex to alleviate CUMS-induced depression-like behaviors

Background: The antidepressant properties of enriched environment have been corroborated by scientific research. The medial prefrontal cortex (mPFC) is a key brain region implicated in depression. However, whether the depression-preventive effects of environmental enrichment are associated with alterations in mPFC and its mechanism remains to be investigated.

Methods: Chronic unpredictable mild stress (CUMS) was used to induce depressive-like behaviors in mice, with mice exposed to two different stressors daily. Alongside stress exposure, mice were subjected to 6 h of EE daily for 3 weeks. Behavioral tests, Golgi staining, sparse labeling, in vivo electrophysiological recordings, western blot, RNA Sequencing were utilized to examine changes in dendritic spines, neuronal firing patterns, gene expression of mPFC neurons and depression-like behavior of mice.

Results: Exposure to EE prevented anxiety and depressive-like behaviors induced by CUMS, prevented the reduction of dendritic spine density, increased the GluA2 and NR1 expression, and restored the firing frequency of mPFC neurons. Activation of AMPA/NMDA receptors with agonist reversed depressive-like behavior in CUMS mice, while antagonist of AMPA/NMDA receptors blocked the antidepressant effects of EE. In addition, EE restore 108 genes expression that were involved in pathways related to neural function, such as cholinergic synapses, distal axons, and ion channels.

Conclusions: The EE prevents the development of depressive-like behaviors induced by CUMS by promoting gene and glutamate receptor expression and increasing spine density in the mPFC, highlighting the potential of EE as a preventive intervention for depression.

Depressive-like behavior; Enriched environment; Glutamate receptor; Medial prefrontal cortex.