The environmental enrichment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive decline by inducing autophagy-mediated inflammation inhibition.

BACKGROUND

People exposed to prolonged chronic unpredictable mild stress (CUMS) are easy to suffer from depression and cognitive impairment. Environmental enrichment (EE) had a beneficial effect on depressive-like and cognition-like behaviors by inhibiting inflammation. However, the specific mechanism involved in the inflammation inhibition that occurs after EE treatment for the depression and cognitive decline induced by CUMS remains unclear. In this study, we evaluated the possible mechanism of the beneficial effects on depression and cognition by EE.

METHODS

Rats were randomly divided into 5 groups as follows: (1) Control + standard environment (SE), (2) CUMS + SE, (3) CUMS + EE, (4) CUMS + EE+ 3-methiladenine (3-MA), (5) CUMS + SE + 3-MA. They were exposed to CUMS procedure for 5 weeks except the control group. After CUMS procedure, rats were housed in the EE or SE for 3 weeks. During EE or SE treatment, rats were injected with normal saline or 3-MA every day. 3-MA as an autophagy inhibitor suppresses autophagy via inhibition of class III PI3K. Behavioral tests were used to investigate depressive-like and cognition-like behaviors after EE treatment. Then, autophagy-related proteins, inflammation-related molecules, transmission electron microscopy (TEM) and immunofluoresence were determined.

RESULTS

We found that CUMS induced depressive-like behaviors and cognitive impairment, reflected in worse behavioral test, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, prolonged immobility and spatial learning and memory impairment. In addition, CUMS rats exhibited the reduced expression of autophagy related proteins including LC3 and Beclin-1 and the increased inflammation activation including microglia cells, NLRP3 inflammasome and proinflammatory cytokines (IL-1β, IL-6 and TNF-α). After EE treatment, these changes were reversed. However, 3-MA, the inhibitor of autophagy, eliminated the neuroprotective effects of EE on depressive-like behaviors and cognitive decline.

CONCLUSION

This study demonstrates that EE can play neuroprotective effects on depression and cognitive impairment by inducing autophagy-mediated inflammation inhibition, which accounts for the reduction of proinflammatory cytokines, including IL-1β, IL-6 and TNF-α.