Enriched environment restores depressive- and anxiety-like behaviors in mice with early life stress exposure by reversing striatal function, structure and metabolism.

Abstract

Early life stress (ELS) has been widely recognized as a major risk factor for the development of depression and anxiety in humans. While clinical studies have established this association, the underlying neural mechanisms remain elusive. To address this gap, rodent models such as maternal separation have been employed to mimic ELS and to explore its long-term effects on the brain and behavior. Environmental enrichment (EE) has further been proposed as a potential intervention to counteract the detrimental consequences of ELS, but its efficacy and underlying mechanisms remain insufficiently characterized. In this study, we utilized multi-parametric magnetic resonance imaging combined with behavioral tests to systematically evaluate the long-term effects of ELS exposure and subsequent EE intervention on brain signatures and behavioral changes in adult male and female ELS mice. ELS mice exhibited depressive- and anxiety-like behaviors, along with increased brain activity in the striatum. These behavioral changes were accompanied by reductions in gray matter volume, white matter integrity and metabolite ratios in the striatum. Importantly, EE intervention effectively reversed the behavioral impairments by restoring the alterations in brain function, structure, and metabolism, especially in the striatum. This study provides comprehensive insights into the detrimental effects of early life stress on brain and behavioral outcomes and reveals that these negative effects can be mitigated by EE intervention. Our findings identify the striatum as a critical region involved in these processes.