Environmental Enrichment Exposure Alleviates Geriatric Depressive-Like Symptoms through Regulating Neurogenesis and Neuroinflammation

Environmental enrichment (EE) is a significant approach to influencing brain function by altering the environment and changing living conditions and has been shown to modulate mood-related diseases, including depression. Among the elderly, depression is particularly prevalent and is often linked to social isolation. However, the specific role of EE in social isolation-related geriatric depression remains imprecise. This study was intended to explore the status of EE exposure in geriatric depression and to uncover its underlying mechanisms. We utilized 19-month-old male C57BL/6J mice, which are equivalent to humans aged 50-60 years, and induced depression through social isolation. After 2 weeks of social isolation, mice were identified as depressive by using the sugar preference test and then classified into either standard or enrichment environment groups for 4 weeks. Subsequently, conventional indices associated with depression, including neurogenesis, neurotrophic factors, and neuroinflammation, were measured. Results display that EE alleviated the depressive-like symptoms in elderly mice and enriched their social activities. Concurrently, EE regulated levels of certain neurotransmitters in the hippocampus, including the systems of glutamate, tyrosine, and histamine. Moreover, the ability of neurogenesis also increased in the hippocampus of EE mice. At the neuroinflammation level, the activation of Natural Killer (NK) cells and ARG1⁺ microglia is considered a major contributor to mediating the effects of EE-regulated geriatric depression. Collectively, these results underline the importance of EE in the treatment of geriatric depression and partially elucidate its underlying mechanism, offering valuable suggestions for treating social isolation--related depression via environmental modulation.