Impact of chronic stress on hippocampal microglia and neurogenesis: implications of the LPA-LPA1 pathway modulation in mice.

Abstract

Chronic stress is widely recognized as a major environmental risk factor contributing to depression, significantly impacting mental health. While prevalent and a heavy societal burden, the exact neurobiological mechanisms linking chronic stress to mood disorders like depression are not fully understood. Chronic stress impairs neurogenesis and triggers neuroinflammatory responses, potentially contributing to depressive symptoms. Emerging evidence highlights microglial cells, the brain's primary immune cells, and the lysophosphatidic acid (LPA) signaling pathway, particularly the LPA1 receptor, as pivotal in these effects. This study explored how chronic unpredictable stress affects microglial activity and neurogenesis in the hippocampus of C57BL/6J mice, focusing on the LPA-LPA1 signaling system. Two approaches were employed: icv administration of LPA and BrP-LPA, a non-classical antagonist that irreversibly inhibits autotaxin, and a 10-day unpredictable stress model using movement restriction. Microglial morphology and activation were analyzed with anti-Iba-1 immunohistochemistry, while neurogenesis through cell proliferation and stages of immature neurons (DCX+ cells). Findings revealed significant alterations in microglial structure and activation, particularly in the SGZ, highly sensitive to stress. Chronic stress increased cell proliferation in the ventral hippocampus but delayed neuronal maturation. Both LPA and BrP-LPA administration had similar effects, delaying neuronal maturation. Interestingly, LPA under stress conditions showed a trend toward compensating for stress-induced proliferation increases, suggesting a complex interplay between stress and LPA signaling. These results underscore the LPA pathway's critical role in mediating neuroinflammatory and neurogenic responses to chronic stress.