Abstract
Early life stress predisposes to mental illness and behavioral dysfunction in adulthood, but the mechanisms underlying these persistent effects are poorly understood. Stress throughout life impairs the structure and function of the hippocampus, a brain system undergoing considerable development in early life. The long-term behavioral consequences of early life stress may therefore be due in part to interference with hippocampal development, in particular with assembly of the dentate gyrus (DG) region of the hippocampus. We investigated how early life stress produces long-term alterations in DG structure by examining DG assembly and the generation of a stable adult stem cell pool in routine housing and after stress induced by the limited bedding/nesting paradigm in mice. We found that early life stress leads to a more immature, proliferative DG than would be expected for the animal’s age immediately after stress exposure, suggesting that early life stress delays DG development. Adult animals exposed to early life stress exhibited a reduction in the number of DG stem cells, but unchanged neurogenesis suggesting a depletion of the stem cell pool with compensation in the birth and survival of adult-born neurons. These results suggest a developmental mechanism by which early life stress can induce long-term changes in hippocampal function by interfering with DG assembly and ultimately diminishing the adult stem cell pool.
Highlights
Stress during early life has been consistently associated with mental illness in adulthood[1,2,3], though the mechanisms underlying the persistent effects are poorly understood
Neurons that develop from this lineage reside in the granule cell layer (GCL) of the dentate gyrus (DG)
The stem and progenitor cells are initially spread throughout the area that will become the GCL, but coalesce into the subgranular zone (SGZ), where they remain into adulthood[23,24]
Summary
Stress during early life has been consistently associated with mental illness in adulthood[1,2,3], though the mechanisms underlying the persistent effects are poorly understood. Neurogenesis[10,30], including recent reports that these measures increase shortly after ELS exposure[5,15] These new findings are surprising because chronic stress in adulthood consistently results in decreased cell proliferation and neurogenesis[21,22,31,32,33]. The appearance of a more proliferative state in the DG after ELS could reflect developmental immaturity, which could progress to life-long dysfunction Both early life stress and chronic adulthood stress alter DG cell proliferation during the stress exposure[5,15,21,22,31,32,34,35,36,37]. We found that ELS delays DG development and diminishes the adult stem cell pool in male and female mice
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