Developmental manipulation of the hippocampal dentate gyrus to investigate effects of early life stress on adult dentate function

Early life stress (ELS) leads to alterations in anatomy and function of the adult hippocampal dentate gyrus (DG), but the mechanisms by which these lasting changes occur have not been fully elucidated. We tested the hypothesis that the immediate decrease in cell proliferation and neurogenesis induced by stress is the key mediator of the negative long-term outcomes of ELS. First, we tested whether inhibition of cell proliferation during early life is sufficient to reproduce the ELS-induced reduction in adult DG neurogenesis. We demonstrate that targeting dividing stem cells for elimination during the first or third postnatal weeks leads to diminished adult neurogenesis and reduction of the stem cell pool. Also, we hypothesized that ELS leads to more persistent effects on DG function than stress later in life because of the stress-induced elimination of specific birth cohorts of DG granule cells (GCs) that have distinct functions. We tested whether different birth cohorts of DG GCs differ in function by assessing behavioral and stress response outcomes of pharmacogenetic elimination or optogenetic activation of adult GCs born during the first or third postnatal week. We demonstrate that dorsal GCs born during the first or third postnatal week may be involved in modulating exploratory and anxiety behavior, but that only third postnatal week born GCs stimulate HPA activity. These results suggest that mature DG GCs may differ in specific functions with birth date determining their functional role. Third, we directly assessed the effect of ELS on DG development to better understand the immediate effects of ELS on the DG and to identify other potential mediators of the long-term effects. We demonstrate that ELS using the limited bedding/nesting paradigm leads to developmental delay of the DG. The work presented in this dissertation contributes to our understanding of the mechanisms by which ELS produces lasting impairments in DG function and also to our knowledge of how DG GC function is specified.