Hippocampal neurogenesis and remodeling

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Stressful experiences during early life have been associated with abnormalities in the hypothalamicpituitary-adrenal (HPA) axis, changes in behavior and the development of psychopathology. Studying the cellular changes that occur in the brain in response to developmental stressors may bring us closer to understanding the mechanisms that underlie these functional consequences. Other projects in this Center grant proposal are designed to explore stress-induced changes in the brain at various levels of analysis, from molecular to behavioral. This project will examine the impact of aversive experience during early life on the structure of the brain. The studies proposed here focus on the hippocampal region, an area that is sensitive to stress and has been implicated in psychopathologies, including depression and posttraumatic stress disorder. The hippocampal region undergoes extensive development during the postnatal period that may render this structure potentially vulnerable to environmental perturbations. In particular, the granule neuron population of the dentate gyms is formed predominantly during the postnatal period. In fact, the production of these cells extends well into adulthood in most mammals, from rodents to primates. Previous studies have shown that the production of these hippocampal neurons is suppressed by stress in adulthood. This proposal is designed to explore the consequences of prolonged early life stress on the development of the granule neuron population, the CA3 pyramidal neuron population and the mossy fiber connections between these two cell groups using the rodent and primate models provided by the cores (PI, Plotsky), (PI, Insel). Using a variety of histological methods, including BrdU labeling, 3H-thymidine autoradiography, immunocytochemistry, Golgi impregnation and neuroanatomical tract tracing, the impact of early life stress on the formation and maintenance of hippocampal neurons will be explored. These studies will contribute to the Center's overall purpose to gain a better understanding of the effects of early life stress on brain structure and function and, ultimately, to the development psychopathology.