The broad, long-term objective of this proposal is to gain a better understanding of the function of adult neurogenesis in the hippocampus. The following approaches will be used to achieve this general goal: 1) examination of the impact of socially and spatially complex experiences on new neurons, hormones levels and learning; 2) Exploration of the interaction between sleep, new neurons and learning; 3) determination of the impact of new neuron depletion on hippocampal function; and 4) characterization of differences between mature and immature neurons. Living under standard laboratory conditions has a profound negative impact on the survival of new neurons in the hippocampus. Therefore, a major goal of the experiments proposed is to identify the elements of a naturalistic, relatively complex environment that are important for hippocampal neurogenesis. The production, survival and phenotype of new cells in the hippocampus will be assessed with bromodeoxyuridine (BrdU) labeling combined with immunocytochemistry for cell-type specific markers, hormone levels will be assessed via radioimmunoassay and hippocampal function will be assessed by a variety of associative learning tasks, including trace eyeblink conditioning, trace fear conditioning, context fear conditioning and spatial learning in a Morris water maze. These techniques will be applied to animals that have been exposed to different social experiences, deprived of different stages of sleep or pharmacologically depleted of new neurons. A final series of studies will examine the structural and biochemical characteristics of neurons generated in adulthood compared to those generated during development. These experiments will use neuroanatomical tract tracing combined with BrdU labeling, electron microscopy combined with 3H-thymidine labeling and confocal microscopy. Because stress, sleep and the hippocampus have been linked to several psychiatric conditions, many of which have a cognitive component, these results may elucidate the brain mechanisms that underlie the development of psychopathology.
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