The dentate gyrus of the hippocampus is unusual because it continues to produce new neurons in adulthood in a variety of mammals, ranging from rodents to primates. Exposure to learning tasks that require the hippocampus for acquisition enhances the survival of adult-generated neurons in the dentate gyrus. In addition, adult female rats produce more new neurons than males, and these sex differences are positively correlated with sex differences in hippocampal-dependent learning. These findings indicate that learning influences the survival of new hippocampal neurons and raise the possibility that adult-generated granule neurons are involved in hippocampal-dependent learning. The broad, long-term objectives of this proposal are to characterize the influence of ovarian steroids and learning on the production, survival and gene expression of hippocampal granule neurons generated in adulthood in both sexes. Moreover, the potential role that new granule neurons play in hippocampal-dependent learning and memory will be explored. Using associative learning paradigms of trace classical eyeblink conditioning and the Morris spatial water maze, the role of hormones and experience in the production and survival of new granule neurons in males and females will be investigated with markers of proliferating cells, such as 3H-thymidine and bromodeoxyuridine, combined with immunocytochemistry for neuronal and glial markers. Combined in situ hybridization and immunocytochemistry will be used to explore changes in expression of genes important for cell survival, synaptic plasticity and/or learning, such as NMDA receptor subunits, BDNF and bcl-2, specifically in adult-generated granule neurons following associative learning. Furthermore, the function of hippocampal granule neurons generated in adulthood will be explored in animals depleted of new neurons by endocrine manipulations or treatment with selective toxins for proliferating neuronal precursors and then tested on tasks that require the hippocampal region for acquisition. This proposal is relevant to disorders or age- and disease-related cognitive decline which can be ameliorated by ovarian steroids. In addition, these studies may provide insight into mechanisms of neuronal regeneration.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-IFCN-7 (01))
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Winsky, Lois M
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Princeton University
Schools of Arts and Sciences
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Leuner, Benedetta; Caponiti, Julia M; Gould, Elizabeth (2012) Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids. Hippocampus 22:861-8
Leuner, Benedetta; Glasper, Erica R; Gould, Elizabeth (2010) Parenting and plasticity. Trends Neurosci 33:465-73
Leuner, Benedetta; Gould, Elizabeth (2010) Dendritic growth in medial prefrontal cortex and cognitive flexibility are enhanced during the postpartum period. J Neurosci 30:13499-503
Leuner, Benedetta; Gould, Elizabeth (2010) Structural plasticity and hippocampal function. Annu Rev Psychol 61:111-40, C1-3
Leuner, Benedetta; Glasper, Erica R; Gould, Elizabeth (2009) Thymidine analog methods for studies of adult neurogenesis are not equally sensitive. J Comp Neurol 517:123-33
Leuner, Benedetta; Mirescu, Christian; Noiman, Liron et al. (2007) Maternal experience inhibits the production of immature neurons in the hippocampus during the postpartum period through elevations in adrenal steroids. Hippocampus 17:434-42
Stranahan, Alexis M; Khalil, David; Gould, Elizabeth (2007) Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus 17:1017-22
Bangasser, Debra A; Waxler, David E; Santollo, Jessica et al. (2006) Trace conditioning and the hippocampus: the importance of contiguity. J Neurosci 26:8702-6
Shors, Tracey J (2006) Significant life events and the shape of memories to come: a hypothesis. Neurobiol Learn Mem 85:103-15
Tanapat, Patima; Hastings, Nicholas B; Gould, Elizabeth (2005) Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner. J Comp Neurol 481:252-65

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