This proposal seeks to address the mechanisms, cellular targets and target proccesses by which gonadal hormones act to recruit new neurons into the adult brain, using the higher vocal center (HVc) and the adjacent neostriatum in adult avian (canary, zebra finch) as a model. Given that estrogen is known to promote neuronal recruitment in the adult, the applicant posulates that this recruitment might be the result of estrogen acting on other paracrine agents to promote survival of post-mitotic neurons during or after migration, promote neuronal departure from the ventricular zone, direct the production and lineage commitment of VZ daughter cells, and/or enhance the recruitment of new neurons into the parenchyma, the latter by modulating the calcium response of migrating cells.
Four aims are presented: 1). To identify estrogen-regulated agents, whether they directly promote neuronal survival, and if so, at what stages during generation, migration, and maturation. 2). To study whether estrogen or its induced paracrine agents, promote neuronal recruitment or departure from the adult ventricular zone. Based on the applicant's finding that this departure is preceded by the down-regulation of N-cadherin by the new migrants, the experiments will address whether the estrogen-associated agents play a role in down-regulation of N-cadherin. 3). To study whether neuronal mitogenesis and later committment is regulated by non-steroidal gonadal peptides (TGF-b, activin, inhibin), shown previously by the applicant to suppress neurogenesis. This will be analyzed by two approaches: a). testing these factors, including other estrogen-induced agests identified in Aim 1, in suspension cultures of microcarrier-born VZ aggreages, allowing low serum, long-term maintenance of adult VZ cells. b). observing effects of these agents on single precursors transfected with a construct under the control of the immature neuronal promoter Talpha1, with a green fluorescent protein reporter gene, in turn faciltiating cell-sorting, to isolate precursor cells derived from fetal and adult VZ. 4. To determine whether estrogen or its induced agents influence the recruitment of new neurons into the adult brain by modulating the NgCAM-triggered calcium signal, which is temporally-restricted to new bipolar migrants.
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