instnjctions): Emphasis on how cells die and protecting against further death after neonatal hypoxic/ischemia (H/l) has provided much needed therapeutic interventions. Recent emphasis has focused on recovery from injury and turned to the stimulatory effects of H/l on a pool of neural stem cells located in the subventricular zone (SVZ), and progenitor cells in the germinal zone of the dentate gyrus. We have recentiy identified an additional source of neuronal progenitor cells located within the neuropil of Ammon's horn in the developing hippocampus (Zhang et al., 2007). In uninjured animals, the rate of proliferation is almost twice as high in male neonates as females and the gonadal steroid, estradiol, is a potent stimulator of cell genesis in this region as well as the dentat gyrus. We will use the Vannuci model of H/l to explore whether proliferating cells in the dentate gyrus or within Ammon's horn are influenced by estradiol and whether sex, steroids and/or normoxic versus hyperoxic conditions post-injury impact on the proliferation response. Pilot data indicates that hyperoxia following H/l quickly results in a massive upregulation of cell proliferation on the injured side ofthe brain and that many of these cells are microglia. We will test a series of related HYPOTHESES;1) H/l injury induces cell genesis in the developing hippocampus in two phases, an eariy microglia proliferation (within hours) followed by a later neurogenesis that peaks 7 days later, 2) estradiol reduces microglial proliferation but enhances neurogenesis. 3) H/l enhances excitatory GABA responses and 4) estradiol enhances it still further, which is the mechanism mediating increased neurogenesis and 5) increased neurogenesis after H/l promotes functional recovery. These hypotheses will be tested by experiments under four Specific Aims which include in vivo an in vitro cellular analyses and extensive characterization of functional outcome. The translational significance of these studies is the potential for new therapeutic treatments to enhance both the proliferation and survival of new neurons following H/l in neonates. The mechanistic significance is identification of the source of sex differences in response to neonatal H/l and the cellular processes by which estradiol can lead to improved outcomes following damage.
Currently available therapeutic options following neonatal H/l focus on prevention of further damage. The experiments proposed here will open the gateway to regenerative therapeutics that can restore lost neurons and provide recovery of function and will do so with consideration of the imporant variable of gender of the injured individual.
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