Volatile anesthetic alteration of neural precursor cell cycle and fate decisions

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DESCRIPTION (provided by applicant): The long-term goal of the PI is develop into an academic anesthesiologist with an independent research program focused on anesthetics and neural development. This proposal outlines a career development plan that includes didactic and laboratory based instruction in neural development and stem cell biology. During its course the PI will obtain several new skills necessary to compete for independent funding in this field in the future. The research and didactic program will be carried out at the University of California, San Francisco in the department of Anesthesia and Perioperative Care, one of the top departments in this field. All general anesthetics act in part at GABA or NMDA receptors and recent research has identified an important role for GABA and NMDA mediated signals in growth and differentiation of neural progenitor cells (NPCs). Therefore, volatile anesthetics acting at these known and other unknown sites may alter proliferation, differentiation and survival of NPCs with implications for long-term effects on CNS function. Neurogenesis in the hippocampal dentate gyrus is necessary for certain types of learning and memory. Our preliminary data show isoflurane decreases proliferation of NPCs both in vitro and in vivo and in rodents and we have observed a hippocampal cognitive deficit 3 weeks to 8 months after isoflurane exposure. We propose that long-term hippocampal-based cognitive deficits following anesthesia are a consequence of anesthetic induced changes in hippocampal NPCs. We will test the hypothesis that anesthetics induce cell cycle exit and premature differentiation in NPCs. Aim 1 will focus on mechanisms of anesthetic action on NPCs in vitro. Aim 2 will investigate changes in the cyto-architecture of the hippocampal dentate gyrus after anesthetic exposure in vivo. Together these aims will begin to define the effect of anesthetics on hippocampal development. PUBLIC HEALTH RELEVANCE: Recent identification of long-term cognitive deficits following general anesthesia in neonatal animals has caused significant concern for clinical practice. This proposal seeks to understand how anesthetics alter neural development and neural precursors in the hippocampus. )