Mechanisms Underlying Neural Stem Cell Heterogeneity in the Adult Hippocampus

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DESCRIPTION (provided by applicant): Adult neural stem cells (NSCs) contribute to brain plasticity and maintain tissue homeostasis. Understanding how NSCs remodel the adult hippocampus may provide key insight into neural adaptability and repair. NSC function is defined by the ability to maintain a precursor state while generating neuronal and glial progeny. Recently, I developed a new in vivo clonal analysis system to reveal stem cell properties at the single cell level within the adult mammalian hippocampus, an area critical for learning and memory. We previously showed that radial glia-like (RGL) cells can act as stem cells, but exhibit significant heterogeneity in their decisions to proliferate, generate progeny and self-renew. A fundamental remaining question is what mechanisms underlie these differences. I hypothesize that divergent RGL behavior results from differences in their proliferative state and responses to changes in environment including GABA signaling and stroke injury. To address these points, I have established independent model systems that preferentially target quiescent and mitotic RGLs. I will first characterize NSC potential within these intrinsically biased RGL subpopulations by performing in vivo single cell lineage tracing. After establishing this foundation, we will assess how GABA signaling acts as an extrinsic molecular mechanism to regulate stem cell decisions in quiescent and active RGLs under physiological condition. Finally, we will determine how stroke injury dictates RGL cell fate decisions and potential in quiescent and active subpopulations under pathological conditions. Importantly, viral-based gene delivery, optogenetics and stroke surgery skills learned during the mentored phase are essential components toward a multidisciplinary approach for investigating extrinsic niche regulation during the independent phase. Collectively, this research seeks to understand NSC behavior in intrinsically different RGLs and how their decisions interact with specific physiological and pathological mechanisms. PUBLIC HEALTH RELEVANCE: Radial glia-like (RGL) cells exhibit significant heterogeneity in their behavior to act as neural stem cells in the adult hippocampus. This study investigates mechanisms underlying differences in RGL function including intrinsic potential and regulation by specific physiological and pathological conditions.