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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS080913-05
Application #
9250219
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lavaute, Timothy M
Project Start
2015-06-15
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
$224,100
Indirect Cost
$78,033
Name
University of Southern California
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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Gebara, Elias; Bonaguidi, Michael Anthony; Beckervordersandforth, Ruth et al. (2016) Heterogeneity of Radial Glia-Like Cells in the Adult Hippocampus. Stem Cells 34:997-1010
Bonaguidi, Michael A; Stadel, Ryan P; Berg, Daniel A et al. (2016) Diversity of Neural Precursors in the Adult Mammalian Brain. Cold Spring Harb Perspect Biol 8:a018838
Ibrayeva, Albina; Bonaguidi, Michael A (2015) Pushing and pulling on adult neural stem cells. Cell Stem Cell 16:451-2
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Sun, Jiaqi; Bonaguidi, Michael A; Jun, Heechul et al. (2015) A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation. Mol Brain 8:52