UC Davis

The adult mammalian brain possesses the remarkable capacity for generating new neurons throughout life. This process of adult neurogenesis is restricted to a few privileged areas of the brain such as dentate gyrus (DG) of the hippocampus. This form of extreme plasticity generates new neurons and glial cells from the resident population of neural progenitor cells (NPCs) that are important for learning and memory while disruption in this process is implicated in many disorders including depression and age-related dementia. The generation of new cells from NPCs can be affected by various intrinsic and extrinsic factors, which range from the local microenvironment of the neurogenic niche to voluntary exercise and diet. The thesis research presented here examines how the process of neurogenesis is regulated by factors such as aging and investigates role of a novel recently identified regulator Brain-specific angiogenesis inhibitor 2 (BAI2).The first part of my thesis examines the age-dependent changes in cell intrinsic properties of NPCs. Application of a modified method allowing to isolate and culture NPCs later in life when neurogenesis is decreased uncovered that while hippocampal precursors from the aged brain display same NPC characteristics as cells from the younger brain, their cell proliferation ability is diminished. Detailed cellular-level analysis demonstrated that neuronal output and NPC fate choice is driven by changes in cell-autonomous properties that contribute to the reduced number of newborn neurons in the aging brain. This study shows that in vitro models of neurogenesis in the adulthood can serve as a platform for investigating important biological questions regarding the development and differentiation of hippocampal neurons generated throughout adult life. iii The second part of my thesis examines the role of BAI2, the adhesion G-protein coupled receptor (aGPCR) family member, in regulation of adult neurogenesis. Constitutive knock out of BAI2 shows a possible cell extrinsic mechanism for regulation NPCs proliferation via VEGF growth factor. At the same time conditional deletion of BAI2 in mice resulted in the decreased cell proliferation in the neural precursor cells suggesting additional cell-autonomous regulation of cell proliferation by BAI2. Applying methodology developed in the first part of this thesis showed allowed me to disentangle extrinsic and cell autonomous role of BAI2 in cell proliferation. Altogether, this work defines BAI2 as a novel regulator of adult neurogenesis and proposes a mechanism of action that could affect future neuronal proliferation studies. Further investigation of BAI2 cellular mechanism in NPCs may inform future human disease studies and treatments associated with neurogenesis pathologies. In summary, my thesis work presented here has contributed significant novel discoveries in neurodevelopment in the adult mouse hippocampus. I have found novel cell extrinsic and cell intrinsic mechanisms for regulating hippocampal neural precursor cell proliferation, differentiation and cell fate decisions.