A Novel Role for C1q in Modulating NSC during Aging
My doctoral research focuses on uncovering how an overactive immune system arrests neurogenesis during aging and leads to cognitive problems. Neurogenesis is the process by which new neurons are born, migrate, and integrate into existing networks, and is essential for the maintenance of cognitive flexibility. As neurogenesis declines with age, brain networks become more vulnerable to inflammation. One large component of this inflammatory response in the aged brain is complement protein C1q, which is deposited within the brain during aging and can directly alter new neuron properties, such as migration, differentiation, metabolism, and cellular quiescence. Through in vitro studies, the first chapter of my dissertation describes how brain-relevant concentrations of C1q can modulate endogenous NSC behavior. The second chapter investigates how C1q inhibits neurogenesis and exploration of aged mice through a global C1q KO model. The third component of my dissertation asks whether the source of C1q, either from blood or locally produced in the brain by microglia, is important to its effects. Lastly, through a transplantation paradigm, the fourth component of my thesis investigates a receptor-mediated mechanism by which C1q alters the behavior of new neurons and therefore potential network integration or support for cognition. We discovered that C1q alters NSC characteristics in aged mice, contributes to aging-related behavior deficits, and can be rescued with via C1q KO. These studies contribute to the neuroimmunology field by identifying novel mechanisms that the immune system uses to modulate neurogenesis, thereby opening the opportunity for specific therapies to target cognitive decline and prevent age-related neurodegenerative disease.