DESCRIPTION (provided by applicant): Candidate: The candidate is a 3rd year postdoctoral fellow at Stanford University in the lab of Dr. Tony Wyss- Coray. The candidate's immediate goals are to gain independence and establish her own lab at an academic research-focused university or institute studying the role of undifferentiated neural stem or progenitor cells in hippocampal function. Her long-term goals are to build a prominent lab in the area of hippocampal plasticity and injury response at an academic research center. She aims to improve our understanding of how the hippocampus, an essential brain area for memory function, responds to the environment, either positively or negatively and thereby inform development of therapeutics for human brain health. She also plans to make high quality mentoring of young scientists a priority in her career. Environment: The proposed Mentored Phase research will be conducted in the lab of Dr. Tony Wyss-Coray at Stanford University. Co-mentors Dr. Theo Palmer and Dr. Tom Rando will also advise the candidate through quarterly individual meetings and yearly meetings of the candidate and the entire mentoring team. The Stanford Neurology department will hold yearly mandatory meetings where the candidate will present her research and career progress to senior faculty, along with other K99 awardees, and receive feedback and further guidance. Coursework at Stanford and Cold Spring Harbor Lab will provide formal instruction in lab management, grant writing and mentoring. A team of several consultants is also in place to help with technical training on several new procedures that the candidate will learn in the Mentored Phase, as well as study design using these new procedures. The transition to independence has defined milestones and will be tangibly supported by the primary mentor and co-mentors in the form of job opportunity referrals, practice with job talks, and advice on offers. The primary mentor will invest significant effort in the establishment of the candidate's lab by: 1) working with the neurology department chair to secure a tenure-track position for the candidate, 2) providing feedback on R01 preparation during the Mentored Phase and 3) promoting the candidate's new lab at national and international conferences. Research: The proposed experiments will investigate a novel functional role for undifferentiated neural stem and progenitor cells (NSPCs) in the adult brain after enhancement and injury. The proliferation of endogenous NSPCs in the adult hippocampus increases dramatically after both beneficial voluntary exercise and injurious seizures. Most previous studies have debated the function of the immature neurons that result from the differentiated products of these NSPCs. This proposal will determine the direct role of undifferentiated NSPCs in hippocampal function via secretion of growth factors after both seizures and exercise. A key motivation for this research is to inform future therapeutic targeting of NSPCs by determining how this important, unique cell population alters injury and plasticity responses in the adult hippocampus. This proposal will introduce functional implications for adult neurogenesis at a cellular age previously thought to be silent. Given the numerous environmental stimuli that impact NSPC proliferation, these findings could have wide-reaching implications for the role of NSPCs in hippocampal plasticity. The first aim of this project will characterize the growth factor response of NSPCs to physiological and pathological stimuli. Fluorescence-activated cell sorting techniques from acutely dissected murine adult hippocampus will be employed to isolate NSPCs after seizures or voluntary wheel running exercise. RNAseq will be used to contrast the profiles of NSPC transcriptional responses to pathological vs physiological stimuli. These findings will represent a rich dataset that will infor many future investigations of how NSPCs participate in regulating hippocampal function. To determine the direct role of NSPC-secreted growth factors, this proposal will use a novel mouse model for inducible, NSPC-specific knockdown of floxed growth factors, starting with an established model for inducible knockdown of the growth factor VEGF in NSPCs. For exercise, knockdown of a growth factor (like VEGF) in NSPCs will be induced in adulthood, followed by exposure to an unlocked running wheel. Behavioral and immunohistochemical markers of exercise-related enhancement of hippocampal function will then be quantified to determine whether loss of that growth factor from NSPCs prevents any benefits of exercise. For seizures, after growth factor knockdown, mice will be exposed to kainic acid either systemically or centrally to induce different levels of seizure severity. Behavioral and structural sequela will thn be quantified to determine whether loss of NSPC-growth factor is beneficial or detrimental to recovery from seizure. These studies will shed light on the function of undifferentiated neural progenitors, a largely uninvestigated cell population but one that may have important implications for design of therapies for disorders that differentially impact the hippocampus such as epilepsy.

PUBLIC HEALTH RELEVANCE: The hippocampus, a key brain area for memory function, changes dramatically in response to both beneficial and detrimental stimuli. This proposal will investigate the role of neural stem and progenitor cells in changes after exercise (which is beneficial) and seizure (which is detrimental). The findings may lead to novel avenues for treatment of seizure disorders, which are a prominent, persistent health concern.