Newborn dentate granule cells (DGCs) are continuously generated in the adult brain. These cells integrate into the pre-existing circuit and participate in hippocampus-engaged behaviors. The mechanism underlying how the adult brain governs hippocampal neurogenesis remains poorly understood. In this proposal, we investigate how coupling of pre-existing neurons to the cerebrovascular system regulates hippocampal neurogenesis. Using a new in vivo imaging method in freely moving mice, we found that hippocampus-engaged behaviors such as exploration in a novel environment rapidly increased microvascular blood flow velocity in the dentate gyrus. We will examine whether blocking this exploration-elevated blood flow dampens experience-induced hippocampal neurogenesis. We next propose to examine what molecules mediate neurovascular coupling network in the dentate gyrus to regulate experience-induced neurogenesis in the adult brain. The findings will provide a novel path to understand how adult brain actively control the number of newborn dentate granule cells. It will also provide a novel approach for analyzing dynamic neurovascular coupling during behaviors and pathological conditions including Alzheimer disease and aging.
Disease, degeneration or traumatic injury of the nervous system are among the greatest public health concerns in the United States and are generally considered irreparable, often causing catastrophic damage to the functional capacity of the individual. Now, however, characterization of neural stem cells residing within specific germinal centers of the brain and in cell culture raises hope that functional regeneration of nervous tissue may be feasible, if we learn to exploit adult neurogenesis for clinical benefit. The research proposal here aims to study how adult brain react and respond to our daily lives to adjust its hippocampal neurogenesis through neurovascular coupling. If successful, this R21 proposal will lead to improved understanding of neural stem cell biology, possibly leading to the development of new drugs for repair and regeneration of the nervous system such as aging brains.
