The dentate gyrus (DG) relays information from the cortex to the hippocampus, a brain region critical for learning and memory. Interestingly, the DG contains a population of neural stem cells that generate new neurons throughout adulthood. The role these cells play in normal hippocampal function is not well understood, but disrupting neurogenesis in the DG disrupts learning, and promoting neurogenesis enhances cognitive performance. Furthermore, neurogenesis is altered in a variety of pathological conditions including diabetes, depression, epilepsy, schizophrenia, and Alzheimer's Disease. In order to contribute to hippocampal function, new neurons must integrate into the existing network. Only a fraction of new dentate granule cells (GCs) survive, while most undergo apoptosis within the first few weeks of maturation. The fate of newborn GCs is influenced by experience. For example, environmental enrichment (EE) increases the survival of adult-generated GCs, but only during an early maturation stage termed the "critical period." Synaptic input has also been shown to be important for survival of newborn GCs, but little is known about how experiences like EE affect synaptic connectivity. Using a transgenic mouse model to identify newborn GCs in the critical period, we have found that EE enhances GABAergic synaptic input to newborn GCs. Housing animals in EE also promotes glutamatergic synaptogenesis. We hypothesize that enhanced GABAergic synaptic depolarization of newborn GCs produced by EE promotes GC survival and excitatory synaptogenesis via the conversion of silent synapses. To address this hypothesis we will 1) investigate how EE increases GABAergic synaptic activity to newborn GCs, 2) test if GABAergic depolarization is necessary and sufficient to convert silent synapses in vitro, and 3) determine whether GABAergic depolarization is necessary for the enhanced survival and excitatory synaptogenesis associated with EE in vivo. These goals will be achieved using a variety of techniques including electrophysiology and immunohistochemistry under the expert guidance of the sponsor. The proposed work will provide a detailed understanding of the mechanisms that promote the survival and integration of endogenous neural stem cells, and could provide pharmacological targets for enhancing or regulating neurogenesis in situations in which neurogenesis is altered, or for improving the efficacy of cell replacement therapies. The training plan for the PI includes participation in yearly seminar speaking opportunities, formal la meetings, journal clubs, presentations at national meetings, formal and informal training in ethical scientific practices, and regular meetings with the mentor.
The proposed study investigates the role of synaptic input on the survival and integration of adult neural stem cells. Understanding the mechanisms underlying the successful integration of neural stem cells may provide targets for enhancing endogenous neurogenesis in pathologies in which neurogenesis is impaired, including depression and Alzheimer's Disease, and may improve neural stem cell replacement therapy for stroke and neurodegenerative diseases.
|Chancey, Jessica H; Poulsen, David J; Wadiche, Jacques I et al. (2014) Hilar mossy cells provide the first glutamatergic synapses to adult-born dentate granule cells. J Neurosci 34:2349-54|
|Chancey, Jessica H; Adlaf, Elena W; Sapp, Matthew C et al. (2013) GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons. J Neurosci 33:6614-22|