This study will study how newly formed adult stem cell derived neurons are capable of activity dependent incorporation into the adult environment and how they make functional connections within mature neural networks. It is my goal to determine whether activity is required for this integration and what effect stimulating or silencing the focal network has on the survival of the new neurons and their dendritic and spine elaboration. In addition 1 will determine what the effect of cell autonomous silencing of the newly formed neurons will have on their integration and survival. Future stem cell based therapies for neurological disorders will require an understanding of the mechanisms of new neuron incorporation into mature, complex neural networks. Previous transplantation studies into the adult brain of patients with Parkinson's disease were unsuccessful due to inadequate survival and integration of the stem cell grafts due to the host environment being hostile to new neuron integration. Understanding endogenous systems of new neuron incorporation, like with adult neurogenesis in the hippocampus and olfactory bulb, will contribute significantly to the development of future stem cell therapies. In our laboratory I established a method for 2-photon in vivo imaging of new neuron incorporation into the olfactory bulbs in the live, anesthetized mouse over multiple time points. This method is superior to previous approaches since I can track and measure the exact same neuron over multiple time points in a live mouse without any cutting of the structure, which is impossible using other methods (histology, cell culture, slice culture). This powerful technique allows for tracking the integration of individual neurons to detect their migration, dendrite and spine pruning and cell death. Using these multiple time point images I developed a method to 3-dimensionally trace and measure the complete dendritic and spine dynamics of the newly formed neurons with complete preservation of their structure. Currently I have characterized the integration of the new neurons over fourteen time points within the same mouse and have measured the integration and have detected new neuron cell death. Activity has been shown to be essential for new neuron survival but the mechanism of their integration and how they elaborate in the adult network is lacking. It is my goal, with the help of the NRSA fellowship, to pursue the fundamental question of activity dependent integration and to contribute to our understanding of adult neurogenesis with future applications in clinical stem cell therapy for various neurological diseases including Parkinson's disease, stroke and epilepsy.
|Sailor, Kurt A; Valley, Matthew T; Wiechert, Martin T et al. (2016) Persistent Structural Plasticity Optimizes Sensory Information Processing in the Olfactory Bulb. Neuron 91:384-96|
|Sun, Gerald J; Sailor, Kurt A; Mahmood, Qasim A et al. (2013) Seamless reconstruction of intact adult-born neurons by serial end-block imaging reveals complex axonal guidance and development in the adult hippocampus. J Neurosci 33:11400-11|