Proper brain function relies on the establishment and maintenance of complex neuronal circuits. Developmental genetic programs largely determine the brain's initial wiring diagram, but synaptic input ultimately sculpts its final form, function, and plasticity. Amazingly, the adult mammalian brain has evolved the ability to maintain and modify certain neural circuits through ongoing neurogenesis. This neurogenic potential is primarily restricted to the hippocampus and olfactory bulb, and is influenced by environmental enrichment, sensory stimulation, and even neurological disease. Although the sites and timing of adult neurogenesis have been well characterized, many ofthe cellular and molecular mechanisms that govern synapse and circuit formation in response to neural activity remain unknown. One hurdle that has limited our knowledge of this process has been the lack of precise control over neuronal activities. To address this we have initiated a series of cell biological, electrophysiological, and genetic experiments directed towards manipulating the activity of neuronal subsets in the olfactory bulb while investigating the cell-specific effects on synapse and circuit formation. Using natural odor stimulation and a mouse model that expresses the lightgated ion channel Channelrhodopsin-2 in subsets of neurons in the brain, we have found that mitral cell activation promotes newborn granule cell synaptogenesis and adult-born neuron survival. To better understand the cellular mechanisms of activity-dependent newborn neuron circuit integration, we have also begun to investigate the roles of NMDA receptor signaling. Preliminary data show that NMDA receptor function is important for proper dendrite and spine morphogenesis, synaptic function, and neuronal survival. The broad goal of the proposed research is to better understand how synaptic input intersects with developmental genetic programs to guide synapse formation and cell survival.
Many neurological diseases, disorders, or traumas result in the selective loss of neuronal subsets. Investigating the natural phenomenon of neurogenesis in the adult mammalian brain presents a unique opportunity to better understand how synaptic activity and developmental genetics merge to drive functional circuit formation. Mechanistic knowledge gained on this dynamic relationship may prove useful towards neural stem cell based therapies.
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