Proper brain function relies on the establishment and maintenance of complex neuronal circuits. The brain's initial wiring diagram is largely determined by developmentally executed genetic programs, but synaptic input ultimately sculpts its final form, function, and plasticity. To deal with a constant barrage of activity input, the adult mammalian brain has evolved the ability to maintain and modify 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 previously characterized, many of the cellular and molecular mechanisms governing synapse and circuit formation in response to neural activity remain unknown. Investigating this process has been the impeded by the lack of precise control over neuronal stimulation. We have initiated a series of cell biological, electrophysiological, and genetic experiments directed towards manipulating activity in the olfactory bulb while investigating the cell-specific effects on synapse and circuit formation. Using a mouse model that expresses the light-gated ion channel Channelrhodopsin-2 in subsets of neurons in the brain, we are able to selectively activate olfactory bulb mitral cells in a spatially restricted manner. Our preliminary data suggest that mitral cell activation promotes granule cell synaptogenesis and adult-born neuron survival. To address the mechanisms of activity-dependent newborn neuron circuit integration, we have begun to investigate the roles of NMDA receptor signaling. Preliminary data show that NMDA receptor function is important for proper dendrite and spine morphogenesis, suggesting that glutamatergic excitation is critical for synapse formation and cell survival. We propose to investigate the cellular and molecular mechanisms utilized by newborn neurons for synapse formation, circuit integration, and cell survival in response to neural stimulation.
The aims outlined in this proposal will establish the framework for a long-term research program designed to implement a multifaceted experimental approach towards investigating proper neuronal development and function.
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