The excitement about neural stem cells arises in large part from the hope that they can be harnessed therapeutically to repair diseased brains. Very little is known, however, about how these new neurons integrate into existing brain circuits by making appropriate connections - this process can be compared to changing the wheels of a car while it is running. In addition, major questions of how adult neurogenesis and functional integration are regulated by local factors as well as by an animal's experience remain largely unanswered. In this proposal, we will conduct innovative experiments to investigate how new neurons are integrated into synaptic circuits in the mouse olfactory bulb. The rodent olfactory bulb is an excellent model system because of the high rate of neurogenesis, its accessibility, modular organization and behavioral relevance. We will describe the natural history of adult-born neurons in their native environment by imaging their morphology and function at high resolution in the intact brains of living mice using multiphoton laser scanning microscopy. We will also begin to uncover the cellular and molecular processes involved in the functional integration of new neurons into existing circuits using genetic perturbations. To achieve our goals, we will use stereotaxic viral injections, genetically-encoded calcium indicators and chronic multiphoton microscopy to examine in real time how newborn granule cells develop their morphological and functional properties. By tracking identified neurons over several weeks using time-lapse imaging in vivo, we will be able to uncover structural and functional changes that are not visible to conventional methods that obtain single snapshots in each animal. We will alter the odor experience of mice in a "critical" period during which labeled newborn cells are integrated into the bulb and investigate how this alters their functional properties and their survival. Experiments in this project will be guided by three Aims.
Aim 1 : To determine the time evolution of sensory responses of identified adult-born neurons over their development using multiphoton microscopy.
Aim 2 : To determine how sensory experience affects the functional properties of adult-born neurons cells and their survival.
Aim 3 : To determine the cellular and molecular mechanisms in the refinement of functional properties of adult-born neurons. The research proposed here will provide a deeper understanding about how newborn cells find appropriate synaptic partners and integrate into the adult brain. Insights gained from this study will inform efforts to treat human brain disorders using neuron replacement therapies.

Public Health Relevance

Developing successful strategies for brain repair based on cell-replacement requires an understanding of how newly generated neurons integrate into pre-existing, functioning neural circuits in the adult brain. The research proposed here will provide a deeper understanding of how newborn cells find appropriate synaptic partners and integrate into the adult brain, and how this integration can be modulated by experience.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Sullivan, Susan L
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Harvard University
Schools of Arts and Sciences
United States
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Hochbaum, Daniel R; Zhao, Yongxin; Farhi, Samouil L et al. (2014) All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat Methods 11:825-33