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Limits of Regeneration and Degeneration

Neuronal birth and death, and the balance between the two, are fundamental processes of adult neural plasticity. Songbirds are an excellent model for exploring the dynamics of neuronal birth and death, and their effects on behavior, as seasonal production of song is under the control of a discrete but plastic neural circuit. This circuit includes the avian song control nucleus HVC and its target, the robust nucleus of the arcopallium. Seasonal plasticity of HVC in Gambel’s white-crowned sparrows involves pronounced changes in neuron number. Within 7 days of transitioning into breeding conditions, 68,000 new neurons integrate into HVC. Likewise, as birds transition into non breeding conditions, an equal number of neurons (both young and old neurons) die via caspase dependent cell death within 3 days. We exploit these dramatic changes in neuron number between seasons to ask questions about how cellular environment, interactions and signaling mechanisms guide reactive neurogenesis (i.e., the birth of new neurons as a response to HVC cell death), homeostatic neural stem cell proliferation, mature neuronal survival, and maintenance of organismal behavior. 

To develop the tools necessary for cellular analyses of mechanisms of environmentally-induced neural plasticity, and especially those that involve classically defined immune cells like microglia, we have annotated the genome of Gambel's white-crowned sparrow and are performing single nuclei indexed RNA sequencing. Using sniRNAseq, we intend to answer questions like:

How many different cells are present in HVC?

How do these cell populations change across environmental conditions, both natural and human-altered?

How do these cell populations interact to drive neural and behavioral plasticity?

We intend to integrate these analyses with in silico simulations of the cellular dynamics within HVC and characterization of cell lineage and behavior across environmental conditions. To facilitate in vivo and in vitro imaging of specific cellular interactions, we are developing cell lineage markers and staining panels for analyses via immunohistochemistry, flow cytometry, and organotypic slice time-lapse imaging.

We follow up on candidate signaling mechanisms with mechanistic in vivo manipulations examining plasticity in cell generation, fate specification, cellular behavior, and organismal (singing) behavior.

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