Adult behavior is the product of neural circuits that have been sculpted during development by genetic programs and experience in the form of neural activity. Developing nervous systems frequently display characteristic spontaneous activity that is essential for circuit refinement. However, the precise mechanisms by which spontaneous neural activity sculpts the refinement and maturation of non-sensorimotor circuits to shape behavior remain poorly understood. The Drosophila mushroom body, with its well characterized anatomy and well-established role in learned behavior, is an ideal system for causally investigating the developmental maturation of higher order neural circuits. The goal of this proposal is to identify mechanisms for the maturation of spontaneous and evoked neural activity to support adult learned behavior. In preliminary studies, I discovered spontaneous, asynchronous oscillatory activity in Kenyon cells, the principal intrinsic neurons of the mushroom body, specifically in very young adult flies, which declines significantly over the first week of adulthood. Our results suggest that Kenyon cell activity in young adult development is required for subsequent expression of robust learned behavior in the mature adult. Moreover, I identified Juvenile Hormone as a critical regulator of the maturation of Kenyon cell spontaneous activity in early adulthood. A multifaceted approach employing molecular genetics, learned behavioral analysis and state of the art functional calcium imaging is proposed to (1) characterize Juvenile Hormone effector genes that regulate the maturation of Kenyon cell spontaneous neural activity over the first week of adulthood and (2) dissect the role of hormonal signaling in the maturation of associative learning behavior. In the independent phase, we will (3) investigate how conditioned odor-evoked neural activity matures over the first week of adulthood in Kenyon cell circuits, improving our understanding of the neural substrates for learned behavior. To achieve these goals, I will pursue comprehensive training in learned behavioral assays, state of the art volumetric imaging technologies and computational neuroscience methods. My primary mentor Dr. Kristin Scott, my Scientific Advisory Committee and Consultants, and the UC Berkeley environment provide stellar opportunities for my scientific growth and professional development, uniquely preparing me to launch a successful independent scientific career. These efforts will lead to significant insights into the fundamentally important question of activity-dependent maturation of neural circuits and learned behavior.
Investigating the activity-dependent development of neural circuits and learned behavior will increase our understanding of fundamental mechanisms of normal brain development. Our work will provide insights into how these essential neurodevelopmental processes may be pathologically misregulated upon developmental hormone deficiencies and in disorders including autism spectrum disorders, fragile X disorder and schizophrenia.
