PROJECT SUMMARY Significance: Neural circuit assembly requires activity-dependent refinement of circuit architecture (e.g. plasticity) to produce stereotyped behavior. Neurons are particularly susceptible to functional and structural plasticity during early developmental windows called critical periods. It is clear that failure to terminate critical period plasticity adversely affects mature circuit function in both animal models and humans (e.g. autism and epilepsy), yet the mechanisms that close critical periods are largely unknown. This Pathway to Independence Award proposal seeks to understand the cellular and molecular mechanisms that promote critical period closure, and to define how critical periods shape circuit architecture to ensure proper locomotor behavior. Candidate and environment: Dr. Ackerman was trained in molecular genetics and developmental neuroscience in the laboratory of Dr. Kelly Monk at WashU School of Medicine, where she used forward and reverse genetic strategies to uncover regulators of myelination (NS087801). She then joined the laboratory of the renowned neurobiologist Dr. Chris Doe (UO, HHMI/NAS). Here, she defined a novel critical period of plasticity in the developing Drosophila motor circuit, and uncovered a series of astrocyte-derived molecular regulators of critical period closure (NS098690). In this proposal, Dr. Ackerman will extend her current skills in molecular genetics, live imaging, and circuit analysis to include training in electrophysiology and single cell RNAseq (scRNAseq), two completely new techniques for her. Further, she will use two model systems (fly and zebrafish) to determine how these novel, astrocyte-derived factors restrict motor circuit plasticity (Aim 1), to define how the critical period contributes to motor circuit connectivity, function, and behavior (Aim 2), and to determine how motor circuit plasticity is developmentally constrained in vertebrates (Aim 3). Career development: In addition to continued mentorship by Dr. Doe, the candidate has assembled an exceptional team of mentors and collaborators from the University of Oregon and beyond. During the mentored phase, the candidate will train in NMJ electrophysiology from Dr. Dion Dickman (USC) in order to define how the level of activity experienced by motor neurons during the critical period shapes motor output and behavior. This training is essential for future studies of motor circuit function in the candidate's own lab. Further, she has gathered a local team of advisors from the zebrafish community, Dr. Judith Eisen and Dr. Adam Miller, who have a combined 40 years of experience in zebrafish motor circuits. Drs. Eisen and Miller will facilitate training in scRNAseq, and will provide critical career development advice from the complementary perspectives of a seasoned (Dr. Eisen) and recently-established (Dr. Miller) principal investigator. Funding of this proposal will equip Dr. Ackerman with the unique skillset required to launch a robust and successful research program that pushes the boundaries of our understanding of circuit plasticity, from molecules to behavior.

PROJECT NARRATIVE Neural circuits in the brain undergo activity-dependent changes in structure and function, called neural plasticity, which is largely restricted to early developmental windows called critical periods. Inappropriate critical period extension is linked to neurological disorders such as autism and epilepsy, yet the mechanisms terminating critical periods are poorly understood. The experiments outlined in this proposal will define the cellular and molecular mechanisms that trigger critical period closure, as well as the physiological contribution of critical periods to mature circuit function and behavior.