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. 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 define conserved cellular and molecular mechanisms that promote critical period closure, and to understand how critical periods shape circuit architecture to ensure proper locomotor behavior. Project Goals: We will leverage the unique strengths of two model systems- Drosophila and zebrafish- to define the cellular and molecular mechanisms that instruct neural plasticity. Specifically, we will determine how astrocyte-neuron signaling governs critical period timing, and how changes in critical period timing influence long-term circuit structure and function. First, we will test how microtubule stability influences motor dendrite structure to test how structural plasticity is executed (Aim 1). Then, we will test how critical period plasticity influences motor circuit maintenance to determine why structural plasticity is temporally restricted (Aim 2). Finally, we will use zebrafish to determine how astrocytes regulate plasticity in distinct neural circuits with different patterns of plasticity (Aim 3). 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). There, 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). Dr. Ackerman has chosen to open her laboratory within the Center for Brain Immunology and Glia at WashU (Department of Pathology and Immunology). The Center brings together faculty and physicians across multiple departments to understand how non-neuronal cells shape nervous system development, function, and disease. With the support of the Center and pre-existing mentors at WashU (Dr. Jim Skeath, Dr. Lila Solnica-Krezel, Dr. Aaron Diantonio, and others), she and her team are well-equipped to uncover how neuron-glia interactions regulate developmental plasticity.