CAREER: Structural and Functional Plasticity Induced By Loss of a Co-Innervating Neuron

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Our nervous system is composed of billions of intricately connected neurons that can actively modify their activity patterns and their influence on the circuit partners they communicate with. Each neuron can receive and process information from thousands of other neurons through discrete connections, called synapses. It is currently not known whether changes made at one synapse between two neurons can influence the development and/or activity of neighboring synapses that the target cell makes with other synaptic partners. For example, it might be the case that a decrease in communication at one synapse triggers increases in communication at other synapses in a brain circuit. The goal of this study is to document the existence of such compensatory programs, and to elucidate their underlying mechanisms. This project is conducted using individual cells in the neuromuscular circuitry of the fruitfly Drosophila melanogaster because of the advantages this preparation presents for studying and manipulating synaptic function, and because of striking functional similarity these cells share with mammalian excitatory brain synapses. The project includes a joint University of Chicago - University of Puerto Rico summer program for undergraduate students, which will integrate underrepresented citizens into cutting edge research labs to facilitate their development as independent researchers. It will additionally strengthen ties with predominantly Hispanic and Black schools on the south side of Chicago through outreach programs that allow high school students and teachers to conduct project-relevant lab experiments and disseminate the work in their respective classrooms. A joint quarter-long laboratory course for undergraduate juniors and seniors at the Woods Hole Biological Laboratories will enable students to gain high levels of competence in advanced neuroscience experimental techniques. This project will advance our understanding of neural circuit function and adaptation, as well as enhance education and participation of underrepresented groups in STEM.Neural circuits have highly complex connectivity patterns in which many inputs congregate on single targets. The number and strength of the synapses provided by each input can vary greatly, but how these synapses respond to perturbations – a process known as synaptic plasticity – is not completely understood. Unlike the densely packed synapses of the brain, motor neuron-muscle connections are easily visualized and differentiated from each other, facilitating examination of all synapses from each input. The central hypothesis of this project is that co-innervation in early circuit development creates an environment in which subsequent functional defects trigger synaptic plasticity in the remaining connections. Rigorous analyses of several co-innervating motor neuron pairs will characterize the contribution of each input to the total muscle activity and examine how perturbations in one input induce structural and functional plasticity phenotypes in the adjacent input(s), a process we refer to as inter-input synaptic plasticity (IISP). Genetic manipulations combined with calcium imaging and electrophysiological recordings will examine IISP in the neuromuscular circuit and help delineate molecular pathways that enable IISP. The results of this project will fundamentally advance understanding of how synaptic inputs develop and interact in a complex nervous system. The educational module expands student research experiences, while the outreach plan combines mentoring and research to train underrepresented high school, undergraduate, and graduate students and expand access to neuroscience.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.