As scientists work to regrow nerves and replace connections in damaged nerves, the ability to create and direct the connection, or synapse, between the nerve and next structure remains illusive. To date, pharmacological treatments and neural implants show promise in generating new synaptic connections; however, neither offers control over where synapses are established. Because a neural circuit's function relies a precise connection, a need exists to generate targeted synaptic connections as part of neural circuit repair. This project focuses on how to correctly pair neurons and differentiate these connections into functionally relevant synapses. Genetic engineering is already utilized to determine how neural circuits assemble and generate behavior. Building on this basic neuroscience research, this work will repurpose genetic engineering tools to achieve a novel goal: engineering neural circuits. These results will develop tools to precisely manipulate neural connections and establish key principles for designing connections to have intended functional behavioral outcomes. This will lay the groundwork for genetic therapies to restore function to injured and diseased circuits thereby enhancing quality of life and reducing financial burden on our healthcare system. Undergraduate students will be integrated into the research team and a biomedical engineering learning series will be developed for juniors at a local high school that serves at risk and underrepresented minority students. The goal of both will be to improve interest and retention in STEM, in particular in biomedical engineering.
Proteins that bind across a synapse, including gap junction subunits connexins, show promise for selective pairing and electrical synapse formation. When expressed ectopically, their homophilic interactions can generate novel connections in vertebrate and invertebrate nervous systems. However, functional characterization of these putative electrical synapses remains limited. Here, the capacity for exogenous connexins (Cx36) to selectively engineer functional synapses will be investigated within an escape circuit of Drosophila melanogaster that contains the required genetic tractability to deliver genes to pre- and postsynaptic candidate neurons and neural accessibility to determine functional and behavioral consequences of engineering new connections. Synaptic function will be assessed through immunolabeling, optogenetics, in vivo whole-cell electrophysiology, and detailed behavioral analysis.
