New classes of optogenetic and chemogenetic tools with a feedback control Project Summary Optogenetic and chemogenetic tools have revolutionized neuroscience research. They also hold great promise for gene therapy of neurological disorders, such as epilepsy, schizophrenia and anxiety disorders. For example, among the ~ 65 million people worldwide affected by epilepsy, 30% of them are resistant to current medicine but could significantly benefit from new therapies that can quickly and effectively suppress the irregular neuronal activities during seizures. However, we currently lack tools for prolonged neuronal silencing with fast response to precisely modulate the irregular neuronal activities in neurological disorders for both neuroscience research and therapeutic development. The state-of-the-art optogenetic tools for neuromodulation provide fast temporal control via light, but they are limited by light-induced tissue heating in long-lasting neuronal silencing experiments. Existing chemogenetic tools are effective for long-term neuronal silencing, however, they are limited by their slow on/off rate due to drug administration. There is a need of new tools that will enable prolonged neuronal silencing in quick response to the irregular neuronal activities in neurological disorders. Our long-term goal is to engineer modular biological designs for controlling the activities of specific neuronal pathways with tunable temporal control and minimal invasiveness for neuroscience research and potential therapeutics. In this application, we propose to design the first closed- loop chemogenetic tool with a feedback control to suppress the irregularly-high neuronal activities, and a highly-light-sensitive optogenetic tool to achieve long-lasting silencing of neuronal activities. These new tools based on membrane-tethered temporally-gated peptide agonists for G-protein-coupled receptors are highly innovative and modular, and will open up a new frontier in designing neuromodulation tools for manipulating neuronal pathways. They will also advance the basic research on neuronal circuitry and facilitate the development of potential therapeutics for manipulating neuronal pathways in patients with neurological disorders.

New classes of optogenetic and chemogenetic tools with a feedback control Project Narrative Neurological disorders, such as epilepsy and schizophrenia, are very debilitating by showing unpredicted episodes of irregular neuronal activities. We propose to develop new optogenetic tools with tunable temporal control and new chemogenetic tools with a feedback control to precisely silence the irregular neuronal activities in neurological disorders. These new tools will significantly facilitate neuroscience studies to advance our understanding of the disease mechanism and provide potential therapeutic treatment.