Project Summary The ability of the brain to learn from and remember experiences lies at the heart of our existence and individuality. Learning has been associated with changes in synaptic strength and circuit dynamics, yet the precise learning rules recruited for behaviorally-relevant information storage in the mammalian brain have remained largely unclear. It has been hypothesized that learning involves alteration in the efficacy of specific synaptic connections through a process called synaptic plasticity, and that memory is thereupon stored as a distribution of altered synaptic strengths in neural circuitry. Numerous forms of synaptic plasticity exist in mammals and have been intensively studied, but in vivo preparations have not been conducive to identifying the specific synaptic changes supporting behaviorally-relevant plasticity in behaving mammals. The objective of this proposal is to measure and manipulate synaptic strength in behaving mammals, and to link activity patterns in specific cells directly and causally with changes in synaptic strengths during association formation. To achieve this, my approach is to develop and apply novel sophisticated all-optical electrophysiological methods, by pairing optogenetic manipulation with genetically targeted voltage imaging. I have developed all-optical electrophysiological methods to all-optically induce and record hippocampal behavioral time scale plasticity in behaving mammals. In the K99 mentored phase, I will develop a novel all-optical technique to measure synaptic strength between genetically targeted CA2/3 and CA1 cells. Real-time synaptic strength and circuit dynamics between CA2/3 and CA1 will be monitored as hippocampal behavioral time scale plasticity occurs in behaving mammals. Using optogenetic stimulation, I will manipulate both pre- and post-synaptic cell spike timing and quantify the relationship between spiking timing and the behavioral time scale plasticity. Through the development of the novel all-optical electrophysiological systems, I will then have the unique capability to measure inhibitory synaptic plasticity of specific cell types during learning in the R00 independent phase. Together, these studies will define the specific synaptic and circuit changes recruited for information storage during learning and provide fundamental insights into how the brain encodes memory and how this process can malfunction during mental illness. During the proposed research and career training plan, I will be mentored by Dr. Karl Deisseroth and co-mentored by Dr. Ivan Soltesz, and advised by an exceptional advisory team. With their support and the tremendous scientific environment at Stanford University, I will gain technical and conceptual training in systems neuroscience, hippocampal physiology, synaptic physiology, and computational neuroscience. These training and skills will put me uniquely at the junction of technology development and systems neuroscience and prepare me well for my lo...