Project Summary / Abstract Ascertaining the neural basis of behavior has been a cornerstone goal since the conception of neurobiology. While activity recording and loss-of-function studies have shed light on brain regions involved and necessary for the expression of certain behaviors, they are unable to determine the information each circuit is responsible for encoding. Therefore, when different nodes in the circuit are removed, the behavioral phenotype is often identical. Synaptic plasticity, the ability of synapses to change functional strength depending on experience, is considered the cellular correlate of learning and memory. Linking changes in the functional strength of synapses following behavior has begun to indicate what information circuits are responsible for encoding. To provide direct evidence, a tool that is able to modulate synaptic plasticity in specific circuit nodes during behavior is needed. The goal of this proposal is to create a photo-activatable inhibitor of presynaptic plasticity that will be input- and region- specific for use in behaving animals. The first aim of the proposal will create and screen constructs of photo-activatable PKI (paPKI) in their efficacy for the inhibition of protein kinase A, a kinase necessary for the induction of presynaptic plasticity. Light-dependency will be ensured and the construct will be evaluated based on its sensitivity and selectivity using advanced imaging techniques (2-photon fluorescence lifetime imaging) and biochemical assays. The second aim of the proposal will use paPKI to determine the role of specific circuit nodes in social memory. Input-specific modulation of plasticity will be paired with in depth behavioral analyses using computer vision to parse out subtle differences in social interaction. These aims directly address the BRAIN Initiative 2025 high priority goal #4: the modulation of neural activity with readouts of behavior using advanced computer vision techniques. The proposed fellowship project provides excellent training potential as it expands from the applicant’s current training in systems/circuit neuroscience to molecular and biophysical neuroscience. The project is an intersection between the mentor’s, Dr. Ryohei Yasuda, expertise in molecular mechanisms of synaptic plasticity and the development and advanced imaging of biomodulators and sensors, and the applicant’s expertise in circuitry underlying social memory, electrophysiology and behavioral analyses using computer vision. The Max Planck Florida Institute for Neuroscience is an intensely collaborative environment filled with leaders in the field and exceptional resources, resulting in an institute that is highly productive and influential. This fellowship proposal presents excellent training potential and aims to produce tools that will advance the field.