PROJECT SUMMARY Anyone who starts learning a new foreign language can attest: sensory stimuli like speech and song are near-continuous streams of complex sounds. With practice, listeners can learn to parse the meaning in streams of Mandarin or Stravinsky. Communication sounds that vary over the course of milliseconds (e.g., songs and speech) are optimally encoded by high-precision, low- jitter neuronal activity. The neurons that process and respond to complex, dense sound streams therefore exhibit fast and precise timing of action potentials. The spike timing of sensory neurons is also shaped by the current context, such as shifts in attention and changes in external or internal states. Mechanisms that account for this dynamic richness in our sensory and cognitive experience are becoming clearer. In the cortex, fast-spiking inhibitory interneurons are essential for coding and learning about sensory stimuli. The activity of fast-spiking interneurons is shaped by the moment-by-moment actions of neuromodulators like oxytocin, dopamine, serotonin, and catecholamines. These mechanisms can help explain how organisms assign different values of valence and salience to sensory stimuli depending on contexts like parenting, aggression, mating, and stress. A recently-discovered neuromodulatory system - the synthesis and action of ‘neuroestrogens’ within the brain - now holds a great deal of promise for deeper understanding of sensory processing and cognition. Estrogen treatments can ameliorate a variety of neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and epilepsy. Yet because the neuromodulatory perspective of brain estrogen synthesis is relatively new, the therapeutic potential of neuroestrogen signaling itself is currently untapped. The research program in this proposal will unpack the specific contribution of ultraprecise, fast inhibitory interneurons to the modulatory actions of neuroestrogens in the cortex. We will test the hypothesis that neuroestrogens directly modulate fast spiking interneurons in the cortex to regulate spike timing precision and behavioral discrimination learning. The proposed projects will take advantage of recent molecular and technological advances to genetically target fast-spiking inhibitory interneurons. This work will therefore address a fundamental gap in our understanding of how estrogen production within the brain guides complex behavior, and could ultimately inform the development of highly-targeted estrogen therapies for cognitive and neurological disorders.