Contact PD/PI: Wright, Emily Clarissa PROJECT SUMMARY Anxiety disorders are the most commonly diagnosed mental illnesses; national prevalence data indicate that about 20% of adults in the US will be diagnosed. Selective serotonin reuptake inhibitors (SSRIs) are one of the most widely used treatments, yet 40% of patients do not respond. Despite decades of targeting serotonin, a consensus on serotonin function and release dynamics is lacking. Consequently, how SSRI administration modulates fine temporal dynamics of serotonin in relation to anxiety is largely unknown. Pharmacological approaches, microdialysis, and chemogenetic manipulations have produced key insights, but none provide millisecond resolution for serotonin release and correlates of specific reactions and behaviors until recently, due to the development of two sensitive genetically encoded serotonin sensors (sLight and iSeroSnFR). I will these sensors combined with fiber-photometry to optically measure behaviorally driven serotonin release in an anxiogenic serotonin circuit with high temporal and spatial resolution. The series of experiments outlined in this proposal are significant because they will: Aim 1) rigorously demonstrate the in vivo utility of serotonin sensors in dissecting anxiety circuit, providing end users important protocols and guidelines for fast technological implementation; Aim2) map dynamics of serotonin release in anxiogenic circuits to anxiety behavior, and discover how activity in this circuit is impacted in anxious animals and determine the mechanistic impacts of acute vs. chronic SSRI administration on anxiogenic serotonin signaling; Aim 3) determine how testosterone impacts the efficacy of SSRI treatment. Project Summary/Abstract Page 6