Project Summary Vocal communication depends on distinguishing our own vocal sounds (vocal feedback) from other sounds. Vocal motor-related corollary discharge (vocal CD) signals that suppress auditory responses to predictable vocal feedback help make this distinction. Notably, vocal CD signals in the human auditory cortex are especially important to speech and their dysfunction is thought to cause auditory hallucinations. Despite the key roles postulated for vocal CD signals, the challenges of monitoring and manipulating their activity in vocalizing animals has prevented systematic analyses. The long-term objective of this application is to understand with synaptic, cellular, and circuit resolution how vocal CD signals modulate auditory cortical responses to vocal feedback, detailed knowledge of which is essential to understand adaptive and maladaptive aspects of audition. We will gain detailed knowledge of synaptic, cellular, and circuit mechanisms underlying this process by studying the mouse, the vertebrate most suited to advanced genetic, electrophysiological, and optical tools. In the prior funding period, we used these tools to advance our understanding the synaptic and circuit mechanisms by which movement-related CD signals modulate auditory cortical activity. These advances included mapping a motor to auditory cortical circuit, determining that various head and body movements activate this pathway to suppress auditory cortical responses to sounds, and showing that this pathway can “learn” to selectively suppress sounds that are predictably yoked to locomotor movements. We also observed auditory cortical suppression in vocalizing male mice, but vocalization occurred during female courtship and was always accompanied by other movements, as well as by social and sexual stimuli. Therefore, whether vocalization-specific CD signals modulate the auditory cortex and suppress predictable vocal feedback remain unknown. Fortunately, we also developed methods for optogenetically gating ultrasonic vocalizations (USVs) and for distorting vocal feedback in the isolated, head-fixed mouse. Here we propose to combine these methods with other state of the art techniques, including multi-electrode arrays, in vivo multiphoton imaging, controlled manipulation of vocalization-related auditory feedback, and novel computational methods for voco-acoustic analysis. In the first Aim, we will test the idea that vocalization suppresses auditory cortical activity and use machine learning methods to rigorously quantify and compare spontaneous and optogenetically-evoked USVs. In the second Aim, we will isolate cortical contributions to the vocal modulation of auditory cortical activity. In the third Aim, we will distort vocal feedback to determine if vocal suppression of the auditory cortex is predictive, and use computational methods to systematically quantify vocal distortion. Together, these Aims will provide novel insights into the synaptic, cellular, and circuit mec...