PROJECT SUMMARY Effective auditory processing of vocalizations including human speech depends on the ability to distinguish self-generated sounds from external sounds. How the brain makes this distinction is still not well understood. Studies in vocalizing humans and monkeys suggest that a vocal motor-related (i.e., corollary discharge) signal that selectively suppresses auditory cortical responses to predictable acoustic features of ensuing vocalizations enables this distinction. Notably, such predictive corollary discharge signals also figure prominently in models of speech learning, while their dysfunction is a possible source of the auditory hallucinations that characterize various neuropsychiatric disorders. Despite their importance, the neural circuits that convey vocalization-related signals to the auditory cortex during vocalization are largely unknown, in large part because detailed circuit interrogation is impractical in humans and monkeys. Here I aim to delineate the neural circuits that convey vocalization-related corollary discharge signals to the auditory cortex of the mouse using a combination of innovative viral genetic tools, optogenetics, and in vivo electrophysiological recordings. I will use a novel genetic method to tag and manipulate a subpopulation of functionally relevant neurons in the midbrain periaqueductal gray whose activity is necessary and sufficient to drive ultrasonic vocalization. I will selectively elicit vocalizations by optogenetically stimulating these neurons, allowing me to systematically map and manipulate the neurons and circuits that convey vocalization-related corollary discharge signals to the auditory cortex. I will use this approach, along with advanced techniques for monitoring neural activity, to demonstrate that, as in primates, the mouse auditory cortex is suppressed by self-generated vocalizations. By harnessing the viral and transgenic strategies uniquely available in the mouse model I aim in the proposed experiments to reveal underlying circuit and synaptic mechanisms of vocalization-related corollary discharge, which would represent a major step forward in our understanding of this phenomenon, a step which would not be feasible in the primate. Completion of these aims would provide mechanistic insight into a phenomenon that is thought to facilitate hearing and auditory-guided motor learning and whose dysfunction is hypothesized to result in auditory hallucinations, a hugely disruptive psychiatric symptom. This project will take place under the mentorship of Dr. Richard Mooney in the Department of Neurobiology at Duke University, an experienced mentor whose research group focuses on the neurobiology of vocal communication in songbirds and mice using a wide variety of circuits, systems, and behavioral neuroscience approaches. The project proposed here, as well as my choice of research sponsor, would provide me the opportunity to master advanced techniques such as in vivo neurophysiology, optogenetics, viral and transgenic methods for neural circuit dissection, and imaging. This fellowship would therefore significantly enhance my technical and intellectual development, ultimately helping me to reach my long-term goal of becoming a successful academic researcher.

PROJECT NARRATIVE Our ability to distinguish self-generated sounds from environmental sounds is essential for normal auditory perception, perhaps most notably during speech and other forms of vocal communication. Moreover, genetic or environmental insults that interfere with the brain's ability to make this distinction are thought to generate the auditory hallucinations common to various neuropsychiatric disorders, such as schizophrenia and drug-induced psychoses. This proposal seeks to use advanced genetic tools in the mouse to identify and manipulate the neural circuits that distinguish self-generated vocalizations from the vocalizations of other nearby individuals.