Project Summary Normal auditory cortex (ACX) function is crucial for speech and language perception. Many disorders that involve ACX, such as Central Auditory Processing Disorders (CAPD), Autism Spectrum Disorder (ASD), and tinnitus are thought to be due to abnormal brain wiring. Moreover, influences on the developing brain interact with each other, e.g., early trauma or drug exposure can alter early sensory processing, resulting in wiring deficits. Thus, correcting disorders would seem to require the ability to rewire the brain. An understanding of brain development and the emergence of sensory function is needed to do so. Sensory experience, especially during early “critical periods,” sculpts connections in the young brain, leading to altered functional responses and functional representation of sensory stimuli, e.g., sounds in the brain. Manipulation or replacement of sensory experience (e.g., by cochlear implants) after the critical period does not lead to successful functional recovery. We recently discovered that sensory experience, even before the traditional “critical period,” can alter circuits associated with subplate neurons in the developing cortex. Thus, sensory experience in this “pre-critical period,” which in humans occurs in utero, might fundamentally shape ACX organization and sound processing, as well as influence mechanisms during the later “classic critical period” within layer 4. We have shown that the earliest sound-responsive neurons in ACX are located in the subplate, an enigmatic, deep cortical layer. Subplate neurons (SPNs) are mainly absent in adults, highlighting their developmental role. SPNs are more numerous in primates than in other species. Thus, some SPNs may be an evolutionary addition enabling complex brain function. Lesioning SPNs in visual and somatosensory cortex alters cortical development, thus SPNs seem essential to development. We have found that ACX SPNs receive thalamic inputs and project to cortical layer 4 before the onset of low-threshold hearing. Moreover, our recent work established that SPN circuits are disrupted in deafness, and neurodevelopmental disorders. However, a role for SPN activity in the development of ACX has yet to be established. As a step towards promoting functional recovery from early sensory disruptions or injury, we will investigate i) how sound stimuli are processed by SPNs; iii) how dysfunction of specific SPN circuits leads to altered ACX wiring; and iii) how SPNs modulate both spontaneous and sound-evoked cortical activity. To achieve our aims, we will utilize state-of-the-art in vivo imaging and stimulation techniques. Our studies will elucidate processes underlying ACX development and contribute to understanding the pathophysiology of many disorders, e.g., deafness, CAPD, ASD, and language impairments. Moreover, our work will inform new treatments and how existing treatments must be modified to consider these changes. 1