Project Summary The brain has the remarkable capability to change in response to experience. This plasticity is essential for learning and memory, and is an important feature of the auditory cortex, especially for learning the significance of sensory signals such as speech, recovery after short-term deafness, and the use of devices such as cochlear implants for hearing restoration. These changes are thought to occur primarily at synapses, basic units of information processing and plasticity. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems which convey behavioral context to local cortical circuits. It is generally believed that these mechanisms are important for initial adaptation and performance with cochlear implants. However, little is known about how single neurons and circuits of the auditory system are modified during cochlear implant training to support performance, or how these mechanisms might be leveraged to improve hearing restoration. Over the last decade, the Froemke and Svirsky labs at NYU School of Medicine have been collaborating with the NYU Department of Otolaryngology and Cochlear Americas to examine unilateral multi-channel implant use in bilaterally profoundly-deafened rats. Rats are ideal for studying the neuroscience of neuroprosthetic use, as we can monitor neurophysiological changes in highly-trained rats reporting auditory percepts, recording in behaving animals to measure single-trial neural correlates and longer-term forms of neuroplasticity over days to weeks of implant use. Furthermore, we can take advantage of recent advances in optogenetics and imaging technologies in transgenic rat lines, to monitor and manipulate neural activity in specific brain regions and in select cell populations. We have found that implanted rats show analogous variable individual performance and learning rates as with human subjects. In our prior publications supporting the proposed experiments, we found that response levels and tuning curves in auditory cortex related to individual rat performance. We also found that activity in the brainstem locus coeruleus- a major source of the modulator noradrenalin- could predict when rats would begin performing well with implant stimulation, and that optogenetic stimulation of locus coeruleus produced high levels of performance in all animals. This indicates that neuromodulation and cortical plasticity are predictive biomarkers and potential avenues for improving performance with cochlear implants. Here in Aim 1 we make µ-electrocorticography and single-unit recordings as rats learn to use cochlear implants to perform an auditory 2-alternative forced-choice task; we will monitor larger-scale cortical cochleotopy and single neuron responses on individual trials during implant training. In Aim 2, we use whole-cell recordings in vivo ask how cortical inhibition shapes cortical responses and regulates plasticity for cortical implant learning. In Aim 3...