PROJECT SUMMARY In all sensory systems, peripheral sensory organ damage leads to compensatory cortical plasticity that supports a remarkable recovery of perceptual capabilities. In the auditory system, while auditory nerve input to the brainstem is significantly reduced after cochlear damage, sound-evoked cortical activity is maintained or even enhanced. This recovery is due to increased cortical sensitivity (gain) to the spared auditory input. Although this plasticity does not support features of sound processing encoded by the precise timing of neuronal firing, such as complex sound discrimination, it provides a remarkable recovery of sound detection. A major gap in knowledge is the lack of a precise mechanism that explains how this plasticity is implemented and distributed over the diverse excitatory and inhibitory cortical neurons, synapses and circuits. Here we propose a strategic, cooperative, time-dependent, cell type- and synapse-specific plasticity program that restores cortical sound processing. The results from our studies will advance the field to a new level of understanding regarding cortical plasticity after peripheral organ damage, and will inspire the development of well-timed, cell-specific treatments and rehabilitative paradigms and cures that may further enhance the recovery of perception after hearing loss, and mitigate the development of brain plasticity-related disorders, such as hyperacusis and tinnitus. Cortical principal neurons (PN) and interneurons (IN) are very diverse and thus capable of supporting a coordinated and collaborative plan for achieving cortical recovery. The major classes of cortical neurons include vasoactive intestinal-peptide (VIP), somatostatin (SOM) and parvalbumin (PV) expressing IN sub-classes, as well as intratelencephalic (IT), layer (L) 5 pyramidal tract (PT), and L6 corticothalamic (CT) PNs. Based on our preliminary results, we propose that: 1) PVs are the network “stabilizers”; 2) VIPs are the “enablers” that regulate SOM activity; and 3) SOMs are the “modulators” that allow for high PN gain. At the cellular and synaptic level, we propose that soon after cochlear damage: 4) PVs and PTs exhibit a decrease in intrinsic excitability; 5) CTs exhibit an increase in intrinsic excitability; and 6) thalamic synaptic input to deep cortical layers is shifted from CT/PT equivalent to CT dominant. Overall, our proposed research and hypotheses provide an experimental platform to probe how multiple cortical neuronal sub-classes restore cortical processing after peripheral input loss (Aims 1 and 3). In combination with Aims 2 and 3, our proposed studies will determine the underlying intrinsic (Aim 2) and synaptic mechanisms (Aim 3) that mediate this plasticity.