Peripheral nerve injury causes sensory dysfunctions that are thought to be attributable not only to the functional, cellular and biochemical events occurring in the peripheral nerve, but also to the functional changes occurring in the cerebral cortical representations of the peripheral regions. Evidence shows that peripheral nerve injury results in reorganization of cortical representation located in the deprived (contralateral to the injured limb) and healthy (ipsilateral to the injured limb) somatosensory cortices. These studies suggest that the bilateral reorganization may originate from modifications occurring in the inter-hemispheric, transcallosal pathway. Moreover, recent human rehabilitation studies suggest that in fact, these newly identified transcallosal neuroplasticity mechanisms may dictate the degree of recovery following peripheral nerve injury. Similar to human studies, peripheral nerve injury (denervation) in the rat results in bilateral reorganization of cortical representations. Our results demonstrate that these neuronal changes can be monitored using functional magnetic resonance imaging (fMRI), electrophysiology, immunostaining and laser speckle contrast optical imaging (LSI). Our findings suggest that indeed the transcallosal pathways mediate the bilateral cortical reorganization and as a result there are increases in the activity of inhibitory interneurons located in the deprived cortex (contralateral to the injured limb). We hypothesize that the increased cortical inhibition observed in the deprived cortex may be the foundation of the poor recovery observed in patients. Here we propose to use a combination of high-resolution electrophysiology measurements and fMRI to identify the key transcallosal neuronal mechanisms that reshape the neuronal behavior following peripheral nerve injury. In addition we propose to develop a novel guided plasticity strategy to promote recovery following peripheral nerve injury by manipulating the activity of the transcallosal connections using optical-genetic (optogenetics) techniques. This will be achieved by transiently reducing transcallosal communication by light activating Cl- pumps (halorhodopsin) in neurons located in the healthy, unaffected cortex. Finally, we propose to develop a non-invasive platform using fMRI to monitor the effect of the optogenetics manipulations on cortical reorganization following injury. Results obtained from this animal study could be directly translated into clinical applications in terms of improving rehabilitation strategies which are based on transcallosal manipulations. It is our expectation that this will facilitate an original and effective approach to restore normal cortical functions following peripheral nerve injury. PUBLIC HEALTH RELEVANCE: The goal of this research is to investigate how modifications in the behavior of inter-hemispheric neuronal pathways affect recovery following peripheral nerve injury and how these pathways can be manipulated in order to promote recovery. Results obtained from this animal study could be directly translated into clinical applications in terms of improving and developing new rehabilitation strategies.