Peripheral nerve injury causes sensory dysfunctions that are thought to be attributable to changes in neuronal activity occurring in somatosensory cortices both contralateral and ipsilateral to the injury. Recent studies suggest that distorted functional response observed in deprived primary somatosensory cortex (S1) may be the result of an increase in inhibitory interneuron activity and is mediated by the transcallosal pathway. The goal of this study was to develop a strategy to manipulate and control the transcallosal activity to facilitate appropriate plasticity by guiding the cortical reorganization in a rat model of sensory deprivation. Since transcallosal fibers originate mainly from excitatory pyramidal neurons somata situated in laminae III and V, the excitatory neurons in rat S1 were engineered to express halorhodopsin, a light-sensitive chloride pump that triggers neuronal hyperpolarization. Results from electrophysiology, optical imaging, and functional MRI measurements are concordant with that within the deprived S1, activity in response to intact forepaw electrical stimulation was significantly increased by concurrent illumination of halorhodopsin over the healthy S1. Optogenetic manipulations effectively decreased the adverse inhibition of deprived cortex and revealed the major contribution of the transcallosal projections, showing interhemispheric neuroplasticity and thus, setting a foundation to develop improved rehabilitation strategies to restore cortical functions.recovery | amputation A lthough 20 million Americans suffer from peripheral nerve injury caused by trauma, metabolic, endocrine, and autoimmune disorders, there are few strategies to promote recovery. Surgical nerve repair and training of the injured limb are the classical rehabilitation approaches. Nevertheless, the clinical outcome in adults is generally poor, with persisting sensory dysfunction and pain (1).Recent evidence suggests that sensory dysfunctions caused by nerve injury should be attributable not only to the functional, cellular, and biochemical events occurring in peripheral nerve but also functional and anatomical changes occurring in cerebral cortical representations. It is well-documented in humans (2), non-human primates (3), cats (4), and rodents (5-7) that peripheral nerve injury can lead to expansion of neighboring cortical representation of peripheral regions within the affected (deprived) hemisphere (intrahemispheric neuroplasticity). Peripheral nerve injury and direct cortical lesions have been shown to also modify functional communication between cortical hemispheres (interhemispheric neuroplasticity) (8-19). Specifically, peripheral inputs normally evoking neuronal responses in the contralateral hemisphere cause inappropriate functional responses in the ipsilateral hemisphere. Previously, using singleunit electrophysiology recordings and juxtacellular labeling, it was shown that the inappropriate ipsilateral functional magnetic resonance imaging (fMRI) responses observed in deprived primary somatosensory cor...