This project involves a novel approach to restore muscle function following motor neuron loss, using a combination of stem cell based replacement of motor neurons and the revolutionary technique of optogenetics. Briefly, we have shown that embryonic stem cell-derived motor neurons (ESC-MNs) can be transplanted into injured peripheral nerves that have lost their endogenous motor neuron axons and that these ESC-MNs can then reinnervate the target muscles (See Bryson et al, 2012, Science). Moreover, we genetically manipulated these ESC-MNs to express the light-sensitive ion channel, channelrhodopsin-2 (ChR2), so that when we optically stimulate these ESC-MNs with blue light, they can induce finely-controlled contraction of reinnervated muscles. This approach has the potential to overcome the normally permanent atrophy and paralysis of skeletal muscles that can occur as a result of diseases such as ALS as well as by traumatic neurological injury (eg. spinal cord injury). Our long-term aim is to use this approach to maintain function of the diaphragm muscle in models of ALS, since loss of function of this respiratory muscle is the main cause of death in ALS patients. To accomplish this, we are currently investigating whether it is possible to restore muscle function in the long term in mouse models of ALS, using an implantable optical stimulator device.