An optogenetic-based control paradigm for neuromodulation of bladder function following spinal cord injury

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PROJECT SUMMARY More than 17,000 Americans suffer from spinal cord injuries every year, and many of these patients suffer from lower urinary tract dysfunction. One of these bladder disorders is detrusor-sphincter dyssynergia, where the detrusor muscle, which constricts to push urine out of the bladder, and the urethral sphincters, which relax to allow urine to pass out the urethra, cannot coordinate their actions to produce a void. Electrical neuromodulation technologies can be effective in improving symptoms of lower urinary tract dysfunction but due the complexity of the circuit and neural systems involved these therapies are unable to initiate a coordinated voiding contraction on-demand. To address these limitations, we plan to develop an optogenetic neuromodulatory approach to target and independently control the two main neuronal systems (parasympathetic and somatic motor) that are integral to the voiding reflex. Optogenetic neuromodulation involves genetically expressing optically activated proteins in neurons to modulate their activity with light stimulus. Using this method, we plan to express excitatory opsins in parasympathetic neurons innervating the detrusor by using promoter restricted expression and anatomically limited viral delivery (Aim 1). Activation of these neurons leads to detrusor/bladder contractions. To inhibit tonic urethral sphincter tone, we will use a similar approach to target the somatic motor neurons innervating the external urethral sphincter with inhibitory opsins (Aim 2). Inhibition of these neurons leads to sphincter relaxation. We will test the specificity of expression, potential off target effects, as well as the physiological effects of opsin activation in naïve and in a rat model of spinal cord injury. Finally, we will develop a control paradigm to coordinate activation of detrusor with urethral sphincter relaxation, to initiate coordinated and complete emptying of the bladder (Aim 3). The proposed project will develop innovative neuromodulatory techniques to control bladder function. Further development of refined and efficient neuromodulation techniques is the first step in developing closed-loop therapies to treat bladder dysfunction associated with spinal cord injury. Additionally, these techniques will have wide applicability in other fields of peripheral nervous system gene delivery and cell- type specific neuromodulation. Advances in neuromodulation of bladder function will bring us closer to goal of improving the lives of patients with spinal cord injury.