Closed Loop Wireless Monitoring and Optogenetic Modulation of Bladder Function

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ABSTRACT Millions of people in the United States suffer from bladder dysfunction and pain caused by interstitial cystitis/bladder pain syndrome and overactive bladder. The underling pathologies for many of these diseases are poorly understood and this is the primary reason why most current treatments are ineffective. To address this issue, our group has designed and tested an implantable wireless optoelectronic system to monitor and modulate bladder function. Our hyper-conformal strain gauge wraps around the bladder and as the bladder expands, changes in geometry of the device linearly increases resistance which can then be directly correlated with bladder size or fullness. We have attached microscale light emitting diodes (μLED) to the strain gauge that can be used to activate light-sensitive opsins for optogenetic regulation of neuronal activity. The strain gauge and μLEDs connect to an implantable base station that allows for wireless control and monitoring of bladder activity. This new technology eliminates the need for implantation of potentially-damaging bladder catheters or electrodes, and provides unique access to bladder functionality in the awake, freely-moving rat. I plan to utilize viral delivery of opsins and a novel strain gauge that measures dynamic changes in bladder circumference, to modulate and monitor bladder function, respectively. My preliminary data show that changes in strain gauge resistance correlates to traditional bladder activity measurements like intravesicular pressure, and that virally delivered inhibitory opsin, Archaerhodopsin (Arch), can delay bladder contractions in anesthetized rats. I plan to test the ability of virally transduced Arch expressed in bladder afferents to reduce frequency and increase voiding volume after cyclophosphamide (CYP) -induced cystitis in awake animals (Aim 1a and b). I also plan to use our newly developed wireless technology to implement a closed-loop system that can recognize increased frequency of bladder contractions and initiate optogenetic inhibition to normalize voiding (Aim 1c). Bladder pain is the most common complaint of patients suffering from IC/BPS. Using our wireless μLED strain gauge, I plan to determine whether activation of activation of virally transduced Arch, in bladder afferents, is sufficient to attenuate bladder hypersensitivity in rats with CYP-induced cystitis. This sensitivity will be assayed by visceromotor response, abdominal sensitivity and real time place preference assays (Aim 2). Implementation of this new technology will provide unique access to understanding bladder functionality without the need for implantation of potentially damaging bladder catheters or electrodes. This technology could thus lead to novel insights into the mechanisms of bladder control and pain. Additionally, the refinement of this novel technology and viral delivery methods for optogenetic channels, could lead to development of future therapies for patients with bladder pain and dysfunction.