Long-term Optogenetic Stimulation of Corticotropin-Releasing Hormone-Specific Neurons in Barrington's Nucleus as a Possible Model of Bladder Hypertrophy
Jason P. Van Batavia, MD1, Stephan Bulter, MS1, Joanna Fesi, BA1, Stefano Vicini, PhD2, Stephen Zderic, MD1.
1The Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2Georgetown University, Washington DC, DC, USA.
BACKGROUND: Symptoms of lower urinary tract dysfunction (LUTD) affect 20% of "normal" children and >40% of adults over the age of 40. A commonly diagnosed LUTD is voiding postponement in which children void infrequently and with large volumes. This condition is modeled in mice subjected to social stress who show decreased voiding frequency and increased voided volumes along with increases in corticotropin-releasing hormone (CRH) expression in Barrington's nucleus (BN), the pontine micturition center. We have previously shown that activation of these neurons using optogenetics leads to larger bladder volumes and longer time periods between voids in the acute setting. Here we examined the effects of optogenetic stimulation of CRH BN neurons on the in vivo voiding phenotype and bladder mass in awake mice during long-term stimulation.
METHODS: Control and double transgenic mice expressing channelrhodopsin-2 (ChR2) in CRH cells had fiberoptic probes implanted into BN at 8 weeks of age (n =6 for each group). In vivo voiding pattern (number of voids/24 hr period and volume per void) were obtained before and during 2 weeks of optogenetic stimulation 25 Hz (15msec pulses, 5 seconds on, repeated every minute) (see Figure 1).
RESULTS: During optogenetic stimulation in the double transgenic mice, the voiding pattern changed from a mean of 13 voids per day at baseline to 3.5 voids per day at the 2-week mark. Similarly, in the double transgenic mice, the mean voided areas increased by 370% between baseline and 2 week mark during optogenetic stimulation. There were no differences in either parameter in the control mice. Furthermore, bladder weight as a ratio of total body weight was increased in the double transgenic mice compared to controls after 2 weeks of stimulation (1.5 vs. 1.05, p <0.05).
CONCLUSIONS: Our results suggest that long term high frequency optogenetic stimulation of CRH-BN neurons produces a sustained change in voiding pattern that mimics the social stress voiding pattern of infrequent, larger voids. After 2 weeks of stimulation, bladder weight also increased in stimulated mice suggesting that optogenetic stimulation of CRH BN neurons may be a reproducible model for bladder hypertrophy. 
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