Leading-edge neuroscience techniques are facilitating Children’s Hospital of Philadelphia researchers’ better understanding of how the brain controls bladder function, and their novel insights have earned them special recognition from the neurourology community.
Jason Van Batavia, MD, a urologist and physician-scientist in the Division of Urology at CHOP, is the grand prize winner in the 2018 Diokno-Lapides Essay Contest. His manuscript described a research project focused on optogenetic stimulation of specific neurons in a section of the brainstem called Barrington’s nucleus, which scientists think is an important “command center” for controlling voiding (urination).
Identifying these neurons’ role in voiding could help scientists to figure out new approaches to treating voiding dysfunction in children. Forty percent of children — that’s around 2,000 new patients a year — who visit CHOP’s DOVE Center for Voiding and Bladder Function have lower urinary tract (LUT) symptoms, which include high urination frequency or leakage of urine during the day or night.
“Those are some of the most common problems that we see in the pediatric urology world,” said Dr. Van Batavia, who also is a clinical instructor of Urology at the Perelman School of Medicine at the University of Pennsylvania. “And yet our understanding of them hasn’t changed much in the last few decades. There are not many new treatment options that have been available. A lot of times these conditions are frustrating for the kids and families. It takes a real commitment to get them into a better situation, but it can make a really big impact on their health and social life.”
One type of LUT condition, called voiding postponement, is when children habitually hold their urine, which results in infrequent voiding with larger volumes. They also experience a high rate of urinary tract infections. Dr. Van Batavia has been trying to mirror those clinical problems that he sees in the clinic through his basic science research in the lab, under the mentorship of urologist Stephen Zderic, MD, who is the John W. Duckett Jr. Endowed Chair in Pediatric Urology and a professor of Urology in Surgery at Penn.
Over the past decade, Dr. Zderic developed a mouse model of a social stress voiding phenotype. These mice have fewer voids and larger voided volumes. They also have elevated levels of a neurohormone called corticotropin-releasing hormone (CRH) in the Barrington’s nucleus. Mice that are not socially stressed do not have as much CRH in this brain area.
Dr. Van Batavia used a new tool in neuroscience technology called optogenetic stimulation to activate a subpopulation of CRH-expressing neurons out of the approximately 6,000 neurons that are found in the very small (about 600 micron) area in the Barrington’s nucleus of the mice. Optogenetic stimulation is a biological technique that uses light to selectively control cells of interest.
Dr. Van Batavia showed that when he stimulated CRH-expressing neurons in the Barrington’s nucleus at higher frequencies, the time between the animals’ voids increased, they had larger voiding volumes, and their bladders became larger. These alterations in voiding functions mimicked the social stress phenotype in mice. The study also showed that female mice were more sensitive to high frequency of optogenetic stimulation compared to male mice. At the same frequencies, male mice had a 50 percent increase in bladder capacity, while female mice had an almost 100 percent increase in bladder capacity.
The study’s results suggest that CRH expression in the brain and CRH receptor activity may be a key factor in some dysfunctional voiding patterns; however, Dr. Van Batavia pointed out that several subpopulations of neurons have been identified in the Barrington’s nucleus, so additional studies will be needed to tease out and define the role of CRH-expressing neurons.
“We’re trying to delineate this one population, but maybe another neuronal population is the ‘go pedal’ that we need to figure out,” Dr. Van Batavia said. “The focus of our lab has become: How is this brainstem region really controlling voiding? We may find new targets for potential therapeutics that could work in a better manner with fewer side effects than the medications that are currently being used for overactive bladder and lower urinary tract symptoms.”
Dr. Van Batavia accepted the prestigious prize at the American Urological Association Annual Meeting May 19 in San Francisco. As part of the award, he also was invited to attend the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction’s winter meeting in Austin, Texas, where he showcased the project during a short presentation and had the opportunity to share research ideas with other urologists.
“To be a really good physician-scientist, it takes a pairing and a marriage of your clinical work and basic science research,” Dr. Van Batavia said. “This is a really nice honor and a great way for others to see how the resources and collaborators here at CHOP are incredible. Our department’s mentality is that research is fundamental to helping kids have better outcomes. You can help children in the clinic all day long, but the developments that come from clinical and basic science research will open new avenues that one day could possibly prevent disease in these kids or get them cured quicker.”
Dr. Van Batavia is grateful to the Urology Care Foundation that funded his work with a research scholar award. He also acknowledges his colleagues for their research contributions and support throughout the project: Dr. Zedric; Douglas Canning, MD, chief of the Division of Urology at CHOP; Rita Valentino, PhD, former director of the Stress Neurobiology Division within the Department of Anesthesiology at CHOP; and research associates Joanna Fesi and Stephan Butler. Dr. Van Batavia also is pursuing a master’s in translational research through Penn’s Institute for Translational Medicine and Therapeutics.