Neuroscience… of the bladder

Posted by Catie Profaci on November 19, 2020 in Sensory Systems, Uncategorized | Leave a comment

When we think of neuroscience, we often think of the brain. If I were to pick my top neuroscience emojis, the brain is my obvious go-to, followed by the microscope and petri dish, or perhaps the little colorful bar graph. But so much of neuroscience is concerned with happenings outside the brain itself. For instance, neural signaling controls and coordinates our muscle movements, alerts us when our stomach is empty, produces a physiological response to arousal, and sends a painful alarm when we damage our skin. Neural signaling is also important for telling us when it’s time to pee. 

How does the brain know what the bladder is doing?

The bladder – like all organs – is set up to send and receive messages to and from the brain. Little bundles of neurons called dorsal root ganglia (or “DRG”), which sit outside the spinal cord, act as relay centers between your spine and your organs. DRG neurons send long arms out to the bladder (or whatever organ they’re in charge of talking to) to pick up signals, and send other long arms to the spinal cord to pass that signal up to the brain. The brain can send signals back to the bladder through different neurons in the spinal cord that then control the muscles involved in urinary reflexes. 

The bladder is a layer of muscle, but the inside of it is lined with a set of cells called umbrella cells. They form an impermeable barrier for all the liquid in the bladder, preventing it from touching the underlying muscle. Umbrella cells have a unique way of changing shape so that they can maintain this barrier as the bladder expands. It had long been understood that the brain must somehow sense this stretching and turn it into a conscious thought of “I need to pee,” but it was unclear exactly who did the primary stretch sensing, the umbrella cells or the DRG neurons, and how. The mechanisms were a mystery until recently, when Dr. Kara Marshall solved a major part of the puzzle [1]. Marshall, part of Dr. Ardem Patapoutian’s research group at The Scripps Research Institute, hypothesized that the mechanotransducer PIEZO2 was involved, and she was right.

Mechanotrans-what?

We have sensory neurons throughout our bodies that translate input from the outside world into electrical signals processed by the brain. For example, when you eat a brownie, molecules of the brownie bind to receptors on cells in your taste buds. This binding creates a set of signals that activate nearby sensory neurons. They dutifully pass the signal along, and your brain produces the conscious perception of something sweet and chocolatey. Something similar happens for all senses, including touch. In the case of touch, the input isn’t microscopic brownie pieces but rather a bit of physical pressure – “mechanosensation”. PIEZO2 is a channel that sits in the cell membrane, and when that cell is exposed to certain types of physical pressure, the PIEZO2 channel opens, allowing ions to flow into the cell and thus creating an electrical signal from the physical one. Because it senses a mechanical force, PIEZO2 can be called a “mechanosensor” or “mechanotransducer”.

Before Dr. Kara Marshall chose to explore the role of PIEZO2 in bladder function, PIEZO2 had already achieved star status as a mechanosensor. Mice without PIEZO2 particular skin cells and skin sensory neurons no longer respond to light touch sensations [2]. The effect is specific to light touch because different mechanosensors are responsible for different types of touch. PIEZO2 is also involved in proprioception, the awareness of the body’s position in space [3].

What if you couldn’t tell when you needed to pee?

So, might PIEZO2 be involved in sensing bladder stretch? To answer this question, Marshall and colleagues first turned to a group of twelve people who were born genetically deficient in PIEZO2, all of whom lacked proprioception and touch discrimination on smooth skin. The researchers designed a questionnaire to understand whether these people also had any pathologies associated with urination. Interestingly, they found that all twelve peed fewer times daily than is typical, and most said that they follow a peeing schedule because they could go all day without feeling a need to do so. Many reported not feeling anything until suddenly feeling that it was a pee-emergency, and three said that they lean over or apply manual pressure to their abdomens to start peeing. It seemed like the researchers might be on the right track.

Next, the researchers turned to study PIEZO2 in the mouse bladder. They saw that a majority of both umbrella cells and DRG neurons associated with the bladder express PIEZO2. To investigate whether it’s necessary for sensing bladder stretch, the researchers created a mouse line that does not have PIEZO2 in its umbrella cells or DRG neurons. They then manually filled the mouse bladders with saline at a constant rate. Mice with functional PIEZO2 experienced bladder contractions at regular intervals, while mice without PIEZO2 had irregular bladder contractions, meaning that they were not properly sensing and responding to the bladder filling. 

Of course, you can’t ask a mouse if it peed on purpose or by accident, but you can make some guesses based on where and how much they pee. The researchers placed mice on a piece of filter paper for four hours. They then analyzed the filter paper for pee spots. Typical mice peed pretty much exclusively in the corners of the paper or around the edges – mice don’t usually like spending time in open spaces. The mice without PIEZO2 didn’t spend any more time overall in the paper’s center than control mice, but they did pee in the center, sometimes in little spurts that looked like leaks and sometimes in large spots that look like they might have been accidents. The PIEZO2-deficient mice also displayed thickening of the bladder wall, which is a common consequence of chronic inefficient peeing. 

Which cells are the most important for sensing bladder stretch?

It was clear from the researchers’ experiments that PIEZO2 is important in sensing bladder stretch, and they had found that PIEZO2 was present in both the umbrella cells and DRG neurons. So which cell type was the most important? They used different methods to delete PIEZO2 from each of the two cell types separately and found that PIEZO2 is actually required in both the umbrella cells and the DRG neurons for proper urinary sensation and reflexes. The next step is to figure out how the two cell types cooperate with each other to tell you when it’s time to head to the bathroom.

So next time you feel an urge to pee, give a little thank you to PIEZO2 for the heads up.

References

1. Marshall, K.L., Saade, D., Ghitani, N. et al. PIEZO2 in sensory neurons and urothelial cells coordinates urination. Nature (2020). https://doi.org/10.1038/s41586-020-2830-7
2. Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bégay V, Coste B, Mainquist J, Wilson AJ, Francisco AG, Reddy K, Qiu Z, Wood JN, Lewin GR, Patapoutian A. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature. 2014 Dec 4;516(7529):121-5. doi: 10.1038/nature13980. PMID: 25471886; PMCID: PMC4380172.
3. Woo SH, Lukacs V, de Nooij JC, Zaytseva D, Criddle CR, Francisco A, Jessell TM, Wilkinson KA, Patapoutian A. Piezo2 is the principal mechanotransduction channel for proprioception. Nat Neurosci. 2015 Dec;18(12):1756-62. doi: 10.1038/nn.4162. Epub 2015 Nov 9. PMID: 26551544; PMCID: PMC4661126.
4. Williams, D. (2012). Management of bladder dysfunction in patients with multiple sclerosis. Nursing Standard, 26(25), 39–46.doi:10.7748/ns2012.02.26.25.39.c8951 
5. Taberner FJ, Prato V, Schaefer I, Schrenk-Siemens K, Heppenstall PA, Lechner SG. Structure-guided examination of the mechanogating mechanism of PIEZO2. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14260-14269. doi: 10.1073/pnas.1905985116. Epub 2019 Jun 24. PMID: 31235572; PMCID: PMC6628815.