Visceral Neurophysiology and Engineering Lab

The Visceral Neurophysiology and Engineering Lab, led by Dr. Aaron Mickle, is based in the Department of Physiology at the Medical College of Wisconsin. Our research focuses on neuronal control of bladder dysfunction and pain. Specifically, we investigate the fundamental mechanisms underlying bladder sensory function, including how sensory information is transmitted from non-neuronal cells within the bladder to sensory neurons. Additionally, we explore how the central nervous system encodes this information. Our lab is committed to developing innovative treatments for various bladder disorders, such as overactive bladder, bladder pain syndrome, and bladder dysfunction following spinal cord injury. We approach this challenge from multiple angles, including:

• Research tool development: Creating advanced tools to study bladder function and dysfunction.

• Implantable biomedicine treatments: Exploring novel approaches for managing bladder-related conditions.

• Validating new pharmacological targets: Identifying potential drug targets to improve patient outcomes.

Furthermore, we extend our interest beyond bladder-related issues to include pelvic organ pain and interoception. Our goal is to enhance our understanding of these complex physiological processes and contribute to better patient care.

Overview of the bladder sensory pathway and bladder anatomy. A Mechanical and chemical stimuli are transduced to convey the state of the bladder, ascending via the hypogastric (T10, L1, and L2) and pelvic (L6, S1) nerves to the periaqueductal gray (PAG) and other supraspinal sites such as the pontine micturition center (PMC). B Major anatomy of the urinary bladder. C The layers of the bladder, traveling up from the outermost adventitia/serosa to the lumen. Published - https://scholarworks.uvm.edu/graddis/1659. Original artwork by Harrison Hsiang https://www.hsiangarts.com/.

Lab Holiday Gathering 2023.

news

Oct 25, 2024	Hannah Anderson published her first first-author paper in American Journal of Physiology-Renal. Her review “Role of Local Angiotensin II Signaling in Bladder Function” evaluates the literature investigating angiotensin II signaling in the bladder. Congrats to all the authors! Read Here Review Graphical Abstract.
Sep 12, 2024	Our dynamic team at the Medical College of Wisconsin is seeking a post-doctoral researcher to join our group studying mechanisms of bladder sensation, interoception, and pain. The candidate would have the opportunity to lead studies involving signaling between nociceptors and non-neuronal cells in models of interstitial cystitis and bladder pain. They would have the opportunity to learn a variety of techniques from animal behavior, cytometric testing, electrophysiology, fMRI, and optogenetics. Additionally, there are resources available to initiate independent projects with the aim of building an independent research career. Interested applicants can reach out to Aaron Mickle directly through email amickle@mcw.edu. More information about the lab can be found at micklelab.com
Sep 01, 2024	The lab has recently received a notice of award for a new 5-year R01 to study the role of urothelial cells in sensory signaling. With Co-investigators Jim Hokanson and Shahab Vahdat (UC -Riverside), we will start to define a role for the sensory component of urothelial cells in bladder sensation, interoception, and pain. This study will use a recently published animal model that allows us to isolate urothelial stimulation using optogenetics. Congrats to the whole team! Diagram of the optogenetic model used to study the role of urothelial cells in bladder sensation
Jul 01, 2024	We have arrived and have started establishing the lab and collaberations at MCW! Medical College of Wisconsin Campus.
Jun 01, 2024	Dr. Mickle was recently interviewed for an article on brain bladder interactions and how urine urgency is perceived. Read Here

selected publications

Acute ampakines increase voiding function and coordination in a rat model of SCI

Sabhya Rana , Firoj Alom , Robert C Martinez , David D Fuller , and Aaron D Mickle

Elife, 2024

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Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague–Dawley rats received a unilateral contusion of the T9 spinal cord (n = 10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed 5 d post-SCI under urethane anesthesia. Data were compared to responses in spinal-intact rats (n = 8). The ‘low-impact’ ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously. The HPCD vehicle had no discernible impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.
Optogenetic urothelial cell stimulation induces bladder contractions and pelvic nerve afferent firing

Gabriella L Robilotto , Olivia J Yang , Firoj Alom , Richard D Johnson , and Aaron D Mickle

Am. J. Physiol. Renal Physiol., Aug 2023

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Urothelial cells, which play an essential role in barrier function, are also thought to play a sensory role in bladder physiology by releasing signaling molecules in response to sensory stimuli that act upon adjacent sensory neurons. However, it is challenging to study this communication due to the overlap in receptor expression and proximity of urothelial cells to sensory neurons. To overcome this challenge, we developed a mouse model where we can directly stimulate urothelial cells using optogenetics. We crossed a uroplakin II (UPK2) cre mouse with a mouse that expresses the light-activated cation channel channelrhodopsin-2 (ChR2) in the presence of cre expression. Optogenetic stimulation of urothelial cells cultured from UPK2-ChR2 mice initiates cellular depolarization and release of ATP. Cystometry recordings demonstrated that optical stimulation of urothelial cells increases bladder pressure and pelvic nerve activity. Increases in bladder pressure persisted, albeit to a lesser extent, when the bladder was excised in an in vitro preparation. The P2X receptor antagonist PPADS significantly reduced optically evoked bladder contractions in vivo and ex vivo. Furthermore, corresponding nerve activity was also inhibited with PPADS. Our data suggest that urothelial cells can initiate robust bladder contractions via sensory nerve signaling or contractions through local signaling mechanisms. These data support a foundation of literature demonstrating communication between sensory neurons and urothelial cells. Importantly, with further use of these optogenetic tools, we hope to scrutinize this signaling mechanism, its importance for normal micturition and nociception, and how it may be altered in pathophysiological conditions.NEW & NOTEWORTHY Urothelial cells play a sensory role in bladder function. However, it has been particularly challenging to study this communication as both sensory neurons and urothelial cells express similar sensory receptors. Here we demonstrate using an optogenetic technique, that specific urothelial stimulation alone resulted in bladder contractions. This approach will have a long-lasting impact on how we study urothelial-to-sensory neuron communication and the changes that occur under disease conditions.