All ETDs from UAB

Advisory Committee Chair

Jennifer J Deberry

Advisory Committee Members

Burel Goodin

Benedict Kolber

Robert Sorge

Christianne E Strang

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Lower urinary tract (LUT) dysfunction is a detrimental ailment that negatively affects a person’s independence, health, and overall quality of life. More specifically, LUT dysfunction as a result of spinal cord injury (SCI) is seen in more than 17,000 cases per year and of those cases, <20% are discharged from care with normal micturition1. Initially, after SCI, there is an acute period of spinal shock when the urinary bladder is flaccid and underactive, while the external urethral sphincter (EUS) that constricts the bladder outlet quickly becomes tonically active. In days to weeks after injury, spinallymediated, reflex bladder contractions re-emerge2-4. Numerous studies have examined aspects of LUT function using various models of SCI, primarily utilizing complete transection injuries. This set of studies first examined the effect of moderate to severe midthoracic contusion SCI on LUT function by examining cystometrogram (CMG) and EUS recordings, bladder/spinal cord morphology, sensory innervation of bladder tissue, and spinal neuronal activation in female mice. This model of SCI produced significant changes in normal bladder function as well as altered bladder morphology, including a robust loss of bladder afferent nerve fibers necessary for micturition. Inhibition of histone deacetylase 6 (HDAC6) has been shown to prevent the loss of sensory nerve fibers in mouse hind paw tissue5, thus HDAC6 inhibition was examined as a possible strategy to prevent the observed loss of sensory nerve fibers in bladder tissue post-SCI. iv Mice were treated using intraperitoneal injections of inhibiting compounds ACY-1083 (10 mg/kg) or Tubacin (5 mg/kg). Treatment resulted in significant improvements in CMG measures and sensory innervation of the bladder wall. Finally, optogenetic stimulation was examined using an adenoassociated virus containing cre-recombinase for cre-dependent expression of channelrhodopsin (ChR2) in both spinal intact and SCI mice. The ability to spare afferent axons in bladder tissue post-SCI through HDAC6 inhibition allowed ChR2 expression in sensory nerve fibers. Direct photostimulation of the bladder using various parameters of duration (1, 2, 5, 10 sec continuous stimulation) and power (0.1mW/mm2, 0.95mW/mm2, 6.50mW/mm2) resulted in the ability to control bladder contractions in both spinal intact (SI) and SCI animals, allowing for on-demand voiding post-injury.

Share

COinS