PROJECT 4 - Spinal cord injury (SCI) at a supralumbar level induces severe lower urinary tract (LUT) dysfunctions including detrusor-sphincter-dyssynergia (DSD) which results in inefficient bladder emptying, high voiding pressure and large residual urine volumes. This project will study the spinal pathways that regulate reflex activity of the external urethral sphincter (EUS) of the rat and analyze the pathophysiological mechanisms underlying the development of DSD after chronic SCI. Based on our recent electrophysiological studies in SCI rats we hypothesize that the EUS exhibits two types of activity that are controlled by circuitry at two levels of the spinal cord. Tonic EUS activity that maintains continence during bladder filling is controlled by pathways at the L6-S1 segmental level and bursting activity which consists of intermittent contractions and relaxations of the EUS that facilitate voiding is controlled by neural circuits in the lumbar spinal coordinating center (LSCC) located in the L3-L4 spinal cord. Increased tonic EUS activity and reduced bursting activity after SCI increases urethral outlet resistance and reduces voiding efficiency leading to urinary retention. We propose that the LSCC is normally regulated by the brain to induce EUS bursting during voiding and this regulation is initially lost after SCI but recovers in chronic SCl animals due to remodeling of spinal synapses. However the recovery of LSCC function is negated by remodeling in the Le- Si cord that enhances tonic EUS activity leading to DSD. The role of spinal remodeling and its consequences on EUS function will be examined as follows.
Aim 1 will use axonal and transneuronal viral tracing methods to characterize the components of the LSCC in intact, acute and chronic SCI rats.
Aim 2 will examine the electrophysiological properties of the LSCC as well as its afferent input and output circuits using optical imaging and electrical recording in in vivo and in vitro spinal cord slice preparations.
Aim 3 will use patch clamp methods and optical mapping of spinal cord slice preparations in combination with transneuronal virus tracing methods to identify the plasticity in L6-S1 spinal circuits controlling the tonic activity in EUS motoneurons that underlies DSD in chronic SCI animals.

Public Health Relevance

More detailed information about the plasticity of LUT spinal circuitry in paraplegic animals, particularly in regard to synaptic remodeling and neurotransmitter mechanisms underlying detrusorrsphincter-dyssynergia could lead to new treatments for the detrusor-sphincter dyssynergia that contributes to neurogenic and myogenic LUT dysfunction.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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University of Pittsburgh
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Kullmann, F Aura; Beckel, Jonathan M; McDonnell, Bronagh et al. (2018) Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice. Naunyn Schmiedebergs Arch Pharmacol 391:1191-1202
Zabbarova, Irina V; Ikeda, Youko; Carder, Evan J et al. (2018) Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. Neurourol Urodyn 37:2452-2461
Shimizu, Nobutaka; Wada, Naoki; Shimizu, Takahiro et al. (2018) Effects of nerve growth factor neutralization on TRP channel expression in laser-captured bladder afferent neurons in mice with spinal cord injury. Neurosci Lett 683:100-103
Ryu, Jae Cheon; Tooke, Katharine; Malley, Susan E et al. (2018) Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 128:1772-1786
Wada, Naoki; Shimizu, Takahiro; Shimizu, Nobutaka et al. (2018) The effect of neutralization of nerve growth factor (NGF) on bladder and urethral dysfunction in mice with spinal cord injury. Neurourol Urodyn :
Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2018) Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type-specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190-201]. Neuroscience 381:161
Beckel, Jonathan M; de Groat, William C (2018) The effect of the electrophilic fatty acid nitro-oleic acid on TRP channel function in sensory neurons. Nitric Oxide :
Ikeda, Youko; Zabbarova, Irina V; Birder, Lori A et al. (2018) Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice. Neurourol Urodyn 37:2441-2451
Shimizu, Takahiro; Majima, Tsuyoshi; Suzuki, Takahisa et al. (2018) Nerve growth factor-dependent hyperexcitability of capsaicin-sensitive bladder afferent neurones in mice with spinal cord injury. Exp Physiol 103:896-904
Kullmann, F A; Chang, H H; Gauthier, C et al. (2018) Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. Acta Physiol (Oxf) 222:

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