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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK093424-01A1
Application #
8463699
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Project Start
Project End
Budget Start
2013-08-20
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$273,308
Indirect Cost
$93,790
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Yunoki, Takakazu; Takimoto, Koichi; Kita, Kaori et al. (2014) Differential contribution of Kv4-containing channels to A-type, voltage-gated potassium currents in somatic and visceral dorsal root ganglion neurons. J Neurophysiol 112:2492-504
Takahashi, Ryosuke; Yoshizawa, Tsuyoshi; Yunoki, Takakazu et al. (2013) Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 ?-subunit in rats with spinal cord injury. J Urol 190:2296-304
Honda, Masashi; Yoshimura, Naoki; Inoue, Seiya et al. (2013) Inhibitory role of the spinal galanin system in the control of micturition. Urology 82:1188.e9-13