Micturition is regulated by neural circuits in the brain and spinal cord that coordinate the activity of the smooth and striated muscles of the lower urinary circuit. Disruption of these voluntary controls, as often occurs with spinal cord injury above the lumbosacral spinal cord, leads to the re-emergence of involuntary (reflex) voiding and incontinence. Detailed information about bladder reflex mechanisms and the manner in which they are modulated within the CNS is essential for understanding the pathophysiology of bladder hyperactivity and incontinence and for developing new therapeutic approaches to treat this disorder. It is proposed that reorganization of spinal micturition circuitry occurs in response to degeneration of bulbospinal axons as well as changes in neuron to target organ interactions. The overall goal of this proposal is to examine the effects of SCI on the neurochemical and organizational properties of spinal neurons (interneurons and preganglionic parasympathetic neurons) involved in the micturition reflex pathway.
Three specific aims are proposed: 1. To determine the organization of urinary bladder interneurons and parasympathetic neurons in the lumbosacral spinal cord (L6-S1) using a combination of transneuronal tracing with pseudorabies virus (PRV) and conventional retrograde dye tracing techniques (Fluorogold) in control and SCI animals. The chemical phenotype of PRV-labeled urinary bladder interneurons in the L6-S1 spinal cord will be determined with immunohistochemistry for neuroactive compounds in control and SCI animals. 2. To determine the chemical phenotype of urinary bladder interneurons specifically responding to bladder afferent information (non-noxious and noxious) in control and SCI animals. Fos protein expression, as an indicator of cellular activation will be combined with immunohistochemistry for neuroactive compounds. 3. Previous studies have demonstrated significant increases in urinary bladder neurotrophic factor mRNA following chronic SCI. Thus, the role of neurotrophic factors (NGF and BDNF) play in mediating neurochemical and organizational plasticity of bladder interneurons following chronic SCI will be examined with chronic administration of neurotrophic factors or neurotrophic factor neutralizing antibodies in vivo.
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