Pelvic organ prolapse (descent of the bladder, vagina, and rectum) and associated bladder and bowel dysfunction are problems for many women. Prolapse results from loss of support by pelvic floor musculature (predominantly levator ani muscles) and connective tissue. Given the high correlation between parity and pelvic organ prolapse, it is our overarching hypothesis that damage to the innervation of the pelvic floor during labor is a predisposing condition for pelvic organ and incontinence. This hypothesis has not been rigorously tested due to lack of a suitable animal model. Recently, we established the squirrel monkey as a model of parturition-associated prolapse. Squirrel monkeys are required to meet the specific aims that examine parturition-induced neuropathy. Studies are also proposed in the rat to provide a less expensive, neurologically well-studied, and phylogenitically lower species in which to establish basic parameters of pelvic floor innervation common to all mammals, e.g. neuronal responses to injury. Despite the obvious importance of pelvic floor innervation for maintenance of pelvic visceral support and continence, there is a considerable degree of confusion regarding normal pelvic floor innervation. While prior studies have thus focused on the pudendal nerve and its damage in pelvic organ prolapse and incontinence, our preliminary data suggest that the levator ani muscle has distinct innervation. Thus, specific aim 1 proposes to carefully define the peripheral innervation of the levator ani (LA), identify LA motor neurons and their dendritic arborizations using retrograde tracing techniques, describe the central distribution of LA primary afferent projections in the spinal cord using transganglionic tracing, and identify and characterize the transmitter phenotype of LA primary afferent neurons using retrograde tracing combined with immunohistochemistry. To test the hypothesis that parturition-associated damage to the LA nerves is a component of prolapse, specific aim 2 will a) compare pelvic organ prolapse produced by LA nerve versus pudendal nerve lesions, b) determine cellular responses of experimentally-induced nerve injury in LA primary afferent neurons and motor neurons and muscle changes that occur following nerve injury, c) examine expression of neurogenic injury markers and muscle changes following parturition, and d) compare neurogenic injury markers and myogenic changes in monkeys with no prolapse to those with severe prolapse.
Specific aim 3 will examine neurotrophin systems associated with LA innervation and mechanisms of denervation, e.g. neuronal apoptosis, axonal atrophy, etc.
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