The cellular and biochemical changes that define ripening of the prepartum cervix occur well before birth. Recent findings indicate that the ripening process is associated with inflammation; immigration and activation of leukocytes coincide with the discovery of an increased local innervation and plasticity of central connections to the murine cervix by the day before birth. Based upon these findings, the main objective of this proposal is to test the hypothesis that neural signals are essential to the mechanism for remodeling the cervix in preparation for birth. A systematic approach is taken in the Research Plan to focus on the contribution of pelvic, hypogastric, and vagus pathways, their sensory and autonomic projections, as well as the role of progesterone withdrawal on inflammation and remodeling in the cervix at the conclusion of pregnancy. Methods were developed to estimate nerve fiber density and to trace neural projections from the cervix to the brain in mice and rats. Although central connections to the nonpregnant cervix have been reported, determination of precisely which pathways are responsible for the increase in nitric oxide-producing fibers and neuropeptidergic fibers at the conclusion of pregnancy is the major objective of this proposal. Three approaches will be taken to understand the importance of innervation for remodeling the pregnant cervix:
In Specific Aim 1, effects of surgical denervation will be assessed histologically to determine the relative contribution of each pathway to enhance the density of nerve fibers into the pregnant cervix before birth. Denervation of specific sensory afferents, but not other neural projections, is proposed to disrupt cervical ripening. A second study will explore the possibility that specific neurotransmitters, as eliminated by chemical neurectomy, block remodeling of cervix.
In Specific Aim 2, retrograde neural tract tracers will be used to study the primary and multisynaptic neural connections between the cervix, spinal cord, and brain. In the last specific aim, regulation of neural projections and their activity in the cervix before term is proposed to depend upon functional withdrawal of progesterone. The reduced trophic action of progesterone is proposed to induce local neural proliferation, central plasticity, and initiation of the inflammatory cascade that ripens the cervix in preparation for birth. Relevant assessments of the time course for neurogenic inflammation in the cervix may foretell the progress of pregnancy and could prove useful to accurately predict when birth will occur at term or, with pathological remodeling, be indicative of preterm delivery. Thus, our findings are expected to provide new insights about the mechanism of ripening and novel neuroimmune therapeutic approaches to either promote dilation of the cervix or inhibit the incidence of preterm birth. ? ? ?
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