Loss of urinary bladder control has a major detrimental impact upon women and men suffering from a variety of trauma and disease including spinal cord injury, interstitial cystitis, stress incontinence, multiple sclerosis, aging, and others. The etiologies of bladder dysfunction are different for each of these groups, but all are neurogenic. My long term goal is to provide data on neural control mechanisms that can be used in the development of drugs which can restore useful bladder function to these populations. To attain this goal, it is necessary to establish the neural pathways and neurotransmitters controlling the bladder and to test how their synaptic connections are altered as a result of experimental injury or disease. These data can then be used to develop drugs that can act on altered pathways to restore bladder function in humans. Though often conducted without regard to gender, experiments in animal models over the past 15 years have made significant progress toward delineating the normal neural circuitry to the bladder. Recent experiments in the sacral spinal cord of the cat have provided new data which challenge current concepts of bladder control mechanisms and which may alter future experimental and clinical approaches to this system. These experiments indicate (1) there may be more than one type of preganglionic neuron innervating the urinary bladder (current thinking includes only one type) and (2) bladder preganglionic neurons have multiple functions within the spinal cord (current thinking includes no central function). They further indicate (3) that bladder preganglionic neurons may belong to a morphologically distinct group of preganglionic neurons that have a unique dendritic structure. The immediate goals of the current experiments will be to test these hypotheses and to determine if gender plays a significant role at this level of organization.In these experiments, the electrophysiological characteristics of sacral preganglionic neurons innervating the bladder in the cat will be examined for evidence of functional subgroups. Additionally, bladder preganglionic neurons will be filled with the tracer neurobiotin and their dendritic and axonal structure examined with light microscopy to provide morphological evidence of subgroups and of central functions, including recurrent inhibition of bladder preganglionic neurons; reciprocal inhibition of non-bladder preganglionic neurons; and reciprocal inhibition of the urethral sphincter muscles during bladder contraction.Electron microscopy will be used to examine axon collateral synapses within the spinal cord as further confirmation of central functions and as a precursor to identification of neurotransmitters in these boutons.Synapses upon specific dendrites of bladder preganglionic neurons will be examined to provide information regarding the central afferent controls made upon these neurons and to provide preliminary information on the neurotransmitters at these sites. These experiments are essential to developing an accurate understanding of bladder reflex pathways and toward achieving the long term goals of bladder control.
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