Characterizing the Neural Pathway Maintaining Urinary Continence and its Role in Hydrocephalic Incontinence

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ABSTRACT Urinary urge incontinence affects nearly 20 million Americans, causing loss of independence and feelings of depression. Among those affected, are patients with Normal Pressure Hydrocephalus (NPH), who experience urge incontinence as one of three symptoms. Despite large economic and caregiver burden associated with incontinence, little is known about the neural pathway responsible for control of continence or how this pathway may be disrupted in NPH. The overall objective of this project is to identify this pathway and determine how it is altered in NPH. Barrington’s nucleus (Bar) in the dorsal pons is considered the micturition center, as it facilitates voiding in response to input from the periaqueductal gray (PAG), which signals bladder stretch. However, this reflex does not explain complex micturition behaviors, like continence, for which other brain regions must be involved. Imaging studies of the medial prefrontal cortex (mPFC) show that this area is involved in micturition and mPFC hypoperfusion in NPH or strokes to this region are associated with incontinence. Additionally, lesions to the preoptic area of the hypothalamus (POA) can also produce incontinence. Furthermore, the POA receives input from the mPFC and sends output directly to Bar. This data suggests a role for both the mPFC and POA in continence control. Our central hypothesis is that the pathway maintaining continence connects excitatory neurons in mPFC to Bar via inhibitory relay neurons in POA, and that disruption of this pathway in the periventricular white matter causes incontinence in NPH. To test this hypothesis, we propose the following aims: 1) Characterize the role of the mPFC → Bar pathway in micturition. I will test the hypothesis that this pathway is necessary for maintaining continence and that stimulation of the latter half of this pathway is sufficient to restore continence. First, I will combine anterograde tracing with immunohistochemistry to identify this multi-synaptic pathway. Secondly, I will test this pathway’s function by lesioning the mPFC and stimulating POA terminals in Bar. We hypothesize that the lesions will create incontinence and the stimulation will restore continence. 2) Identify and overcome differences in NPH incontinent mice. We have already created a progressive hydrocephalus in mice that is often accompanied by incontinence. I will expand this study by assessing the tissue of these incontinent mice for axonal injuries, hypothesizing that we will see demyelination in the white matter tracts connecting the mPFC to the POA, running alongside the ventricles. Then we will stimulate POA terminals in Bar in these mice. We hypothesize that stimulation here will improve incontinence caused by hydrocephalus. By the end of this project, I will have identified the pathway connecting the medial prefrontal cortex to Barrington’s nucleus, determined its role in the maintenance of continence, identified structural differences of this pathway in mice with hydrocephalus, and manipulated this pathway to restore continence to incontinent mice. This work will expand current treatment options for patients suffering from incontinence, both with and without NPH, by identifying new therapeutic targets.