Leveraging a Novel Neural Circuit for Urinary and Fecal Incontinence

About This Grant

Project Summary/Abstract Interorgan communication between the brain and peripheral tissues maintains a range of adaptive responses that can degrade with aging. Using mouse models, we found a powerful neural circuit that simultaneously motivates spontaneous activity and overrides spinal reflexes that control bladder and colonic function. Our preliminary findings show a strong direct neural circuit between estrogen-responsive neurons in the hypothalamus and the major micturition center in the hindbrain that controls urination, the Pontine Micturition Center (PMC) or Barrington’s nucleus (BAR). When activated, this VMHvl-BAR monosynaptic circuit blocks all voiding, even when animals have been pre-loaded with saline; when inhibited, urine release increases. Similarly, when a glass bead is inserted into the colon, excretion of this pellet takes up to fifteen times longer (20 minutes versus 5 hours) if chemogenetics is used to activate this neurocircuit. In vivo cystometry results confirm the potency of this hypothalamic-hindbrain circuit in modulating urine and fecal release. Here, we will define how neurons in BAR override normal spinal reflexes in the pelvic region. We outline three independent aims to: 1) identify the molecular nature of the inhibitory neurons in BAR responsible for this change in urinary and colon function and map projections from BAR to the spinal cord controlling the bladder or colon, 2) determine the sufficiency of VMHvl-BAR circuity components in urine release, and finally, 3) determine the initiating signals in the hypothalamus that control this voiding and defecation neurocircuit. This last aim will bring us closer to translating our preclinical research to human health. Our research program adds to emerging work on brain-body physiology to advance strategies for improving health and blends the team’s expertise in neuroendocrinology and neurocircuits. We are using state-of-the-art methods to pursue hypothesis-driven questions to decode a robust neuroendocrine circuit that controls two essential processes—urination and defecation. Both functions degrade with aging, especially in older women. Eventually, we wish to translate these preclinical studies to mitigate the loss of pelvic control in the older adult US population.