PROJECT SUMMARY Multiple sclerosis (MS) is an auto-inflammatory disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States and more than 2.1 million people worldwide. Lower urinary tract symptoms (LUTS) are present in 70–90% of MS patients, and include urinary frequency, urgency, incontinence, nocturia, incomplete bladder emptying, weak stream, and retention of urine. We recently characterized a new mouse model of neurogenic bladder dysfunction induced by a coronavirus. The virus triggers acute inflammation in the CNS (coronavirus-induced encephalomyelitis, CIE model) followed by progressive demyelination in the brain and spinal cord. CIE mice develop a significant neurologic deficit associated with voiding dysfunction that is comparable with neurogenic LUTS observed in MS patients. The mechanisms underlying neurogenic LUTS in CIE mice include morphological changes in the neuronal centers controlling micturition, activation of spinal glia, increased expression of pro-inflammatory cytokines during acute phase of infection, and enhanced purinergic responses of bladder contractions. Our recent study performed a long-term follow up of CIE mice and revealed 3 differential phenotypes of neurodegenerative symptom development: 1-chronic progression of neurodegeneration with continuous presence of symptoms (C-PRO group), 2 – presence of several remission-relapsing episodes (C-RELAP group), and 3 - recovery from initial symptoms after acute phase of the disease (REC group). Urodynamic evaluation of voiding patterns in each subgroup revealed that mice in C-RELAP group showed the most severe neurogenic bladder overactivity associated with lower bladder capacity, reduced inter-micturition interval, and decreased pressure at micturition. Therefore, the CIE model provides a unique opportunity for the comparison of neurogenic LUTS in three major types of human MS (remissive, chronic and relapsing-remitting). This application builds upon our initial findings, and will uncover the detailed systemic and cellular mechanisms of neurogenic LUTS in order to improve the assessment, diagnosis, and care of LUTS in MS patients. Specific Aim 1 will determine the role of spinal glia activation (gliosis) in modulation of neuronal signaling in the central (spinal) and peripheral (sensory and motor autonomic ganglia) centers involved in the control of micturition. We will evaluate the mechanistic link between glial activation in the spinal cord and functional changes in bladder innervating neurons during early, advanced and chronic stages of MS progression. Specific Aim 2 will test the ability of targeted immunotherapy to improve neurogenic LUTS in a murine model of MS. The proposed experiments will utilize neuroanatomical, biochemical, electrophysiological, pharmacological, pharmacogenetic, immunotherapeutic, and behavioral experiments to provide a comprehensive assessment of the mechanisms underlying the development of neurogen...