Corticotropin-Releasing Hormone Expressing Neurons of the Pontine Micturition Center Inhibit Volitional Micturition

Abstract

Lower urinary tract or voiding disorders are prevalent across all ages and affect over 40% of adults over 40 years old leading to decreased quality of life and high healthcare costs. The pontine micturition center (PMC) contains a large population of neurons that co-localize the stress-related neuropeptide, corticotropin-releasing hormone (CRH) and project to neurons in the spinal cord to regulate micturition. How the PMC and CRH-expressing neurons in the PMC control volitional micturition is of critical importance for human voiding disorders. To investigate the specific role of these CRH-expressing PMC neurons, these neurons were optogenetically stimulated during in vivo cystometry in unanesthetized mice. Optogenetic activation of CRH-PMC neurons led to increased intermicturition interval and voided volume, similar to the altered voiding phenotype produced by social stress. These effects were eliminated by CRH-receptor 1 antagonist pretreatment. In a cyclophosphamide cystitis model of bladder overactivity, optogenetic stimulation of CRH-PMC neurons returned the voiding pattern to normal. Collectively, our findings demonstrate that CRH in PMC spinal projections has an inhibitory function on micturition and may be a potential therapeutic target for human disease states such as voiding postponement, urinary retention, and under- or over-active bladder.