Corticotropin-Releasing Hormone from the Pontine Micturition Center Plays an Inhibitory Role in Micturition

Abstract

Lower urinary tract or voiding disorders are prevalent across all ages and affect .40% of adults over 40 years old, leading to decreased quality of life and high health care costs. The pontine micturition center (PMC; i.e., Barrington's nucleus) contains a large population of neurons that 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 CRH in the PMC, neurons in the PMC-expressing CRH were optogenetically activated during in vivo cystometry in unanesthetized mice of either sex. Optogenetic activation of CRH-PMC neurons led to increased intermicturition interval and voided volume, similar to the altered voiding phenotype produced by social stress. Female mice showed a significantly more pronounced phenotype change compared with male mice. These effects were eliminated by CRH-receptor 1 antagonist pretreatment. Optogenetic inhibition of CRH-PMC neurons led to an altered voiding phenotype characterized by more frequent voids and smaller voided volumes. Last, in a cyclophosphamide cystitis model of bladder overactivity, optogenetic activation of CRH-PMC neurons returned the voiding pattern to normal. Collectively, our findings demonstrate that CRH from PMC spinal-projecting neurons has an inhibitory function on micturition and is a potential therapeutic target for human disease states, such as voiding postponement, urinary retention, and underactive or overactive bladder.

Male Lower Urinary Tract Dysfunction: An Underrepresented Endpoint in Toxicology Research

“…During the voiding phase, corticotropin releasing hormone-positive and estrogen receptor 1-positive neurons within Barrington's nucleus activate efferent pathways to drive detrusor contraction [62,70,71]. Additional neurons in Barrington's nucleus send inhibitory signals to the external urethral sphincter, driving its relaxation and allowing urine to flow unimpeded from the bladder into the urethra [71][72][73]. Though there is widespread evidence that environmental contaminants can disrupt connectivity, complexity, arborization, and signaling of neurons within the peripheral and central nervous system, whether environmental chemicals impact bladder ascending and descending neural pathways is rarely examined [74][75][76][77][78][79][80].…”

Full regeneration of descending corticotropin-releasing hormone axons after a complete spinal cord injury in lampreys

“…Interestingly, we have recently discovered the presence of a descending system of neurons that express the neuropeptide corticotropin-releasing hormone (CRH) in the sea lamprey brain [34] . CRH is a neuropeptide of interest in the SCI context because descending CRH projections from the Barrington’s nucleus (pontine micturition center) to the spinal cord control micturition behavior in mammals [35] , [36] . Specifically, CRH from Barrington’s nucleus spinal cord-projecting neurons inhibits micturition [36] , [37] , [38] .…”

“…CRH is a neuropeptide of interest in the SCI context because descending CRH projections from the Barrington’s nucleus (pontine micturition center) to the spinal cord control micturition behavior in mammals [35] , [36] . Specifically, CRH from Barrington’s nucleus spinal cord-projecting neurons inhibits micturition [36] , [37] , [38] . Restoration of urination control is one of the main aims in SCI patient management [39] .…”

Somatostatin Neurons in the Mouse Pontine Nucleus Activate GABAA Receptor Mediated Synaptic Currents in Locus Coeruleus Neurons

“…In the BRN, neurons expressing corticotropin-releasing factor (CRF + ) are of particular importance due to their regulation of bladder function (Hou et al, 2016;Keller et al, 2018;Van Batavia et al, 2021). These CRF + neurons in the BRN are glutamatergic, while those that are CRF − are thought to be either GABAergic or glutamatergic (Hou et al, 2016) and may include SST + GABAergic neurons.…”