Non-Crh Glutamatergic Neurons in Barrington’s Nucleus Control Micturition via Glutamatergic Afferents from the Midbrain and Hypothalamus

• Published in: Current biology 2019-09, Vol.29 (17), p.2775-2789.e7
• Main Authors: Verstegen, Anne M.J., Klymko, Nataliya, Zhu, Lin, Mathai, John C., Kobayashi, Reina, Venner, Anne, Ross, Rachel A., VanderHorst, Veronique G., Arrigoni, Elda, Geerling, Joel C., Zeidel, Mark L.
• Format: Article
• Language: English
• Subjects: Animals; Barrington's nucleus; Barrington's Nucleus - physiology; bladder; corticotropin-releasing hormone; Corticotropin-Releasing Hormone - metabolism; cystometry; Female; Hypothalamus - metabolism; lateral hypothalamic area; Male; Mesencephalon - metabolism; Mice; micturition; micturition video thermography; neural circuits; Neurons - physiology; Neurons, Afferent; neuroscience; periaqueductal gray; Urination - physiology
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2019.07.009

Lower urinary tract symptoms (LUTS) are exceptionally common and debilitating, and they are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. An incomplete understanding of neural control of bladder function limits our ability to clinically address LUTS. Barrington’s nucleus (Bar) provides descending control of bladder and sphincter function, and its glutamatergic neurons expressing corticotropin releasing hormone (BarCrh/Vglut2) are implicated in bladder control. However, it remains unclear whether this subset of Bar neurons is necessary for voiding, and the broader circuitry providing input to this control center remains largely unknown. Here, we examine the contribution to micturition behavior of BarCrh/Vglut2 neurons relative to the overall BarVglut2 population. First, we identify robust, excitatory synaptic input to Bar. Glutamatergic axons from the periaqueductal gray (PAG) and lateral hypothalamic area (LHA) intensely innervate and are functionally connected to Bar, and optogenetic stimulation of these axon terminals reliably provokes voiding. Similarly, optogenetic stimulation of BarVglut2 neurons triggers voiding, whereas stimulating the BarCrh/Vglut2 subpopulation causes bladder contraction, typically without voiding. Next, we genetically ablate either BarVglut2 or BarCrh/Vglut2 neurons and found that only BarVglut2 ablation replicates the profound urinary retention produced by conventional lesions in this region. Fiber photometry recordings reveal that BarVglut2 neuron activity precedes increased bladder pressure, while activity of BarCrh/Vglut2 is phase delayed. Finally, deleting Crh from Bar neurons has no effect on voiding and related bladder physiology. Our results help identify the circuitry that modulates Bar neuron activity and identify subtypes that may serve different roles in micturition. [Display omitted] •In vivo neuroscience techniques and thermography combined to study urinary continence•PAG and LHA neurons provide direct excitatory innervation of Barrington’s nucleus•Optogenetic stimulation of neural afferents leads to different void-behavior sequence•The glutamatergic Bar population is necessary and sufficient for micturition behavior Verstegen et al. shine light on Barrington’s nucleus, in which neuron subpopulations have distinct activity patterns important for coordinating downstream bladder control. Furthermore, they identify nodes on the pathway to activate the micturition control c