Journal
CURRENT BIOLOGY
Volume 29, Issue 17, Pages 2775-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2019.07.009
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Funding
- NIH [P20DK103086, RO1DK113030]
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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 (Bar(crh/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 Bar(crh/vglut2) neurons relative to the overall Bar(Vglut2) 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 Bar(Vglut2) neurons triggers voiding, whereas stimulating the Bar(crh/vglut2) subpopulation causes bladder contraction, typically without voiding. Next, we genetically ablate either Bar(Vglut2) or Bar(crh/vglut2) neurons and found that only Bar(vglut2) ablation replicates the profound urinary retention produced by conventional lesions in this region. Fiber photometry recordings reveal that Bar(vglut2) neuron activity precedes increased bladder pressure, while activity of Bar(crh/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.
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