The role of lumbosacral innervating noradrenergic neurons in micturition control

Abstract

A long-standing observation is that the micturition reflex receives supraspinal descending control. Although one supraspinal nucleus (Barrington's nucleus) is identified as the pontine micturition center, it remains largely unknown whether and how other supraspinal tracts are involved in micturition control. Here, we focused on the role of lumbosacral projecting neurons located in the Locus Coeruleus (LC) in modulating micturition, since previous studies indicated that the LC is involved in controlling bladder contraction. First, by performing an AAV mediated retrograde labeling using a TH-iCre mouse line, we demonstrated specific targeting of LC noradrenergic neurons innervating the lumbosacral spinal cord with high efficiency. Next, by lumbosacral injection of a retro-AAV carrying Cre-dependent human diphtheria toxin receptors (DTR), we achieved specific ablation of LC NA⁺ neurons with lumbosacral projections upon the administration of diphtheria toxin. Our results showed that specific ablation of theseneurons led to overflow incontinence leaks and lower void efficiency. Mechanistically, by performing the urodynamics analysis, we showed that ablation of lumbosacral innervating NAneurons resulted in detrusor-sphincter dyssynergia. Taken together, our study provided novel insights into the underlying mechanisms of supraspinal control of micturition reflex and thus shed light on developing novel treatment to improve micturition control in patients with SCI or lower urinary tract symptoms.

Keywords: Dyssynergia; Locus coeruleus (LC); Micturition; Noradrenergic neuron; Urodynamics; tyrosine hydroxylase (TH).