Bumetanide Strengthens Residual Brain–Bladder Communication After Spinal Cord Injury

Abstract

Neurogenic bladder is one of the most disabling consequences of spinal cord injury (SCI), yet it remains unclear whether residual brain–bladder communication persists after injury and can be therapeutically strengthened. Here, we integrated analysis of a clinical SCI cohort with studies in a mouse model that recapitulates key features of human neurogenic bladder. SCI markedly impaired both descending and ascending limbs of the spinobulbospinal micturition reflex, reducing bladder responses evoked by stimulation of the pontine micturition center (PMC) and bladder filling-induced activation of the periaqueductal gray. Despite this marked functional impairment, pseudorabies virus tracing, optogenetics, and machine learning-assisted three-dimensional imaging revealed persistent bladder-connected neurons within the spared T8–T9 interlesion region. Neurons within this region remained responsive to descending PMC input, identifying the interlesion network as a candidate substrate for residual brain–bladder communication. Early continuous intrathecal bumetanide improved urinary storage and emptying, enhanced descending PMC-to-bladder and ascending bladder-to-brain signaling, and increased the functional engagement of bladder-connected T8–T9 neurons without increasing urine production. Bumetanide also increased trans-synaptic labeling between the bladder and PMC, consistent with enhanced polysynaptic brain–bladder connectivity. Together, these findings indicate that brain–bladder communication is not completely lost after SCI and may be supported by a functionally compromised residual spinal network that remains amenable to therapeutic reinforcement. Targeting spared autonomic circuitry may therefore provide a strategy for improving bladder function after SCI. Highlights SCI disrupts bidirectional communication within the brain–bladder circuit. Spared T8–T9 interlesion neurons remain engaged in residual brain–bladder signaling. Intrathecal bumetanide strengthens brain–bladder signaling and improves urinary function. Graphic abstract