Compensation and failure of spinal circuits for urination in Multiple System Atrophy: from synaptic mechanisms to therapeutic interventions

Spinal circuits exhibit compensatory plasticity in early neurodegeneration, temporarily preserving function despite ongoing neuronal loss. Lumbosacral circuits coordinate the control of urination, whose impairment affects billions of people worldwide. In Multiple System Atrophy (MSA), urinary dysfunction is often the earliest symptom, yet it emerges only after more than half of the motoneurons innervating the bladder and sphincter degenerate. This delay between neurodegeneration and symptom onset suggests that spinal circuits initially compensate to maintain function before eventually transitioning to failure. This project aims to define the timeline and mechanisms underlying circuit transition from early-stage compensation to late-stage failure. I will combine state-of-the-art electrophysiology, spatial transcriptomics and viral circuit tracing to identify cellular substrates and the progression of urinary dysfunction, linking circuit alterations to functional decline in MSA mouse models. In parallel, longitudinal high-density electromyography will track the trajectory of motoneuron and circuit alterations in MSA patients. Finally, I will test neuromodulatory and viral interventions to determine whether circuit compensation can be supported to preserve urinary function. This translational research bridges synaptic mechanisms and therapeutic interventions for MSA, while establishing a comprehensive mechanistic framework for urination, paving the way to improve urinary function on a global scale. Keywords: spinal circuits, neurodegeneration, urination