Spinal microcircuit resilience in Amyotrophic Lateral Sclerosis (ALS): mechanisms, translational insights and therapeutic windows (360G-Wellcome-323415_Z_24_Z)

Neural circuits exhibit remarkable resilience in early-stages of neurological disease to maintain near-normal behaviour. In amyotrophic lateral sclerosis (ALS) more than 50% of motoneurons die before muscle weakness is detected. Human studies have shown deterioration of spinal pathways in late-symptomatic ALS patients, but new evidence from mice demonstrated pro-homeostatic changes in spinal microcircuits long before symptom onset, implicating microcircuit plasticity in early-stage resilience. Through concomitant animal and human experiments, this research will elucidate the course and mechanisms of spinal circuit plasticity driving resilience in pre-symptomatic ALS, and leverage such insights to improve tools for diagnosis, prognosis and quantifying responses to treatment. In vitro, ex vivo and in vivo mouse electrophysiology will first establish the timing and nature of alterations in spinal microcircuits, motoneurons and muscle fibres from ALS mice. Concurrently, longitudinal high-density surface electromyography (HDsEMG) recordings will map the temporal evolution of motoneuron and microcircuit alterations in ALS patients, from pre-symptomatic through symptomatic stages. I will then test antisense therapies and whether circuit-driven therapeutic windows maximize benefits by extending microcircuit resilience thus delaying neuromuscular decline. This integrative mouse-human approach will directly contribute towards earlier and more precise ALS diagnosis, improved disease monitoring, and the identification of critical early-stage therapeutic windows.