Harnessing spinal electrical stimulation to modulate autonomic function after spinal cord injury

Descrizione del progetto

Neuroprotesi di riabilitazione per la lesione midollare

La lesione midollare grave può danneggiare i nervi simpatici responsabili del controllo cardiovascolare e condurre a ipertensione o ipotensione ortostatica. Queste condizioni non solo possiedono opzioni di trattamento limitate, ma sono inoltre associate a un rischio maggiore di malattie cardiovascolari. Per prevenire queste condizioni cliniche, il progetto symESTIM, finanziato dall’UE, sta sviluppando una neuroprotesi elettrica capace di ripristinare la funzione autonoma dopo una lesione midollare. I ricercatori stanno impiegando tecnologie all’avanguardia per sezionare i circuiti neuronali danneggiati dopo una lesione midollare in modelli animali sperimentali. Ciò permetterà loro di mappare le connessioni neurali nel midollo spinale che necessitano di essere stimolate elettricamente in un approccio di neuroriabilitativo dopo una lesione midollare.

Obiettivo

Severe spinal cord injury (SCI) interrupts descending sympatho-excitatory axons responsible for cardiovascular control. Devoid of supraspinal input, sympathetic circuits within the spinal cord undergo significant plastic changes. These changes lead to a debilitating clinical scenario that includes frequent bouts of hypertension (autonomic dysreflexia) and orthostatic hypotension, conditions which have extremely limited treatment options and lead to increased risk for cardiovascular disease. Here, I propose to deconstruct the sympathetic circuitry within the spinal cord in order to develop a targeted electrical neuroprosthesis that prevents the development of these clinical conditions. To dissect the sympathetic circuitry that drives sympathetic dysfunction after SCI, I will deploy judicious associations of optogenetics, chemogenetics, calcium imaging, virus-mediated tract-tracing and whole brain-spinal cord imaging in transgenic rats. For example, the catecholaminergic specificity of TH:Cre rats will enable the visualization of the residual descending sympatho-excitatory axons following severe contusion SCI, and will provide specific access to splanchnic ganglia neurons. This understanding of the sympathetic circuitry will allow me to map the hemodynamic responses following electrical spinal cord stimulation to the modulation of specific circuits and connections. This knowledge will then guide the development of a tailored neuroprosthesis targeting these circuits in order to regulate sympathetic dysfunction after SCI. Finally, I will exploit this neuroprosthesis to rehabilitate the sympathetic system after SCI, which I will demonstrate with longitudinal functional assessments and detailed anatomical evaluations. My ultimate goal is to develop targeted autonomic neurorehabilitation—a novel method to treat autonomic dysfunction after SCI that will improve the quality of life of those suffering from this condition.