[R01] Cortical dystonia of prematurity

Ente: National Institute of Neurological Disorders and Stroke

Scadenza: 2030-05-31

Importo max: 594.604 EUR

Paese: US

Descrizione

PROJECT SUMMARY Preterm birth is the most common cause of cerebral palsy (CP) in the US and, consequently, the most common cause of childhood dystonia, a disabling condition affecting 2 of every 1000 Americans. Despite its high prevalence, dystonia in CP remains difficult to treat because 1) it is hard to predict, preventing early treatment when it is most effective; 2) its neuropathology after preterm birth is unclear; and 3) few treatment targets exist. This proposal addresses these gaps by investigating a novel cortical cause of dystonia after preterm birth. We and others have shown that striatal injury, namely chronic excitation of striatal cholinergic interneurons (ChINs), causes dystonia. Yet, anticholinergic dystonia treatments are variably effective in CP, necessitating a search for other treatment targets. We have shown that cortical injury, more than striatal injury, best predicts dystonia in children born preterm. Cortical pathology is also seen in adults with non-CP dystonias who demonstrate abnormal sensorimotor cortex inhibition, suggesting dysfunction of cortical GABAergic interneurons. The largest class of these interneurons are parvalbumin-positive (PVINs). Our preliminary data show that chemogenetic inhibition of sensorimotor cortex PVINs in mice causes dystonia and that mice born preterm have reduced cortical parvalbumin immunoreactivity and fewer PVINs. Sensorimotor PVINs may cause dystonia via targeted modulation of striatal ChIN activity. Sensorimotor PVINs inhibit glutamatergic cortical output neurons and striatal ChINs receive glutamatergic cortical input. Yet, it is unknown if sensorimotor PVINs modulate striatal ChIN activity via these excitatory corticostriatal neurons. These data support our central hypothesis: sensorimotor cortex PVIN inhibition causes dystonia after preterm birth via striatal ChIN excitation. We will leverage two of our recent scientific advances to test our innovative hypothesis: 1) our novel mouse model of preterm birth that demonstrates dystonia by postnatal day 42, and 2) quantitative dystonia measures in mice that we developed and clinically validated. In Aim 1, we determine whether cortical dysfunction precedes, and potentially predicts, dystonia onset in mice born preterm by longitudinally assessing sensorimotor PVIN number and cortical oscillatory activity using electroencephalography, and dystonic behavior using our innovative clinically-validated dystonia measures. In Aim 2, we determine whether inhibition of sensorimotor PVINs excites striatal ChINs using fiber photometry and chemogenetic inhibition of sensorimotor PVINs and corticostriatal neurons. In Aim 3, we determine whether chemogenetic sensorimotor PVIN excitation can reduce dystonia in mice born preterm and whether this chemogenetic treatment prior to dystonia onset at postnatal day 42 is more effective than treatment after dystonia onset. These studies will establish the critical role of sensorimotor PVINs in dystonia prediction ( Istituzione: WASHINGTON UNIVERSITY PI: BHOOMA ARAVAMUTHAN Progetto: 5R01NS140701-02

Settori: National Institute of Neurological Disorders and Stroke

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