Mechanism of Motor Learning Impacting Cognitive and Emotional State

Rett syndrome is a severe neurodevelopmental disorder caused by mutations on the MECP2 gene located on the X chromosome, predominantly affecting females. Resulting symptoms include impairments in speech, motor coordination, learning and memory, cognition, and social functioning. Importantly, motor learning paradigms have shown promise in improving physical impairments associated with Rett syndrome. Our lab’s unique motor learning paradigm has demonstrated benefits including increased lifespan, reduced anxiety, and changes in synchrony between select neuronal pairs in the motor cortex. However, its effects on related cognitive domains, such as spatial learning and memory, remains unexplored. The proposed study will investigate how motor learning impacts cognitive function, associated neural circuitry, and molecular function in the medial prefrontal cortex (mPFC) of a rodent model of Rett syndrome. Given that global loss of Mecp2 in Rett syndrome disrupts the brain’s excitation/inhibition (E/I) balance, this study aims to understand how behavioral interventions can modulate a disrupted circuit and ameliorate cognitive deficits. I will use established genetic Rett models, an innovative motor learning paradigm, and in-vivo miniaturized microscope imaging to Aim 1) characterize the behavioral impact of dynamic motor training in female RTT mice and Aim 2) elucidate the neural circuit mechanisms underlying motor training benefits. The fellowship training plan includes comprehensive training in advanced neuroimaging techniques, behavioral assays, and calcium imaging data analysis. In Aim 1, I will use established behavioral paradigms to assess cognition, emotional regulation, and coordination. In Aim 2, I will use AAV viral vectors and Inscopix miniscopes to determine how motor training alters pyramidal neuron activity in the mPFC and causally test circuit function using optogenetic manipulation. This training will provide the necessary skills to lead innovative research in neurological disease and contribute to developing effective therapeutic interventions for Rett syndrome. Project Number: 1F31NS143400-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Natalie Boyle | Institution: GEORGE WASHINGTON UNIVERSITY, WASHINGTON, DC | Award Amount: $43,138 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F02A-D (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31NS14340001A1