Grant: Project Grant

Autism Spectrum Disorder (ASD) is composed of a set of neurodevelopmental syndromes. While core symptoms such as impaired social interactions, disrupted communication, and stereotyped behaviors have been well characterized, motor skill dysfunctions have also been reported in many ASD patients as they often present a delay in motor skill development during childhood. These motor deficits could frustrate patients with ASD and interfere heavily with their everyday routines and social interactions. Therefore, a more detailed understanding of the mechanisms underlying motor dysfunctions in ASD is necessary for developing potential therapies. In the case of 16p11.2 deletion, a common copy number variation (CNV) associated with ASD, more than 70% of the carriers have abnormal speech control and motor learning-related deficits during childhood. Our lab has previously demonstrated that the 16p11.2 deletion mouse model of autism exhibits a delayed motor learning phenotype, which is caused by a reduction in locus coeruleus noradrenaline (LC-NA) activity. Furthermore, by using the chemogenetic approach to selectively activate LC-NA neurons, the delayed motor learning phenotype was rescued. Since NA exerts powerful neuromodulatory control on brain plasticity, we hypothesize that the dysfunction of local LC-NA activity may lead to abnormal brain plasticity in the primary motor cortex (M1) in the 16p11.2 deletion mice, which results in the delayed learning phenotype. Here, we propose a series of experiments employing a head-fixed motor learning task with chronic in vivo two-photon NA-sensor and Ca2+ imaging in behaving 16p11.2 deletion mice to probe the dynamics and contributions of NA in M1 during motor learning. The proposed experiments will help us to further understand ASD-related motor performance impairments down to the level of individual receptors and aid in the development of earlier intervention, diagnoses, and treatment.