Mammals exhibit an incredible amount of flexibility in motor control, which is believed to be due to the remarkable ability of brain circuits to rapidly undergo structural and functional plasticity to fluidly modifying body movements through learning. Disrupting these processes can often lead to impaired motor learning in both normal and diseased conditions. Our lab research focuses on bridging the gap between cellular and molecular signaling underlying the plasticity of neural circuits involved in motor skill learning. In the first part of the talk, I will present our current work, in which we revealed a critical role of a functional distinct NPAS4-expressing somatostatin- interneuron ensemble in motor learning, using chronic in vivo two-photon imaging in head-fixed behaving mice. In the second part of the talk, I will present a recently published work from the lab, in which we examined mice with a syntenic deletion of chromosome 16p11.2, a common copy number variation associated with ASD. We found 16p11.2 deletion mice display a delay in motor learning, which reminiscent of the motor learning-related deficits in children with ASD, without showing gross movement deficits. In addition, we identified a dysfunctional locus coeruleus noradrenergic (LC-NA) neuromodulatory system that leads to abnormal structural and functional changes in the motor cortex, which resulted in delayed motor learning in the 16p11.2 deletion mice.