Deficits in forelimb reach learning in a mouse model of Fragile X syndrome

Abstract

Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of Fragile X syndrome, the Fmr1 knockout (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in Fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating more complex human behaviors to mouse models, simple motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in Fmr1 KO mice, precisely quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results demonstrated that the presence or absence of a cue that signals reward alleviates some of the deficits. In addition to a single metric of success in learning, we determined the specific parameters of the motor behavior that were responsible for that success or failure. In particular, our results suggested that Fmr1 KO mice showed impaired improvement in the trajectory of the reach, reflected by a greater likelihood of completely missing the target, and in a lower learning index for the optimal reach trajectory. In addition, we fully described the features underlying learning, including categorizing the first attempt during trials, failed reaches where mice make contact with the reward, the number of trials where no attempts were made, as well as how the pattern of these different behaviors varies in Fmr1 KO mice. Our findings provide an essential framework for linking specific behavioral impairments in motor learning to the cellular and circuit mechanisms that support them.