Wednesday, January 15, 2025
1/15/2025
Project Summary/Abstract The broad, long-term goals of the proposed research are to better understand the neural underpinnings of healthy motor function and motor dysfunction in Rett syndrome and to promote undergraduate involvement in health-related research. Rett syndrome (RTT) is a neurological disorder, caused by disrupted function of the gene MeCP2, typically resulting in severe cognitive and motor disability. What goes wrong in the motor signals sent from the brain to the body, leading to motor dysfunction in RTT, remains largely unknown. Based on our recent work in rodent models, together with the fact that seizures are prevalent in RTT, here we hypothesize that excessive synchrony among neurons in the motor system may disrupt motor coding by limiting the dimensionality of motor signals. The essential idea here is that extreme synchrony entails many neurons doing the same thing, which precludes the complexity of signals required for controlling complex body movements. A complete and quantitative understanding of this idea is best approached using the framework of high-dimensional geometry. In this framework, excessive synchrony causes a collapse of the motor coding subspace, which is likely to entangle signals and collapse the complexity of body movements. The proposed work has three promising potential outcomes. First, we leverage state-of-the-art ideas from high- dimensional geometry of population motor coding to advance RTT etiology. Second, we provide an important counter-example of what can go wrong when high-dimensional geometry is disrupted, thus advancing basic knowledge of motor systems neuroscience. Third, we will test new RTT treatment strategies with potential for future translation from lab to clinic. Our first specific aim is to determine how MeCP2 dysfunction alters population coding in motor cortex and striatum. We hypothesize that excessive synchrony will result in reduced dimensionality of the population motor code, which manifests as motor dysfunction. Our second specific aim is to test two promising treatment strategies, one pharmacological, and one based on physical therapy. We hypothesize that these treatments will partially recover wild-type dimensionality of motor coding. To test these hypotheses, the proposed research would use high-density multi- electrode measurements to monitor the spiking activity of many single neurons in motor cortex and striatum of head-fixed mice as the animal runs on a computer controlled wheel. The research will be performed by a team of three undergraduate students and one postdoc. The proposed work would build upon the success of another recent R15 grant which resulted in a PNAS publication including an undergraduate author.
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