Combining Physiological, Genetic, and Computational Approaches with Naturalistic Climbing Behavior to Elucidate the Funcitonal Elements of Descending

Many mammals are distinguished by the exceptional diversity and agility of their limb movement. These qualities are critical to the fitness certain movements confer, and so to the evolutionary success of many species. While brain regions important for limb control have been identified, the neural signal processing that ultimately governs motor commands sent to muscles has remained stubbornly opaque. Mechanistic models of motor system operation in real time during movement are thus lacking. This obscures the etiology of motor deficits caused by neurological disease and stroke, which in turn stymies the development of effective treatments. A primary cause of this opacity of motor system processing is the ambiguity of the basic functional elements comprising relevant neural circuits. An emerging view posits that these elements may be neuronal subtypes defined by features like axonal target region, target cell identity, and gene expression. Yet the fundamental question of what are the appropriate cellular features for defining functional units remains unanswered. This ambiguity stems from a host of technical limitations. We expect that functionally salient neuronal subtypes will make characteristic contributions to specific phases of movement. Yet traditional methods for silencing neural activity to assess function lack the temporal resolution to discern such specific influence. We also expect that functionally salient subtypes will exhibit distinct activity patterns and interactions with other neuronal populations. But classical methods for measuring neural firing are typically blind to key cellular features. Moreover, the behavioral paradigms used for motor system studies have not captured essential aspects of natural mammalian movement, for which motor system organization may have been adapted over evolution. Fortunately though, systems neuroscience is currently being revolutionized by advances in physiological, genetic, and computational techniques. I plan to leverage many of these advances and pursue an innovative approach to resolve the basic functional elements within a model motor system population – the subcerebral projection neurons (SPNs) found in motor areas of the neocortex. We will employ a naturalistic climbing paradigm for mice engineered in my lab to overcome limitations of previous motor behavior paradigms. New genetically-mediated targeting strategies will provide access to potential functional subtypes for activity measurement and perturbation. We will novelly couple optogenetic probes, electromyography, and automated behavior decomposition to distinguish precise phases of neuronal subtype influence. Large-scale, multi-area activity recording, optogenetic identification, and machine learning will parse subtypes by their activity and interactions with other neuronal populations. Our work will articulate an interdisciplinary approach applicable to the fundamental question of functional units in other neural systems as well. The mechanistic insight our work begins to build will help elucidate the etiology of movement deficits stemming from conditions like ALS and Huntington’s disease, and following stroke.