Monday, January 20, 2025
1/20/2025
Project Summary/Abstract: Spinal cord circuits are the final step in motor computations and are a site where descending signals are integrated with sensory cues to drive motor behavior. Eleven cardinal spinal interneuron types have been identified with distinct developmental origins, neurotransmitter phenotypes, and ipsi- versus contra-lateral connections. Elegant genetic approaches have targeted these cardinal interneurons revealing roles in motor control, but understanding of how spinal neural networks comprised of heterogenous cells from multiple cardinal domains function together to control features such as precision, coordination, and automaticity of motor behaviors remains unclear. This grant focuses on a recent discovery (Osseward et al., Science 2021) that each cardinal interneuron population is profoundly divided into genetically-distinct local and long-range neurons (1). The goal of this grant is to determine if these local/long range divisions of cardinal neurons correspond to distinct circuit modules for motor control. Transcriptomic profiling revealed a code spanning each cardinal interneuron domain in which medially-located neurons with short range connections are marked by NeuroD2 (called N-type) and laterally-located cells with long range projections express Zfhx3 (called Z-type). Here this proposal will test whether these N/Z-markers define functional neural units for controlling coherent features of motor behavior by comparing the connectivity, function, and neural-activity of N-type and Z-type cells within two distinct cardinal interneuron populations: inhibitory V1 and excitatory V2a neurons. This grant hypothesizes that long range Z-type neurons have critical functions related to “broadcasting” motor commands across multiple spinal segments to facilitate dexterity and interlimb coordination, whereas N-type neurons process local information for rapid reflexes and L/R limb control. Although inhibitory-V1 and excitatory-V2a interneurons are physiologically different, this grant explores the possibility that the N- versus Z-cell types from each cardinal class may have related functions that transcend even their neurotransmitter status. By defining the foundational organizational features of motor circuits, these studies may reveal a higher logic for how circuit modules are constructed with different cardinal neuron types. To explore the innovative hypothesis that functional units span cardinal cell types, a novel set of mouse intersectional genetic tools for labeling/targeting the N/Z divisions of the V1 and V2a neurons was generated. A new method for multi-electrode in vivo neuronal recording of spinal neurons in behaving animals was also established. Aim 1 (outputs) and Aim 2 (inputs) will define V1- and V2a-N/Z connections to understand the anatomical similarities and differences of N/Z-neurons within two distinct cardinal populations. Aim 3 will perturb the function of V1- and V2a-N/Z subtypes to understand their role in motor behavior. Aim 4 will record the neural activity of V1- and V2a-N/Z subtypes during motor behavior to determine whether their activity is linked to specific motor functions. These studies aim to reveal entirely new organizational features of spinal motor circuitry.
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