Karim Fouad - US grants

? DESCRIPTION (provided by applicant): A primary goal for recovery following spinal cord injury (SCI) is restoration of locomotor capacity (e.g. walking). This is feasible because the core neuronal circuitry for locomotion resides within the spinal cord, and usually remains intact with spinal cord injury. However, a major problem for restoration of locomotion is that sensory input to the spinal cord often induces muscle spasms that can interfere with locomotion. On the other hand, intense locomotor training has been reported to inhibit spasms. We suggest that these opposing actions of locomotion and spasms arise from separate mutually inhibitory neuronal mechanisms in the spinal cord, including separate networks of interneurons and separate ionic currents in motoneurons. Thus, these differing mechanisms can be selectively targeted to promote locomotion and at the same time reduce spasms. Aim 1: In our previous studies, we showed that L-type calcium channels on motoneurons produce large persistent inward currents (Ca PICs) that are fundamental for generating long-lasting spasms after SCI. We have also demonstrated that NMDA receptors on motoneurons induce equally large persistent inward currents (NMDA PICs), but these are followed by large persistent outward currents (NMDA POCs), which terminate all PICs. These NMDA currents potentially contribute to controlling the amplitude and duration of rhythmic locomotor activity. Thus, in this proposal we examine the hypothesis that after SCI activation of NMDA receptors on motoneurons during rhythmic locomotor activity amplifies motor output (via NMDA PICs) and at the same time terminates Ca PIC driven spasms (via NMDA POCs). Aim 2: Our preliminary studies suggest that after SCI interneurons in the deep dorsal horn generate a burst of firing following sensory stimulation, which could trigger PICs in motoneurons and spasms. We hypothesize that: bursting interneurons in the deep dorsal horn are strongly involved in triggering of spasms, but at the same time inhibit locomotor activity. Aim 3: If the interneurons involved in locomotion and spasm are mutually inhibitory, then increasing the activation of locomotor interneurons should decrease spasms. To test this idea we examine the V3 interneurons known to be involved in locomotion in normal mice, and hypothesize that after SCI the V3 interneurons promote locomotion and inhibit spasms, transforming tonic spastic activity to coordinated locomotor drive. We employ optogenetic activation of V3 neurons after SCI. The novel concept that the interneurons that generate locomotion are different and mutually inhibitory to the interneurons that generate spasms opens up promising new avenues to treating spasms and promoting locomotion after SCI, especially when combined with potential therapeutic viral/genetic manipulation of these interneurons. From a general point of view, the tonic spasm generating interneurons and ionic currents (Ca PICs) are likely related to normal postural activity, and thus our studies shed light on the general interplay of neuronal circuits that differentially control posture and locomotion.

PROJECT SUMMARY/ABSTRACT Trauma to the central nervous system (CNS: spinal cord and brain) together affect more than 2.5 million people per year in the US, with economic costs of $80 billion in healthcare and loss-of-productivity. Yet, the precise pathophysiological processes impairing recovery remain poorly understood. This lack of knowledge is exacerbated by poor reproducibility of findings in animal models and limits translation of therapeutics across species and into humans. Part of the problem is that neurotrauma is intrinsically complex, involving heterogeneous damage to the central nervous system (CNS), by far the most complex organ system in the body. This results in a multifaceted CNS syndrome reflected across heterogeneous endpoints and multiple scales of analysis. Multi-scale heterogeneity makes traumatic brain injury (TBI) and spinal cord injury (SCI) difficult to understand using traditional analytical approaches that focus on a single endpoint for testing therapeutic efficacy. Single endpoint-testing provides a narrow window into the complex system of changes that describe SCI and TBI. Understanding these disorders involves managing datasets that include high volume anatomy data, high velocity physiology decision-support data, the high variety functional/behavioral data, and assessing correlations among these endpoints. In this sense, neurotrauma is fundamentally a data management problem that involves the classic ?3Vs of big data? (volume, velocity, variety). Of these, variety is perhaps the greatest data challenge in neurotrauma research for reproducibility in basic discovery, cross-species translation, and ultimately clinical implementation. For the proposed Data Repositories Cooperative Agreement (U24) we will build on our prior work managing data variety in the Open Data Commons for SCI (odc-sci.org) and TBI (odc-tbi.org) to make neurotrauma data Findable, Accessible, Interoperable, and Reusable (FAIR). The milestone-driven aims will: 1) further develop and harden our data lifecycle management system with end-to-end data version control and provenance tracking, data certification, and data citation; 2) develop in-cloud data dashboards and visualizations to monitor data quality and to promote data reuse, exploration, and hypothesis generation; 3) establish a pan- neurotrauma (PANORAUMA) data commons that brings together separate data assets currently supported by our multi-PI (MPI) team by aligning a patchwork of governance structures and policies. The goal of the proposed project is to develop a pooled repository for preclinical discovery, reproducibility testing, and translational discovery both within and across neurotrauma types. Our team is well-positioned to execute this project given that we developed some of the largest multicenter, multispecies neurotrauma data repositories of neurotrauma to-date (N>10,000 subjects 20,000 curated variables); the Neuroscience Information Framework (NIF); data terminologies and standards for these fields (MIASCI, NIFSTD); and policy work with the International Neuroinformatics Coordinating Facility (INCF). The PANORAUMA cooperative agreement is highly responsive to PAR-20-089, leveraging early successes in SCI and TBI data sharing to improve quality and sustainability.