A Standards Organization for Open and FAIR Neuroscience: the International Neuroinformatics Coordinating Facility.

There is great need for coordination around standards and best practices in neuroscience to support efforts to make neuroscience a data-centric discipline. Major brain initiatives launched around the world are poised to generate huge stores of neuroscience data. At the same time, neuroscience, like many domains in biomedicine, is confronting the issues of transparency, rigor, and reproducibility. Widely used, validated standards and best practices are key to addressing the challenges in both big and small data science, as they are essential for integrating diverse data and for developing a robust, effective, and sustainable infrastructure to support open and reproducible neuroscience. However, developing community standards and gaining their adoption is difficult. The current landscape is characterized both by a lack of robust, validated standards and a plethora of overlapping, underdeveloped, untested and underutilized standards and best practices. The International Neuroinformatics Coordinating Facility (INCF), an independent organization dedicated to promoting data sharing through the coordination of infrastructure and standards, has recently implemented a formal procedure for evaluating and endorsing community standards and best practices in support of the FAIR principles. By formally serving as a standards organization dedicated to open and FAIR neuroscience, INCF helps evaluate, promulgate, and coordinate standards and best practices across neuroscience. Here, we provide an overview of the process and discuss how neuroscience can benefit from having a dedicated standards body.

Trainingspace: Neuroeducation Without Borders.

Advancements in the field of neuroinformatics have resulted in a massive explosion of raw data of many varieties, yet many traditional neuroscience training programs have not changed their curricula to reflect the urgent need for improved computational skills that would enable trainees to handle, organize, and interrogate such large, multimodal datasets. Thus, the objective of this project was to build an open access hub of neuroscience educational resources to fill the gap between current neuroscience curricula and the computationally focused skillset required to work with big data. To achieve this aim, we invited representatives from the world's leading neuroscience societies and large-scale brain initiatives to form the INCF Training and Education Committee that would provide oversight over the content and capabilities of the online hub. As a result, we developed TrainingSpace (https://training.incf.org/), an open access hub of nearly 500 multimedia courses, lectures, and tool tutorials covering the subspecialisms of neuroscience and neuroinformatics, as well as computer science, data science, and ethics. In addition to course content, TrainingSpace also provides users with access to publicly available datasets through KnowledgeSpace, a discoverability portal and community encyclopedia for neuroscience, as well as a question and answer forum, Neurostars.org. Since its launch in 2019, TrainingSpace has steadily increased in popularity with both trainees and trainers alike. It has also become popular with content providers that want to make their training materials available to the neuroscience community-at-large, as well as integrate their content into the larger TrainingSpace ecosystem.

Teaching Computation in Neuroscience: Notes on the 2019 Society for Neuroscience Professional Development Workshop on Teaching.

The 2019 Society for Neuroscience Professional Development Workshop on Teaching reviewed current tools, approaches, and examples for teaching computation in neuroscience. Robert Kass described the statistical foundations that students need to properly analyze data. Pascal Wallisch compared MATLAB and Python as programming languages for teaching students. Adrienne Fairhall discussed computational methods, training opportunities, and curricular considerations. Walt Babiec provided a view from the trenches on practical aspects of teaching computational neuroscience. Mathew Abrams concluded the session with an overview of resources for teaching and learning computational modeling in neuroscience.

Delayed Imatinib Treatment for Acute Spinal Cord Injury: Functional Recovery and Serum Biomarkers.

With no currently available drug treatment for spinal cord injury, there is a need for additional therapeutic candidates. We took the approach of repositioning existing pharmacological agents to serve as acute treatments for spinal cord injury and previously found imatinib to have positive effects on locomotor and bladder function in experimental spinal cord injury when administered immediately after the injury. However, for imatinib to have translational value, it needs to have sustained beneficial effects with delayed initiation of treatment, as well. Here, we show that imatinib improves hind limb locomotion and bladder recovery when initiation of treatment was delayed until 4 h after injury and that bladder function was improved with a delay of up to 24 h. The treatment did not induce hypersensitivity. Instead, imatinib-treated animals were generally less hypersensitive to either thermal or mechanical stimuli, compared with controls. In an effort to provide potential biomarkers, we found serum levels of three cytokines/chemokines--monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-3α, and keratinocyte chemoattractant/growth-regulated oncogene (interleukin 8)--to increase over time with imatinib treatment and to be significantly higher in injured imatinib-treated animals than in controls during the early treatment period. This correlated to macrophage activation and autofluorescence in lymphoid organs. At the site of injury in the spinal cord, macrophage activation was instead reduced by imatinib treatment. Our data strengthen the case for clinical trials of imatinib by showing that initiation of treatment can be delayed and by identifying serum cytokines that may serve as candidate markers of effective imatinib doses.

Interleukin-6 secretion by astrocytes is dynamically regulated by PI3K-mTOR-calcium signaling.

After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-κB transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI.

Spatial and cellular characterization of mTORC1 activation after spinal cord injury reveals biphasic increase mainly attributed to microglia/macrophages.

Mechanistic target of rapamycin complex 1 (mTORC1) is an intracellular kinase complex that regulates energy homeostasis and transcription. Modulation of mTORC1 has proven beneficial in experimental spinal cord injury, making this molecular target a candidate for therapeutic intervention in spinal cord injury. However, both inactivation and activation of mTORC1 have been reported beneficial for recovery. To obtain a more complete picture of mTORC1 activity, we aimed to characterize the spatiotemporal activation pattern of mTORC1 and identify activation in particular cell types after contusion spinal cord injury in rats. To be able to provide a spatial characterization of mTORC1 activation, we monitored activation of downstream target S6. We found robust mTORC1 activation both at the site of injury and in spinal segments rostral and caudal to the injury. There was constitutive mTORC1 activation in neurons that was biphasically reduced caudally after injury. We found biphasic mTORC1 activation in glial cells, primarily activated microglia/macrophages. Furthermore, we found mTORC1 activation in proliferating cells, suggesting this may be a function affected by mTORC1 modulation. Our results reveal potential windows of opportunity for therapeutic interference with mTORC1 signaling and immune cells as targets for inhibition of mTORC1 in spinal cord injury.

Rat substrains differ in the magnitude of spontaneous locomotor recovery and in the development of mechanical hypersensitivity after experimental spinal cord injury.

A number of different rodent experimental models of spinal cord injury have been used in an attempt to model the pathophysiology of human spinal cord injury. As a result, interlaboratory comparisons of the outcome measures can be difficult. Further complicating interexperiment comparisons is the fact that the rodent response to different experimental models is strain-dependent. Moreover, the literature is abundant with examples in which the same injury model and strain result in divergent functional outcomes. The objective of this research was to determine whether substrain differences influence functional outcome in experimental spinal cord injury. We induced mild contusion spinal cord injuries in three substrains of Sprague-Dawley rats purchased from three different European breeders (Scanbur, Charles River, and Harlan) and evaluated the impact of injury on spontaneous locomotor function, hypersensitivity to mechanical stimulation, and bladder function. We found that Harlan rats regained significantly more hindlimb function than Charles River and Scanbur rats. We also observed substrain differences in the recovery of the ability to empty the bladder and development of hypersensitivity to mechanical stimulation. The Harlan substrain did not show any signs of hypersensitivity in contrast to the Scanbur and Charles River substrains, which both showed transient reduction in paw withdrawal thresholds. Lastly, we found histological differences possibly explaining the observed behavioral differences. We conclude that in spite of being the same strain, there might be genetic differences that can influence outcome measures in experimental studies of spinal cord injury of Sprague-Dawley rats from different vendors.

Imatinib enhances functional outcome after spinal cord injury.

We investigated whether imatinib (Gleevec®, Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury.