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Astrocytes are known to play many important roles in brain function. However, research underscoring the extent to which astrocytes modulate neuronal activity is still underway. Here we review the latest evidence regarding the contribution of astrocytes to neuronal oscillations across the brain, with a specific focus on how astrocytes respond to changes in brain state (e.g., sleep, arousal, stress). We then discuss the general mechanisms by which astrocytes signal to neurons to modulate neuronal activity, ultimately driving changes in behavior, followed by a discussion of how astrocytes contribute to respiratory rhythms in the medulla. Finally, we contemplate the possibility that brain stem astrocytes could modulate brainwide oscillations by communicating the status of oxygenation to higher cortical areas.

Mammals must continuously regulate the levels of O2 and CO2, which is particularly important for the brain. Failure to maintain adequate O2/CO2 homeostasis has been associated with numerous disorders including sleep apnoea, Rett syndrome and sudden infant death syndrome. But, O2/CO2 homeostasis poses major regulatory challenges, even in the healthy brain. Neuronal activities change in a differentiated, spatially and temporally complex manner, which is reflected in equally complex changes in O2 demand. This raises important questions: is oxygen sensing an emergent property, locally generated within all active neuronal networks, and/or the property of specialized O2‐sensitive CNS regions? Increasing evidence suggests that the regulation of the brain's redox state involves properties that are intrinsic to many networks, but that specialized regions in the brainstem orchestrate the integrated control of respiratory and cardiovascular functions. Although the levels of O2 in arterial blood and the CNS are very different, neuro‐glial interactions and purinergic signalling are critical for both peripheral and CNS chemosensation. Indeed, the specificity of neuroglial interactions seems to determine the differential responses to O2, CO2 and the changes in pH. Open in a separate window

TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial-to-mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self-renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss-of-function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW-associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time, we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM.

Spinal cord trauma leads to destruction of the highly organized cytoarchitecture that carries information along the axis of the spinal column. Currently, there are no clinically accepted strategies that can help regenerate severed axons after spinal cord injury. Experimental neuroregenerative efforts include the creation of optimal biomaterials with aligned topography to support enhanced neuronal regeneration. Hydrogels are soft biomaterials with high water content that are widely used as scaffolds to interface with the central nervous system (CNS). Current available methods to create topography within the 3D amorphous hydrogels are typically complex. Here we examine a simple and reproducible method that results in consistently aligned fibrils within 3D matrices using thermally gelling biomimetic polymers that are compatible with neuronal cells. A collagen type I (Col)-based thermally gelling hydrogel system was used in combination with two other native extracellular matrix proteins: laminin I (LN), and hyaluronic acid (HA). Gelling kinetics for all gel types (Col, Col LN, Col HA) were examined, and we found that all three combinations of polymer formed consistent gels at 37°C. Col solution was faster to form gels (17 min), while Col LN and Col HA took longer (~22 minutes). A method of aspiration and ejection was used to produce Col-based hydrogels containing aligned fibrils. Gels were then examined using scanning electron microscopy (SEM). SEM images confirmed successful alignment in all gel types, and the size of fibers was consistent with reported values for collagen (~250 nm in diameter). We found that embryonic spinal cord neurons survive and produce processes aligned to collagen fibrils after 14 days in vitro. Next, we investigated the functionality of aligned and non-aligned Col hydrogels implanted acutely after a contusion type spinal cord injury to the thoracic spinal cord at T7/T8. Pan neuronal antibody-positive fibrils were found within all implants, aligned hydrogels supported neurite growth along the parallel direction of the implanted hydrogels. Our data indicate that thermally gelling biomimetic hydrogels can produce aligned matrices by a method of aspiration and ejection. The material composition and process of aligning hydrogels outlined here presents a novel platform for regenerative therapies for the CNS that is compatible with the survival and growth of neuronal cells in vitro and in vivo.