Journal Description

Neuroglia

Neuroglia is a peer-reviewed, open access journal that investigates a wide range of neuroglia-related topics, published quarterly online by MDPI.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14 days after submission; acceptance to publication is undertaken in 5.5 days (median values for papers published in this journal in the second half of 2022).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.

Imprint Information Journal Flyer Open Access ISSN: 2571-6980

Latest Articles

Open AccessArticle

Focused Ultrasound-Mediated Blood–Brain Barrier Opening Best Promotes Neuroimmunomodulation through Brain Macrophage Redistribution

Alina R. Kline-Schoder

and

Neuroglia 2023, 4(2), 141-157; https://doi.org/10.3390/neuroglia4020010 - 31 May 2023

Abstract

Neuroimmunomodulation is a promising form of drug-free treatment for neurological diseases ranging from Alzheimer’s disease to depression. The evidence supporting the efficacy of focused ultrasound (FUS) neuroimmunomodulation is encouraging; however, the method has yet to be standardized, and its mechanism remains poorly understood. Methods of FUS neuroimmunomodulation can be categorized into three paradigms based on the parameters used. In the first paradigm, focused ultrasound blood–brain barrier opening (FUS-BBBO) combines FUS with microbubbles (MB) to transiently and safely induce BBB opening. In the second paradigm, focused ultrasound neuromodulation (FUS-N) harnesses the acoustic effects of FUS alone (without MB). In the third paradigm, focused ultrasound with microbubbles without BBBO (FUS + MB) combines MB with FUS below the BBBO pressure threshold—harnessing the mechanical effects of FUS without opening the barrier. Due to the recent evidence of brain macrophage modulation in response to FUS-BBBO, we provide the first direct comparison of brain macrophage modulation between all three paradigms both in the presence and absence of Alzheimer’s disease (AD) pathology. Flow cytometry and single-cell sequencing are employed to identify FUS-BBBO as the FUS paradigm, which maximizes brain macrophage modulation, including an increase in the population of neuroprotective, disease-associated microglia and direct correlation between treatment cavitation dose and brain macrophage phagocytosis. Next, we combine spatial and single-cell transcriptomics with immunohistochemical validation to provide the first characterization of brain macrophage distribution in response to FUS-BBBO. Given their relevance within neurodegeneration and perturbation response, we emphasize the analysis of three brain macrophage populations—disease- and interferon-associated microglia and central-nervous-system-associated macrophages. We find and validate the redistribution of each population with an overall trend toward increased interaction with the brain–cerebrospinal fluid barrier (BCSFB) after FUS-BBBO, an effect that is found to be more pronounced in the presence of disease pathology. This study addresses the prior lack of FUS neuroimmunomodulation paradigm optimization and mechanism characterization, identifying that FUS-BBBO best modulates brain macrophage response via complex redistribution. Full article

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Open AccessPerspective

The Role of Lactylation in Mental Illness: Emphasis on Microglia

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Christina V. Andronescu

Neuroglia 2023, 4(2), 119-140; https://doi.org/10.3390/neuroglia4020009 - 16 May 2023

Abstract

A paradigm shift is currently taking place in the etiopathogenesis of neuropsychiatric disorders as immunometabolism is replacing the earlier neurotransmitter model. According to the new concept, cellular bioenergetics drives information processing in the central nervous system; therefore, neuropathology is conceptualized as a direct consequence of impaired metabolism. Along the same lines, endoplasmic reticulum stress and gut barrier dysfunction are emerging as novel targets in schizophrenia and affective disorders, linking immune responses to cellular distress. Furthermore, microglia, the brain’s innate immune cells, acquire energy through oxidative phosphorylation, while in the resting state, and glycolysis upon activation, contributing to lactate accumulation and reduced brain pH. The same metabolic signature characterizes neuropsychiatric disorders as the central nervous system derives adenosine triphosphate from aerobic glycolysis, upregulating lactate and generating an acidic environment. Although known for over three decades, the link between dysmetabolism and neuropathology was poorly defined until the discovery of brain-resident innate lymphoid cells, including natural killer cells, and lactylation of histone and nonhistone proteins. In this perspective article, we examine three anti-inflammatory microglial systems relevant for neuropsychiatry: lactate, oxytocin, and the aryl hydrocarbon receptor. We also discuss potential interventions for restoring microglial homeostasis. Full article

(This article belongs to the Special Issue New Insights into the Anti-inflammatory Role of Microglia)

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Open AccessArticle

Q1VA, a Synthetic Chalcone, Induces Apoptosis and Decreases Invasion on Primary Culture of Human Glioblastoma

Anderson Togni

Tetsade Piermartiri

Luiz Felipe Schmitz de Souza

Louise Domeneghi Chiaradia Delatorre

Ricardo José Nunes

Carla Inês Tasca

and

Cláudia Beatriz Nedel

Neuroglia 2023, 4(2), 102-118; https://doi.org/10.3390/neuroglia4020008 - 30 Apr 2023

Abstract

Glioblastoma (GBM) is the most commonly occurring type of primary tumor of the central nervous system (CNS) and is considered the worst type of glioma. Despite the current standard treatment for newly diagnosed GBM, which involves surgery followed by chemotherapy with temozolomide (TMZ) and radiation therapy, the average survival time for patients with GBM is only about 15 months. This is due to GBM’s tendency to recur, its high proliferative rates, its ability to evade apoptosis, and its ability to invade healthy tissue. Therefore, it is crucial to explore new treatment options for GBM. This study investigated the potential anticancer activities of a new series of synthetic chalcones, which are natural compounds found in the biosynthesis of flavonoids in plants. Primary cell culture of glioblastoma (GBM1) from surgical resection was used to evaluate the effects of synthetic chalcones on viability, cell death, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), cell cycle, and invasion. One chalcone, Q1VA (at concentrations of 10, 50, and 100 μM for 24 h) induced cytotoxicity by increasing apoptosis levels and depolarizing the mitochondrial membrane, as evidenced by a TMRE assay. Further analysis using the molecular fluorescent probe H2DCFDA indicated that the increased levels of reactive oxygen species (ROS) might be linked to altered mitochondrial membrane potential and cell death. Furthermore, viable cells were observed to be delayed in the cell cycle, primarily in the M phase, and the invasion process was reduced. The findings of this study indicate that Q1VA is a potential adjuvant therapeutic agent for GBM due to its significant antitumor effects. If its safety and efficacy can be confirmed in animal models, Q1VA may be considered for clinical trials in humans. However, additional research is required to determine the optimal dosage, treatment schedule, and potential side effects of Q1VA. Full article

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Open AccessReview

Convergence of Pro-Stress and Pro-Inflammatory Signaling in the Central Noradrenergic System: Implications for Mood and Anxiety Disorders

Arthur Anthony A. Reyes

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Daniel J. Chandler

Neuroglia 2023, 4(2), 87-101; https://doi.org/10.3390/neuroglia4020007 - 29 Apr 2023

Abstract

Mood and anxiety disorders are heterogeneous psychiatric diagnoses affecting millions. While the disease etiology is complex, various risk factors have been identified, such as stress. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive processes and behavior. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic–pituitary–adrenal (HPA) axis. In addition to its effects on the HPA axis, stress activates the locus coeruleus (LC), a bilateral brainstem nucleus that projects broadly throughout the central nervous system and releases the catecholamine transmitter norepinephrine (NE). The combined activities of the LC–NE system and HPA axis work synergistically to produce timely adaptive physiological and behavioral responses to stress. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of several neuropsychiatric disease states. Notably, recent studies have also implicated neuroinflammation mediated by microglia as a risk factor in mood and anxiety disorders. Despite their combined association with mood and anxiety disorders, the potential links between stress and inflammation, and possible interactions between their respective signaling cascades, have not been well-explored. This brief review aims to summarize how LC is uniquely positioned to respond to both pro-stress and pro-inflammatory cues, and how their convergence in this site may contribute to the development of mood and anxiety disorders. Full article

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Open AccessArticle

Targeting Bioinformatics Predicted Biomarkers Associated with Cell Proliferation and Migration for Treating Gliomas: Preclinical Studies in a GL261 Mouse Model

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Neuroglia 2023, 4(1), 69-86; https://doi.org/10.3390/neuroglia4010006 - 15 Mar 2023

Abstract

We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies against these three biomarkers in a preclinical mouse GL261 high-grade glioma model. Efficacies for antibody therapies against these biomarkers were assessed by survival and tumor volumes, biomarker expressions, cell invasion and proliferation, and bioinformatics gene/protein associations. Antibodies against PLXNB2, SLIT3, or SPON1 were effective in significantly reducing tumor volumes and increasing animal survival. With immunohistochemistry (IHC), these biomarkers were highly expressed in human HGGs, as well as in mice tumors. From IHC, CD44v6 was significantly decreased for all three antibody treatments, compared to UT GL261 tumors. Bioinformatics suggested that targeting either PLXNB2 or SPON1 may have a major effect on HGG cell migration and invasion (validated with CD44v6 IHC), whereas targeting SLIT3, in addition to affecting cell invasion, may also affect cell proliferation (not validated with Ki67 IHC). These results indicate that targeting these three biomarkers could add to the therapeutic arsenal against high-grade gliomas and that antibodies against them could be considered for clinical translation. Full article

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Open AccessArticle

Modest Reduction in CAG Repeat Length Rescues Motor Deficits but Not Purkinje Cell Pathology and Gliosis in Spinocerebellar Ataxia Type 1 Mice

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Neuroglia 2023, 4(1), 52-68; https://doi.org/10.3390/neuroglia4010005 - 07 Mar 2023

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by the early and prominent pathology of the cerebellar Purkinje cells that results in balance and coordination deficits. We previously demonstrated that cerebellar astrocytes contribute to SCA1 pathogenesis in a biphasic, stage of disease-dependent manner. We found that pro-inflammatory transcriptional regulator nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in astrocytes has a neuroprotective role during early-stage SCA1. Here, we sought to examine whether further inducing NF-κB activation in astrocytes of SCA1 model mice at an early stage of the disease has therapeutic benefits. To perform this task, we created a novel Slc1a3-CreER^T/IKKβ_CA/ATXN1[82Q] triple transgenic mouse model in which TMX injection at 4 weeks of age results in the expression of constitutively active inhibitor of kB kinase beta (IKKβ_CA), the main activator of NF-κB signaling. As we evaluated SCA1-like phenotypes, we noticed that ATXN1[82Q] mice did not exhibit motor deficits anymore, even at very late stages of the disease. We sequenced the mutant ATXN1 gene and discovered that the CAG repeat number had decreased from 82 to 71. However, despite the loss of motor phenotype, other well-characterized SCA1-changes, including atrophy of Purkinje cell dendrites, hallmarks of cerebellar astrogliosis and microgliosis, and Purkinje cell disease-associated gene expression changes, were still detectable in ATXN1[71Q] mice. We found delayed PC atrophy and calbindin reduction in SCA1 mice expressing IKKβ_CA in astrocytes implicating beneficial effects of increased NF-κB signaling on Purkinje cell pathology. The change in the motor phenotype of SCA1 mice with CAG reduction prevented us from evaluating the neuroprotective potential of IKKβ_CA on motor deficits in these mice. Full article

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Open AccessReview

Role of Neuroglia in the Habenular Connection Hub of the Dorsal Diencephalic Conduction System

Anton J. M. Loonen

Neuroglia 2023, 4(1), 34-51; https://doi.org/10.3390/neuroglia4010004 - 26 Feb 2023

Abstract

Astrocytes and microglia play important roles in organizing the structure and function of neuronal networks in the central nervous system (CNS). The dorsal diencephalic connection system (DDCS) is a phylogenetically ancient regulatory system by which the forebrain influences the activity of cholinergic and ascending monoaminergic pathways in the midbrain. The DDCS is probably important in inducing aspects of mental disorders, such as depression and addiction. The habenula is the small but highly complex connecting center of the DDCS in the epithalamus that consists of a medial (MHb) and lateral (LHb) division. MHb and LHb are built differently and connect different brain structures. Studies in animal models and human biomarker research provide good evidence that astroglia and microglia also affect the symptoms of mental disorders (such as depression). The significance of these neuroglia in habenular neurotransmission has not been extensively studied. This review article provides arguments for doing so more thoroughly. Full article

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Open AccessReview

ONC201 for Glioma Treatment: Adding an Important Weapon to Our Arsenal

Athina-Maria Aloizou

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Dimitra Aloizou

Neuroglia 2023, 4(1), 28-33; https://doi.org/10.3390/neuroglia4010003 - 01 Feb 2023

Abstract

Glioma, specifically gliobastoma, represents the commonest central nervous system malignancy and is notoriously challenging to treat, with only a minimal number of patients surviving beyond a year after diagnosis. The available treatment options include surgical resection, radiotherapy, and chemotherapy, mainly with temozolomide. However, gliomas can be particularly treatment resistant and novel options are currently being researched. One such agent is ONC201, the first member of the imipridone class and a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound, which has shown positive results in the first preliminary clinical reports about its application in glioma patients, while also being safe and well-tolerated. Particular promise has been shown for the H3K27M mutated glioblastomas, with more trials focusing on this patient subset. It is likely that this compound will be added in the treatment algorithms of glioma in the future, although more research is still needed. Full article

Open AccessReview

Contribution of Central and Peripheral Glial Cells in the Development and Persistence of Itch: Therapeutic Implication of Glial Modulation

Parisa Gazerani

Neuroglia 2023, 4(1), 15-27; https://doi.org/10.3390/neuroglia4010002 - 17 Jan 2023

Abstract

Chronic itch (CI) is an unpleasant skin sensation accompanied by an intense scratching desire that lasts 6 weeks or longer. Despite the high prevalence and negative impact on affected individuals and a huge healthcare burden, CI mechanisms are only partially understood, and consequently, treatment of CI remains sub-optimal. The complexity of CI treatment also stems from the comorbid existence of persistent itch with other somatic and psychological disorders. Etiologies of CI are multiple and diverse, although CI is often a result of dermatologically related conditions such as atopic dermatitis and psoriasis. Unfolding the pathophysiology of CI can provide possibilities for better therapy. Itch signaling is complex and neurons and non-neuronal cells play a role. This review focuses on recent findings on the role of glial cells in itch. Central glia (astrocytes and microglia) and peripheral glia (satellite glial cells and Schwann cells) are found to contribute to the development or persistence of itch. Hence, glial modulation has been proposed as a potential option in CI treatment. In experimental models of itch, the blockade of signal transducer and the activator of transcription (STAT) 3-mediated reactive astrogliosis have been shown to suppress chronic itch. Administration of a microglial inhibitor, minocycline, has also been demonstrated to suppress itch-related microglial activation and itch. In sensory ganglia, gap-junction blockers have successfully blocked itch, and hence, gap-junction-mediated coupling, with a potential role of satellite glial cells have been proposed. This review presents examples of glial involvement in itch and opportunities and challenges of glial modulation for targeting itch. Full article

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Open AccessHypothesis

On the Potential Therapeutic Roles of Taurine in Autism Spectrum Disorder

Alberto Rubio-Casillas

Elrashdy M. Redwan

and

Vladimir N. Uversky

Neuroglia 2023, 4(1), 1-14; https://doi.org/10.3390/neuroglia4010001 - 23 Dec 2022

Abstract

Contemporary research has found that people with autism spectrum disorder (ASD) exhibit aberrant immunological function, with a shift toward increased cytokine production and unusual cell function. Microglia and astroglia were found to be significantly activated in immuno-cytochemical studies, and cytokine analysis revealed that the macrophage chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and transforming growth factor β-1 (TGFB-1), all generated in the neuroglia, constituted the most predominant cytokines in the brain. Taurine (2-aminoethanesulfonic acid) is a promising therapeutic molecule able to increase the activity of antioxidant enzymes and ATPase, which may be protective against aluminum-induced neurotoxicity. It can also stimulate neurogenesis, synaptogenesis, and reprogramming of proinflammatory M1 macrophage polarization by decreasing mitophagy (mitochondrial autophagy) and raising the expression of the markers of the anti-inflammatory and pro-healing M2 macrophages, such as macrophage mannose receptor (MMR, CD206) and interleukin 10 (IL-10), while lowering the expression of the M1 inflammatory factor genes. Taurine also induces autophagy, which is a mechanism that is impaired in microglia cells and is critically associated with the pathophysiology of ASD. We hypothesize here that taurine could reprogram the metabolism of M1 macrophages that are overstimulated in the nervous system of people suffering from ASD, thereby decreasing the neuroinflammatory process characterized by autophagy impairment (due to excessive microglia activation), neuronal death, and improving cognitive functions. Therefore, we suggest that taurine can serve as an important lead for the development of novel drugs for ASD treatment. Full article

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Open AccessArticle

Sex-Dimorphic Glucocorticoid Receptor Regulation of Hypothalamic Primary Astrocyte Glycogen Metabolism: Interaction with Norepinephrine

Prabhat R. Napit

Abdulrahman Alhamyani

Khaggeswar Bheemanapally

Paul W. Sylvester

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Karen P. Briski

Neuroglia 2022, 3(4), 144-157; https://doi.org/10.3390/neuroglia3040010 - 17 Nov 2022

Abstract

Astrocyte glycogen is a critical metabolic variable that affects hypothalamic control of glucostasis. Glucocorticoid hormones regulate peripheral glycogen, but their impact on hypothalamic glycogen is not known. A hypothalamic astrocyte primary culture model was used to investigate the premise that glucocorticoids impose sex-dimorphic independent and interactive control of glycogen metabolic enzyme protein expression and glycogen accumulation. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) down-regulated glycogen synthase (GS), glycogen phosphorylase (GP)–brain type (GPbb), and GP–muscle type (GPmm) proteins in glucose-supplied male astrocytes, but enhanced these profiles in female. The catecholamine neurotransmitter norepinephrine (NE) did not alter these proteins, but amplified DEX inhibition of GS and GPbb in male or abolished GR stimulation of GPmm in female. In both sexes, DEX and NE individually increased glycogen content, but DEX attenuated the magnitude of noradrenergic stimulation. Glucoprivation suppressed GS, GPbb, and GPmm in male, but not female astrocytes, and elevated or diminished glycogen in these sexes, respectively. Glucose-deprived astrocytes exhibit GR-dependent induced glycogen accumulation in both sexes, and corresponding loss (male) or attenuation (female) of noradrenergic-dependent glycogen build-up. Current evidence for GR augmentation of hypothalamic astrocyte glycogen content in each sex, yet divergent effects on glycogen enzyme proteins infers that glucocorticoids may elicit opposite adjustments in glycogen turnover in each sex. Results document GR modulation of NE stimulation of glycogen accumulation in the presence (male and female) or absence (female) of glucose. Outcomes provide novel proof that astrocyte energy status influences the magnitude of GR and NE signal effects on glycogen mass. Full article

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Open AccessCommentary

Olfactory Ensheathing Cells for Spinal Cord Injury: The Cellular Superpowers for Nerve Repair

Francesca Oieni

Ronak Reshamwala

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James St John

Neuroglia 2022, 3(4), 139-143; https://doi.org/10.3390/neuroglia3040009 - 04 Nov 2022

Cited by 2

Abstract

Neurotrauma injuries are notoriously difficult to deal with both clinically as well as experimentally, as the cellular and molecular events ensuing after injury complicate the neuroinflammatory processes. Spinal cord injuries are further complicated by the formation of scars at the injury sites, which can provide a physical barrier to repair. The lack of effective clinical therapy for spinal cord injury underscores the need for experimental approaches to generate effective therapies. To repair the injury, cell transplantation offers the potential to replace lost cells and create a permissive bridge to promote neural regeneration across the injury site. Olfactory ensheathing cells (OECs), which are the glia of the olfactory nerve, stand apart from other candidate cell types due to their innate natural abilities to manage nerve injury and promote repair and regeneration. This is evidenced by their physiological role in the daily repair and maintenance of the olfactory nerve. Here, we explain their properties in relation to their physiological role and their most relevant cellular attributes, including cellular interactions, phagocytosis, migration, axonal guidance and support, and modulation of neuroinflammation. We highlight some critical drawbacks in the current approaches and identify some ways to address them. Full article

(This article belongs to the Special Issue Exclusive Papers Collection of Editorial Board Members in Neuroglia)

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Open AccessReview

Overview of Neuroglia Activation, Chronic Neuroinflammation, Remodeling, and Impaired Cognition Due to Perivascular Adipose Tissue-Derived Extracellular Vesicle Exosomes in Obesity and Diabetes

Melvin R. Hayden

Neuroglia 2022, 3(4), 112-138; https://doi.org/10.3390/neuroglia3040008 - 04 Oct 2022

Cited by 2

Abstract

Perivascular adipose tissue (PVAT)-derived extracellular vesicles (EVs) with small exosome(s) (PVAT-dEVexos) from the descending aorta are capable of entering capillaries and systemic circulation. These PVAT-dEVexos are delivered to the central nervous system (CNS) in preclinical, obese, insulin and leptin resistant, diabetic, db/db mouse models and humans with T2DM. Once within the CNS, these exosomes are capable of traversing the blood–brain barrier and the blood-cerebrospinal fluid barrier resulting in activation of the neuroglia microglia cell(s) (aMGCs) and the formation of reactive astrocytes (rACs). The chronic peripheral inflammation in the PVAT via crown-like structures consists of activated macrophages and mast cells, which harbor peripheral adipokines, cytokines, and chemokines (pCC) in addition to the EV exosomes. These pCC are transported to the systemic circulation where they may act synergistically with the PVAT-dEVexos to amplify the activation of neuroglia and result in chronic neuroinflammation. Once activated, the MGCs and ACs will contribute to even greater neuroinflammation via central nervous cytokines/chemokines (cnsCC). Activated neuroglia results in an increase of cnsCC and the creation of a vicious cycle of ongoing chronic neuroinflammation and increased redox stress. The increase in reactive oxygen species (ROS) involves the reactive species interactome that not only include reactive oxygen but also reactive nitrogen and sulfur species wherein a vicious cycle of ROS begetting inflammation and inflammation begetting ROS develops. Thus, the CNS perceives peripheral systemic inflammation from the obese PVAT depots as an injury and a response to injury wound healing mechanism develops with activation of neuroglia, cellular remodeling, neurodegeneration, and impaired cognition. Full article

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Open AccessArticle

Temporal Profile of Reactive Astrocytes after Ischemic Stroke in Rats

Bhairavi Srinageshwar

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Neuroglia 2022, 3(3), 99-111; https://doi.org/10.3390/neuroglia3030007 - 16 Sep 2022

Cited by 1

Abstract

Ischemic stroke is a debilitating neurological disease most commonly resulting from an occlusion within the cerebral vasculature. Ischemia/reperfusion injury is oftentimes a consequence of stroke, characterized by oxidative stress, neuroinflammation, and the activation of surrounding glial cells following restoration of blood supply. Astrocytes are regarded as the most prominent glial cell in the brain and, under pathologic conditions, display, among other pathologies, activated (GFAP) relatively proportional to the degree of reactivity. The primary objective of the study was to determine the temporal profile of astrocyte reactivity following ischemic stroke. Thirty-four Sprague-Dawley rats were assigned to surgery consisting of either 90-min middle cerebral artery occlusion (MCAo) or sham surgery. Animals were sub-grouped by postoperative euthanization day; 2 days (n = 10), 4 days (n = 11), and 7 days (n = 13). Fluorescence microscopy and densitometry were utilized to quantify GFAP immunoreactivity, which indicated a non-linear relationship following ischemia/reperfusion. Results demonstrated substantially higher GFAP levels in MCAo groups than in sham, with peak GFAP reactivity being shown in the brains of rats euthanized on day 4. These findings are applicable to future research, especially in the investigation of interventions that target reactive astrocytes following ischemic injury. Full article

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Open AccessArticle

Antioxidants Derived from Natural Products Reduce Radiative Damage in Cultured Retinal Glia to Prevent Oxidative Stress

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Neuroglia 2022, 3(3), 84-98; https://doi.org/10.3390/neuroglia3030006 - 20 Jul 2022

Cited by 2

Abstract

Retinal pathologies have been heavily studied in response to radiation and microgravity, including spaceflight-associated neuro-ocular syndrome (SANS), which is commonly developed in space flight. SANS has been characterized in clinical studies of astronauts returning to Earth and includes a range of symptoms, such as globe flattening, optic-disc edema, retinal folds, and retinal ischemia. In cases of retinal insult, Müller glia (MG) cells respond via neuroprotective gliotic responses that may become destructive to produce glial scarring and vison loss over time. Retinal pathology is further impacted by the production of excessive reactive oxygen species (ROS) that stimulate retinal inflammation and furthers the gliosis of MG. Neuroprotectants derived from natural products (NPs) able to scavenge excess ROS and mitigate long-term, gliotic responses have garnered recent interest, especially among mature and aging adults. The natural antioxidants aloin and ginkgolide A flavonoids, derived from Aloe vera and Ginkgo biloba species, respectively, have been of particular interest due to their recent use in other nervous-system studies. The current study examined MG behaviors in response to different doses of aloin and ginkgolide A over time by measuring changes in morphology, survival, and ROS production within microscale assays. The study was further enhanced by using galactic cosmic rays (GCR) at the Brookhaven NASA Space Radiation Laboratory to simulate ionizing radiation in low- and high-radiation parameters. Changes in the survival and ROS production of radiation-treated MG were then measured in response to varying dosage of NPs. Our study used in vitro systems to evaluate the potential of NPs to reduce oxidative stress in the retina, highlighting the underexplored interplay between NP antioxidants and MG endogenous responses both in space and terrestrially. Full article

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Open AccessArticle

Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice

William M. Vanderheyden

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Neuroglia 2022, 3(2), 73-83; https://doi.org/10.3390/neuroglia3020005 - 13 May 2022

Abstract

Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called “Single Prolonged Stress” (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light–dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene (Fabp7) influence changes in stress-dependent sleep disturbances and associated anxiety behavior. Full article

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Open AccessArticle

Establishment of a Simple and Versatile Evaporation Compensation Model for In Vitro Chronic Ethanol Treatment: Impact on Neuronal Viability

Meera Rath

Ariana M. Figueroa

Ping Zhang

Stanley M. Stevens, Jr.

and

Bin Liu

Neuroglia 2022, 3(2), 61-72; https://doi.org/10.3390/neuroglia3020004 - 06 Apr 2022

Abstract

Alcohol overconsumption is a major cause of preventable mental disorders and death in the United States and around the world. The pathogenesis of alcohol dependence, abuse, and toxicity to the central nervous system remains incompletely understood. Cell culture-based models have been highly valuable in studying the molecular and cellular mechanisms underlying the contribution of individual CNS cell types to ethanol’s effects on the brain. However, conventional cell culture model systems carry the inherent disadvantage of rapid loss of ethanol due to evaporation following a bolus addition of ethanol at the start of the treatment. In this study, we have established a multi-well cell culture plate-based ethanol evaporation compensation model that utilizes the inter-well space as a reservoir to compensate for the evaporative loss of ethanol in the cell treatment wells. Following a single bolus addition at the start, ethanol concentration in the treatment wells rapidly decreased over time. Through compensation using the multi-well plate platform, maintenance of ethanol concentrations ranging from 10–100 mM was achieved for up to 72 h in a cell-free system. Furthermore, greater effects on ethanol-induced decrease in the viability of human dopaminergic neuronal cells were observed with than without evaporation compensation. Our method effectively compensates for the evaporative loss of ethanol typically observed in the traditional treatment method and provides a simple and economic in vitro model system for ethanol treatment over an extended timeframe where maintenance of a relatively constant concentration of ethanol is desired. Full article

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Open AccessArticle

Unique Astrocyte Cytoskeletal and Nuclear Morphology in a Three-Dimensional Tissue-Engineered Rostral Migratory Stream

Erin M. Purvis

John C. O’Donnell

and

D. Kacy Cullen

Neuroglia 2022, 3(1), 41-60; https://doi.org/10.3390/neuroglia3010003 - 06 Mar 2022

Abstract

Neural precursor cells (NPCs) are generated in the subventricular zone (SVZ) and travel through the rostral migratory stream (RMS) to replace olfactory bulb interneurons in the brains of most adult mammals. Following brain injury, SVZ-derived NPCs can divert from the RMS and migrate toward injured brain regions but arrive in numbers too low to promote functional recovery without experimental intervention. Our lab has biofabricated a “living scaffold” that replicates the structural and functional features of the endogenous RMS. This tissue-engineered rostral migratory stream (TE-RMS) is a new regenerative medicine strategy designed to facilitate stable and sustained NPC delivery into neuron-deficient brain regions following brain injury or neurodegenerative disease and an in vitro tool to investigate the mechanisms of neuronal migration and cell–cell communication. We have previously shown that the TE-RMS replicates the basic structure and protein expression of the endogenous RMS and can direct immature neuronal migration in vitro and in vivo. Here, we further describe profound morphological changes that occur following precise physical manipulation and subsequent self-assembly of astrocytes into the TE-RMS, including significant cytoskeletal rearrangement and nuclear elongation. The unique cytoskeletal and nuclear architecture of TE-RMS astrocytes mimics astrocytes in the endogenous rat RMS. Advanced imaging techniques reveal the unique morphology of TE-RMS cells that has yet to be described of astrocytes in vitro. The TE-RMS offers a novel platform to elucidate astrocyte cytoskeletal and nuclear dynamics and their relationship to cell behavior and function. Full article

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Open AccessArticle

Glia Excitation in the CNS Modulates Intact Behaviors and Sensory-CNS-Motor Circuitry

Shelby McCubbin

Douglas A. Harrison

and

Robin L. Cooper

Neuroglia 2022, 3(1), 23-40; https://doi.org/10.3390/neuroglia3010002 - 28 Feb 2022

Abstract

Glial cells play a role in many important processes, though the mechanisms through which they affect neighboring cells are not fully known. Insights may be gained by selectively activating glial cell populations in intact organisms utilizing the activatable channel proteins channel rhodopsin (ChR2XXL) and TRPA1. Here, the impacts of the glial-specific expression of these channels were examined in both larval and adult Drosophila. The Glia > ChR2XXL adults and larvae became immobile when exposed to blue light and TRPA1-expressed Drosophila upon heat exposure. The chloride pump expression in glia > eNpHR animals showed no observable differences in adults or larvae. In the in situ neural circuit activity of larvae in the Glia > ChR2XXL, the evoked activity first became more intense with concurrent light exposure, and then the activity was silenced and slowly picked back up after light was turned off. This decrease in motor nerve activity was also noted in the intact behaviors for Glia > ChR2XXL and Glia > TRPA1 larvae. As a proof of concept, this study demonstrated that activation of the glia can produce excessive neural activity and it appears with increased excitation of the glia and depressed motor neuron activity. Full article

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Open AccessReview

Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System

Quentin Delarue

and

Nicolas Guérout

Neuroglia 2022, 3(1), 1-22; https://doi.org/10.3390/neuroglia3010001 - 28 Jan 2022

Cited by 1

Abstract

The primary olfactory system (POS) is in permanent renewal, especially the primary olfactory neurons (PON) are renewed with a turnover of around four weeks, even in adulthood. The re-growth of these axons is helped by a specific population of glial cells: the olfactory ensheathing cells (OECs). In the POS, OECs constitute an “open-channel” in which the axons of PON cause regrowth from peripheral nervous system (PNS) to central nervous system (CNS). The remarkable role played by OECs into the POS has led scientists to investigate their properties and potential beneficial effects after transplantation in different lesion models of the CNS and PNS. In this review, we will resume and discuss more than thirty years of research regarding OEC studies. Indeed, after discussing the embryonic origins of OECs, we will describe the in vitro and in vivo properties exert at physiological state by these cells. Thereafter, we will present and talk over the effects of the transplantation of OECs after spinal cord injury, peripheral injury and other CNS injury models such as demyelinating diseases or traumatic brain injury. Finally, the mechanisms exerted by OECs in these different CNS and PNS lesion paradigms will be stated and we will conclude by presenting the innovations and future directions which can be considered to improve OECs properties and allow us to envisage their use in the near future in clinical applications. Full article

(This article belongs to the Special Issue Transplantation of Glial Cells to Repair Injuries and Diseases of the Nervous System)

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