Central Nervous System Pathology Research Articles

Substrate viscosity impairs temozolomide-mediated inhibition of glioblastoma cells' growth

BackgroundThe mechanical state of the extracellular environment of the brain cells considerably affects their phenotype during the development of central nervous system (CNS) pathologies, and when the cells respond to drugs. The reports on the evaluation of the viscoelastic properties of different brain tumors have shown that both tissue stiffness and viscosity can be altered during cancer development. Although a compelling number of reports established the role of substrate stiffness on the proliferation, motility, and drug sensitivity of brain cancer cells, there is a lack of parallel data in terms of alterations in substrate viscosity. MethodsBased on viscoelasticity measurements of rat brain samples using strain rheometry, polyacrylamide (PAA) hydrogels mimicking elastic and viscous parameters of the tissues were prepared. Optical microscopy and flow cytometry were employed to assess the differences in glioblastoma cells morphology, proliferation, and cytotoxicity of anticancer drug temozolomide (TMZ) due to increased substrate viscosity. ResultsOur results indicate that changes in substrate viscosity affect the proliferation of untreated glioma cells to a lesser extent, but have a significant impact on the apoptosis-associated depolarization of mitochondria and level of DNA fragmentation. This suggests that viscosity sensing and stiffness sensing machinery can activate different signaling pathways in glioma cells. ConclusionCollected data indicate that viscosity should be considered an important parameter in in vitro polymer-based cell culture systems used for drug screening.

Key role of Rho GTPases in motor disorders associated with neurodevelopmental pathologies.

Growing evidence suggests that Rho GTPases and molecules involved in their signaling pathways play a major role in the development of the central nervous system (CNS). Whole exome sequencing (WES) and de novo examination of mutations, including SNP (Single Nucleotide Polymorphism) in genes coding for the molecules of their signaling cascade, has allowed the recent discovery of dominant autosomic mutations and duplication or deletion of candidates in the field of neurodevelopmental diseases (NDD). Epidemiological studies show that the co-occurrence of several of these neurological pathologies may indeed be the rule. The regulators of Rho GTPases have often been considered for cognitive diseases such as intellectual disability (ID) and autism. But, in a remarkable way, mild to severe motor symptoms are now reported in autism and other cognitive NDD. Although a more abundant litterature reports the involvement of Rho GTPases and signaling partners in cognitive development, molecular investigations on their roles in central nervous system (CNS) development or degenerative CNS pathologies also reveal their role in embryonic and perinatal motor wiring through axon guidance and later in synaptic plasticity. Thus, Rho family small GTPases have been revealed to play a key role in brain functions including learning and memory but their precise role in motor development and associated symptoms in NDD has been poorly scoped so far, despite increasing clinical data highlighting the links between cognition and motor development. Indeed, early impairements in fine or gross motor performance is often an associated feature of NDDs, which then impact social communication, cognition, emotion, and behavior. We review here recent insights derived from clinical developmental neurobiology in the field of Rho GTPases and NDD (autism spectrum related disorder (ASD), ID, schizophrenia, hypotonia, spastic paraplegia, bipolar disorder and dyslexia), with a specific focus on genetic alterations affecting Rho GTPases that are involved in motor circuit development.

The role of spinal cord tractography in detecting lesions following selective bladder afferent and efferent fibers injury: A novel method for induction of neurogenic lower urinary tract dysfunction in rabbit.

Neurogenic lower urinary tract dysfunction (NLUTD), a challenging disorder, is defined by lack of bladder control due to the abnormalities in neural pathways and can be classified based on the location of lesions within the nervous system, thus investigating the neural pathways can help us to know the site of the lesion and specify the class of the NLUTD. Diffusion Tensor Imaging (DTI) tractography, a noninvasive advanced imaging method, is capable of detecting central nervous system pathologies, even if routine magnetic resonance imaging shows no abnormality. Accordingly, tractography is an ideal technique to evaluate patients with NLUTD and visualize the pathology site within the spine. This study aimed to introduce a novel method of spinal cord injury (SCI) to establish NLUTD in the rabbit and to investigate the potential of tractography in tracing neural tracts of the spinal cord in an induced NLUTD animal model. An animal model of NLUTD was induced through cauterization of the spinal cord at the level T12-L1 in 12 rabbits. Then rabbits were assessed via DTI, urodynamic studies (UDS), voiding cystourethrogram (VCUG), and pathology assessments using antineurofilament 200 (NF200) antibody, anti-S100, anti-Smooth Muscle Actin, anti-Myogenin, and anti-MyoD1. The tractography visualized lesions within spinal cord fibers. DTI parameters including fractional anisotropy (FA) value and tract density were significantly decreased (FA: p-value = 0.01, Tract density: p-value = 0.05) after injury. The mean diffusivity (MD) was insignificantly increased compared to before the injury. Also, the results of UDS and pathology assessments corroborated that applying SCI and the establishment of the NLUTD model was completely successful. In the present study, we investigated the auxiliary role of tractography in detecting the spinal cord lesions in the novel established rabbit model of NLUTD. The introduced method of NLUTD induction was without the leg's neurological deficit, easily applicable, low-cost, and was accompanied by minimal surgical preparation and a satisfactory survival rate in comparison with other SCI animal models.

Brain and spinal cord trauma: what we know about the therapeutic potential of insulin growth factor 1 gene therapy.

Although little attention has been paid to cognitive and emotional dysfunctions observed in patients after spinal cord injury, several reports have described impairments in cognitive abilities. Our group also has contributed significantly to the study of cognitive impairments in a rat model of spinal cord injury. These findings are very significant because they demonstrate that cognitive and mood deficits are not induced by lifestyle changes, drugs of abuse, and combined medication. They are related to changes in brain structures involved in cognition and emotion, such as the hippocampus. Chronic spinal cord injury decreases neurogenesis, enhances glial reactivity leading to hippocampal neuroinflammation, and triggers cognitive deficits. These brain distal abnormalities are recently called tertiary damage. Given that there is no treatment for Tertiary Damage, insulin growth factor 1 gene therapy emerges as a good candidate. Insulin growth factor 1 gene therapy recovers neurogenesis and induces the polarization from pro-inflammatory towards anti-inflammatory microglial phenotypes, which represents a potential strategy to treat the neuroinflammation that supports tertiary damage. Insulin growth factor 1 gene therapy can be extended to other central nervous system pathologies such as traumatic brain injury where the neuroinflammatory component is crucial. Insulin growth factor 1 gene therapy could emerge as a new therapeutic strategy for treating traumatic brain injury and spinal cord injury.

A shared disease-associated oligodendrocyte signature among multiple CNS pathologies.

Alzheimer's disease (AD) is a complex neurodegenerative disease, perturbing neuronal and non-neuronal cell populations. In this study, using single-cell transcriptomics, we mapped all non-immune, non-neuronal cell populations in wild-type and AD model (5xFAD) mouse brains. We identified an oligodendrocyte state that increased in association with brain pathology, which we termed disease-associated oligodendrocytes (DOLs). In a murine model of amyloidosis, DOLs appear long after plaque accumulation, and amyloid-beta (Aβ) alone was not sufficient to induce the DOL signature in vitro. DOLs could be identified in a mouse model of tauopathy and in other murine neurodegenerative and autoimmune inflammatory conditions, suggesting a common response to severe pathological conditions. Using quantitative spatial analysis of mouse and postmortem human brain tissues, we found that oligodendrocytes expressing a key DOL marker (SERPINA3N/SERPINA3 accordingly) are present in the cortex in areas of brain damage and are enriched near Aβ plaques. In postmortem human brain tissue, the expression level of this marker correlated with cognitive decline. Altogether, this study uncovers a shared signature of oligodendrocytes in central nervous system pathologies.

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects.SIGNIFICANCE STATEMENTThis work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.

A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders

Astrocytes are one of the most numerous glial cells in the central nervous system (CNS) and provide essential support to neurons to ensure CNS health and function. During a neuropathological challenge, such as during human immunodeficiency virus (HIV)-1 infection or (METH)amphetamine exposure, astrocytes shift their neuroprotective functions and can become neurotoxic. Identifying cellular and molecular mechanisms underlying astrocyte dysfunction are of heightened importance to optimize the coupling between astrocytes and neurons and ensure neuronal fitness against CNS pathology, including HIV-1-associated neurocognitive disorders (HAND) and METH use disorder. Mitochondria are essential organelles for regulating metabolic, antioxidant, and inflammatory profiles. Moreover, endoplasmic reticulum (ER)-associated signaling pathways, such as calcium and the unfolded protein response (UPR), are important messengers for cellular fate and function, including inflammation and mitochondrial homeostasis. Increasing evidence supports that the three arms of the UPR are involved in the direct contact and communication between ER and mitochondria through mitochondria-associated ER membranes (MAMs). The current study investigated the effects of HIV-1 infection and chronic METH exposure on astrocyte ER and mitochondrial homeostasis and then examined the three UPR messengers as potential regulators of astrocyte mitochondrial dysfunction. Using primary human astrocytes infected with pseudotyped HIV-1 or exposed to low doses of METH for 7 days, astrocytes had increased mitochondrial oxygen consumption rate (OCR), cytosolic calcium flux and protein expression of UPR mediators. Notably, inositol-requiring protein 1α (IRE1α) was most prominently upregulated following both HIV-1 infection and chronic METH exposure. Moreover, pharmacological inhibition of the three UPR arms highlighted IRE1α as a key regulator of astrocyte metabolic function. To further explore the regulatory role of astrocyte IRE1α, astrocytes were transfected with an IRE1α overexpression vector followed by activation with the proinflammatory cytokine interleukin 1β. Overall, our findings confirm IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake, highlighting a novel potential target for regulating astrocyte dysfunction. Finally, these findings suggest both canonical and non-canonical UPR mechanisms of astrocyte IRE1α. Thus, additional studies are needed to determine how to best balance astrocyte IRE1α functions to both promote astrocyte neuroprotective properties while preventing neurotoxic properties during CNS pathologies.

Utility of the ALSFRS-R for predicting ALS and comorbid disease neuropathology: The Veterans Affairs Biorepository Brain Bank.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) is commonly used to track ALS disease progression; however, there are gaps in the literature regarding the extent to which the ALSFRS-R relates to underlying central nervous system (CNS) pathology. The current study explored the association between ALSFRS-R (total and subdomain) scores and postmortem neuropathology (both ALS-specific and comorbid disease). Within our sample of 93 military veterans with autopsy-confirmed ALS, we utilized hierarchical cluster analysis (HCA) to identify discrete profiles of motor dysfunction based on ALSFRS-R subdomain scores. We examined whether emergent clusters were associated with neuropathology. Separate analyses of variance and covariance with post-hoc comparisons were performed to examine relevant cluster differences. Analyses revealed significant correlations between ALSFRS-R total and subdomain scores with some, but not all, neuropathological variables. The HCA illustrated three groups: Cluster 1-predominantly diffuse functional impairment; Cluster 2-spared respiratory/bulbar and impaired motor function; and Cluster 3-spared bulbar and impaired respiratory, and fine and gross motor function. Individuals in Cluster 1 (and to a lesser degree, Cluster 3) exhibited greater accumulation of ALS-specific neuropathology and less comorbid neuropathology than those in Cluster 2. These results suggest that discrete patterns of motor dysfunction based on ALSFRS-R subdomain scores are related to postmortem neuropathology. Findings support use of ALSFRS-R subdomain scores to capture the heterogeneity of clinical presentation and disease progression in ALS, and may assist researchers in identifying endophenotypes for separate assessment in clinical trials.

The tryptophan metabolism, kynurenine pathway and oxidative stress – implications for glioma pathobiology

The kynurenine pathway receives increasing attention due to its involvement in central nervous system pathologies, i.a. neurodegenerative and psychiatric disorders, but also due to the contribution to the pathomechanism of neoplasms, including brain tumors. The present review focuses on kynurenine pathway activity in gliomas, brain tumors of glial origin. The upregulation of kynurenine pathway enzyme, indoleamine 2,3-dioxygenase (IDO), resulting in a decreased level of tryptophan and augmented kynurenine synthesis (increased (KYN/Trp ratio) are the most recognised hallmark of malignant transformation, characterised with immunomodulatory adaptations, providing an escape from defence mechanisms of the host, growth-beneficial milieu and resistance to some therapeutics. The review addresses, however, the oxidative/nitrosative stress-associated mechanisms of tryptophan catabolism, mainly the kynurenine pathway activity, linking them with glioma pathobiology.

Pneumonia in Nervous System Injuries: An Analytic Review of Literature and Recommendations.

Pneumonia is one of the most common complications in intensive care units and is the most common nosocomial infection in this setting. Patients with neurocritical conditions who are admitted to ICUs are no exception, and in fact, are more prone to infections such as pneumonia because of factors such as swallow dysfunction, need for mechanical ventilation, longer length of stay in hospitals, etc. Common central nervous system pathologies such as ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, neuromuscular disorders, status epilepticus, and demyelinating diseases can cause long in-hospital admissions and increase the risk of pneumonia each with a mechanism of its own. Brain injury-induced immunosuppression syndrome is usually considered the common mechanism through which patients with critical central nervous system conditions become susceptible to different kinds of infection including pneumonia. Evaluating the patients and assessment of the risk factors can lead our attention toward better infection control in this population and therefore decrease the risk of infections in central nervous system injuries.

Systematic validation and assessment of immunohistochemical markers for central nervous system pathology in cetaceans, with emphasis on auditory pathways.

Cetacean neuropathology is a developing field that aims to assess structural and neurochemical changes involved in neurodegenerative, infectious and traumatic processes, however markers used previously in cetaceans have rarely undergone systematic validation. This is a prerequisite to investigating the potential damage inflicted on the cetacean auditory system by anthropogenic noise. In order to assess apoptotic, neuroinflammatory and structural aberrations on a protein level, the baseline expression of biomarker proteins has to be characterized, implementing a systematic approach to validate the use of anti-human and anti-laboratory animal antibodies in dolphin tissues. This approach was taken to study 12 different antibodies associated with hypoxic-ischemic, inflammatory, plastic and excitatory-inhibitory changes implicated in acoustic trauma within the ventral cochlear nuclei and inferior colliculi of 20 bottlenose dolphins (Tursiops truncatus). Out of the 12 tested antibodies, pro-apoptotic protease factor 1 (Apaf-1), diacylglycerolkinase-ζ (DGK-ζ), B-cell lymphoma related protein 2 (Bcl-2), amyloid-β peptide (Aβ) and neurofilament 200 (NF200) were validated employing Western blot analyses and immunohistochemistry (IHC). The results of the validation process indicate specific patterns of immunoreactivity that are comparable to those reported in other mammals, thus suggesting a key panel of IHC biomarkers of pathological processes in the cetacean brain. As a consequence, the antibodies tested in this study may constitute a valid tool for supporting existing diagnostic methods in neurological diseases. The approach of systematic validation of IHC markers in cetaceans is proposed as a standard practice, in order for results to be transparent, reliable and comparable.

Phenomenology and content of the inhaled N, N-dimethyltryptamine (N, N-DMT) experience

Understanding the phenomenology and content of the inhaled N, N, dimethyltryptamine (N, N-DMT) experience is critical to facilitate and support ongoing research and therapeutic models targeting mental health conditions and central nervous system pathology. A qualitative analysis was conducted of all N, N-DMT experiences posted to the r/DMT Reddit community over a 10-year period from 2009 to 2018. A total of 3778 experiences from 3305 posts were included in this study. A median dose of N, N-DMT of 40.0 mg [interquartile range (IQR), 27.5 to 50.0] and a median experience duration of 10 min (IQR, 5.0 to 15.0) were identified. The most common somatic effects were somaesthesias (n = 1415, 37.5%) and an auditory ringing (n = 583, 15.4%). Visualizations predominantly consisted of fractals, shapes, patterns (n = 1231, 32.6%) and vivid colours (n = 953, 25.2%). Entity encounters were reported in 45.5% (n = 1719) of the experiences and involved predominantly a feminine phenotype (n = 416, 24.2%); deities (n = 293, 17.0%); aliens (n = 281, 16.3%); creature-based entities (n = 158, 9.2%, including reptilian and insectoid beings); mythological beings (n = 144, 8.4%, including machine elves); and jesters (n = 112, 6.5%). Entity interactions were predominantly positive (n = 600, 34.9% of encounters) involving benevolent, comforting, protecting, or outwardly caring interactions. A companion-type, pedagogical, or guide-type interaction was identified 32.4% of encounters (n = 557). Common typology, architecture, and structural features of the “DMT world” included descriptions of alternate or higher dimensions (n = 952, 25.2%); rooms [n = 582, 15.4%, including the “waiting room” (n = 105, 2.8%)], and a tunnel (n = 390, 10.3%). Features of mystical and ego-dissolution experiences were common. Additional rewarding aspects were identified, including a sense of familiarity and the acceptance/removal of the fear of death. Challenging and difficult responses were less frequent but also documented. Statements of profundity were identified in 232 experiences (6.1%), including pronouncing the experience or an aspect of the experience as the most “beautiful” or feeling the most “beautiful” of their life (n = 47, 1.2%). This study identified common phenomenological themes and content of naturalistic inhaled N, N-DMT experiences. Major thematic domains included (1) physical and somatic experiences; (2) visualizations and imagery; (3) entity encounters including entity phenotype, descriptors, attributes, disposition, and characteristics of the interaction; (4) typology, architectural features, structural characteristics, and scenery of the “DMT world”; (5) alerations in consciousness (including mystical experiences, out-of-body experiences, and ego-dissolution); (6) emotional responses (including positive, rewarding, difficult, and challenging); and (7) statements of profundity.

Efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen for prevention of seizure recurrence during the same fever episode in children with suspected simple febrile seizures.

This study was undertaken to evaluate the efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen in comparison with as-needed acetaminophen alone for prevention of seizure recurrence during the same fever episode in suspected pediatric simple febrile seizures (SFS). This single-center, prospective, observational study was conducted from July 29, 2019 to February 15, 2021 at a children's hospital. Children aged 6months to 60months presenting to the emergency department with suspected SFS were included. Participants receiving both diazepam suppositories and as-needed acetaminophen were compared with those receiving as-needed acetaminophen alone. The primary outcome was seizure recurrence during the same fever episode. The secondary outcomes included the incidence of central nervous system (CNS) pathologies, adverse events, and medical costs. Of the 316 participants, 228 (72.2%) had their first febrile seizure. Diazepam (.3-.5mg/kg for up to two doses) was administered to 88 of 316 patients (27.8%). The outcomes were available for 306 patients. The recurrence rate was 3.5% (3/85) in the patients receiving diazepam with as-needed acetaminophen and 12.2% (27/221) in the patients receiving as-needed acetaminophen alone (relative risk = .29, 95% confidence interval [CI] = .09-.93, p=.03). The adjusted odds ratio of diazepam administration against recurrence was .23 (95% CI = .07-.78, p=.02). None of the patients had a CNS pathology. No severe adverse events occurred, although mild ataxia was observed significantly more often in the patients receiving diazepam and as-needed acetaminophen (29.4% vs. 18.7%, p=.04). The median medical cost was US $199 (interquartile range [IQR] = 86-244) for the group receiving both medications and US $202 (IQR = 114-242) for the group receiving as-needed acetaminophen alone. Compared with as-needed acetaminophen alone, diazepam with as-needed acetaminophen may reduce seizure recurrence more during the same fever episode without severe adverse events or additional costs in children with suspected SFS.

Early detection of cerebrovascular pathology and protective antiviral immunity by MRI.

Central nervous system (CNS) infections are a major cause of human morbidity and mortality worldwide. Even patients that survive, CNS infections can have lasting neurological dysfunction resulting from immune and pathogen induced pathology. Developing approaches to noninvasively track pathology and immunity in the infected CNS is crucial for patient management and development of new therapeutics. Here, we develop novel MRI-based approaches to monitor virus-specific CD8+ T cells and their relationship to cerebrovascular pathology in the living brain. We studied a relevant murine model in which a neurotropic virus (vesicular stomatitis virus) was introduced intranasally and then entered the brain via olfactory sensory neurons - a route exploited by many pathogens in humans. Using T2*-weighted high-resolution MRI, we identified small cerebral microbleeds as an early form of pathology associated with viral entry into the brain. Mechanistically, these microbleeds occurred in the absence of peripheral immune cells and were associated with infection of vascular endothelial cells. We monitored the adaptive response to this infection by developing methods to iron label and track individual virus specific CD8+ T cells by MRI. Transferred antiviral T cells were detected in the brain within a day of infection and were able to reduce cerebral microbleeds. These data demonstrate the utility of MRI in detecting the earliest pathological events in the virally infected CNS as well as the therapeutic potential of antiviral T cells in mitigating this pathology.

Magnetic resonance tractogtaphy: possibilities and limitations, modern approach to data processing

Purpose: systematization of the knowledge about diffusion tensor magnetic resonance tomography; analysis of literature related to current limitations of this method and possibilities of overcoming these limitations.Materials and methods. We have analyzed 74 publications (6 Проанализировано 74 публикации (6 Russian, 68 foreign), published in the time period from 1986 to 2021years. More, than half of these articles were published in the last ten years, 19 studies-in the time period from 2016 to 2021years.Results. In this article we represent the physical basis of diffusion weighted techniques of magnetic resonance tomography, principles of obtaining diffusion weighted images and diffusion tensor, cover the specific features of the probabilistic and deterministic approaches of the diffusion tensor MRI data processing, describe methods of evaluation of the diffusion characteristics of tissues in clinical practice. Article provides a thorough introduction to the reasons of existing limitations of diffusion tensor MRI and systematization the main developed approaches of overcoming these limitations, such as multi-tensor model, high angular resolution diffusion imaging, diffusion kurtosis visualization. The article consistently reviews the stages of data processing of diffusion tensor magnetic resonance tomography (preprocessing, processing and post processing). We also describe the special aspects of the main approaches to the quantitative data analysis of diffusion tensor magnetic resonance tomography (such as analysis of the region of interest, analysis of the total data amount, quantitative tractography).Conclusion. Magnetic resonance tractography is a unique technique for noninvasive in vivo visualization of brain white matter tracts and assessment of the structural integrity of their constituent axons. In the meantime this technique, which has found applications in numerous pathologies of central nervous system, has a number of significant limitations, and the main of them are the inability to adequately visualize the crossing fibers and the relatively low reproducibility of the results. Standardization of the data postprocessing algorithms, further upgrading of the magnetic resonance scanners and implementation of the alternative tractography methods have the potential of partially reducing of the current limitations.

Inositol‐requiring enzyme 1 alpha (IRE1α) regulates astrocyte metabolic and inflammatory phenotypes: Implications in (METH)amphetamine use disorder and HIV‐associated neurocognitive disorders

Human immunodeficiency virus 1 (HIV‐1) invades the central nervous system (CNS) early during infection and can persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV‐associated neurocognitive disorders (HAND). Astrocytes are the most numerous glial cells in the CNS and provide essential support to neurons. During a neuropathological challenge, such as HIV‐1 infection, astrocytes can shift their neurotrophic functions to become neurotoxic and even serve as latent reservoirs for HIV‐1 infection. Notably, substance use disorders, including methamphetamine (METH) are disproportionately elevated among people living with HIV‐1. METH use can induce neurotoxic and neurodegenerative consequences, which can increase one’s risk and severity of HAND. Thus, a better understanding of HIV‐1 infection and METH exposure both alone and in combination on astrocyte function could help identify key cellular or molecular targets that can regulate astrocyte neuroprotective versus neurotoxic phenotypes to optimize astrocyte and neuronal coupling and combat CNS pathology.Direct contact sites between the endoplasmic reticulum (ER) and the mitochondria, termed mitochondria‐associated ER membranes (MAMs), are central hubs for regulating several cellular processes, including inflammation and mitochondrial function and dynamics. In fact, the transfer of calcium from the ER to mitochondria is essential for mitochondrial bioenergetics. Interestingly, increasing evidence supports that the three arms of the unfolded protein response (UPR) are key cell signaling messengers within the ER‐mitochondrial interface, beyond their classical ER stress functions. Briefly, protein kinase RNA‐like endoplasmic reticulum kinase (PERK) has been determined as a regulator for MAM tethering and mitochondrial morphology. Inositol‐requiring enzyme 1 alpha (IRE1α) is implicated in regulating MAM‐mediated calcium transfer. Activating transcription factor 6 (ATF6) is suspected to participate in MAM formation as it is known to mediate ER elongation and lipid homeostasis. However, these regulatory mechanisms have not yet been fully elucidated.Our studies specifically highlight IRE1α as a key regulator of astrocyte metabolic and inflammatory phenotypes. Using primary human astrocytes infected with pseudotyped HIV and/or exposed to low doses of METH for seven days, astrocytes have increased protein expression of select UPR/MAM mediators. Under the same paradigms, we see increased cytosolic calcium flux and mitochondrial oxygen consumption rate, which were associated with increased mitochondria calcium uptake. Manipulation of IRE1α using both pharmacological inhibitors and an overexpression plasmid, confirms IRE1α modulates astrocyte calcium signaling, metabolic activity, glutamate clearance, and cytokine release. These findings identify a novel target for regulating astrocyte metabolic and inflammatory phenotypes, which could help combat astrocyte‐mediated neurotoxicity and potentially promote a neurotrophic phenotype during CNS pathologies.

Sequence similarity between SARS-CoV-2 Nucleocapsid and CNS proteins provides mechanistic insight into viral neuropathogenesis following infection

Abstract The novel coronavirus SARS-CoV-2 emerged in 2019 and continues to cause death and disease throughout the world. To date, there have been 272 million infections and 5.3 million deaths worldwide, underscoring the necessity of understanding the virus and host immune response as well as developing novel therapeutics for severe disease. From the start of the pandemic, a prominent pattern of central nervous system (CNS) pathologies – including cases similar to Multiple Sclerosis (MS) - has emerged that suggest a related, underlying mechanism of viral mimicry to proteins expressed by CNS tissues. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins typically associated with MS. Using Pepmatch, a bioinformatics package which predicts peptide similarity in the context of MHC presentation, we discovered that Nucleocapsid protein, but not Spike or Membrane proteins, of SARS-CoV-2 shares significant overlap with 22 MS-associated proteins. To provide further physiological relevance, we used an MHC binding prediction tool to determine whether these Nucleocapsid peptides would bind preferentially to MS-associated alleles. While we did not find any significant binding pattern among MS-associated alleles, we did discover that Nucleocapsid peptides which overlap with CD99 Antigen were among the top HLA-peptide predictions. This finding provides a plausible mechanism by which the targeting of CD99 by lymphocytes leads to compromised blood-brain-barrier integrity and exacerbated viral neuropathogenesis. This work provides a deeper understanding of the unique viral dynamics with the human immune system and corroborates the targeting of CD99 to ameliorate neurological complications of SARS-CoV-2.

Mechanotransduction: Exploring New Therapeutic Avenues in Central Nervous System Pathology.

Cells are continuously exposed to physical forces and the central nervous system (CNS) is no exception. Cells dynamically adapt their behavior and remodel the surrounding environment in response to forces. The importance of mechanotransduction in the CNS is illustrated by exploring its role in CNS pathology development and progression. The crosstalk between the biochemical and biophysical components of the extracellular matrix (ECM) are here described, considering the recent explosion of literature demonstrating the powerful influence of biophysical stimuli like density, rigidity and geometry of the ECM on cell behavior. This review aims at integrating mechanical properties into our understanding of the molecular basis of CNS disease. The mechanisms that mediate mechanotransduction events, like integrin, Rho/ROCK and matrix metalloproteinases signaling pathways are revised. Analysis of CNS pathologies in this context has revealed that a wide range of neurological diseases share as hallmarks alterations of the tissue mechanical properties. Therefore, it is our belief that the understanding of CNS mechanotransduction pathways may lead to the development of improved medical devices and diagnostic methods as well as new therapeutic targets and strategies for CNS repair.

Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape.

Once believed to be part of the nervenkitt or “nerve glue” network in the central nervous system (CNS), oligodendroglial cells now have established roles in key neurological functions such as myelination, neuroprotection, and motor learning. More recently, oligodendroglia has become the subject of intense investigations aimed at understanding the contributions of its energetics to CNS physiology and pathology. In this review, we discuss the current understanding of oligodendroglial metabolism in regulating key stages of oligodendroglial development and health, its role in providing energy to neighboring cells such as neurons, as well as how alterations in oligodendroglial bioenergetics contribute to disease states. Importantly, we highlight how certain inputs can regulate oligodendroglial metabolism, including extrinsic and intrinsic mediators of cellular signaling, pharmacological compounds, and even dietary interventions. Lastly, we discuss emerging studies aimed at discovering the therapeutic potential of targeting components within oligodendroglial bioenergetic pathways.

Endocannabinoid signaling in oligodendroglia.

In the central nervous system, oligodendrocytes synthesize the myelin, a specialized membrane to wrap axons in a discontinuous way allowing a rapid saltatory nerve impulse conduction. Oligodendrocytes express a number of growth factors and neurotransmitters receptors that allow them to sense the environment and interact with neurons and other glial cells. Depending on the cell cycle stage, oligodendrocytes may respond to these signals by regulating their survival, proliferation, migration, and differentiation. Among these signals are the endocannabinoids, lipidic molecules synthesized from phospholipids in the plasma membrane in response to cell activation. Here, we discuss the evidence showing that oligodendrocytes express a full endocannabinoid signaling machinery involved in physiological oligodendrocyte functions that can be therapeutically exploited to promote remyelination in central nervous system pathologies.