ASN NEURO最新文献

{"title":"Understanding the Myelin <i>g</i> Ratio from First Principles, Its Derivation, Uses and Artifacts.","authors":"Alexander Gow","doi":"10.1080/17590914.2024.2445624","DOIUrl":"https://doi.org/10.1080/17590914.2024.2445624","url":null,"abstract":"<p><p>In light of the increasing importance for measuring myelin <i>g</i> ratios - the ratio of axon-to-fiber (axon + myelin) diameters in myelin internodes - to understand normal physiology, disease states, repair mechanisms and myelin plasticity, there is urgent need to minimize processing and statistical artifacts in current methodologies. Many contemporary studies fall prey to a variety of artifacts, reducing study outcome robustness and slowing development of novel therapeutics. Underlying causes stem from a lack of understanding of the myelin <i>g</i> ratio, which has persisted more than a century. An extended exploratory data analysis from first principles (the axon-fiber diameter relation) is presented herein and has major consequences for interpreting published <i>g</i> ratio studies. Indeed, a model of the myelin internode naturally emerges because of (1) the strong positive correlation between axon and fiber diameters and (2) the demonstration that the relation between these variables is one of direct proportionality. From this model, a robust framework for data analysis, interpretation and understanding allows specific predictions about myelin internode structure under normal physiological conditions. Further, the model establishes that a regression fit to <i>g</i> ratio plots has zero slope, and it identifies the underlying causes of several data processing artifacts that can be mitigated by plotting <i>g</i> ratios against fiber diameter (not axon diameter). Hypothesis testing can then be used for extending the model and evaluating myelin internodal properties under pathophysiological conditions (forthcoming). For without a statistical model as anchor, hypothesis testing is aimless like a rudderless ship on the ocean.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2445624"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Statistically-Robust Model of the Axomyelin Unit under Normal Physiologic Conditions with Application to Disease States.","authors":"Alexander Gow, Jeffrey L Dupree, Douglas L Feinstein, Anne Boullerne","doi":"10.1080/17590914.2024.2447336","DOIUrl":"https://doi.org/10.1080/17590914.2024.2447336","url":null,"abstract":"<p><p>Despite tremendous progress in characterizing the myriad cellular structures in the nervous system, a full appreciation of the interdependent and intricate interactions between these structures is as yet unfulfilled. Indeed, few more so than the interaction between the myelin internode and its ensheathed axon. More than a half-century after the ultrastructural characterization of this axomyelin unit, we lack a reliable understanding of the physiological properties, the significance and consequence of pathobiological processes, and the means to gauge success or failure of interventions designed to mitigate disease. Herein, we highlight shortcomings in the most common statistical procedures used to characterize the myelin <i>g</i> ratio, with particular emphasis on the underlying principles of simple linear regression. These shortcomings lead to insensitive detection and/or ambiguous interpretation of normal physiology, disease mechanisms and remedial methodologies. To address these problems, we syndicate insights from early seminal myelin studies and use a statistical model of the axomyelin unit that is established in Gow (2025). Herein, we develop and demonstrate a statistically-robust analysis pipeline with which to examine and interpret axomyelin physiology and pathobiology in two disease states, experimental autoimmune encephalomyelitis and the <i>rumpshaker</i> mouse model of leukodystrophy. On a cautionary note, our pipeline is a relatively simple and streamlined approach that is not necessarily a panacea for all <i>g</i> ratio analyses. Rather, it approximates a minimum effort needed to elucidate departures from normal physiology and to determine if more comprehensive studies may lead to deeper insights.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2447336"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5.","authors":"Chloe A Simons, Sarah Kim, Yun K Hahn, Ama Boake-Agyei, Sara R Nass, Phu Vo, Kurt F Hauser, Pamela E Knapp","doi":"10.1080/17590914.2024.2447338","DOIUrl":"https://doi.org/10.1080/17590914.2024.2447338","url":null,"abstract":"<p><p>People living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND), even though combination antiretroviral therapy (cART) suppresses HIV replication. HIV-1 transactivator of transcription (HIV-1 Tat) contributes to the development of HAND through neuroinflammatory and neurotoxic mechanisms. C-C chemokine 5 receptor (CCR5) is important in immune cell targeting and is a co-receptor for HIV viral entry into CD4+ cells. Notably, CCR5 has been implicated in cognition unrelated to HIV infection. Inhibition of CCR5 has been shown to improve learning and memory. To test whether CCR5 is involved in cognitive changes in HAND, we used a non-infectious, transgenic model in which HIV-1 Tat is inducibly expressed. Well-powered cohorts of male and female mice were placed on a diet containing doxycycline to induce Tat expression for 8-wks. Males showed Tat-mediated deficits in the Barnes maze test of spatial learning and memory; females showed no impairments. Deficits in the males were fully reversed by the CCR5 antagonist, maraviroc (MVC). Tat-mediated deficits were not found in novel object recognition or contextual fear conditioning in either sex. Based on earlier work, we hypothesized that MVC might increase brain-derived neurotrophic factor (BDNF), which is essential in maintaining synaptodendritic function. MVC did increase the mBDNF to proBDNF ratio in males, perhaps contributing to improved cognition.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2447338"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurons Are Not All the Same: Diversity in Neuronal Populations and Their Intrinsic Responses to Spinal Cord Injury.","authors":"Justin R Siebert, Kiersten Kennedy, Donna J Osterhout","doi":"10.1080/17590914.2024.2440299","DOIUrl":"https://doi.org/10.1080/17590914.2024.2440299","url":null,"abstract":"<p><p>Functional recovery following spinal cord injury will require the regeneration and repair of damaged neuronal pathways. It is well known that the tissue response to injury involves inflammation and the formation of a glial scar at the lesion site, which significantly impairs the capacity for neuronal regeneration and functional recovery. There are initial attempts by both supraspinal and intraspinal neurons to regenerate damaged axons, often influenced by the neighboring tissue pathology. Many experimental therapeutic strategies are targeted to further stimulate the initial axonal regrowth, with little consideration for the diversity of the affected neuronal populations. Notably, recent studies reveal that the neuronal response to injury is variable, based on multiple factors, including the location of the injury with respect to the neuronal cell bodies and the affected neuronal populations. New insights into regenerative mechanisms have shown that neurons are not homogenous but instead exhibit a wide array of diversity in their gene expression, physiology, and intrinsic responses to injury. Understanding this diverse intrinsic response is crucial, as complete functional recovery requires the successful coordinated regeneration and reorganization of various neuron pathways.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2440299"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Atg9 Phosphorylation Sites Regulate Autophagic Trafficking in Glia.","authors":"Linfang Wang, Shuanglong Yi, Shiping Zhang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Honglei Wang, Margaret S Ho","doi":"10.1080/17590914.2024.2443442","DOIUrl":"https://doi.org/10.1080/17590914.2024.2443442","url":null,"abstract":"<p><p>We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. The enhanced Atg9 phosphorylation in the absence of dAux promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phosphomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. In relation to pathophysiology, Atg9 phosphorylation at T62 and T69 contributes to dopaminergic neurodegeneration and locomotor dysfunction in a <i>Drosophila</i> PD model. Notably, increased expression of the master autophagy regulator Atg1 promotes dAux-Atg9 interaction. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"17 1","pages":"2443442"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of Iron in Ferroptosis, Necroptosis, and Pyroptosis as Potential Players in TBI Morbidity and Mortality.","authors":"Makenzie Nolt, James Connor","doi":"10.1080/17590914.2024.2394352","DOIUrl":"10.1080/17590914.2024.2394352","url":null,"abstract":"<p><p>Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2394352"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robert Paul Skoff (1942-2023).","authors":"Joyce Benjamins, Pamela Knapp, Anne Boullerne","doi":"10.1080/17590914.2024.2393559","DOIUrl":"10.1080/17590914.2024.2393559","url":null,"abstract":"","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2393559"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse Responses of Oligodendrocytes to Different FGF-Family Members: Uncoupling Structure-Function Relationship Within FGF Subfamilies.","authors":"Hebe M Guardiola-Diaz, Brett T DiBenedictis, Erealda Prendaj, Rashmi Bansal","doi":"10.1080/17590914.2024.2371163","DOIUrl":"10.1080/17590914.2024.2371163","url":null,"abstract":"<p><p>The fifteen canonical paracrine fibroblast growth factors (FGFs) are organized in five subfamilies that interact with four FGF-receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. Many of these FGFs are expressed in CNS regions where oligodendrocyte (OL) progenitors originate, migrate or differentiate. FGF2 (basic FGF) is considered a prototype FGF and the information about the effects of FGF signaling on OL-lineage cells has evolved largely from the study of FGF2. However, other FGFs from four subfamilies ((FGF1 (FGF1,-2), FGF4 (FGF4,-5,-6), FGF8 (FGF8,-17,-18) and FGF9 (FGF9,-16,-20)) that can interact with the isoforms of FGFRs expressed in OL-lineage cells may also play important roles. We previously reported OL-responses to FGF8 family members. Here, we investigate the effects of members of the FGF1,-4, and -9 subfamilies on proliferation and differentiation of OL progenitors (OPCs), and on cell cycle re-entry and down-regulation of myelin proteins by mature OLs. We found that while FGF2 induced all these responses strongly, FGF4,-6,-9 could do so only transiently and in the presence of exogenous HSPGs, and that FGF5,-16,-20 could not do so even in the presence of heparin or at higher concentrations. Furthermore, we noted that structurally similar FGFs within subfamilies did not always show similarities in their biological effects on OL-lineage cells. Taken together, these studies reveal that FGFs differ in the way they regulate the OL-lineage cells, emphasizes the selectivity and importance of HSPGs as FGF co-receptors in OL-lineage cells and suggests that structural similarity among FGF-subfamily members may not always predict their overlapping biological functions.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2371163"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pannexin1 Mediates Early-Life Seizure-Induced Social Behavior Deficits.","authors":"Price Obot, Antonio Cibelli, Jian Pan, Libor Velíšek, Jana Velíšková, Eliana Scemes","doi":"10.1080/17590914.2024.2371164","DOIUrl":"10.1080/17590914.2024.2371164","url":null,"abstract":"<p><p>There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2371164"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Analysis of Early White Matter Damage in Cuprizone Mouse Model of Demyelination Using 7.0 T MRI Multiparametric Approach.","authors":"Emma Friesen, Maxina Sheft, Kamya Hari, Vanessa Palmer, Shenghua Zhu, Sheryl Herrera, Richard Buist, Depeng Jiang, Xin-Min Li, Marc R Del Bigio, Jonathan D Thiessen, Melanie Martin","doi":"10.1080/17590914.2024.2404366","DOIUrl":"10.1080/17590914.2024.2404366","url":null,"abstract":"<p><p>Magnetic Resonance Imaging (MRI) is commonly used to follow the progression of neurodegenerative conditions, including multiple sclerosis (MS). MRI is limited by a lack of correlation between imaging results and clinical presentations, referred to as the clinico-radiological paradox. Animal models are commonly used to mimic the progression of human neurodegeneration and as a tool to help resolve the paradox. Most studies focus on later stages of white matter (WM) damage whereas few focus on early stages when oligodendrocyte apoptosis has just begun. The current project focused on these time points, namely weeks 2 and 3 of cuprizone (CPZ) administration, a toxin which induces pathophysiology similar to MS. <i>In vivo</i> T₂-weighted (T₂W) and Magnetization Transfer Ratio (MTR) maps and <i>ex vivo</i> Diffusion Tensor Imaging (DTI), Magnetization Transfer Imaging (MTI), and relaxometry (T₁ and T₂) values were obtained at 7 T. Significant changes in T₂W signal intensity and non-significant changes in MTR were observed to correspond to early WM damage, whereas significant changes in both corresponded with full demyelination. Some DTI metrics decrease with simultaneous increase in others, indicating acute demyelination. MTI metrics T₂^A, T₂^B, <i>f</i> and R were observed to have contradictory changes across CPZ administration. T₁ relaxation times were observed to have stronger correlations to disease states during later stages of CPZ treatment, whereas T₂ had weak correlations to early WM damage. These results all suggest the need for multiple metrics and further studies at early and late time points of demyelination. Further research is required to continue investigating the interplay between various MR metrics during all weeks of CPZ administration.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"16 1","pages":"2404366"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}