Frontiers in Cellular Neuroscience

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ISSN / EISSN : 1662-5102 / 1662-5102
Published by: Frontiers Media SA (10.3389)
Total articles ≅ 4,809
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Xue Jiang, Hui He, Li Mo, Qin Liu, Fan Yang, Ying Zhou, Liangyuan Li, Dapeng Su, Saini Yi, Jinqiang Zhang
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.811061

Abstract:
Microglia exert diverse functions by responding in diverse ways to different stimuli, yet little is known about the plasticity of various phenotypes that microglia display. We used interferon (IFN)-γ, interleukin (IL)-4 and IL-10 to induce different phenotypes in mouse primary microglia. RNA sequencing was used to identify genes differentially expressed in response to stimulation, and the different stimulated populations were compared in terms of morphology, proliferative capacity, phagocytic ability and neurotoxicity. IFN-γ induced an “immunodefensive” phenotype characterizing both induction of filopodia and upregulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor α. Microglia with this phenotype mediated an acute inflammatory response accompanied by excellent proliferative capacity and neurotoxicity, and remained susceptible to remodeling for up to 48 h after initial stimulation. IL-4 induced an enduring “neuroimmunoregulatory” phenotype involving induction of lamellipodium and persistent upregulation of arginase (Arg)-1 and YM-1 expression. Microglia with this phenotype remained susceptible to remodeling for up to 24 h after initial stimulation. IL-10 induced an “immunosuppressive” phenotype involving induction of ameba-like morphology and upregulation of transforming growth factor β and IL-10 as well as inhibition of inflammation. This phenotype was accompanied by inhibition of self-proliferation, while its morphology, molecular properties and function were the least susceptible to remodeling. IFN-γ, IL-4, or IL-10 appear to induce substantially different phenotypes in microglia. The immunodefensive microglia induced by IFN-γ showed remarkable plasticity, which may help repair CNS inflammation damage under pathological condition. Chronic activation with IL-10 decreases microglial plasticity, which may help protect the brain form the immune response. Our research justifies and guides further studies into the molecular pathways that operate in each phenotype to help multitasking microglia regulate homeostasis in the brain.
Blake J. Laham,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.814287

Abstract:
Diffuse and structured extracellular matrix (ECM) comprise ∼20% of the brain’s volume and play important roles in development and adult plasticity. Perineuronal nets (PNNs), specialized ECM structures that surround certain types of neurons in the brain, emerge during the postnatal period, making their development and maintenance potentially sensitive to experience. Recent studies have shown that stress affects diffuse ECM as well as PNNs, and that such effects are dependent on life stage and brain region. Given that the ECM participates in synaptic plasticity, the generation of neuronal oscillations, and synchronous firing across brain regions, all of which have been linked to cognition and emotional regulation, ECM components may be candidate therapeutic targets for stress-induced neuropsychiatric disease. This review considers the influence of stress over diffuse and structured ECM during postnatal life with a focus on functional outcomes and the potential for translational relevance.
Elena G. Govorunova, Oleg A. Sineshchekov,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.800313

Abstract:
Cation and anion channelrhodopsins (CCRs and ACRs, respectively) from phototactic algae have become widely used as genetically encoded molecular tools to control cell membrane potential with light. Recent advances in polynucleotide sequencing, especially in environmental samples, have led to identification of hundreds of channelrhodopsin homologs in many phylogenetic lineages, including non-photosynthetic protists. Only a few CCRs and ACRs have been characterized in detail, but there are indications that ion channel function has evolved within the rhodopsin superfamily by convergent routes. The diversity of channelrhodopsins provides an exceptional platform for the study of structure-function evolution in membrane proteins. Here we review the current state of channelrhodopsin research and outline perspectives for its further development.
Katherine R. Long,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.804649

Abstract:
Extracellular matrix (ECM) has long been known to regulate many aspects of neural development in many different species. However, the role of the ECM in the development of the human neocortex is not yet fully understood. In this review we discuss the role of the ECM in human neocortex development and the different model systems that can be used to investigate this. In particular, we will focus on how the ECM regulates human neural stem and progenitor cell proliferation and differentiation, how the ECM regulates the architecture of the developing human neocortex and the effect of mutations in ECM and ECM-associated genes in neurodevelopmental disorders.
Susanna Pucci, Michele Zoli, Francesco Clementi,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.805123

Abstract:
Neuronal nicotinic acetylcholine receptors containing the α9 or the α9 and α10 subunits are expressed in various extra-neuronal tissues. Moreover, most cancer cells and tissues highly express α9-containing receptors, and a number of studies have shown that they are powerful regulators of responses that stimulate cancer processes such as proliferation, inhibition of apoptosis, and metastasis. It has also emerged that their modulation is a promising target for drug development. The aim of this review is to summarize recent data showing the involvement of these receptors in controlling the downstream signaling cascades involved in the promotion of cancer.
, Brigitta Buttari, Elisabetta Profumo, Paolo Tucci, Luciano Saso
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.787258

Abstract:
Neuroinflammation plays a pivotal role in Alzheimer's disease (AD) and Parkinson's disease (PD), the leading causes of dementia. These neurological disorders are characterized by the accumulation of misfolded proteins such as amyloid-ß (Aß), tau protein and α-synuclein, contributing to mitochondrial fragmentation, oxidative stress, and neuroinflammation. Misfolded proteins activate microglia, which induces neuroinflammation, expression of pro-inflammatory cytokines and subsequently facilitates synaptic damage and neuronal loss. So far, all the proposed drugs were based on the inhibition of protein aggregation and were failed in clinical trials. Therefore, the treatment options of dementia are still a challenging issue. Thus, it is worthwhile to study alternative therapeutic strategies. In this context, there is increasing data on the pivotal role of transcription factor NF- E2 p45-related factor 2 (Nrf2) on the redox homeostasis and anti-inflammatory functions in neurodegenerative disorders. Interestingly, Nrf2 signaling pathway has shown upregulation of antioxidant genes, inhibition of microglia-mediated inflammation, and improved mitochondrial function in neurodegenerative diseases, suggesting Nrf2 activation could be a novel therapeutic approach to target pathogenesis. The present review will examine the correlation between Nrf2 signaling with neuroinflammation in AD and PD.
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.741984

Abstract:
In 2007, drawing inspiration from her previous experiments on chick embryos, Rita Levi-Montalcini, at the age of 98, proposed a new project, and a research group, in which I was included, was formed at the European Brain Research Institute (EBRI). Looking back on this experience, I can say that Professor Levi-Montalcini’s approach and the relationships she formed with my colleagues and me, contributed to my growth as a researcher. With her welcoming and warm-hearted disposition, she taught me how to consider other people’s ideas without prejudice, to reason and not to exclude any hypothesis. I also learned from her how to overcome those difficulties that are so frequent in the research field, always keeping in mind the starting point and looking toward the objective, with a factual optimism. I was just a young researcher and deeply flattered that a Nobel Laureate, with an incredible career and extraordinary life, treated me as her equal. My experience with Professor Levi-Montalcini has also provided me with a reliable path to follow, and when I encounter difficulties and challenges, I ask myself what would she have done. This approach has always helped me to move forward. Indeed, I believe the best way to celebrate Rita Levi-Montalcini as a woman in neuroscience is to recount how her exceptional example is a constant reminder as to why I have chosen to be a scientist. I hope she will always continue to be a source of inspiration for scientists in the future.
Linhao Xu, Qian Li, ,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.784045

Abstract:
Chronic intermittent hypoxia (CIH) occurs in obstructive sleep apnea (OSA), a common sleep-disordered breathing associated with malfunctions in multiple organs including the brain. How OSA-associated CIH impacts on brain activities and functions leading to neurocognitive impairment is virtually unknown. Here, by means of in vivo electrophysiological recordings via chronically implanted multi-electrode arrays in male rat model of OSA, we found that both putative pyramidal neurons and putative interneurons in the hippocampal CA1 subfield were hyper-excitable during the first week of CIH treatment and followed by progressive suppression of neural firing in the longer term. Partial recovery of the neuronal activities was found after normoxia treatment but only in putative pyramidal neurons. These findings correlated well to abnormalities in dendritic spine morphogenesis of these neurons. The results reveal that hippocampal neurons respond to CIH in a complex biphasic and bidirectional manner eventually leading to suppression of firing activities. Importantly, these changes are attributed to a larger extent to impaired functions of putative interneurons than putative pyramidal neurons. Our findings therefore revealed functional and structural damages in central neurons in OSA subjects.
Jie Lin, Binbin Tan, Yuhong Li, ,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.819182

Abstract:
Sepsis susceptibility is significantly increased in patients with intracerebral hemorrhage (ICH), owing to immunosuppression and intestinal microbiota dysbiosis. To date, ICH with sepsis occurrence is still difficult for clinicians to deal with, and the mortality, as well as long-term cognitive disability, is still increasing. Actually, intracerebral hemorrhage and sepsis are mutually exacerbated via similar pathophysiological mechanisms, mainly consisting of systemic inflammation and circulatory dysfunction. The main consequence of these two processes is neural dysfunction and multiple organ damages, notably, via oxidative stress and neurotoxic mediation under the mediation of central nervous system activation and blood-brain barrier disruption. Besides, the comorbidity-induced multiple organ damages will produce numerous damage-associated molecular patterns and consequently exacerbate the severity of the disease. At present, the prospective views are about operating artificial restriction for the peripheral immune system and achieving cross-tolerance among organs via altering immune cell composition to reduce inflammatory damage.
David Wasilewski, Nelson David Villalba-Moreno, Inke Stange, Markus Glatzel, Diego Sepulveda-Falla,
Frontiers in Cellular Neuroscience, Volume 15; https://doi.org/10.3389/fncel.2021.739411

Abstract:
Pathological hallmarks of Alzheimer’s disease (AD) include deposition and accumulation of amyloid- β (Aβ), neurofibrillary tangle formation, and neuronal loss. Pathogenesis of presymptomatic disease stages remains elusive, although studies suggest that the early structural and functional alterations likely occur at neuronal dendritic spines. Presymptomatic alterations may also affect different CNS cell types. However, specific contributions of these cell types as cause or consequence of pathology are difficult to study in vivo. There is a shortage of relatively simple, well-defined, and validated in vitro models that allow a straightforward interpretation of results and recapitulate aspects of pathophysiology. For instance, dissecting the AD-related processes (e.g., neurotoxicity vs. synaptotoxicity) may be difficult with the common cell-based systems such as neuronal cell lines or primary neurons. To investigate and characterize the impact of reactive astrocytes on neuronal morphology in the context of AD-related cues, we modified an in vitro co-culture assay of primary mouse neurons and primary mouse astrocytes based on the so-called Banker “sandwich” co-culture assay. Here, we provide a simple and modular assay with fully differentiated primary mouse neurons to study the paracrine interactions between the neurons and the astrocytes in the co-culture setting. Readouts were obtained from both cell types in our assay. Astrocyte feeder cells were pre-exposed to neuroinflammatory conditions by means of Aβ42, Aβ40, or lipopolysaccharide (LPS). Non-cell autonomous toxic effects of reactive astrocytes on neurons were assessed using the Sholl analysis to evaluate the dendritic complexity, whereas synaptic puncta served as a readout of synaptotoxicity. Here, we show that astrocytes actively contribute to the phenotype of the primary neurons in an AD-specific context, emphasizing the role of different cell types in AD pathology. The cytokine expression pattern was significantly altered in the treated astrocytes. Of note, the impact of reactive astrocytes on neurons was highly dependent on the defined cell ratios. Our co-culture system is modular, of low cost, and allows us to probe aspects of neurodegeneration and neuroinflammation between the two major CNS cell types, neurons, and astrocytes, under well-defined experimental conditions. Our easy-to-follow protocol, including work-flow figures, may also provide a methodological outline to study the interactions of astrocytes and neurons in the context of other diseases in the future.
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