scholarly journals Diphtheria toxin induced but not CSF1R inhibitor mediated microglia ablation model leads to the loss of CSF/ventricular spaces in vivo that is independent of cytokine upregulation

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Alicia Bedolla ◽  
Aleksandr Taranov ◽  
Fucheng Luo ◽  
Jiapeng Wang ◽  
Flavia Turcato ◽  
...  
Keyword(s):  
Diphtheria Toxin ◽  
Pathological Condition ◽  
Underlying Mechanism ◽  
Cytokine Profile ◽  
Edema Formation ◽  
Functional Changes ◽  
Genetic Ablation ◽  
The Brain ◽  
Ablation Model

Abstract Background Two recently developed novel rodent models have been reported to ablate microglia, either by genetically targeting microglia (via Cx3cr1-creER: iDTR + Dtx) or through pharmacologically targeting the CSF1R receptor with its inhibitor (PLX5622). Both models have been widely used in recent years to define essential functions of microglia and have led to high impact studies that have moved the field forward. Methods Using either Cx3cr1-iDTR mice in combination with Dtx or via the PLX5622 diet to pharmacologically ablate microglia, we compared the two models via MRI and histology to study the general anatomy of the brain and the CSF/ventricular systems. Additionally, we analyzed the cytokine profile in both microglia ablation models. Results We discovered that the genetic ablation (Cx3cr1-iDTR + Dtx), but not the pharmacological microglia ablation (PLX5622), displays a surprisingly rapid pathological condition in the brain represented by loss of CSF/ventricles without brain parenchymal swelling. This phenotype was observed both in MRI and histological analysis. To our surprise, we discovered that the iDTR allele alone leads to the loss of CSF/ventricles phenotype following diphtheria toxin (Dtx) treatment independent of cre expression. To examine the underlying mechanism for the loss of CSF in the Cx3cr1-iDTR ablation and iDTR models, we additionally investigated the cytokine profile in the Cx3cr1-iDTR + Dtx, iDTR + Dtx and the PLX models. We found increases of multiple cytokines in the Cx3cr1-iDTR + Dtx but not in the pharmacological ablation model nor the iDTR + Dtx mouse brains at the time of CSF loss (3 days after the first Dtx injection). This result suggests that the upregulation of cytokines is not the cause of the loss of CSF, which is supported by our data indicating that brain parenchyma swelling, or edema are not observed in the Cx3cr1-iDTR + Dtx microglia ablation model. Additionally, pharmacological inhibition of the KC/CXCR2 pathway (the most upregulated cytokine in the Cx3cr1-iDTR + Dtx model) did not resolve the CSF/ventricular loss phenotype in the genetic microglia ablation model. Instead, both the Cx3cr1-iDTR + Dtx ablation and iDTR + Dtx models showed increased activated IBA1 + cells in the choroid plexus (CP), suggesting that CP-related pathology might be the contributing factor for the observed CSF/ventricular shrinkage phenotype. Conclusions Our data, for the first time, reveal a robust and global CSF/ventricular space shrinkage pathology in the Cx3cr1-iDTR genetic ablation model caused by iDTR allele, but not in the PLX5622 ablation model, and suggest that this pathology is not due to brain edema formation but to CP related pathology. Given the wide utilization of the iDTR allele and the Cx3cr1-iDTR model, it is crucial to fully characterize this pathology to understand the underlying causal mechanisms. Specifically, caution is needed when utilizing this model to interpret subtle neurologic functional changes that are thought to be mediated by microglia but could, instead, be due to CSF/ventricular loss in the genetic ablation model.

scholarly journals Neurons expressing pathological Tau protein trigger dramatic changes in microglial morphology and dynamics

2019 ◽  
Author(s):  
Rahma Hassan-Abdi ◽  
Alexandre Brenet ◽  
Mohamed Bennis ◽  
Constantin Yanicostas ◽  
Nadia Soussi-Yanicostas
Keyword(s):  
Morphological Changes ◽  
Pathological Process ◽  
Wild Type ◽  
Zebrafish Model ◽  
Genetic Ablation ◽  
Microglial Morphology ◽  
First Time ◽  
The Brain ◽  
Heterogeneous Class

AbstractMicroglial cells, the resident macrophages of the brain, are important players in the pathological process of numerous neurodegenerative disorders, including tauopathies, a heterogeneous class of diseases characterized by intraneuronal Tau aggregates. However, microglia response in Tau pathologies remains poorly understood. Here we exploit a genetic zebrafish model of tauopathy, combined with live microglia imaging, to investigate the behaviour of microglia in vivo in the disease context. Results show that while microglia were almost immobile and displayed long and highly dynamic branches in a wild-type context, in presence of diseased neurons cells became highly mobile and displayed morphological changes, with highly mobile cell bodies together with fewer and shorter processes. We also imaged, for the first time to our knowledge, the phagocytosis of apoptotic tauopathic neurons by microglia in vivo and observed that microglia engulfed about as twice materials as in controls. Finally, genetic ablation of microglia in zebrafish tauopathy model significantly increased Tau hyperphosphorylation, suggesting that microglia provide neuroprotection to diseased neurons. Our findings demonstrate for the first time the dynamics of microglia in contact with tauopathic neurons in vivo and open perspectives for the real-time study of microglia in many neuronal diseases.

Effects of Short Duration Overpressure on Astrocytes: An In Vitro Study

2007 ◽  
Author(s):  
Lai Yee Leung ◽  
Pamela J. VandeVord ◽  
Warren Hardy ◽  
Roche De Guzman ◽  
King H. Yang ◽  
...  
Keyword(s):  
Short Duration ◽  
Neuronal Degeneration ◽  
In Vitro Study ◽  
Underlying Mechanism ◽  
Blast Waves ◽  
Body Armor ◽  
The Brain ◽  
Physiological Systems

Blast wave overpressure from detonations can injure physiological systems ‘silently.’ Experimental and clinical studies have revealed the damaging effects of shock waves on different physiological systems, such as ears, lungs and gastrointestinal tracts [1, 2]. Despite the improved helmet and body armor, many veterans returning from wars suffered from neurological disorders that are being diagnosed as mild traumatic brain injury. Warden (2006) reported that most of these veterans were exposed to blast [3]. In vivo study illustrated neuronal degeneration in the brain after exposure to blast waves [4]. As with many neuronal diseases, blast-induced neuronal injury may be related to microglia and astrocyte activation. However, the underlying mechanism is not clearly understood. This study was aimed at investigating the effects of short duration overpressure on astrocytes, in terms of cell proliferation and mRNA expression of several apoptotic genes and glial fibrillary acidic protein (GFAP).

scholarly journals Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy

2019 ◽  
Vol 20 (1) ◽  
pp. 220 ◽  
Author(s):  
Sandesh Reddy ◽  
Iyan Younus ◽  
Vidya Sridhar ◽  
Doodipala Reddy
Keyword(s):  
Animal Models ◽  
Refractory Epilepsy ◽  
Single Photon ◽  
Neuronal Damage ◽  
Photon Emission ◽  
Brain Magnetic Resonance Imaging ◽  
Functional Changes ◽  
Neuroimaging Biomarkers ◽  
The Brain

This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.

scholarly journals Retinal correlates of psychiatric disorders

2020 ◽  
Vol 11 ◽  
pp. 204062232090521 ◽  
Author(s):  
Melanie T. Almonte ◽  
Pamela Capellàn ◽  
Timothy E. Yap ◽  
Maria Francesca Cordeiro
Keyword(s):  
Psychiatric Disorders ◽  
Clinical Symptoms ◽  
Brain Dysfunction ◽  
Microscopic Level ◽  
Robust Methods ◽  
Functional Changes ◽  
Self Reports ◽  
Progression Of Disease ◽  
The Brain

Diagnosis and monitoring of psychiatric disorders rely heavily on subjective self-reports of clinical symptoms, which are complicated by the varying consistency of accounts reported by patients with an impaired mental state. Hence, more objective and quantifiable measures have been sought to provide clinicians with more robust methods to evaluate symptomology and track progression of disease in response to treatments. Owing to the shared origins of the retina and the brain, it has been suggested that changes in the retina may correlate with structural and functional changes in the brain. Vast improvements in retinal imaging, namely optical coherence tomography (OCT) and electrodiagnostic technology, have made it possible to investigate the eye at a microscopic level, allowing for the investigation of potential biomarkers in vivo. This review provides a summary of retinal biomarkers associated with schizophrenia, bipolar disorder and major depression, demonstrating how retinal biomarkers may be used to complement existing methods and provide structural markers of pathophysiological mechanisms that underpin brain dysfunction in psychiatric disorders.

Metabolic Seizure Resistance via BAD and KATP Channels

2016 ◽  
Author(s):  
Juan Ramón Martínez-François ◽  
Nika N. Danial ◽  
Gary Yellen
Keyword(s):  
Glucose Metabolism ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Katp Channels ◽  
Anticonvulsant Effect ◽  
Metabolic Function ◽  
Genetic Ablation ◽  
Electrographic Seizures ◽  
The Brain

On a ketogenic diet, ketone bodies provide an alternative fuel, replacing much of the glucose used ordinarily by the brain. This switch is thought to underlie its anticonvulsant effects. Brain fuel utilization can also be modified by a nondietary approach: genetic alteration of the protein BAD, which has known roles in regulating both apoptosis and glucose metabolism. When the metabolic function of BAD is genetically altered in mice, it produces reduced glucose and increased ketone body metabolism in neurons and astrocytes. This effect is related to regulation of BAD by phosphorylation and is independent of its apoptotic function. Mice with BAD modifications that produce decreased glucose metabolism exhibit a marked increase in the activity of neuronal ATP-sensitive potassium (KATP) channels and strong resistance to behavioral and electrographic seizures in vivo. This seizure resistance is lost upon genetic ablation of KATP channels, suggesting that KATP channels mediate BAD’s anticonvulsant effect.

scholarly journals In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A

genesis ◽  
2005 ◽  
Vol 43 (3) ◽  
pp. 129-135 ◽  
Author(s):  
Anna Ivanova ◽  
Massimo Signore ◽  
Nadia Caro ◽  
Nicholas D.E. Greene ◽  
Andrew J. Copp ◽  
...  
Keyword(s):  
Diphtheria Toxin ◽  
Genetic Ablation

scholarly journals MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Chao Zhong ◽  
Kisuk Min ◽  
Zhiqiang Zhao ◽  
Cheng Zhang ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
P38 Mapk ◽  
Cardiac Fibrosis ◽  
Pathological Condition ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Mitogen Activated Protein Kinase ◽  
Functional Changes ◽  
Map Kinase Phosphatase

Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.

scholarly journals Roscovitine Attenuates Microglia Activation and Monocyte Infiltration via p38 MAPK Inhibition in the Rat Frontoparietal Cortex Following Status Epilepticus

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 746 ◽  
Author(s):  
Ji-Eun Kim ◽  
Hana Park ◽  
Seo-Hyeon Choi ◽  
Min-Jeong Kong ◽  
Tae-Cheon Kang
Keyword(s):  
Status Epilepticus ◽  
P38 Mapk ◽  
Vasogenic Edema ◽  
Microglia Activation ◽  
Mitogen Activated Protein Kinase ◽  
Edema Formation ◽  
In Vivo Models ◽  
Frontoparietal Cortex ◽  
The Brain

Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by brain-blood barrier. Following status epilepticus (SE, a prolonged seizure activity), microglia are rapidly activated and blood-derived monocytes that infiltrate the brain; therefore, the regulations of microglia activation and monocyte infiltration are one of the primary therapeutic strategies for inhibition of undesirable consequences from SE. Roscovitine, a potent (but not selective) cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models, although the underlying mechanisms have not been clarified. In the present study, roscovitine attenuated SE-induces monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC), accompanied by reducing expressions of monocyte chemotactic protein-1 (MCP-1) and lysosome-associated membrane protein 1 (LAMP1) in resident microglia, while it did not affect microglia transformation to amoeboid form. Furthermore, roscovitine ameliorated the up-regulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, but not nuclear factor-κB-S276 phosphorylation. Similar to roscovitine, SB202190, a p38 MAPK inhibitor, mitigated monocyte infiltration and microglial expressions of MCP-1 and LAMP1 in the FPC following SE. Therefore, these findings suggest for the first time that roscovitine may inhibit SE-induced neuroinflammation via regulating p38 MAPK-mediated microglial responses.

scholarly journals Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

2015 ◽  
Vol 112 (48) ◽  
pp. E6673-E6682 ◽  
Author(s):  
Gangadhara R. Sareddy ◽  
Quanguang Zhang ◽  
Ruimin Wang ◽  
Erin Scott ◽  
Yi Zou ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Glutamic Acid ◽  
Glycogen Synthase ◽  
Underlying Mechanism ◽  
Global Cerebral Ischemia ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Extranuclear Signaling ◽  
The Brain

17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3β (GSK3β)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3β, E2 modulates interaction of PELP1 with GSK3β, and PELP1 is a novel substrate for GSK3β. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/β-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.

scholarly journals MiR-127-3p targeting CISD1 regulates autophagy in hypoxic–ischemic cortex

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Zi-Bin Zhang ◽  
Liu-Lin Xiong ◽  
Lu-Lu Xue ◽  
Yan-Ping Deng ◽  
Ruo-Lan Du ◽  
...  
Keyword(s):  
Underlying Mechanism ◽  
Perinatal Period ◽  
Neurological Injury ◽  
Neuroprotective Effects ◽  
Bioinformatics Analyses ◽  
New Treatment ◽  
Related Proteins ◽  
The Brain

AbstractNeonatal hypoxic–ischemic (HI) injury derived from asphyxia during perinatal period, is a serious complication of neonatal asphyxia and the main cause of neonatal acute death and chronic neurological injury. Aberrant autophagy occurs in many nervous system diseases, but its role and underlying mechanism in HI injury is largely unknown. Here, we successfully constructed a newborn rat model of HI brain injury, and the knockout-miR-127-3p (KO-miR-127-3p) rats were structured by using CRISPR/Cas9. Subsequently, the in vitro functional experiments, in vivo zea-longa scores, as well as bioinformatics analyses and biological experiments were applied. The expression of autophagy-related proteins, including ATG12, P62, Beclin-1, LC3II in HI cortex with miR-127-3p knockout was significantly decreased, and autophagic vacuoles were disappeared. Moreover, miR-127-3p has a specific regulatory effect on CISD1 expression, another crucial molecule in autophagy process. Accordingly, the overexpression of CISD1 effectively inhibited the autophagic cell death and physiological dysfunction in the brain of HI injury, whereas si-CISD1 reversed the neuroprotective effects of KO-miR-127-3p. Our findings explained the underlying mechanism for HI injury, and miR-127-3p targeting CISD1 signal could be supposed as a new treatment strategy to prevent and treat HI injury.

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