Stojiljkovic, Milan R.Schmeer, ChristianWitte, Otto W.
9页
查看更多>>摘要：Chronic macrophage activation was implicated as one of the main culprits for chronical, low-grade inflammation which significantly contributes to development of age-related diseases. Microglia as the brain macrophages have been recently implicated as key players in neuroinflammation and neurodegeneration in the aged brain. Microglial cell functions are indispensable in early development, however, activation or senescence of microglia in aging cells may be detrimental. Depletion of microglia using genetical or pharmacological approaches leads to opposite results regarding effects on brain cognition. In this study we pharmacologically depleted microglia using orally delivered low and high doses of the CSF1R inhibitor PLX5622 and assessed the expression levels of known inflammation markers (TNF-a, IL1-b, IL-6, IL-10), glia markers (Iba-1 and Gfap) and specific senescence marker p16Ink4a in the aged murine brain. Our results indicate that treatment with low and high doses of PLX5622 leads to a dose-dependent depletion of microglial cells with similar levels in young and aged mice. We also show that treatment with low and high PLX5622 differentially affected cytokine levels in young and old brains. By using low doses we could achieve reduction in inflammation circumventing the astrocyte activation. Removal of microglia cells led to decreased expression of the senescence marker p16Ink4a in the aged brain, indicating a relevant contribution of these cells to the expression of this marker and their senescent status in the healthy aging brain. Our results indicate that increased and detrimental brain inflammation in aged murine brain can be impaired by selectively reducing the microglial cell population. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ 4.0/).
查看更多>>摘要：neurophysiological studies had revealed that regional excitation-inhibition imbalance in the brain played a key role in the pathogenesis of migraine. This study aimed to explore the alterations in gammaaminobutyric acid (GABA) and glutamate/glutamine complex (Glx) levels in the anterior cingulate gyrus (ACC) and medial prefrontal lobe (mPFC) of patients with migraine without aura (MWoA) and investigate the correlation between neurotransmitter levels and clinical indicators. A total of 28 patients with MWoA and 28 sex-, age-, and education level-matched healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy scanning at 3.0 Tesla. MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) sequence was performed to acquire the spectral data of GABA and Glx in the ACC and mPFC. The clinical indicators and anxiety-depression states of all participants were assessed. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. We observed that GABA+/Cr levels were significantly lower in ACC and mPFC of patients with MWoA than of HCs, with no significant difference in Glx levels. Negative correlations between GABA+/Cr levels and attack frequency were found in the ACC and mPFC regions of patients. These results suggested that there might be a close relationship between ACC and mPFC GABAergic neurons abnormalities and the pathophysiological mechanisms of MWoA. It might be beneficial to targeted treatment for patients with MWoA. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
查看更多>>摘要：Neuropathic pain is a type of chronic pain with complex mechanisms, and current treatments have shown limited success in treating patients suffering from chronic pain. Accumulating evidence has shown that the pathogenesis of neuropathic pain is mediated by the plasticity of excitatory neurons in the dorsal horn of the spinal cord, which provides insights into the treatment of hyperalgesia. In this study, we found that Schnurri-2 (Shn2) was significantly upregulated in the L4-L6 segments of the spinal cord of C57 mice with spared nerve injury, which was accompanied by an increase in GluN2D subunit and glutamate receptor subunit 1 (GluR1) levels. Knocking down the expression of Shn2 using a lentivirus in the spinal cord decreased the GluN2D subunit and GluR1 levels in spared nerve injury mice and eventually alleviated mechanical allodynia. In summary, Shn2 regulates neuropathic pain, promotes the upregulation of GluN2D in glutamatergic neurons and increases the accumulation of GluR1 in excitatory neurons. Taken together, our study provides a new underlying mechanism for the development of neuropathic pain. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
查看更多>>摘要：is a gene highly expressed in the human brain and encodes ganglioside-induced differentiation-associated protein 2 (GDAP2). At present, little is known about the function of GDAP2. In recent years, it has been reported that mutations in the GDAP2 gene may be involved in hereditary cerebellar ataxia. In this study, we first conducted a preliminary study on the effect of GDAP2 overexpression on cultured primary hippocampal neurons in vitro. By analysing neuronal morphology, it was found that the complexity of neurons and the number of dendritic spines increased when GDAP2 was upregulated. The electrophysiological recordings showed that GDAP2 overexpression significantly increased the frequency of mEPSCs, suggesting that GDAP2 overexpression dysregulates excitatory synaptic transmission in cultured primary hippocampal neurons in vitro. On the other hand, behavioural and field-potential recordings of epileptic mouse models showed that GDAP2 overexpression was associated with increased seizure frequency. In summary, this preliminary study suggested that GDAP2 overexpression may have a certain pathogenic effect, providing a new perspective for the study of gene-related diseases such as epilepsy.(c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
Bhandari, AshishWard, Thomas W.Smith, JennieVan Hook, Matthew J....
16页
查看更多>>摘要：Within the nervous system, plasticity mechanisms attempt to stabilize network activity following disruption by injury, disease, or degeneration. Optic nerve injury and age-related diseases can induce homeostatic-like responses in adulthood. We tested this possibility in the thalamocortical (TC) neurons in the dorsolateral geniculate nucleus (dLGN) using patch-clamp electrophysiology, optogenetics, immunostaining, and single-cell dendritic analysis following loss of visual input via bilateral enucleation. We observed progressive loss of vGlut2-positive retinal terminals in the dLGN indicating degeneration post-enucleation that was coincident with changes in microglial morphology indicative of microglial activation. Consistent with the decline of vGlut2 puncta, we also observed loss of retinogeniculate (RG) synaptic function assessed using optogenetic activation of RG axons while performing whole-cell voltage clamp recordings from TC neurons in brain slices. Surprisingly, we did not detect any significant changes in the frequency of miniature post-synaptic currents (mEPSCs) or corticothalamic feedback synapses. Analysis of TC neuron dendritic structure from single-cell dye fills revealed a gradual loss of dendrites proximal to the soma, where TC neurons receive the bulk of RG inputs. Finally, analysis of action potential firing demonstrated that TC neurons have increased excitability following enucleation, firing more action potentials in response to depolarizing current injections. Our findings show that degeneration of the retinal axons/optic nerve and loss of RG synaptic inputs induces structural and functional changes in TC neurons, consistent with neuronal attempts at compensatory plasticity in the dLGN. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
查看更多>>摘要：Adverse effects of changing climate have been associated with increase average global temperature resulting in environmental changes. We set out to investigate effects of environmental stress due to increased heat exposure on developmental milestones, behaviour, gut microbiota and neuroarchitecture in rat pups. Pregnant Wistar rats were held in standard temperature (ST) (26 +/- 2 degrees C; control) or high temperature (HT) (40 +/- 2 degrees C) housing. After parturition, a cohort of the HT group and their pups were moved to the control/ST housing (gestational-only-exposed pup [GE]) while the other subset remained in the HT housing (gestational and postnatal exposed pups [GE + PE]). At different time points, we examined neurodevelopmental milestones and behaviour in the pups. Following sacrifice changes in gut microbiota, neuroarchitecture, cytokine levels (TNF-a, IL-4, IL-10), SOD, MDA, expression of MBP, NeUN and GFAP were determined. We observed impaired positioning and placing of paws, prolonged righting reflex, delayed ear opening and significant decreased body weight gain in HT pups when compared with control. We identified Firmicutes and Proteobacteria and noted a significant difference in Firmicutes count between GE and GE + PE pups at P15. Furthermore, TNF-a, IL-4, IL-10 and MDA levels were increased in GE and GE + PE pups. There was also a reduction in MBP expression in the HT pups. Taken together, our results revealed a delay in neurodevelopmental milestones in pups exposed to high HT during gestation and post natal life. Pups whose dam were exposed to high HT during gestation also showed some set back but improved over the course of testing. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
da Silva, Stephanya CovasBeggiora, Pamella da SilvaRocha Catalao, Carlos HenriqueDutra, Mauricio...
19页
查看更多>>摘要：Hydrocephalus is characterized by the accumulation of CSF within the cerebral ventricles and the subarachnoid space. Ventricular volume can progressively increase and generate serious damage to the nervous system, with cerebral hypoxia/ischemia as one of the most important factors involved. Hyperbaric oxygen therapy (HBOT) improves oxygen supply to tissues, which can reduce the progression of lesions secondary to ventricular enlargement. We evaluated whether HBOT associated with CSF diversion can promote neuroprotective effects to structures damaged by ventriculomegaly and understand its role. Seven-day-old male Wistar Hannover rats submitted to hydrocephalus by intracisternal injection of 15% kaolin were used. The animals were divided into six groups, with ten animals in each: control, control associated with hyperbaric therapy, hydrocephalic without treatment, hydrocephalic treated with hyperbaric oxygen therapy, hydrocephalic treated with CSF deviation, and hydrocephalic treated with hyperbaric oxygen therapy associated with CSF deviation. To assess the response to treatment, behavioral tests were performed such as modified Morris water maze and object recognition, evaluation by transcranial ultrasonography, histology by Hematoxylin-Eosin and Luxol Fast Blue, immunohistochemistry for GFAP, Ki-67, Caspase-3, COX-2, NeuN and SOD1, and biochemical ELISA assay for GFAP and MBP. The results show that the association of treatments exerts neuroprotective effects such as neurobehavioral improvement, preservation of periventricular structures, antioxidant effect, and reduction of damage resulting from ischemia and the neuroinflammatory process. We conclude that HBOT has the potential to be used as an adjuvant treatment to CSF deviation surgery in experimental hydrocephalus. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
查看更多>>摘要：neuroimaging studies have highlighted the role of the prefrontal-subcortical circuits in personality trait of novelty seeking (NS), thought to be mediated by the dopaminergic system. However, it remains largely unknown whether cortico-basal-cerebellar connections, heavily influenced by dopamine, are implicated in this temperament dimension as well. The present study aimed to further investigate the relationship between the NS trait and the cortico-basal-cerebellar pathways by using structural covariance network analysis. Ninetyfive healthy female volunteers were included in this work, and NS was assessed with the Temperament and Character Inventory (TCI). Our results showed that NS scores were associated with structural connections between the cerebellum and the cerebral cortex, thalamus, and basal ganglia, substantiating the implication of the corticobasal-cerebellar circuits in the NS construct. In addition, structural connections between visual and sensorimotor regions were also associated with NS scores, indicating that sensory and motor information processing may contribute to NS-related behaviors. Overall, the current findings may deepen our understanding of brain structural circuits related to this temperament dimension. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
查看更多>>摘要：Excessive microglia activation occurred in many neurodegenerative diseases. Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1, ARFGEF1) is involved in cell migration and neurite growth. In the present study, we aimed to explore the effects and potential mechanisms of BIG1 in LPS-mediated neuro -inflammation and migration in BV2 cells. Loss-of-function and gain-of-function experiments were performed. Inflammatory cytokines (TNF-a, IL-1p, IL-6, IL-10) mRNA levels and concentrations were analyzed by Quantitative Real-time PCR (RT-qPCR) and ELISA kits. The NO concentration was tested by ELISA kit. iNOS and COX-2 mRNA and protein levels were measured by RT-qPCR and western blot. Cell migration was determined by transwell assay. The results demonstrated that BIG1 silencing reduced TNF-a, IL-1p, and IL-6 expression, while increased IL-10 expression. The NO production, iNOS and COX-2 expression were clearly inhibited by BIG1 knockdown in the presence of LPS. Furthermore, ablation of BIG1 attenuated the migration capacity of BV2 cells. Overexpres-sion of BIG1 displayed the opposite trends. Moreover, we found BIG1 suppression inhibited PI3K/Akt/NF-jB path-way activation. 740Y-P, an agonist of PI3K, abolished the roles of BIG1 silencing in neuro-inflammation and migration. Additionally, ChIP-qPCR and Dual-luciferase reporter assay determined that KLF4 binds to the pro -moter of BIG1, western blot analysis demonstrated that KLF4 could regulate BIG1 positively. In addition, we observed that BIG1 overexpression partly rescued the biological activities of KLF4 silencing in neuro -inflammation and migration in LPS-stimulated BV2 cells. Taken together, BIG1 was mediated by KLF4 regulated LPS-mediated neuro-inflammation and migration in BV2 cells via PI3K/Akt/NF-kB signaling pathway. (C) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
查看更多>>摘要：acid (GABA) activity within the primary motor cortex (M1) is essential for motor learning in cortical plasticity, and a recent study has suggested that real-time neurofeedback training (NFT) can self-regulate GABA activity. Therefore, this study aimed to investigate the effect of GABA activity strengthening via NFT on subsequent motor learning. Thirty-six healthy participants were randomly assigned to either an NFT group or control group, which received sham feedback. GABA activity was assessed for short intracortical inhibition (SICI) within the right M1 using paired-pulse transcranial magnetic stimulation. During the NFT intervention period, the participants tried to modulate the size of a circle, which was altered according to the degree of SICI in the NFT group. However, the size was altered independently of the degree of SICI in the control group. We measured the reaction time before, after (online learning), and 24 h after (offline learning) the finger-tapping task. Results showed the strengthening of GABA activity induced by the NFT intervention, and the suppression of the online but not the offline learning. These findings suggest that prior GABA activity modulation may affect online motor learning. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.
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