The retina as a window into the brain.
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ABSTRACT:
SUBMITTER: Frith P
PROVIDER: S-EPMC7611980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ischemia-induced cerebral injury is a major cause of dementia or death worldwide. The pre-diagnosis is still challenging due to the retarded symptoms. The retina is regarded as the extension of cerebral tissue. Circular RNAs have emerged as the crucial regulators in gene regulatory network and disease progression. However, it is still unknown whether circRNAs can be used as the common regulators and diagnostic markers for cerebral neurodegeneration and retinal neurodegeneration. Methods: C57BL/6J mice were subjected to transient middle cerebral artery occlusion and circRNA microarray profiling was performed to identify neurodegeneration-related circRNAs. Quantitative reverse-transcription PCR (qRT-PCR) assays were performed to verify circRNA expression pattern. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to determine the biologic modules and signaling pathway. TTC staining, Nissl's staining, and immunofluorescence staining assays were performed to investigate the role of circRNA in cerebral neurodegeneration and retinal neurodegeneration in vivo. MTT assay, Propidium iodide (PI)/Calcein-AM staining, and Rhodamine 123 assays were performed to investigate the role of circRNA in neuronal injury in vitro. Bioinformatics, RIP, and luciferase activity assays were performed to determine the regulatory mechanism of circRNA in neurodegeneration. Results: 217 differentially expressed circRNAs were identified between ischemic cerebral tissues and normal controls. Among them, cGLIS3 was shown as the common regulator of cerebral neurodegeneration and retinal neurodegeneration. cGLIS3 silencing alleviated ischemia-induced retinal neurodegeneration and MCAO-induced cerebral neurodegeneration in vivo. cGLIS3 silencing protected against OGD/R-induced RGC injury in vitro. The circulating levels of cGLIS3 were significantly increased in the patients with ischemic stroke compared to healthy subjects. cGLIS3 levels were also increased in the aqueous humor of the patients with retinal vein occlusion. cGLIS3 regulated neuronal cell injury by acting as miR-203 sponge and its level was controlled by EIF4A3. Conclusions: This study provides molecular evidence that the retina is window of the brain from circRNA perspective. cGLIS3 is a common regulator and diagnostic marker of cerebral neurodegeneration and retinal neurodegeneration.
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Project description:The sliding window correlation (SWC) analysis is a straightforward and common approach for evaluating dynamic functional connectivity. Despite the fact that sliding window analyses have been long used, there are still considerable technical issues associated with the approach. A great effort has recently been dedicated to investigate the window setting effects on dynamic connectivity estimation. In this direction, tapered windows have been proposed to alleviate the effect of sudden changes associated with the edges of rectangular windows. Nevertheless, the majority of the windows exploited to estimate brain connectivity tend to suppress dynamic correlations, especially those with faster variations over time. Here, we introduced a window named modulated rectangular (mRect) to address the suppressing effect associated with the conventional windows. We provided a frequency domain analysis using simulated time series to investigate how sliding window analysis (using the regular window functions, e.g. rectangular and tapered windows) may lead to unwanted spectral modulations, and then we showed how this issue can be alleviated through the mRect window. Moreover, we created simulated dynamic network data with altering states over time using simulated fMRI time series, to examine the performance of different windows in tracking network states. We quantified the state identification rate of different window functions through the Jaccard index, and observed superior performance of the mRect window compared to the conventional window functions. Overall, the proposed window function provides an approach that improves SWC estimations, and thus the subsequent inferences and interpretations based on the connectivity network analyses.
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Project description:The development of the mammalian cerebral cortex involves a series of mechanisms: from patterning, progenitor cell proliferation and differentiation, to neuronal migration. Many factors influence the development of the cerebral cortex to its normal size and neuronal composition. Of these, the mechanisms that influence the proliferation and differentiation of neural progenitor cells are of particular interest, as they may have the greatest consequence on brain size, not only during development but also in evolution. In this context, causative genes of human autosomal recessive primary microcephaly, such as ASPM and MCPH1, are attractive candidates, as many of them show positive selection during primate evolution. MCPH1 causes microcephaly in mice and humans and is involved in a diverse array of molecular functions beyond brain development, including DNA repair and chromosome condensation. Positive selection of MCPH1 in the primate lineage has led to much insight and discussion of its role in brain size evolution. In this review, we will present an overview of MCPH1 from these multiple angles, and whilst its specific role in brain size regulation during development and evolution remain elusive, the pieces of the puzzle will be discussed with the aim of putting together the full picture of this fascinating gene.
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Project description:Homocysteine (Hcy) is an amino acid that requires vitamins B12 and folic acid for its metabolism. Vitamins B12 and folic acid deficiencies lead to hyperhomocysteinemia (HHcy, elevated Hcy), which is linked to the development of diabetic retinopathy (DR), age-related macular degeneration (AMD), and Alzheimer's disease (AD). The goal of the current study was to explore inflammation as an underlying mechanism of HHcy-induced pathology in age related diseases such as AMD, DR, and AD. Mice with HHcy due to a lack of the enzyme cystathionine-?-synthase (CBS) and wild-type mice were evaluated for microglia activation and inflammatory markers using immuno-fluorescence (IF). Tissue lysates isolated from the brain hippocampal area from mice with HHcy were evaluated for inflammatory cytokines using the multiplex assay. Human retinal endothelial cells, retinal pigment epithelial cells, and monocyte cell lines treated with/without Hcy were evaluated for inflammatory cytokines and NF?B activation using the multiplex assay, western blot analysis, and IF. HHcy induced inflammatory responses in mouse brain, retina, cultured retinal, and microglial cells. NF?B was activated and cytokine array analysis showed marked increase in pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines. Therefore, elimination of excess Hcy or reduction of inflammation is a promising intervention for mitigating damage associated with HHcy in aging diseases such as DR, AMD, and AD.
| S-EPMC7175372 | biostudies-literature
Project description:ObjectiveOptical contrast agents for brain tumor delineation have been previously evaluated in ex vivo specimens from animals with implanted gliomas and may not reflect the true visual parameters encountered during surgery. This study describes a novel model system designed to evaluate optical contrast agents for tumor delineation in vivo.MethodsBiparietal craniectomies were performed on 8-week-old Sprague-Dawley rats. 9L glioma cells were injected intraparenchymally. A cover slip was bonded to the cranial defect with cyanoacrylate glue. When the tumor radius reached 1 mm, Coomassie Blue was administered intravenously while the appearance of the cortical surface was recorded. Computerized image analysis of the red/green/blue color components was used to quantify visible differences between tumor and nonneoplastic tissue and to compare delineation in the brain tumor window (BTW) model with the conventional 9L glioma model.ResultsThe tumor margin in the BTW model was poorly defined before contrast administration but readily apparent after contrast administration. Based on red component intensity, tumor delineation improved 4-fold at 50 minutes after contrast administration in the BTW model (P < .002). The conventional 9L glioma model overestimated the degree of delineation compared with the BTW model at the same dose of Coomassie Blue (P < .03).ConclusionWindow placement overlying an implanted glioma is technically possible and well tolerated in the rat. The BTW model is a valid system for evaluating optical contrast agents designed to delineate brain tumor margins. To our knowledge, we have described the first in vivo model system for evaluating optical contrast agents for tumor delineation.
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Project description:Noise sensitive individuals are more likely to experience negative emotions from unwanted sounds and they show greater susceptibility to adverse effects of noise on health. Noise sensitivity does not originate from dysfunctions of the peripheral auditory system, and it is thus far unknown whether and how it relates to abnormalities of auditory processing in the central nervous system. We conducted a combined electroencephalography and magnetoencephalography (M/EEG) study to measure neural sound feature processing in the central auditory system in relation to the individual noise sensitivity. Our results show that high noise sensitivity is associated with altered sound feature encoding and attenuated discrimination of sound noisiness in the auditory cortex. This finding makes a step towards objective measures of noise sensitivity instead of self-evaluation questionnaires and the development of strategies to prevent negative effects of noise on the susceptible population.
| S-EPMC5157031 | biostudies-literature
Project description:The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson's disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity.
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Project description:Sanfilippo syndrome is an untreatable form of childhood-onset dementia. Whilst several therapeutic strategies are being evaluated in human clinical trials including i.v. delivery of AAV9-based gene therapy, an urgent unmet need is the availability of non-invasive, quantitative measures of neurodegeneration. We hypothesise that as part of the central nervous system, the retina may provide a window through which to 'visualise' degenerative lesions in brain and amelioration of them following treatment. This is reliant on the age of onset and the rate of disease progression being equivalent in retina and brain. For the first time we have assessed in parallel, the nature, age of onset and rate of retinal and brain degeneration in a mouse model of Sanfilippo syndrome. Significant accumulation of heparan sulphate and expansion of the endo/lysosomal system was observed in both retina and brain pre-symptomatically (by 3 weeks of age). Robust and early activation of micro- and macroglia was also observed in both tissues. There was substantial thinning of retina and loss of rod and cone photoreceptors by?~?12 weeks of age, a time at which cognitive symptoms are noted. Intravenous delivery of a clinically relevant AAV9-human sulphamidase vector to neonatal mice prevented disease lesion appearance in retina and most areas of brain when assessed 6 weeks later. Collectively, the findings highlight the previously unrecognised early and significant involvement of retina in the Sanfilippo disease process, lesions that are preventable by neonatal treatment with AAV9-sulphamidase. Critically, our data demonstrate for the first time that the advancement of retinal disease parallels that occurring in brain in Sanfilippo syndrome, thus retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored.
| S-EPMC7672954 | biostudies-literature
Project description:Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.
| S-EPMC6190605 | biostudies-literature
Project description:BackgroundIschemic stroke is often complicated by brain edema, disruption of blood-brain barrier (BBB), and uncontrolled release of arginine-vasopressin (AVP). Conivaptan, a V1a and V2 receptor antagonist, reduces brain edema and minimizes damage to the blood-brain barrier after stroke. Most stroke patients do not receive treatment immediately after the onset of brain ischemia. Delays in therapy initiation may worsen stroke outcomes. Therefore, we designed a translational study to explore the therapeutic time window for conivaptan administration.MethodsMice were treated with conivaptan beginning 3, 5, or 20 hours after 60-minute focal middle cerebral artery occlusion. Treatments were administered by continuous IV infusion for a total of 48 hours. Brain edema and blood-brain barrier (BBB) disruption were evaluated at endpoint.ResultsConivaptan therapy initiated at 3 hours following ischemia reduced edema in the ipsilateral hemisphere, which corresponded with improvements in neurological deficits. Stroke-triggered BBB disruption was also reduced in mice when conivaptan treatments were initiated at 3 hours of reperfusion. However, 5 and 20-hour delays of conivaptan administration failed to reduce edema or protect BBB.ConclusionTiming of conivaptan administration is important for successful reduction of brain edema and BBB disruption. Our experimental data open new possibilities to repurpose conivaptan, and make an important "bench-to-bedside translation" of the results into clinical practice.
| S-EPMC5576654 | biostudies-literature