-
Journal of Neuroinflammation Jun 2024The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for...
The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.
Topics: Nucleotidyltransferases; Membrane Proteins; Animals; Humans; Mice; Neuroinflammatory Diseases; Mice, Inbred C57BL; Choroidal Neovascularization; Signal Transduction; Mice, Knockout; Diabetic Retinopathy
PubMed: 38918759
DOI: 10.1186/s12974-024-03155-y -
Advances in Experimental Medicine and... 2024Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent... (Review)
Review
Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent studies on nonhuman primates. In the studies presented in the first half of the chapter, monkeys were trained to make eye movements when a certain amount of time had elapsed since the onset of the visual cue (time production task). The animals had to report time lapses ranging from several hundred milliseconds to a few seconds based on the color of the fixation point. In this task, the saccade latency varied with the time length to be measured and showed stochastic variability from one trial to the other. Trial-to-trial variability under the same conditions correlated well with pupil diameter and the preparatory activity in the deep cerebellar nuclei and the motor thalamus. Inactivation of these brain regions delayed saccades when asked to report subsecond intervals. These results suggest that the internal state, which changes with each trial, may cause fluctuations in cerebellar neuronal activity, thereby producing variations in self-timing. When measuring different time intervals, the preparatory activity in the cerebellum always begins approximately 500 ms before movements, regardless of the length of the time interval being measured. However, the preparatory activity in the striatum persists throughout the mandatory delay period, which can be up to 2 s, with different rate of increasing activity. Furthermore, in the striatum, the visual response and low-frequency oscillatory activity immediately before time measurement were altered by the length of the intended time interval. These results indicate that the state of the network, including the striatum, changes with the intended timing, which lead to different time courses of preparatory activity. Thus, the basal ganglia appear to be responsible for measuring time in the range of several hundred milliseconds to seconds, whereas the cerebellum is responsible for regulating self-timing variability in the subsecond range. The second half of this chapter presents studies related to periodic timing. During eye movements synchronized with alternating targets at regular intervals, different neurons in the cerebellar nuclei exhibit activity related to movement timing, predicted stimulus timing, and the temporal error of synchronization. Among these, the activity associated with target appearance is particularly enhanced during synchronized movements and may represent an internal model of the temporal structure of stimulus sequence. We also considered neural mechanism underlying the perception of periodic timing in the absence of movement. During perception of rhythm, we predict the timing of the next stimulus and focus our attention on that moment. In the missing oddball paradigm, the subjects had to detect the omission of a regularly repeated stimulus. When employed in humans, the results show that the fastest temporal limit for predicting each stimulus timing is about 0.25 s (4 Hz). In monkeys performing this task, neurons in the cerebellar nuclei, striatum, and motor thalamus exhibit periodic activity, with different time courses depending on the brain region. Since electrical stimulation or inactivation of recording sites changes the reaction time to stimulus omission, these neuronal activities must be involved in periodic temporal processing. Future research is needed to elucidate the mechanism of rhythm perception, which appears to be processed by both cortico-cerebellar and cortico-basal ganglia pathways.
Topics: Animals; Cerebellum; Basal Ganglia; Time Perception; Saccades; Time Factors; Humans
PubMed: 38918348
DOI: 10.1007/978-3-031-60183-5_6 -
Child's Nervous System : ChNS :... Jun 2024The extent of resection of pediatric low-grade glioma mostly improves progression-free survival. In chiasmatic hypothalamic glioma (CHG), complete resections are limited...
OBJECTIVE
The extent of resection of pediatric low-grade glioma mostly improves progression-free survival. In chiasmatic hypothalamic glioma (CHG), complete resections are limited due to the relevantly high risk of associated neurological and endocrinological deficits. Still, surgery might have its role in the framework of a multidisciplinary team (MDT) approach. We report our retrospective experience from two centers on surgical options and their impact on long-term outcomes.
METHODS
Medical records of surgically treated pediatric CHG patients between 2004 and 2022 were analyzed. Patient characteristics, surgical interventions, histology, and non-surgical therapy were retrieved together with outcome measures such as visual acuity, endocrine function, and survival.
RESULTS
A total of 63 patients (33 female, NF-1, n = 8) were included. Age at first diagnosis was 4.6 years (range 0.2-16.9) and cohort follow-up was 108 ± 72 months. Twenty patients were surgically treated with a biopsy and 43 patients with debulking at a median age of 6.5 years (range 0.16-16.9). Patients received a median of 2 tumor surgeries (range 1-5). Cyst drainage was accomplished in 15 patients, and 27 patients had ventriculoperitoneal shunt implantation. Non-surgical therapy was given in 69.8%. At the end of follow-up, 74.6% of patients had stable disease. The cohort had a median Karnofsky score of 90 (range 0-100). Four patients died. Hormone substitution was necessary in 30.2%, and visual acuity was impaired in 66% of patients.
CONCLUSION
Pediatric CHG is a chronic disease due to overall high survival with multiple progressions. Surgical therapy remains a key treatment option offering biopsy, limited tumor-debulking, cyst fenestration, and hydrocephalus management in the framework of MDT decision-making. Team experience contributes to reducing possible deficits in this challenging cohort.
PubMed: 38918262
DOI: 10.1007/s00381-024-06498-2 -
ENeuro Jun 2024The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae....
The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae. In this study, we examined the involvement of the anterior tuberal nucleus (AT) in auditory processing in adult zebrafish. Our tract-tracing experiments revealed that the dorsal subdivision of AT is strongly bidirectionally connected to the central nucleus of the torus semicircularis (TSc), a major auditory nucleus in fishes. Immunohistochemical visualisation of the ribosomal protein S6 (pS6) phosphorylation to map neural activity in response to auditory stimulation substantiated this finding: the dorsal but not the ventral part of AT responded strongly to auditory stimulation. A similar response to auditory stimulation was present in the TSc but not in the nucleus isthmi (NI), a visual region, which we used as a control for testing if the pS6 activation was specific to the auditory stimulation. We also measured the time course of pS6 phosphorylation, which was previously unreported in teleost fish. After auditory stimulation, we found that pS6 phosphorylation peaked between 100-130 minutes and returned to baseline levels after 190 minutes. This information will be valuable for the design of future pS6 experiments. Our results suggest an anatomical and functional subdivision of AT, where only the dorsal part connects to the auditory network and processes auditory information. We investigated the involvement of the anterior tuberal nucleus in zebrafish in auditory processing. Our study revealed a functional and anatomical subdivision of this region. We show that its dorsal subdivision is strongly connected to the central nucleus of the torus semicircularis, a major auditory nucleus in fishes. pS6 phosphorylation, as an indirect marker of neuronal activity after auditory stimulation, substantiated that only the dorsal anterior tuberal nucleus, processes auditory information. We also show that after auditory stimulation, pS6 phosphorylation peaked between 100-130 minutes and returned to baseline levels after 190 minutes, providing valuable information for future studies.
PubMed: 38918052
DOI: 10.1523/ENEURO.0062-24.2024 -
Bioinspiration & Biomimetics Jun 2024Flying insects rely mainly upon visual motion to detect and track objects. There has been a lot of research on fly inspired algorithms for object detection, but few have...
Flying insects rely mainly upon visual motion to detect and track objects. There has been a lot of research on fly inspired algorithms for object detection, but few have been developed based on visual motion alone. One of the daunting difficulties is that the neural and circuit mechanisms underlying the foreground-background segmentation are still unclear. Our previous modeling study proposed that the lobula held parallel pathways with distinct directional selectivity, each of which could retinotopically discriminate figures moving in its own preferred direction based on relative motion cues. The previous model, however, didn't address how the multiple parallel pathways gave the only detection output at their common downstream. Since the preferred directions of the pathways along either horizontal or vertical axis were opposite to each other, the background moving in the opposite direction to an object also activated the corresponding lobula pathway. Indiscriminate or ungated projection from all the pathways to their downstream would mix objects with the moving background, making the previous model fail with non-stationary background. Here, we extend the previous model by proposing that the background motion-dependent gating of individual lobula projections is the key to object detection. Large-field lobula plate tangential cells are hypothesized to perform the gating to realize bioinspired background subtraction. The model is shown to be capable of implementing a robust detection of moving objects in video sequences with either a moving camera that induces translational optic flow or a static camera. The model sheds light on the potential of the concise fly algorithm in real-world applications.
PubMed: 38917814
DOI: 10.1088/1748-3190/ad5ba3 -
Neuron Jun 2024Inhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway, but little is known...
Inhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway, but little is known about their function. Given their anatomy, they are expected to be multiplexors, integrating many different retinal channels along their dendrites. Here, using targeted single-cell-initiated rabies tracing, we found that mouse dLGN interneurons exhibit a degree of retinal input specialization similar to thalamocortical neurons. Some are anatomically highly specialized, for example, toward motion-selective information. Two-photon calcium imaging performed in vivo revealed that interneurons are also functionally specialized. In mice lacking retinal horizontal direction selectivity, horizontal direction selectivity is reduced in interneurons, suggesting a causal link between input and functional specialization. Functional specialization is not only present at interneuron somata but also extends into their dendrites. Altogether, inhibitory interneurons globally display distinct visual features which reflect their retinal input specialization and are ideally suited to perform feature-selective inhibition.
PubMed: 38917805
DOI: 10.1016/j.neuron.2024.06.001 -
Investigative Ophthalmology & Visual... Jun 2024Neutrophils are known mediators of innate immunity, yet their effector function in herpesvirus infections remains poorly understood. Here, we elucidate the mechanistic...
PURPOSE
Neutrophils are known mediators of innate immunity, yet their effector function in herpesvirus infections remains poorly understood. Here, we elucidate the mechanistic action and pivotal role of neutrophil extracellular traps (NETs) during herpes simplex virus type 1 (HSV-1) ocular infection.
METHODS
Neutrophils were collected from mice for HSV-1 infection, fluorescence imaging, and immunoblotting assay. Tear samples from healthy subjects and patients with HSV-1 and mice were collected at L. V. Prasad Eye Institute, India, and at the University of Illinois, USA, respectively. For the in vivo study, C57BL/6 mice as well as diversity outbred mice were infected with HSV-1 (McKrae strain) followed by tear fluid collection at various time points (0-10 days). Samples were used for Flow cytometry, ELISA, and immunofluorescence assay. Human transcriptomic profile of keratitis dataset was used evaluate NETosis signaling pathways. We also performed neutrophil depletion studies.
RESULTS
Our data revealed a discernible temporal NET formation (NETosis) predominantly in the infected eye, across normal and diversity outbred murine models and human cases of HSV-1 infection. HSV-1 instigates swift NETosis governed by caspase-1 activation and myeloperoxidase secretion. Distinct accumulations of neutrophils, remaining unengaged in NET release in the contralateral eye post-infection, hinting at a proactive defensive posture in the uninfected eye. Moreover, neutrophil depletion accentuated ocular pathology, augmented viral load, and escalated disease scores, substantiating the protective effects of NETs in curtailing viral replication.
CONCLUSIONS
Our report uncovers a previously unexplored mechanism of NETosis through pro-inflammatory cell death in response to ocular HSV-1 infection, and HPSE up-regulation, identifying new avenues for future studies.
Topics: Animals; Mice; Mice, Inbred C57BL; Extracellular Traps; Herpesvirus 1, Human; Keratitis, Herpetic; Humans; Disease Models, Animal; Neutrophils; Tears; Female; Flow Cytometry; Enzyme-Linked Immunosorbent Assay; Immunity, Innate; Eye Infections, Viral
PubMed: 38916883
DOI: 10.1167/iovs.65.6.36 -
Aging and Disease May 2024Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of...
Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.
PubMed: 38916728
DOI: 10.14336/AD.2024.0346 -
Frontiers in Human Neuroscience 2024Numerous studies have demonstrated that second language (L2) comprehension is often accompanied by activations in the first language (L1). Using both behavioral...
Numerous studies have demonstrated that second language (L2) comprehension is often accompanied by activations in the first language (L1). Using both behavioral measurement and event-related potential (ERP), this study conducted two experiments to investigate whether a direct activation pathway exists from L2 lexical representation to L1 lexical representation (the lexical pathway) in intermediate proficient bilinguals. In Experiment 1, we designed a vowel letter search task on English word pairs, which enables bilinguals to prevent semantic priming in the first 300 ms processing stage after the words' onset. In Experiment 2, Mandarin-English bilinguals were recruited to complete this task on English word pairs with occasional first character repetition between the Chinese counterparts of a word pair. Results showed a significant main effect within both the P200 and N400 time windows, indicating the activation of bilinguals' L1 lexical representation during these intervals. However, the main effect of semantic relatedness was only significant in the N400 time window. These results suggest that bilinguals can activate their L1 lexical representation directly before engaging in conceptual representation. This finding supported a lexical pathway of activation from L2 lexical representation to L1 lexical representation during visual-word recognition in intermediate proficient bilinguals.
PubMed: 38915819
DOI: 10.3389/fnhum.2024.1270377 -
Biological Research Jun 2024Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness....
BACKGROUND
Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice.
METHODS
In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining.
RESULTS
Our results indicate that 3-4% H does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression.
CONCLUSIONS
Collectively, our results indicate that H could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.
Topics: Animals; Hydrogen; Oxygen; Retinal Neovascularization; Neuroglia; Mice; Disease Models, Animal; Retinopathy of Prematurity; Mice, Inbred C57BL; Retina; Animals, Newborn; Regeneration; Immunohistochemistry; Retinal Vessels
PubMed: 38915069
DOI: 10.1186/s40659-024-00515-z