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MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons

Neural Regeneration Research 2024年第12期19卷 2698-2707页

作者： Bhupender Sharma Melissa MTorres Sheryl Rodriguez Laxman Gangwani Subodh Kumar center of emphasis in neuroscience Department of Molecular and Translational MedicinePaul L.Foster School of MedicineTexas Tech University Health Sciences CenterEl PasoTXUSA Bond Life Sciences center and Department of Veterinary Pathobiology University of MissouriColumbiaMOUSA L.Frederick Francis Graduate School of Biomedical Sciences Texas Tech University Health Sciences CenterEl PasoTXUSA

Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse f

关键词： Alzheimer's disease GABAergic synapse gamma-aminobutyric acid type A receptor subunitα-1(GABRα1) microRNA-502-3p(miR-502-3p) miRNA in situ hybridization Patch-clamp

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Movement Trend Alterations in the Periaqueductal Gray(PAG)-Employed Ratbot Navigation Are Correlated with Stimulation Parameters

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Journal of Bionic Engineering 2024年第2期21卷 866-876页

作者： Sina Khajei Abed Khorasani Mohammad Reza Afarinesh Vahid Sheibani neuroscience Research center Institute of NeuropharmacologyKerman University of Medical SciencesKerman***Iran Cognitive neuroscience Research center Institute of NeuropharmacologyKerman University of Medical SciencesKerman***Iran

In previous studies,Periaqueductal Gray(PAG)stimulation was used to stop ratbots from moving.Due to the homology between the PAG and the intercollicular nucleus,which has been used for forward movement in birds,we investigated the possibility of PAG application to induce forward locomotion for the first time.Using a corridor maze,the traveled distances via PAG electrical stimulation were examined in nine Wistar male rats during three sessions.A custom-designed stimulator was developed to apply the stimulation.The results showed reductions in responses to stimulation over time.Accordingly,the traveled distances had negative slopes during the consecutive trials(in 8 out of the 9 rats),and the slope mean was significantly different from zero.There was a strong correlation between the stimulation parameters(electric Charge per Phase(CPP)and the Number of Pulses(NP))and the observed slopes.The negative Movement Slopes(MS)were highly correlated with the CPP and the NP,as the Pearson's linear correlation coefficients were−0.87 and−0.79,respectively.The MS-CPP coefficients of determination(R-squared)were also between 0.76 and 0.95.In addition,the MS-NP coefficients of determination were between 0.63 and 0.87.Thus,it is concluded that the electrical stimulation parameters influence the behavioral outcomes directly.Furthermore,the PAG area may be considered a suitable candidate for forward locomotion control in the future if the area is harnessed effectively to prevent undesirable chaotic behaviors.

关键词： Periaqueductal Gray(PAG) Navigation Ratbot Animal-robot Forward locomotion Movement slope

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Blood-brain barrier pathology in cerebral small vessel disease

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Neural Regeneration Research 2024年第6期19卷 1233-1240页

作者： Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan Department of Medical Imaging Anatomy Radboud University Medical Center Donders Institute for Brain Cognition & Behavior Center for Medical Neuroscience Preclinical Imaging Center PRIME Radboud Alzheimer Center

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

关键词： blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction hypertension inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions transcytosis

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Beyond functional MRI signals:molecular and cellular modifiers of the functional connectome and cognition

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Neural Regeneration Research 2024年第5期19卷 937-938页

作者： Lorenzo Pini Alessandro Salvalaggio Maurizio Corbetta Padova neuroscience center University of PadovaItaly Veneto Institute of Molecular Medicine VIMMPadovaItaly Department of neuroscience University of PadovaItaly

Our brain is constantly active.Even at rest,the brain carries out essential functions such as maintenance of resting potentials,subthreshold synaptic activity,and spiking activity related to information processing.This resting activity can be assessed with several in vivo tools,such as resting-state functional magnetic resonance imaging.This technique measures subtle changes in blood flow,volume,and oxygenation that occur over time.Although vascular in nature,resting-state functional magnetic resonance imaging is considered a reliable proxy of neural activity and several studies have shown that the brain is functionally divided into interacting neural networks called the“functional connectome”.

关键词： functional neural measures

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Translating Pathological Brain Activity Primers in Parkinson’s Disease Research

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Research 2024年第1期2023卷 735-752页

作者： Daniela Mirzac Svenja L.Kreis Heiko J.Luhmann Gabriel Gonzalez-Escamilla Sergiu Groppa Movement Disorders and Neurostimulation Department of NeurologyFocus Program Translational NeuroscienceRhine Main Neuroscience NetworkUniversity Medical Center of the Johannes Gutenberg University Mainz55131 MainzGermany Institute of Physiology University Medical Center of the Johannes Gutenberg University Mainz55131 MainzGermany

Translational experimental approaches that help us better trace Parkinson’s disease(PD)pathophysiological mechanisms leading to new therapeutic targets are urgently needed.In this article,we review recent experimental and clinical studies addressing abnormal neuronal activity and pathological network oscillations,as well as their underlying mechanisms and modulation.Our aim is to enhance our knowledge about the progression of Parkinson's disease pathology and the timing of its symptom’s manifestation.Here,we present mechanistic insights relevant for the generation of aberrant oscillatory activity within the cortico-basal ganglia circuits.We summarize recent achievements extrapolated from available PD animal models,discuss their advantages and limitations,debate on their differential applicability,and suggest approaches for transferring knowledge on disease pathology into future research and clinical applications.

关键词： clinical knowledge insight

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A divergent pattern in functional connectivity: a transdiagnostic perspective

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Neural Regeneration Research 2024年第9期19卷 1885-1886页

作者： Lu Zhang Lorenzo Pini Padova neuroscience center Universitàdegli Studi di PadovaPadovaItaly

Functional magnetic resonance imaging(fMRI)is a popular tool used to investigate not only how the brain responds to specific stimuli during sensorimotor or cognitive tasks,but also brain activity at rest.The physics b... 详细信息

关键词： pattern connectivity functional

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Neural Stem Cell Competition

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neuroscience Bulletin 2024年第2期40卷 277-279页

作者： Yanan Li Jie He State Key Laboratory of neuroscience Institute of NeuroscienceCenter for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China

Cell competition is an adaptive surveillance mechanism to ensure the robustness of developmental outputs,maintain tissue integrity,and regulate tumor progression in multicellular organisms,which is highly conserved from invertebrates to vertebrates[1].At the cellular level,cell competition represents a non-cell-autonomous process in that cells can sense the fitness of their neighbors through cellular interactions,thereby eliminating low-fitness cells and expanding high-fitness counterparts,however,cells develop normally in homogenous populations.

关键词： thereby maintain eliminating

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Distributions of Visual Receptive Fields from Retinotopic to Craniotopic Coordinates in the Lateral Intraparietal Area and Frontal Eye Fields of the Macaque

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neuroscience Bulletin 2024年第2期40卷 171-181页

作者： Lin Yang Min Jin Cong Zhang Ning Qian Mingsha Zhang Key Laboratory of Cognitive neuroscience and Learning Division of PsychologyBeijing Normal UniversityBeijing 100875China Institute of neuroscience Key Laboratory of Primate NeurobiologyCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China Department of neuroscience and Zuckerman Institute Columbia UniversityNew York 10027USA

Even though retinal images of objects change their locations following each eye movement,we perceive a stable and continuous world.One possible mechanism by which the brain achieves such visual stability is to construct a craniotopic coordinate by integrating retinal and extraretinal information.There have been several proposals on how this may be done,including eye-position modulation(gain fields)of retinotopic receptive fields(RFs)and craniotopic RFs.In the present study,we investigated coordinate systems used by RFs in the lateral intraparietal(LIP)cortex and frontal eye fields(FEF)and compared the two areas.We mapped the two-dimensional RFs of neurons in detail under two eye fixations and analyzed how the RF of a given neuron changes with eye position to determine its coordinate representation.The same recording and analysis procedures were applied to the two brain areas.We found that,in both areas,RFs were distributed from retinotopic to craniotopic representations.There was no significant difference between the distributions in the LIP and FEF.Only a small fraction of neurons was fully craniotopic,whereas most neurons were between the retinotopic and craniotopic representations.The distributions were strongly biased toward the retinotopic side but with significant craniotopic shifts.These results suggest that there is only weak evidence for craniotopic RFs in the LIP and FEF,and that transformation from retinotopic to craniotopic coordinates in these areas must rely on other factors such as gain fields.

关键词： Reference frames Eye-centered Headcentered Visual stability

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The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

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Neural Regeneration Research 2024年第6期19卷 1206-1211页

作者： Matihias T.Wyss Christine Heuer Marina Herwerth Institute of Pharmacology and Toxicology University of Zurich neuroscience center Zurich (ZNZ) University of Zurich and ETH Zurich 3. Neurology Department University Hospital of Zurich

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors(P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies. Thus, interference with P2 receptors may be a promising strategy for the modulation of immune responses. Although only a few clinical studies have been conducted in isolated entities with limited success, preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases. Despite the association of P2 receptors with several disorders from this field, the use of P2 receptor antagonists in clinical therapy is still very scarce. In this narrative review, we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes. We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events. Using suramin, a non-specific purinergic inhibitor, as an example, we further show that off-target effects could be responsible for observed effects in immunological settings, which may have interesting implications. Overall, we believe that it is worthwhile to further investigate this hitherto underexplored area.

关键词： autoimmune diseases neurological disorders P2 receptor inhibitors purinergic system suramin

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Neuron-to-astrocyte proteostatic stress signaling in response to tau pathology

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Neural Regeneration Research 2024年第3期19卷 505-506页

作者： Kevin Llewelyn Batenburg Wiep Scheper Amsterdam UMC location Vrije Universiteit Amsterdam Department of Human GeneticsAmsterdam Neuroscience-NeurodegenerationAmsterdamThe Netherlands Department of Functional Genomics Center for Neurogenomics and Cognitive ResearchVrije Universiteit AmsterdamAmsterdam Neuroscience-NeurodegenerationAmsterdamThe Netherlands

Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime.Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges.The integrated stress response(ISR)is one of the key proteostatic stress responses in the cell(Costa-Mattioli and Walter,2020).The ISR is the downstream convergence point for the four stress-induced eIF2αkinases(EIF2AK1-4)that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α.ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs,including that encoding the activating transcription factor 4(ATF4).Together,the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.

关键词： translation stress Together

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