Critical role for inhibitory neurons in modulation of synaptic signaling in ex vivo neuronal networks

2013 ◽  
Vol 31 (5) ◽  
pp. 308-310 ◽  
Author(s):  
Jill M. Zemianek ◽  
Sangmook Lee ◽  
Mary Guaraldi ◽  
Thomas B. Shea
Keyword(s):  
Neuronal Networks ◽  
Ex Vivo ◽  
Critical Role ◽  
Inhibitory Neurons ◽  
Synaptic Signaling

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

scholarly journals Cell–cell coupling and DNA methylation abnormal phenotypes in the after-hours mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Federico Tinarelli ◽  
Elena Ivanova ◽  
Ilaria Colombi ◽  
Erica Barini ◽  
Edoardo Balzani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Neuronal Networks ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Neuronal Cultures ◽  
Functional Impairments ◽  
After Hours ◽  
The Impact

Abstract Background DNA methylation has emerged as an important epigenetic regulator of brain processes, including circadian rhythms. However, how DNA methylation intervenes between environmental signals, such as light entrainment, and the transcriptional and translational molecular mechanisms of the cellular clock is currently unknown. Here, we studied the after-hours mice, which have a point mutation in the Fbxl3 gene and a lengthened circadian period. Methods In this study, we used a combination of in vivo, ex vivo and in vitro approaches. We measured retinal responses in Afh animals and we have run reduced representation bisulphite sequencing (RRBS), pyrosequencing and gene expression analysis in a variety of brain tissues ex vivo. In vitro, we used primary neuronal cultures combined to micro electrode array (MEA) technology and gene expression. Results We observed functional impairments in mutant neuronal networks, and a reduction in the retinal responses to light-dependent stimuli. We detected abnormalities in the expression of photoreceptive melanopsin (OPN4). Furthermore, we identified alterations in the DNA methylation pathways throughout the retinohypothalamic tract terminals and links between the transcription factor Rev-Erbα and Fbxl3. Conclusions The results of this study, primarily represent a contribution towards an understanding of electrophysiological and molecular phenotypic responses to external stimuli in the Afh model. Moreover, as DNA methylation has recently emerged as a new regulator of neuronal networks with important consequences for circadian behaviour, we discuss the impact of the Afh mutation on the epigenetic landscape of circadian biology.

scholarly journals Intrinsic Dynamics in Neuronal Networks. I. Theory

2000 ◽  
Vol 83 (2) ◽  
pp. 808-827 ◽  
Author(s):  
P. E. Latham ◽  
B. J. Richmond ◽  
P. G. Nelson ◽  
S. Nirenberg
Keyword(s):  
Firing Rate ◽  
Firing Pattern ◽  
Neuronal Networks ◽  
Network Connectivity ◽  
Excitatory Input ◽  
High Rate ◽  
Inhibitory Neurons ◽  
Inhibitory Input ◽  
Dynamic Interactions ◽  
Firing Patterns

Many networks in the mammalian nervous system remain active in the absence of stimuli. This activity falls into two main patterns: steady firing at low rates and rhythmic bursting. How are these firing patterns generated? Specifically, how do dynamic interactions between excitatory and inhibitory neurons produce these firing patterns, and how do networks switch from one firing pattern to the other? We investigated these questions theoretically by examining the intrinsic dynamics of large networks of neurons. Using both a semianalytic model based on mean firing rate dynamics and simulations with large neuronal networks, we found that the dynamics, and thus the firing patterns, are controlled largely by one parameter, the fraction of endogenously active cells. When no endogenously active cells are present, networks are either silent or fire at a high rate; as the number of endogenously active cells increases, there is a transition to bursting; and, with a further increase, there is a second transition to steady firing at a low rate. A secondary role is played by network connectivity, which determines whether activity occurs at a constant mean firing rate or oscillates around that mean. These conclusions require only conventional assumptions: excitatory input to a neuron increases its firing rate, inhibitory input decreases it, and neurons exhibit spike-frequency adaptation. These conclusions also lead to two experimentally testable predictions: 1) isolated networks that fire at low rates must contain endogenously active cells and 2) a reduction in the fraction of endogenously active cells in such networks must lead to bursting.

Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2

2008 ◽  
Vol 294 (6) ◽  
pp. C1521-C1530 ◽  
Author(s):  
Shuji Kondo ◽  
Yixin Tang ◽  
Elizabeth A. Scheef ◽  
Nader Sheibani ◽  
Christine M. Sorenson
Keyword(s):  
Cell Migration ◽  
Vascular System ◽  
Ex Vivo ◽  
Vascular Development ◽  
Critical Role ◽  
Endothelial Cell Migration ◽  
Cellular Functions ◽  
Capillary Morphogenesis ◽  
Angiogenesis Assay ◽  
Ischemic Retinopathy

Apoptosis plays a critical role during development and in the maintenance of the vascular system. B-cell leukemia lymphoma 2 (bcl-2) protects endothelial cells (EC) from apoptosis in response to a variety of stimuli. Previous work from this laboratory demonstrated attenuation of postnatal retinal vascular development and retinal neovascularization during oxygen-induced ischemic retinopathy in bcl-2-deficient (bcl-2−/−) mice. To gain further insight into the function of bcl-2 in the endothelium, we isolated retinal EC from bcl-2+/+ and bcl-2−/− mice. Retinal EC lacking bcl-2 demonstrated reduced cell migration, tenascin-C expression, and adhesion to vitronectin and fibronectin. The bcl-2−/− retinal EC also failed to undergo capillary morphogenesis in Matrigel. In addition, using an ex vivo angiogenesis assay, we observed reduced sprouting from aortic rings grown in culture from bcl-2−/− mice compared with bcl-2+/+ mice. Furthermore, reexpression of bcl-2 was sufficient to restore migration and capillary morphogenesis defects observed in bcl-2−/− retinal EC. Mechanistically, bcl-2−/− cells expressed significantly less endothelial nitric oxide synthase, an important downstream effecter of proangiogenic signaling. This may be attributed to increased oxidative stress in the absence of bcl-2. In fact, incubation of retinal EC or aortic rings from bcl-2−/− mice with the antioxidant N-acetylcysteine rescued their capillary morphogenesis and sprouting defects. Thus, bcl-2-mediated cellular functions play important roles not only in survival but also in proangiogenic phenotype of EC with a significant impact on vascular development and angiogenesis.

scholarly journals Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

2017 ◽  
Author(s):  
Hilary K. Finucane ◽  
Yakir A. Reshef ◽  
Verneri Anttila ◽  
Kamil Slowikowski ◽  
Alexander Gusev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Ex Vivo ◽  
Cell Types ◽  
Inhibitory Neurons ◽  
Biliary Cirrhosis ◽  
Expression Data ◽  
Specific Expression

ABSTRACTGenetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources, including the GTEx and PsychENCODE consortia, together with genome-wide association study (GWAS) summary statistics for 48 diseases and traits with an average sample size of 169,331, to identify disease-relevant tissues and cell types. We develop and apply an approach that uses stratified LD score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We detect tissue-specific enrichments at FDR < 5% for 34 diseases and traits across a broad range of tissues that recapitulate known biology. In our analysis of traits with observed central nervous system enrichment, we detect an enrichment of neurons over other brain cell types for several brain-related traits, enrichment of inhibitory over excitatory neurons for bipolar disorder but excitatory over inhibitory neurons for schizophrenia and body mass index, and enrichments in the cortex for schizophrenia and in the striatum for migraine. In our analysis of traits with observed immunological enrichment, we identify enrichments of T cells for asthma and eczema, B cells for primary biliary cirrhosis, and myeloid cells for Alzheimer's disease, which we validated with independent chromatin data. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signal.

scholarly journals Molecular Characterization of Superficial Layers of the Presubiculum During Development

2021 ◽  
Vol 15 ◽  
Author(s):  
Jiayan Liu ◽  
Tetsuhiko Kashima ◽  
Shota Morikawa ◽  
Asako Noguchi ◽  
Yuji Ikegaya ◽  
...  
Keyword(s):  
Spatial Representation ◽  
Critical Role ◽  
Glutamate Transporter ◽  
Direction Selectivity ◽  
Inhibitory Neurons ◽  
Head Direction ◽  
Anterior Thalamic Nucleus ◽  
Functional Development ◽  
Eye Opening ◽  
Anterograde Tracer

The presubiculum, a subarea of the parahippocampal region, plays a critical role in spatial navigation and spatial representation. An outstanding aspect of presubicular spatial codes is head-direction selectivity of the firing of excitatory neurons, called head-direction cells. Head-direction selectivity emerges before eye-opening in rodents and is maintained in adulthood through neurophysiological interactions between excitatory and inhibitory neurons. Although the presubiculum has been physiologically profiled in terms of spatial representation during development, the histological characteristics of the developing presubiculum are poorly understood. We found that the expression of vesicular glutamate transporter 2 (VGluT2) could be used to delimit the superficial layers of the presubiculum, which was identified using an anterograde tracer injected into the anterior thalamic nucleus (ATN). Thus, we immunostained slices from mice ranging in age from neonates to adults using an antibody against VGluT2 to evaluate the VGluT2-positive area, which was identified as the superficial layers of the presubiculum, during development. We also immunostained the slices using antibodies against parvalbumin (PV) and somatostatin (SOM) and found that in the presubicular superficial layers, PV-positive neurons progressively increased in number during development, whereas SOM-positive neurons exhibited no increasing trend. In addition, we observed repeating patch structures in presubicular layer III from postnatal days 12. The abundant expression of VGluT2 suggests that the presubicular superficial layers are regulated primarily by VGluT2-mediated excitatory neurotransmission. Moreover, developmental changes in the densities of PV- and SOM-positive interneurons and the emergence of the VGluT2-positive patch structures during adolescence may be associated with the functional development of spatial codes in the superficial layers of the presubiculum.

scholarly journals The Y14-p53 Regulatory Circuit in Megakaryocyte Differentiation and Thrombocytopenia

2020 ◽  
Author(s):  
Chun-Hao Su ◽  
Wei-Ju Liao ◽  
Wei-Chi Ke ◽  
Ruey-Bing Yang ◽  
Woan-Yuh Tarn
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Ex Vivo ◽  
Critical Role ◽  
Platelet Production ◽  
Noncoding Regions ◽  
Regulatory Circuit ◽  
Hel Cells ◽  
Absent Radius ◽  
Megakaryocyte Differentiation

SUMMARYThrombocytopenia-absent radius syndrome is caused by a deletion in chromosome 1q21.1 in trans with RBM8A mutations in the noncoding regions. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, indicating a disorder of platelet production. Rbm8aKOMK mice accumulated immature megakaryocytes in the bone marrow and spleen. Depletion of Y14/RBM8A in human erythroleukemia (HEL) cells inhibited phorbol ester-induced polyploidy and downregulated the signaling pathways associated with megakaryocyte maturation. Accordingly, Rbm8aKOMK mice had reduced expression of surface glycoproteins on platelets and impaired coagulation. Moreover, p53 level was increased in Y14-depleted HEL cells and Rbm8aKOMK megakaryocytes. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Knockout of Trp53 in part restored the platelet count of Rbm8aKOMK mice. These results indicate that the Y14-p53 circuit plays a critical role in megakaryocyte differentiation and platelet production.

scholarly journals My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-44-SCI-44
Author(s):  
Xiaoxia Li
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

scholarly journals Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

2010 ◽  
Vol 42A (2) ◽  
pp. 103-113 ◽  
Author(s):  
Matthew S. Barnabei ◽  
Nathan J. Palpant ◽  
Joseph M. Metzger
Keyword(s):  
Cardiac Function ◽  
Genetic Divergence ◽  
Ex Vivo ◽  
Inbred Mouse ◽  
Critical Role ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Cardiac Decompensation

Inbred mouse strains play a critical role in biomedical research. Genetic homogeneity within inbred strains and their general amenability to genetic manipulation have made them an ideal resource for dissecting the physiological function(s) of individual genes. However, the inbreeding that makes inbred mice so useful also results in genetic divergence between them. This genetic divergence is often unaccounted for but may be a confounding factor when comparing studies that have utilized distinct inbred strains. Here, we compared the cardiac function of C57BL/6J mice to seven other commonly used inbred mouse strains: FVB/NJ, DBA/2J, C3H/HeJ, BALB/cJ, 129X1/SvJ, C57BL/10SnJ, and 129S1/SvImJ. The assays used to compare cardiac function were the ex vivo isolated Langendorff heart preparation and in vivo real-time hemodynamic analysis using conductance micromanometry. We report significant strain-dependent differences in cardiac function between C57BL/6J and other commonly used inbred strains. C57BL/6J maintained better cardiac function than most inbred strains after ex vivo ischemia, particularly compared with 129S1/SvImJ, 129X1/SvJ, and C57BL/10SnJ strains. However, during in vivo acute hypoxia 129X1/SvJ and 129S1/SvImJ maintained relatively normal cardiac function, whereas C57BL/6J animals showed dramatic cardiac decompensation. Additionally, C3H/HeJ showed rapid and marked cardiac decompensation in response to esmolol infusion compared with effects of other strains. These findings demonstrate the complex effects of genetic divergence between inbred strains on cardiac function. These results may help inform analysis of gene ablation or transgenic studies and further demonstrate specific quantitative traits that could be useful in discovery of genetic modifiers relevant to cardiac health and disease.

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