UV-Induced Neuronal Degeneration in the Rat Cerebral Cortex.
Ontology highlight
ABSTRACT:
SUBMITTER: Nakata M
PROVIDER: S-EPMC8152860 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:It is commonly assumed that cortical activity in non-rapid eye movement sleep (NREMS) is spatially homogeneous on the mesoscopic scale. This is partly due to the limited observational scope of common metabolic or imaging methods in sleep. We used the recently developed technique of thallium-autometallography (TlAMG) to visualize mesoscopic patterns of activity in the sleeping cortex with single-cell resolution. We intravenously injected rats with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC) during spontaneously occurring periods of NREMS and mapped the patterns of neuronal uptake of the potassium (K+) probe thallium (Tl+). Using this method, we show that cortical activity patterns are not spatially homogeneous during discrete 5-min episodes of NREMS in unrestrained rats-rather, they are complex and spatially diverse. Along with a relative predominance of infragranular layer activation, we find pronounced differences in metabolic activity of neighboring neuronal assemblies, an observation which lends support to the emerging paradigm that sleep is a distributed process with regulation on the local scale.
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Project description:Many neurons in the nervous systems express afterhyperpolarizations that are mediated by a slow calcium-activated potassium current. This current shapes neuronal firing and is inhibited by neuromodulators, suggesting an important role in the regulation of neuronal function. Surprisingly, very little is currently known about the molecular basis for this current or how it is gated by calcium. Recently, the neuronal calcium sensor protein hippocalcin was identified as a calcium sensor for the slow afterhyperpolarizing current in the hippocampus. However, while hippocalcin is very strongly expressed in the hippocampus, this protein shows a relatively restricted distribution in the brain. Furthermore, the genetic deletion of this protein only partly reduces the slow hyperpolarizing current in hippocampus. These considerations question whether hippocalcin can be the sole calcium sensor for the slow afterhyperpolarizing current. Here we use loss of function and overexpression strategies to show that hippocalcin functions as a calcium sensor for the slow afterhyperpolarizing current in the cerebral cortex, an area where hippocalcin is expressed at much lower levels than in hippocampus. In addition we show that neurocalcin ?, but not VILIP-2, can also act as a calcium sensor for the slow afterhyperpolarizing current. Finally we show that hippocalcin and neurocalcin ? both increase the calcium sensitivity of the afterhyperpolarizing current but do not alter its sensitivity to inhibition by carbachol acting through the G?q-11-PLC? signaling cascade. These results point to a general role for a subgroup of visinin-like neuronal calcium sensor proteins in the activation of the slow calcium-activated afterhyperpolarizing current.
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Project description:Changes in the transcription factor (TF) expression are critical for brain development, and they may also underlie neurodevelopmental disorders. Indeed, T-box brain1 (Tbr1) is a TF crucial for the formation of neocortical layer VI, and mutations and microdeletions in that gene are associated with malformations in the human cerebral cortex, alterations that accompany autism spectrum disorder (ASD). Interestingly, Tbr1 upregulation has also been related to the occurrence of ASD-like symptoms, although limited studies have addressed the effect of increased Tbr1 levels during neocortical development. Here, we analysed the impact of Tbr1 misexpression in mouse neural progenitor cells (NPCs) at embryonic day 14.5 (E14.5), when they mainly generate neuronal layers II-IV. By E18.5, cells accumulated in the intermediate zone and in the deep cortical layers, whereas they became less abundant in the upper cortical layers. In accordance with this, the proportion of Sox5+ cells in layers V-VI increased, while that of Cux1+ cells in layers II-IV decreased. On postnatal day 7, fewer defects in migration were evident, although a higher proportion of Sox5+ cells were seen in the upper and deep layers. The abnormal neuronal migration could be partially due to the altered multipolar-bipolar neuron morphologies induced by Tbr1 misexpression, which also reduced dendrite growth and branching, and disrupted the corpus callosum. Our results indicate that Tbr1 misexpression in cortical NPCs delays or disrupts neuronal migration, neuronal specification, dendrite development and the formation of the callosal tract. Hence, genetic changes that provoke ectopic Tbr1 upregulation during development could provoke cortical brain malformations.
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Project description:Thiele2013 - Cerebral cortex neuronal cells
The model of cerebral cortex neuronal cells metabolism is derived from the community-driven global reconstruction of human metabolism (version 2.02, MODEL1109130000
).
This model is described in the article:
A community-driven global reconstruction of human metabolism.
Thiele I, et al
.
Nature Biotechnology
Abstract:
Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven,
consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared
with its predecessors, the reconstruction has improved topological and functional features, including ~2x more reactions and ~1.7x more unique metabolites. Using
Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic
data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically
generated a compendium of 65 cell type-specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will
facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/.
This model is hosted on BioModels Database
and identified by: MODEL1310110033
.
To cite BioModels Database, please use: BioModels Database: An enhanced,
curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer
to CC0 Public Domain Dedication
for more information.
2005-01-01 | MODEL1310110033 | BioModels
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Project description:The emergence of functional neuronal connectivity in the developing cerebral cortex depends on 1) neural progenitor differentiation, which leads to the generation of appropriate number and types of neurons, and 2) neuronal migration, which enables the appropriate positioning of neurons so that the correct patterns of functional synaptic connectivity between neurons can emerge. In this review, we discuss 1) currently available methods to study neural progenitor development and differentiation in the developing cerebral cortex and emerging technologies in this regard, 2) assays to study the migration of descendents of progenitors (i.e., neurons) in vitro and in vivo, and 3) the use of these assays to probe the molecular control of these events in the developing brain and evaluation of gene functions disrupted in human neurodevelopmental disorders.
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Project description:BackgroundThe morphogenesis of the cerebral cortex depends on the precise control of gene expression during development. Small non-coding RNAs, including microRNAs and other groups of small RNAs, play profound roles in various physiological and pathological processes via their regulation of gene expression. A systematic analysis of the expression profile of small non-coding RNAs in developing cortical tissues is important for clarifying the gene regulation networks mediating key developmental events during cortical morphogenesis.ResultsGlobal profiling of the small RNA transcriptome was carried out in rat cerebral cortex from E10 till P28 using next-generation sequencing technique. We found an extraordinary degree of developmental stage-specific expression of a large group of microRNAs. A group of novel microRNAs with functional hints were identified, and brain-enriched expression and Dicer-dependent production of high-abundant novel microRNAs were validated. Profound editing of known microRNAs at "seed" sequence and flanking sequence was observed, with much higher editing events detected at late postnatal stages than embryonic stages, suggesting the necessity of microRNA editing for the fine tuning of gene expression during the formation of complicated synaptic connections at postnatal stages.ConclusionOur analysis reveals extensive regulation of microRNAs during cortical development. The dataset described here will be a valuable resource for clarifying new regulatory mechanisms for cortical development and diseases and will greatly contribute to our understanding of the divergence, modification, and function of microRNAs.
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Project description:BackgroundTraumatic brain injury (TBI) initiates a complex sequence of destructive and neuroprotective cellular responses. The initial mechanical injury is followed by an extended time period of secondary brain damage. Due to the complicated pathological picture a better understanding of the molecular events occurring during this secondary phase of injury is needed. This study was aimed at analysing gene expression patterns following cerebral cortical contusion in rat using high throughput microarray technology with the goal of identifying genes involved in an early and in a more delayed phase of trauma, as genomic responses behind secondary mechanisms likely are time-dependent.ResultsAmong the upregulated genes 1 day post injury, were transcription factors and genes involved in metabolism, e.g. STAT-3, C/EBP-delta and cytochrome p450. At 4 days post injury we observed increased gene expression of inflammatory factors, proteases and their inhibitors, like cathepsins, alpha-2-macroglobulin and C1q. Notably, genes with biological function clustered to immune response were significantly upregulated 4 days after injury, which was not found following 1 day. Osteopontin and one of its receptors, CD-44, were both upregulated showing a local mRNA- and immunoreactivity pattern in and around the injury site. Fewer genes had decreased expression both 1 and 4 days post injury and included genes implicated in transport, metabolism, signalling, and extra cellular matrix formation, e.g. vitronectin, neuroserpin and angiotensinogen.ConclusionThe different patterns of gene expression, with little overlap in genes, 1 and 4 days post injury showed time dependence in genomic responses to trauma. An early induction of factors involved in transcription could lead to the later inflammatory response with strongly upregulated CD-44 and osteopontin expression. An increased knowledge of genes regulating the pathological mechanisms in trauma will help to find future treatment targets. Since trauma is a risk factor for development of neurodegenerative disease, this knowledge may also reduce late negative effects.
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Project description:Emerging evidence indicates that 481 regions of the genome (>200 bp) that actively transcribe noncoding RNAs shows 100% homology between humans, rats and mice. These transcribed ultraconserved regions (T-UCRs) are thought to control the essential regulatory functions basic for life in rodents and mammals. Using microarray analysis, we presently show that 107 T-UCRs are actively expressed in adult rat cerebral cortex. They are grouped into intragenic (61) and intergenic (46) based on their genic location. Interestingly, 10 T-UCRs are expressed at unusually high levels in cerebral cortex. Additionally, many T-UCRs also showed cogenic expression. We further analyzed the correlation of intragenic T-UCRs with their host protein coding genes. Surprisingly, most of the expressed intragenic T-UCRs (54 out of 61) displayed a negative correlation with their host gene expression. T-UCRs are thought to control the splicing and transcription of the protein-coding genes that host them and flank them. Bioinformatics analysis indicated that the protein products of majority of these genes are nuclear in localization, share protein domains and are involved in the regulation of diverse biological and molecular functions including metabolism, development, cell cycle, binding and transcription factor regulation. In conclusion, this is the first study to shows that many T-UCRs are expressed in rodent brain and they might play a role in physiological brain functions.
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