Similar Datasets
Project description:As a means to understand human neuropsychiatric disorders from human brain samples, we compared the transcription patterns and histological features of postmortem brain to fresh human neocortex isolated immediately following surgical removal. Compared to a number of neuropsychiatric disease-associated postmortem transcriptomes, the fresh human brain transcriptome had an entirely unique transcriptional pattern. To understand this difference, we measured genome-wide transcription as a function of time after fresh tissue removal to mimic the postmortem interval. Within a few hours, a selective reduction in the number of neuronal activity-dependent transcripts occurred with relative preservation of housekeeping genes commonly used as a reference for RNA normalization. Gene clustering indicated a rapid reduction in neuronal gene expression with a reciprocal time-dependent increase in astroglial and microglial gene expression that continued to increase for at least 24 h after tissue resection. Predicted transcriptional changes were confirmed histologically on the same tissue demonstrating that while neurons were degenerating, glial cells underwent an outgrowth of their processes. The rapid loss of neuronal genes and reciprocal expression of glial genes highlights highly dynamic transcriptional and cellular changes that occur during the postmortem interval. Understanding these time-dependent changes in gene expression in post mortem brain samples is critical for the interpretation of research studies on human brain disorders.
| S-EPMC7988150 | biostudies-literature
Project description:Selective time-dependent changes in activity- and cell-specific gene expression in human postmortem brain
| PRJNA643583 | ENA
Project description:Postmortem redistribution (PMR) can result in artificial drug concentration changes following death and complicate forensic case interpretation. Currently, no accurate methods for PMR prediction exist. Hence, alternative strategies were developed investigating the time-dependent postmortem behavior of diazepam, nordiazepam, morphine, codeine, mirtazapine and citalopram. For 477 authentic postmortem cases, femoral blood samples were collected at two postmortem time-points. All samples were quantified for drugs of abuse (targeted; liquid chromatography-tandem mass spectrometry LC-MS/MS) and characterized for small endogenous molecules (untargeted; gas chromatography-high resolution MS (GC-HRMS). Trends for significant time-dependent concentration decreases (diazepam (n = 137), nordiazepam (n = 126)), increases (mirtazapine (n = 55), citalopram (n = 50)) or minimal median postmortem changes (morphine (n = 122), codeine (n = 92)) could be observed. Robust mathematical mixed effect models were created for the generalized postmortem behavior of diazepam and nordiazepam, which could be used to back-calculate drug concentrations towards a time-point closer to the estimated time of death (caution: inter-individual variability). Significant correlations between time-dependent concentration changes of morphine, mirtazapine and citalopram with individual endogenous molecules could be determined; no correlation was deemed strong enough for successful a posteriori estimation on the occurrence of PMR for specific cases. The current dataset did successfully lead to a significant knowledge gain in further understanding the time-dependent postmortem behavior of the studied drugs (of abuse).
| S-EPMC8466227 | biostudies-literature
Project description:We examined global gene expression profiles in amygdala (AMY), nucleus accumbens (NAC), prefrontal cortex (PFC) and Liver of male C57BL/6J mice exposed to 4 cycles of chronic intermittent ethanol (CIE) vapor. Animals were sacrificed at 0, 8, and 120 hr following the last ethanol exposure. Mice were exposed to 4 cycles of intermittent vapor [4 days of 16 hours vapor/ 8 hours air] with a week between each cycle. Before entry into the vapor chambers, animals were injected with pyrazole (1 mMol/kg) and either ethanol (1.6 g/kg) or saline (controls). Animals were sacrificed at 0, 8, and 120 hr following the last ethanol exposure. The liver 0 hr control group contained 7 animals. Otherwise there were 8 animals per group (treated, control) at each time point.
2015-05-26 | E-GEOD-60676 | biostudies-arrayexpress
Project description:The neuroinflammatory response to traumatic brain injury (TBI) is critical to both neurotoxicity and neuroprotection, and has been proposed as a potentially modifiable driver of secondary injury in animal and human studies. Attempts to broadly target immune activation have been unsuccessful in improving outcomes, in part because the precise cellular and molecular mechanisms driving injury and outcome at acute, subacute, and chronic time points after TBI remain poorly defined. Microglia play a critical role in neuroinflammation and their persistent activation may contribute to long-term functional deficits. Activated microglia are characterized by morphological transformation and transcriptomic changes associated with specific inflammatory states. We analyzed the temporal course of changes in inflammatory genes of microglia isolated from injured brains at 2, 14, and 60 days after controlled cortical impact (CCI) in mice, a well-established model of focal cerebral contusion. We identified a time dependent, injury-associated change in the microglial gene expression profile toward a reduced ability to sense tissue damage, perform housekeeping, and maintain homeostasis in the early stages following CCI, with recovery and transition to a specialized inflammatory state over time. This later state starts at 14 days post-injury and is characterized by a biphasic pattern of IFNγ, IL-4, and IL-10 gene expression changes, with concurrent proinflammatory and anti-inflammatory gene changes. Our transcriptomic data sets are an important step to understand microglial role in TBI pathogenesis at the molecular level and identify common pathways that affect outcome. More studies to evaluate gene expression at the single cell level and focusing on subacute and chronic timepoint are warranted.
| S-EPMC6694299 | biostudies-literature
Project description:To acquire the time profiling of miRNA levels in microglial exosomes from injured brain after rmTBI, we employed a developed rmTBI mice model, and harvested the microglial exosomes at 1, 3, 7, 14, 21, 28, 35 and 42 DPI. The exosomes were first identified by TEM scanning, NTA measurement and Western Blot. miRNA microArray was performed to detect the miRNA levels in microglial exosomes after rmTBI. 3, 14 and 42 DPI were selected to respectively represents the time-point of acute phase, sub-acute phase and chronic phase after rmTBI. 10 miRNAs had an expression change of more than two-folds (up- or down-regualted) with a P value less than 0.05 at the 3 time-points. Among them, the expression changes of miR-124-3p were particularly evident. In addition, miR-124-3p was the only miRNA that up-regulated at 3 and 14 DPI, and down-regulated (reversely expressed) at 42 DPI, suggesting that its low expression in the chronic phase after rmTBI may exert a reverse impact on neural pathology, compared with that in the acute and sub-acute phase.
2019-07-10 | GSE133997 | GEO
Project description:Sub-cortical volumetric differences were associated with attention-deficit/hyperactivity disorder (ADHD) in a recent multi-site, mega-analysis of 1713 ADHD persons and 1529 controls. As there was a wide range of effect sizes among the sub-cortical volumes, it is possible that selective neuronal vulnerability has a role in these volumetric losses. To address this possibility, we used data from Allen Brain Atlas to investigate variability in gene expression profiles between subcortical regions of typically developing brains. We tested the hypothesis that the expression of genes in a set of curated ADHD candidate genes and five a priori selected, biological pathways would be associated with the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) findings. Across the subcortical regions studied by ENIGMA, gene expression profiles for three pathways were significantly correlated with ADHD-associated volumetric reductions: apoptosis, oxidative stress and autophagy. These correlations were strong and significant for children with ADHD, but not for adults. Although preliminary, these data suggest that variability of structural brain anomalies in ADHD can be explained, in part, by the differential vulnerability of these regions to mechanisms mediating apoptosis, oxidative stress and autophagy.
| S-EPMC6985986 | biostudies-literature
Project description:Repeated ethanol exposure and withdrawal in mice increases voluntary drinking and represents an animal model of physical dependence. We examined time- and brain region-dependent changes in gene coexpression networks in amygdala (AMY), nucleus accumbens (NAC), prefrontal cortex (PFC), and liver after four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure in C57BL/6J mice. Microarrays were used to compare gene expression profiles at 0-, 8-, and 120-hours following the last ethanol exposure. Each brain region exhibited a large number of differentially expressed genes (2,000-3,000) at the 0- and 8-hour time points, but fewer changes were detected at the 120-hour time point (400-600). Within each region, there was little gene overlap across time (~20%). All brain regions were significantly enriched with differentially expressed immune-related genes at the 8-hour time point. Weighted gene correlation network analysis identified modules that were highly enriched with differentially expressed genes at the 0- and 8-hour time points with virtually no enrichment at 120 hours. Modules enriched for both ethanol-responsive and cell-specific genes were identified in each brain region. These results indicate that chronic alcohol exposure causes global 'rewiring' of coexpression systems involving glial and immune signaling as well as neuronal genes.
| S-EPMC4372440 | biostudies-literature
Project description:Schizophrenia (SCZ) is a psychiatric disorder that can include symptoms of disorganized speech and thoughts with uncertain underlying mechanisms possibly linked to over-activated microglia. In this study, we used brain samples from sixteen donors with SCZ and thirteen control donors to assess the differential activation of microglia by quantifying density and 3D reconstruction of microglia stained with ionized calcium-binding adaptor molecule-1 (Iba1). Our samples consisted of sections from the frontal, temporal, and cingulate cortical gray matter, subcortical white matter regions (SCWM), and included the anterior corpus callosum. In the first series of studies, we performed a density analysis followed by a spatial analysis to ascertain the microglial density, distribution, and soma size in SCZ brains. Second, we performed a series of morphological quantification techniques to investigate the arborization patterns of the microglia in SCZ. The results demonstrated an increase in microglia density in the cortical gray matter regions in SCZ cases, while in the SCWM, there was a significant increase in microglia density in the frontal and temporal, but not in the other brain regions of interest (ROIs). Spatial analysis using the "nearest neighbor" demonstrated that there was no effect in "clustering", but there were shorter distances between microglia seen in the SCZ cases. The morphological measures showed that there was a region-dependent increase in the microglia soma size in the SCZ cases while the Sholl analysis revealed a significant decrease in the microglia arborization in the SCZ cases across all the ROI's studied. An in-depth 3D reconstruction of microglia in Brodmann area 9 cortical region found that there was a significant association between age and reduced microglial arborization in the SCZ cases. This region-dependent age association can help determine whether longitudinal changes in microglial activation across age are brain region-dependent, which may point to potential therapeutic targets.
| S-EPMC8713533 | biostudies-literature
Project description:Different cell types are commonly defined by their distinct response features. But several studies proved substantial variability between cells of the same type, suggesting rather the appraisal of response feature distributions than a limitation to "typical" responses. Moreover, there is growing evidence that time-dependent changes of response features contribute to robust and functional network output in many neuronal systems. The individually characterized Touch (T), Pressure (P), and Retzius (Rz) cells in the medicinal leech allow for a rigid analysis of response features, elucidating differences between and variability within cell types, as well as their changes over time. The initial responses of T and P cells to somatic current injection cover a wide range of spike counts, and their first spike is generated with a high temporal precision after a short latency. In contrast, all Rz cells elicit very similar low spike counts with variable, long latencies. During prolonged electrical stimulation the resting membrane potential of all three cell types hyperpolarizes. At the same time, Rz cells reduce their spiking activity as expected for a departure from the spike threshold. In contrast, both mechanoreceptor types increase their spike counts during repeated stimulation, consistent with previous findings in T cells. A control experiment reveals that neither a massive current stimulation nor the hyperpolarization of the membrane potential is necessary for the mechanoreceptors' increase in excitability over time. These findings challenge the previously proposed involvement of slow K+-channels in the time-dependent activity changes. We also find no indication for a run-down of HCN channels over time, and a rigid statistical analysis contradicts several potential experimental confounders as the basis of the observed variability. We conclude that the time-dependent change in excitability of T and P cells could indicate a cell-type-specific shift between different spiking regimes, which also could explain the high variability in the initial responses. The underlying mechanism needs to be further investigated in more naturalistic experimental situations to disentangle the effects of varying membrane properties versus network interactions. They will show if variability in individual response features serves as flexible adaptation to behavioral contexts rather than just "randomness".
| S-EPMC9092978 | biostudies-literature