Gene expression profile of single-cell level alterations in hippocampal tissue in a rat model of radiation-induced cognitive dysfunction
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE249426 | GEO | 2023/12/12
REPOSITORIES: GEO
Similar Datasets
Project description:More than half of all brain tumour survivors experience debilitating and often progressive cognitive decline after treatment with radiotherapy. Microglia, the tissue-resident macrophages of the brain, have been implicated in this decline. In response to various insults microglia can develop innate immune memory (IMM), which can either enhance (priming) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigated whether radiation can affect the IMM of microglia by irradiating the brains of rats and later exposing them to a second inflammatory challenge. Transcriptomic profiling of microglia isolated from irradiated rats showed a stronger immune response to a second inflammatory insult demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of post-mortem non-tumour brain tissue of glioblastoma patients indicates that radiation-induced microglial priming is conserved in humans. Targeting microglial priming after radiotherapy or avoiding further inflammatory insults could decrease progressive radiotherapy-induced cognitive decline.
2024-02-19 | GSE229940 | GEO
Project description:Cranial and craniospinal irradiation are the oldest central nervous system prophylaxis treatments considered for pediatric patients with lymphoblastic leukemia (ALL). However, survivors of childhood ALL that received cranial radiotherapy are at increased risk for deficits in neurocognitive skills. The continuous and dynamic response of normal tissue after irradiation has been identified as one of the causative factors for cognitive changes after cranial radiation therapy. The aim of our study was to investigate the radiation effects on social behavior and neuronal morphology in the hippocampus of adult mice. Twenty-one-day-old male C57BL/6 mice were irradiated with the small-animal radiation research platform (SARRP). Animals were given a single 10-Gy dose of radiation of X-ray cranial radiation. One month following irradiation, animals underwent behavioral testing in the Three-Chamber Sociability paradigm. Radiation affected social discrimination during the third stage eliciting an inability to discriminate between the familiar and stranger mouse, while sham successfully spent more time exploring the novel stranger. Proteomic analysis revealed dysregulation of metabolic and signaling pathways associated with neurocognitive dysfunction such as mitochondrial dysfunction, Rac 1 signaling, and synaptogenesis signaling. We observed significant decreases in mushroom spine density in the Cornu Ammonis 2 of the hippocampus, which is associated sociability processing.
2022-02-15 | PXD017596 | Pride
Project description:Background: The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. Aim: The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of hippocampus to irradiation and to elucidate the mechanisms involved. Material and Methods: C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted in the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Results: Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI was similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF- signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in NSCs self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health
2021-09-10 | PXD024975 | Pride
Project description:The impact of low-dose ionizing radiation (IR) on human brain has recently attracted attention due to increased use of IR for diagnostic purposes. The aim of this study was to investigate low-dose radiation response in hippocampus. Female C57Bl/6 mice were irradiated with 0 (control), 0.063, 0.125 or 0.5 Gy and quantitative label-free proteomic analysis of hippocampus was performed after 24 months. Key pathways were validated by immunoblotting. CREB signaling and CREB-associated pathways were the most affected ones at all doses. The two lower doses seemed to induce CREB pathway, whereas the exposure to 0.5 Gy deactivated CREB. Similarly, the lowest dose (0.063 Gy) was anti-inflammatory reducing the number of activated microglia (IBA1), whilst induction of activated microglia and reactive astroglia (GFAP) was found at 0.5 Gy suggesting increased inflammation and astrogliosis, respectively. Apoptotic markers BAX and cleaved CASP-3 and oxidative stress markers (carbonylation, NRF-2) were increased only at the highest dose. Since activated CREB pathway plays a central role in learning and memory, these data suggest neuroprotection at the lowest dose (0.063 Gy) but neurodegeneration at 0.5 Gy. These effects become significant only in old animals (24 m) and support the hypothesis of radiation-induced accelerated aging in the brain.
2019-11-06 | PXD015729 | Pride
Project description:Background: The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. The negative impact of poor dietary patterns on brain development and neurological function may be related to gut microbiota disturbance. The role of phlorizin in mitigating glucose and lipid metabolism disorders is well documented. However, the protective effect of phlorizin on diabetes-related cognitive dysfunction is unclear. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. Results: Dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Moreover, integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Conclusions: These results indicate that gut microbiota and their metabolites mediate the ameliorative effect of phlorizin on HFFD-induced cognitive impairment. Therefore, phlorizin can be used as an easy-to-implement nutritional therapy to prevent and alleviate metabolism-related neurodegenerative diseases by targeting the regulation of the microbiome-gut-brain axis.
2024-03-20 | GSE261887 | GEO
Project description:By using RNA sequencing (RNA-seq), we analyzed gene expression profiles in the cortex and hippocampus of the adult brain to demonstrate the molecular mechanisms of radiation-induced brain dysfunction.
2022-08-10 | GSE204993 | GEO
Project description:Understanding the relationship between radiation-induced breast cancer and obesity, together with information on underlying mechanisms, are potentially useful in risk management and prevention of second cancer in patients receiving radiotherapy. The present study aims to develop a novel animal model to study the relationship by combining two Sprague-Dawley rat models of radiation carcinogenesis and diet-induced obesity. Mammary carcinomas were induced in female obese and lean rats by irradiation with 4 Gy of gamma rays. Gene expression of mammary carcinomas and normal mammary tissues were analyzed with Agilent Whole Rat Genome DNA microarray. The result indicated that genes related to translation and oxidative phosphorylation were upregulated in carcinomas of obese rats.
2016-12-25 | GSE72004 | GEO
Project description:The prevention or delay of brain senescence would enhance the quality of life for older persons. We investigated the effects of soybean extracts in senescence-accelerated (SAMP10) mice. This mouse is a model of brain senescence with a short life span, cerebral atrophy and cognitive dysfunction. Mice were fed a diet containing soybean extracts from 1 to 12 months of age. The effects of green and yellow soybean extracts were compared with a control diet without soybean extracts. Cognitive functions were higher in aged mice fed green soybean than age-matched control mice and mice fed yellow soybean. We further investigated transcriptome of the SAMP10 hippocampus indicated that expression levels of 36 genes were significantly higher and 19 genes were lower in mice that ingested green soybean than in mice that ingested yellow soybean. Some of the evidences were reconfirmed by real time PCR analysis; the levels of Cdh1 and Ptgds mRNA were significantly higher and that the level of Aplp1 was significantly lower in aged SAMP10 mice fed green soybean than mice ingested yellow soybean and control mice. Additionally, the amount of amyloid beta 40 and 42 was lower in the insoluble fraction of aged SAMP10 mice fed green soybean than control mice and mice fed yellow soybean, although the levels of amyloid beta 40 and 42 in the soluble fraction were not different. Lipocalin-type prostaglandin D2 synthase (L-PGDS) has been proposed as the endogenous amyloid beta - chaperone, suggesting that amyloid aggregation was lower in mice fed green soybean than control mice and mice fed yellow soybean. These results indicate that the intake of green soybean improved cognitive function in aged mice, and suppressed amyloid beta accumulation. Green soybean might help healthy aging of the brain in older persons. The effect of green and yellow soybean extracts on cognitive function in aged SAMP10 mice. Mice were fed a CE-2 diet containing 3.0% soybean extracts taken from both yellow and green soybean species, from 1 to 12 months of age. Total RNA was extracted from the stored hippocampus for DNA microarray analysis.
2014-06-26 | E-GEOD-58811 | biostudies-arrayexpress
Project description:Radiotherapy is a commonly used treatment modality for the local control of breast cancer. However, the clinical signs of radiotherapy response are often not apparent for several weeks post-treatment. We currently lack tools to predict and/or monitor tumor responses during treatment. The aim of this study was to identify tumor secreted biomarkers of radiotherapy response. Estrogen receptor positive (ER+) MCF-7 cells were serum-starved for 2 h, and were then exposed to various doses of radiation (0, 2, 4, 6, 8 or 10 Gy). Conditioned media (CM) was harvested at 1, 2, 4, 8 and 24 h post-radiation for each radiation dose. Samples underwent processing for liquid chromatography-mass spectrometry (LC-MS) following collection. 33 proteins at the 24 h time point were found to have significantly increased secretion levels (up to 12-fold) at all radiation doses compared to untreated cells. To validate the secretomic results and to further investigate the potential use of these proteins as biomarkers of radiosensitivity, the secreted protein levels of candidate biomarkers were assessed through western blot (WB). WB analysis was performed using CM samples to assess the secretion levels from parental and radioresistant (RR) cell lines (developed within our lab) 24 h after the cells had received a single radiation dose of 2 Gy. Secretion levels of our candidate biomarkers were found to be significantly increased from the radiosensitive MCF-7 cells treated with 2 Gy of radiation at 24 h compared to 24 h untreated controls. In comparison, candidate biomarker levels in the CM samples from untreated and radiation-treated MCF-7 RR cells remained low. Currently there are no validated predictive biomarkers to monitor radiotherapy responses during treatment. These biomarkers could have a clinical role in personalising radiotherapy dosing schedules and durations for solid tumours in the neoadjuvant and palliative setting.
2021-08-13 | PXD027572 | Pride
Project description:To investigate the beneficial effects of DHA (omega-3) on affecting fructose induced brain dysfunction and metabolic disorders by sequencing the methylome (RRBS) in the hypothalamus and hippocampus of male SD rats.
2016-10-19 | GSE64816 | GEO