Age and Sex Influence the Hippocampal Response and Recovery Following Sepsis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA529377 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8791730.fastq.gz | Fastqsanger.gz | |||
| SRR8791740.fastq.gz | Fastqsanger.gz | |||
| SRR8791750.fastq.gz | Fastqsanger.gz | |||
| SRR8791760.fastq.gz | Fastqsanger.gz | |||
| SRR8791770.fastq.gz | Fastqsanger.gz |
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Project description:Although in-hospital mortality rates for sepsis have decreased, survivors often experience lasting physical and cognitive deficits. Moreover, older adults are more vulnerable to long-term complications associated with sepsis. We employed a murine model to examine the influence of age and sex on the brain’s response and recovery following sepsis. Young (~4 months) and old (~20 months) mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with restraint stress. The hippocampal transcriptome was examined in age and sex-matched controls at 1 and 4 days post-CLP. In general, immune and stress-related genes increased while neuronal, synaptic, and glial genes decreased one day after CLP-induced sepsis. However, specific age and sex differences were observed for the initial responsiveness to sepsis as well as the rate of recovery examined on day 4. Young females exhibited a muted transcriptional response relative to young males and old females. Old females exhibited a robust shift in gene transcription on day 1 and, while most genes recovered, genes linked to neurogenesis and myelination continued to be downregulated by day 4. In contrast, old males exhibited a more delayed or prolonged response to sepsis, such that neuronal and synaptic genes continued to decrease while immune response genes continued to increase on day 4. These results suggest that aging is associated with delayed recovery from sepsis, which is particularly evident in males.
2019-07-22 | GSE128925 | GEO
Project description:Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. Sepsis results in an excessive host inflammatory response that can induce immediate and persistent cognitive decline, and this is known to be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. These differences likely involve sex steroids, sex chromosomes, and possibly epigenetic mechanisms. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young (~ 4 months) and old (~ 20 months) adult mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Differential expression of hippocampal miR was examined in age- and sex-matched controls at 1 and 4 days post-CLP. A sexually dimorphic miR response was observed. Similar to previous work examining the transcription profile, young females exhibited a better recovery of the miR profile from day1 to day4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day1 and day4, with 22 miR upregulated across days. Examination of the relationship of these 22 upregulated miR with mRNA expression indicated downregulation of mRNA with time from induction of sepsis and was more pronounced for mRNA that were associated with multiple upregulated miR. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute sexually dimorphic responses to sepsis.
2022-02-23 | GSE188874 | GEO
Project description:Influence of Age and Sex on microRNA Response and Recovery in the Hippocampus Following Sepsis
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Project description:Although in-hospital mortality rates for sepsis have decreased, survivors often experience lasting physical and cognitive deficits. Moreover, older adults are more vulnerable to long-term complications associated with sepsis. We employed a murine model to examine the influence of age and sex on the brain's response and recovery following sepsis. Young (~ 4 months) and old (~ 20 months) mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with restraint stress. The hippocampal transcriptome was examined in age- and sex-matched controls at 1 and 4 days post-CLP. In general, immune- and stress-related genes increased, while neuronal, synaptic, and glial genes decreased 1 day after CLP-induced sepsis. However, specific age and sex differences were observed for the initial responsiveness to sepsis as well as the rate of recovery examined on day 4. Young females exhibited a muted transcriptional response relative to young males and old females. Old females exhibited a robust shift in gene transcription on day 1, and while most genes recovered, genes linked to neurogenesis and myelination continued to be downregulated by day 4. In contrast, old males exhibited a more delayed or prolonged response to sepsis, such that neuronal and synaptic genes continued to decrease while immune response genes continued to increase on day 4. These results suggest that aging is associated with delayed recovery from sepsis, which is particularly evident in males.
| S-EPMC6834928 | biostudies-literature
Project description:Millions of sepsis survivors annually face long-term neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered in sepsis, and their use affects neuropsychiatric outcomes, but the mechanisms are unknown. We used the cecal ligation and puncture method to induce acute infection in mice and test the hypothesis that corticosteroid treatment during illness has long-term effects on hippocampal function. Functional phenotyping and hippocampal RNA-sequencing were performed in the same survivor mice to identify underlying mechanisms of behavioral and neuroendocrine outcomes. Long-term CLP survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal (HPA) axis activity, and persistent systemic and neuro-inflammation. The relationship between gene expression and behavior suggested a protective role for inflammation and oxidative metabolism after CLP. Corticosterone treatment during illness had distinct effects on hippocampal function in survivors, including object memory impairment. The long-term behavioral effects of corticosterone treatment were associated with persistent downregulation of activity-dependent gene expression in the hippocampus. The results suggest that corticosteroid treatment for sepsis influences hippocampal function in survivors via long-lasting changes to basal hippocampal activity. Neural activity, inflammation, and oxidative metabolism should be explored as future treatment targets to modify neuropsychiatric outcomes in sepsis survivors.
2023-07-31 | GSE225868 | GEO
Project description:Sepsis, defined as a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. The excessive host inflammatory response can induce immediate and persistent cognitive decline, which can be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young and old mice of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Expression of hippocampal miR was examined in age- and sex-matched controls at 1 and 4 days post-CLP. Few miR were modified in a similar manner across age or sex and these few miR were generally associated with neuroprotection against inflammation. Similar to previous work examining transcription, young females exhibited a better recovery of the miR profile from day 1 to day 4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day 1 and day 4 and many of the miR upregulated on day 1 and day 4 were linked to neurodegeneration, increased neuroinflammation, and cognitive impairment. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute to susceptibility or resilience to cognitive impairment due to sepsis.
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Project description:Corticosteroid treatment during sepsis influences hippocampal function in survivors
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Project description:Our experiments examined T-lymphocyte numbers and effector-functions in peritoneal contamination and infection (PCI) a mouse model of sepsis. One of our main questions was how T-lymphocytes reconstitute after sepsis-induced lymphopenia. We investigated the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Sepsis is an immunological dysfunction against pathogens leading to inflammation with massive cytokine production. Simultaneously immunosuppression occurs e.g. lymphopenia, which is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. More than 50% of T-cells undergo apoptosis shortly after sepsis-induction. However, 8 days after sepsis onset, surviving mice present normal lymphocyte counts. Theoretically, T-cells could reconstitute in two different ways. Firstly, the diminished pool of T-cells is replenished by newly in thymus produced T-cells with new diverse T-cell-receptors (TCRs). Alternatively, remaining T-cells start to proliferate until reaching normal cell count. If this was the case all divided cells shared the same TCRs as primary cells. This could lead to a narrowed TCR diversity within a quantitative normalized T-cell pool and would be an explanation for the long-lasting immune incompetence. To address the question how T-cells recover from lymphopenia we applied next generation sequencing (NGS) to analyse TCR diversity in septic and healthy mice. One group of septic mice received Interleukin-7 (IL-7), an interleukin which regulates T-cell homeostasis and is a promising therapeutically approach for septic patients. 50000 sequences per mouse were analyzed and the three different groups (controls, sepsis, sepsis + IL-7 treatment) compared regarding their diversity. The sequenced raw data (fastq) are uploaded in this library.
2019-10-02 | E-MTAB-7483 | biostudies-arrayexpress
Project description:Calorie restriction (CR) enhances longevity and mitigates aging phenotypes in numerous species. Physiological responses to CR are cell-type specific and variable throughout the lifespan; however, the mosaic of molecular changes responsible CR benefits remain unclear, particularly in brain regions susceptible to deterioration throughout aging. Thus, we examined the influence of long-term CR on the CA1 hippocampal region, a key learning and memory brain area that is vulnerable to age-related pathologies, such as Alzheimerâs disease (AD). Through mRNA sequencing and NanoString nCounter analysis, we demonstrate that one year of CR feeding suppresses an age-dependent signature of 882 genes functionally associated with synaptic transmission-related pathways, including calcium signaling, long-term potentiation (LTP), and Creb signaling in wild-type mice. By comparing the influence of CR on hippocampal CA1 region transcriptional profiles at younger- (5 months) and older-adult (15 months) timepoints, we identify conserved upregulation of proteome quality control and calcium buffering genes, including heat shock 70 kDa proteins 1b and 5 (Hspa1b and Hspa5), protein disulfide isomerase family A members 4 and 6 (Pdia4 and Pdia6), and calreticulin (Calr). Expression levels of putative neuroprotective factors, klotho (Kl) and transthyretin (Ttr), are also elevated by CR throughout adulthood, although the global CR-specific expression profiles at young and older timepoints are highly divergent. At a previously unachieved resolution, our results demonstrate conserved activation of neuroprotective gene signatures and broad CR-suppression of age-dependent hippocampal CA1 region expression changes, indicating that CR functionally maintains a more youthful transcriptional state within hippocampal CA1 throughout aging. Hippocampal CA1 region mRNA profiles of younger- (5 months) and older-adult (15 months) mice on calorie-restricted (CR) and normal (AD) diets were generated by deep sequencing using Illumina HiSeq 2500.
2015-07-14 | E-GEOD-69952 | biostudies-arrayexpress
Project description:Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. While most information on these cells comes from in vitro studies in humans or in vivo studies in mice, little is known about monocytes under human disease conditions. We investigated the role of monocytes during sepsis and its resolution in humans. A transcriptomal and functional analysis of blood monocytes from patients during gram negative sepsis and at recovery was performed. Monocytes from sepsis patients showed upregulation of a large number of pro-inflammatory genes and cytokines/chemokines, consistent with an ongoing systemic inflammation. However, these cells showed impairment to ex vivo endotoxin (LPS) challenge, displaying a quantitative decrease in the number of LPS-inducible genes. Moreover, they downregulated the expression of several pro-inflammatory cytokine/chemokine genes, activation marker genes and transcription factors associated with monocyte/macrophage activation, upon ex vivo LPS stimulation. Functionally, they downregulated expression of inflammatory cytokines/chemokines and antigen presentation-related molecules and functions. In contrast, genes and functions related to phagocytosis, anti-microbial activity and tissue remodeling where remained unaffected or even enhanced . Collectively, our observations suggest a genetic and functional re-programming of these cells during human sepsis progression. Understanding the molecular mechanisms which regulate this re-programming will allow to devise strategies which could modulate the response of these cells and hence, disease progression. Blood monocytes from gram-negative sepsis patients during sepsis (Sepsis) and following their recovery (Recovery/Basal) as well as healthy donor (control) were isolated. Thereafter, these cells were treated ex vivo with or without LPS for 3h and analysed for transcriptomic study.
2014-05-14 | E-GEOD-46955 | biostudies-arrayexpress