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Project description:While the exact mechanisms for a sex bias in the development of neuropsychiatric disorders remain only vaguely understood, there is increasing evidence that an early life immune activation contributes to the disease pathogenesis. By administering the double stranded RNA analogue polyriboinosinic:polyribocytidilic acid (poly(I:C)) we mimicked an early viral infection in neonatal female and male mice. As a consequence, male adolescent mice presented long-term behavioral deficits including impaired social behavior and defective spatial working and recognition memory. Notably, behavioral changes were completely absent in female mice. In male mice, poly(I:C) led to an increased number of infiltrating T cells in the brain parenchyma, an enhanced interferon-g (IFNg) signaling, and an epigenetic reprogramming of microglial cells. These reprogrammed microglial cells showed increased phagocytic activity, which resulted in the excessive loss of dendritic spines in male mice only. We corroborated these findings in a murine neonatal infection of mice with murine cytomegalovirus (MCMV) and found sustained aversive behavioral effects and a lower number of excitatory synapses within the hippocampal brain region in young adult male, but not in female mice. Together, our results highlight the crucial role of the early postnatal period for normal brain development: identical immune stimulation during this period led to distinct sex-specific long-term behavioral deficits, indicating that sex is potentially an underappreciated factor when investigating neuropsychiatric disorders.
2023-03-24 | GSE147443 | GEO
Project description:Poly(I:C)-induced long-term behavioral deficits are accompanied by epigenetic changes in microglia of male mice
| PRJNA614639 | ENA
Project description:Poly(I:C)-induced long-term behavioral deficits are accompanied by epigenetic changes in microglia of male mice (ChIP-seq)
| PRJNA614640 | ENA
Project description:BackgroundMaternal hormones, like testosterone, can strongly influence developing offspring, even generating long-term organizational effects on adult behavior; yet, the mechanisms facilitating these effects are still unclear. Here, we experimentally elevated prenatal testosterone in the eggs of zebra finches (Taeniopygia guttata) and measured male aggression in adulthood along with patterns of neural gene expression (RNA-seq) and DNA methylation (MethylC-Seq) in two socially relevant brain regions (hypothalamus and nucleus taenia of the amygdala). We used enrichment analyses and protein-protein interaction networks to find candidate processes and hub genes potentially affected by the treatment. We additionally identified differentially expressed genes that contained differentially methylated regions.ResultsWe found that males from testosterone-injected eggs displayed more aggressive behaviors compared to males from control eggs. Hundreds of genes were differentially expressed, particularly in the hypothalamus, including potential aggression-related hub genes (e.g., brain derived neurotrophic factor). There were also enriched processes with well-established links to aggressive phenotypes (e.g., somatostatin and glutamate signaling). Furthermore, several highly connected genes identified in protein-protein interaction networks also showed differential methylation, including adenylate cyclase 2 and proprotein convertase 2.ConclusionsThese results highlight genes and processes that may play an important role in mediating the effects of prenatal testosterone on long-term phenotypic outcomes, thereby providing insights into the molecular mechanisms that facilitate hormone-mediated maternal effects.
| S-EPMC7937265 | biostudies-literature
Project description:Moderate traumatic brain injury (TBI) in children often happen when there's a sudden blow to the frontal bone, end with long unconscious which can last for hours and progressive cognitive deficits. However, with regard to the influences of moderate TBI during children adulthood, injury-induced alterations of locomotive ability, long-term memory performance, and hippocampal electrophysiological firing changes have not yet been fully identified. In this study, lateral fluid percussion (LFP) method was used to fabricate moderate TBI in motor and somatosensory cortex of the 6-weeks-old mice. The motor function, learning and memory function, extracellular CA1 neural spikes were assessed during acute and subacute phase. Moreover, histopathology was performed on day post injury (DPI) 16 to evaluate the effect of TBI on tissue and cell morphological changes in cortical and hippocampal CA1 subregions. After moderate LFP injury, the 6-weeks-old mice showed severe motor deficits at the early stage in acute phase but gradually recovered later during adulthood. At the time points in acute and subacute phase after TBI, novel object recognition (NOR) ability and spatial memory functions were consistently impaired in TBI mice; hippocampal firing frequency and burst probability were hampered. Analysis of the altered burst firing shows a clear hippocampal theta rhythm drop. These electrophysiological impacts were associated with substantially lowered NOR preference as compared to the sham group during adulthood. These results suggest that moderate TBI introduced at motorsenory cortex in 6-weeks-old mice causes obvious motor and cognitive deficits during their adulthood. While the locomotive ability progressively recovers, the cognitive deficits persisted while the mice mature as adult mice. The cognitive deficits may be attributed to the general suppressing of whole neural network, which could be labeled by marked reduction of excitability in hippocampal CA1 subregion.
| S-EPMC5308857 | biostudies-literature
Project description:Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes, and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. As systemically administering interleukin-1 β (IL-1β) to neonatal mice recapitulates many of the brain abnormalities seen in premature babies including developmental delays, the goal of this study was to determine whether IL-1-mediated neuroinflammation would affect hippocampal growth during development to produce cognitive and behavioral abnormalities. For these studies, 10 ng/g IL-1β was administered twice daily to Swiss Webster mice during the first 5 days of life, which increased hippocampal levels of IL-1α and acutely reduced the proliferation of Tbr2+ neural progenitors in the DG. In vitro, both IL-1α and IL-1β produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transit amplifying progenitor cell cohort. By contrast, IL-1β treatment increased neural stem cell frequency. Upon terminating IL-1β treatment, the progenitor cell pool regained its proliferative capacity. An earlier study that used this in vivo model of perinatal inflammation showed that mice that received IL-1β as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered, mice were tested in tasks designed to assess exploratory and anxiety behavior as well as working and spatial memory. Interestingly, mice that received IL-1β as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. Additionally, these mice did not display working memory deficits in adulthood, but they did display deficits in long-term spatial memory. Altogether, these data support the view that perinatal inflammation negatively affects the developing hippocampus by producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely-born sick infants.
| S-EPMC8474668 | biostudies-literature
Project description:Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are increased peripheral pro-inflammatory cytokines, subsequent induction of indoleamine-2,3-dioxygenase (IDO) and activation of the kynurenine pathway. In the MRL/MpJ-Faslpr (MRL/lpr) murine model of lupus, depression-like behavior and cognitive dysfunction is evident before significant levels of autoantibody titers and nephritis are present. We examined the behavioral profile of MRL/lpr mice and their congenic controls, a comprehensive plasma cytokine and chemokine profile, and brain levels of serotonin and kynurenine pathway metabolites. Consistent with previous studies, MRL/lpr mice had increased depression-like behavior and visuospatial memory impairment. Plasma levels of different inflammatory molecules (Haptoglobin, interleukin 10 (IL-10), interferon γ-inducible protein 10 (IP-10/CXCL10), lymphotactin, macrophage inhibitory protein 3β (MIP-3β/CCL19), monocyte chemotactic protein 1, 3 and 5 (MCP-1/CCL2, MCP-3/CCL7, MCP-5/CCL12), vascular cell adhesion molecule 1 (VCAM-1), lymphotactin and interferon γ (IFN-γ)) were increased in MRL/lpr mice. In cortex and hippocampus, MRL/lpr mice had increased levels of kynurenine pathway metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxynthranilic acid and quinolinic acid). Therefore, our study suggests that increased cytokine expression may be critical in the regulation subtle aspects of brain function in NP-SLE via induction of IDO and tryptophan/kynurenine metabolism.
| S-EPMC4519892 | biostudies-literature
Project description:BACKGROUND:Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer's disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation. METHODS:Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2 -/- ) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2 -/- mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF. RESULTS:DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2 -/- mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation. CONCLUSIONS:DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.
| S-EPMC5877396 | biostudies-literature
Project description:Epidemiological studies suggest exposures to anesthetic agents and/or sedative drugs (AASDs) in children under three years old, or pregnant women during the third trimester, may adversely affect brain development. Evidence suggests lengthy or repeated AASD exposures are associated with increased risk of neurobehavioral deficits. Animal models have been valuable in determining the type of acute damage in the developing brain induced by AASD exposures, as well as in elucidating long-term functional consequences. Few studies examining very early exposure to AASDs suggest this may be a critical period for inducing long-term functional consequences, but the impact of repeated exposures at these ages has not yet been assessed. To address this, we exposed mouse pups to a prototypical general anesthetic, isoflurane (ISO, 1.5% for 3 hr), at three early postnatal ages (P3, P5 and P7). We quantified the acute neuroapoptotic response to a single versus repeated exposure, and found age- and brain region-specific effects. We also found that repeated early exposures to ISO induced subtle, sex-specific disruptions to activity levels, motor coordination, anxiety-related behavior and social preference. Our findings provide evidence that repeated ISO exposures may induce behavioral disturbances that are subtle in nature following early repeated exposures to a single AASD.
| S-EPMC6391407 | biostudies-literature
Project description:Transcriptomic data for 48 and 120 hpf zebrafish embryos developmentally exposed to 3.5 GHz of radiofrequency radiation.
2022-04-20 | GSE197627 | GEO