Molecular Targets of Aging-Triggered Memory Decline in a Stress-Reactive Rat Strain
应激反应性大鼠品系中衰老引发的记忆衰退的分子靶点
基本信息
- 批准号:9895135
- 负责人:
- 金额:$ 24.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAge-MonthsAge-associated memory impairmentAgingAlzheimer&aposs DiseaseAnimal ModelAnimalsAntioxidantsAttenuatedAutopsyBehaviorBehavioralBrainBrain regionBreedingCognitiveDataDementiaEpigenetic ProcessExhibitsExposure toFemaleGenderGene ExpressionGenerationsGenesGeneticGenetic ModelsGenomeHippocampus (Brain)HousingHumanImpaired cognitionInbred StrainInbred WKY RatsIndividualKnowledgeLeadLearningLifeMajor Depressive DisorderMeasuresMemoryMemory LossMental DepressionMental disordersMethylationMolecularMolecular TargetPhenotypePhysiologicalPopulationPrevalenceProteinsRat StrainsRattusReactive depressionResearch PersonnelRestReverse Transcriptase Polymerase Chain ReactionRiskRisk FactorsRoleSex DifferencesSingle Nucleotide PolymorphismStressTestingTissuesTranscriptTranslatingVariantWomanage relatedbasebiological adaptation to stressbisulfite sequencingcatalaseconditioned feardepression modeldepressive symptomsdifferential expressionenvironmental enrichment for laboratory animalsfear memoryforced swim testgenome analysisgenome sequencinghuman old age (65+)malemenmethylomemiddle agemodifiable riskmorris water mazeneuropsychiatric disordernew therapeutic targetnovelobject recognitionpredictive modelingprematurereference genomesexstress reactivitystress related disorderstressortraittranscriptometranscriptome sequencingtranscriptomicswhole genome
项目摘要
PROJECT SUMMARY
In addition to aging, major risk factors for cognitive decline include female gender, stress, and stress-related
disorders such as depression. Both major depressive disorder (MDD) and dementia are more common in
women than in men. In this proposal, we aim to investigate the sex and strain-specific epigenetic changes
that parallel cognitive decline in an animal model of increased stress-reactivity and depression-like traits.
Through selective and long-term full-sib breeding, we obtained two inbred strains from the parental Wistar
Kyoto (WKY) rat strain: the WKY More Immobile (WMI), and its isogenic control, the WKY Less Immobile
(WLI). Compared to WLIs, both male and female WMIs show consistently greater despair-like behavior in the
forced swim test. Hippocampus-dependent contextual fear memory did not differ between young WLI and
WMI males and females. However, by 12 months of age (middle-age), female WMIs showed a significant
decline in fear memory compared to young WMI females, while no decrease in fear memory was observed in
female WLIs and male WLIs and WMIs. We propose to test the hypothesis that age-induced strain-specific
changes in the hippocampal methylome and transcriptome of female WMIs are associated with the decline in
their fear memory.
Aim 1 will evaluate the sex-specific strain differences between young (6 months) and middle-aged (12
months) WMI and WLI in the contextual fear conditioning, novel object recognition and Morris water maze
paradigms. Additionally, WMI and WLI males and females will be maintained from 6 to 12 months of age in
an enriched environment (EE), that is known to enhance memory, and at 12 months of age tested in the same
learning/memory tests. Aim 2 will identify differentially expressed genes (DEG) within differentially methylated
regions using integrative analysis of Reduced Representation Bisulfite Sequencing and RNA-seq between
additional groups of young and middle-aged WMI and WLI males and females after being exposed to the
contextual fear conditioning test. Comparisons will be prioritized to those DEGs that differ exclusively between
WMI females of 6- and 12-months of age. The WMI and WLI genome have been sequenced and will serve
as the reference genomes for these analyses. Expression of DEGs within differentially methylated regions
will be measured by quantitative RT-PCR in the hippocampus of young and middle-aged male and female
WMIs and WLIs with and without enriched environment housing from 6 to 12 months of age (Aim 1) to identify
changes induced by age and EE. Candidate DEGs will also be measured in the hippocampi of all animals
from Aim 2, when expression data of DEGs will be associated with contextual fear memory in the same
animals. Prediction models for memory will be built using the obtained and confirmed DEGs and methylation
data.
项目总结
除了年龄增长,认知能力下降的主要风险因素还包括女性、压力和压力相关因素。
精神障碍,如抑郁症。严重抑郁障碍(MDD)和痴呆症在
女性多于男性。在这项提案中,我们的目标是研究性别和品系特异性的表观遗传学变化。
在压力反应性增强和类似抑郁的特征的动物模型中,认知能力也出现了类似的下降。
通过长期的全同胞选育,我们从亲本Wistar中获得了两个自交系
京都(WKY)大鼠品系:WKY多不动(WMI)及其同源对照WKY少不动
(WLI)。与WLI相比,男性WMI和女性WMI在
强迫游泳试验。依赖海马体的情景恐惧记忆在年轻WLI和WLI之间没有差异
WMI男性和女性。然而,在12个月大的时候(中年),女性的腰围指数显示出显著的
与年轻的WMI女性相比,恐惧记忆有所下降,而
女性WLI和男性WLI和WMI。我们建议检验年龄诱导的特定品系的假设
女性WMI海马区甲基组和转录组的变化与脑功能减退有关
他们的恐惧记忆。
目标1将评估年轻人(6个月)和中年人(12个月)之间的性别差异
WMI和WLI在情境恐惧条件反射、新物体识别和Morris水迷宫中的作用
范例。此外,WMI和WLI雄性和雌性将维持6至12个月的年龄在
一个丰富的环境(EE),已知可以增强记忆,并在12个月龄时在相同的环境中进行测试
学习/记忆测试。目标2将鉴定差异甲基化的差异表达基因(DEG
利用亚硫酸盐还原表示测序和RNA-SEQ之间的区域综合分析
另外一组中青年WMI和WLI男性和女性在暴露于
情境恐惧条件反射测验。比较将优先考虑仅在以下各项之间存在差异的DEG
6个月和12个月大的WMI雌性。WMI和WLI基因组已经测序,将提供
作为这些分析的参考基因组。DEGS在差异甲基化区域的表达
将用定量RT-PCR方法在青年和中年男性和女性的海马区测定
6至12个月龄的WMI和WLI,有无丰富的环境住房(目标1)以确定
年龄和EE引起的变化。候选DEGS也将在所有动物的海马体中进行测量
从目标2开始,当DEG的表情数据将与同一环境中的恐惧记忆相关联时
动物。将使用获得和确认的DEGS和甲基化来建立记忆的预测模型
数据。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Wistar Kyoto Rat: A Model of Depression Traits.
- DOI:10.2174/1570159x21666221129120902
- 发表时间:2023
- 期刊:
- 影响因子:5.3
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Eva E Redei其他文献
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{{ truncateString('Eva E Redei', 18)}}的其他基金
Epigenetic Consequences of Prenatal Alcohol Exposure
产前酒精暴露的表观遗传后果
- 批准号:
7737620 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Prenatal alcohol: Hormone-regulated genes and behavior
产前酒精:激素调节的基因和行为
- 批准号:
7856231 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Epigenetic Consequences of Prenatal Alcohol Exposure
产前酒精暴露的表观遗传后果
- 批准号:
8099745 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Epigenetic Consequences of Prenatal Alcohol Exposure
产前酒精暴露的表观遗传后果
- 批准号:
8299081 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Epigenetic Consequences of Prenatal Alcohol Exposure
产前酒精暴露的表观遗传后果
- 批准号:
7890535 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Epigenetic Consequences of Prenatal Alcohol Exposure
产前酒精暴露的表观遗传后果
- 批准号:
8497549 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Epigenetic Consequences of Prenatal Alcohol Exposure
产前酒精暴露的表观遗传后果
- 批准号:
8901348 - 财政年份:2009
- 资助金额:
$ 24.89万 - 项目类别:
Molecular markers of chronic stress vulnerability/resilience
慢性应激脆弱性/恢复力的分子标记
- 批准号:
7540479 - 财政年份:2006
- 资助金额:
$ 24.89万 - 项目类别:
Molecular markers of chronic stress vulnerability/resilience
慢性应激脆弱性/恢复力的分子标记
- 批准号:
7213600 - 财政年份:2006
- 资助金额:
$ 24.89万 - 项目类别: