Discriminating hormonal and sex chromosomal origins of sex differences in the septohippocampal circuit
区分隔海马回路中性别差异的激素和性染色体起源
基本信息
- 批准号:10389770
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-06 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffectiveAtlasesBeautyBehavioralBrainBrain regionCategoriesCell CommunicationCell modelCellsCognitive deficitsCommunitiesCorticotropin-Releasing HormoneCorticotropin-Releasing Hormone ReceptorsDiseaseDoseElementsEngineeringFemaleFour Core GenotypesGenesGenetic TranscriptionGenomicsGonadal HormonesGonadal structureHippocampus (Brain)HormonalHormonesImpairmentIndividualInferiorLibidoLinkLocationMagnetic Resonance ImagingMajor Depressive DisorderMedialMediatingMemoryMental DepressionMental disordersModelingMolecularMolecular AnalysisMood DisordersMusNeurogliaNeuronal DifferentiationNeuronsNeuropeptidesNeurosciencesOutcomeOvarian hormoneOvaryPaired-Associate LearningPathway interactionsPlayPloidiesPopulationPrecipitating FactorsRattusRegulationReportingReproductionResourcesRodent ModelRoleSex BiasSex ChromosomesSex DifferencesSex DifferentiationSocial supportSourceStressStressful EventStructureSymptomsTestingTestisWomanWorkYangbasebiological adaptation to stressbrain behaviorcell typedesignexperimental studygenotypic seximaging studyinsightmalemenmouse modelneuronal circuitrynovelprogramsresilienceseptohippocampalsexual dimorphismsingle-cell RNA sequencingspatial memorytheoriestool
项目摘要
PROJECT SUMMARY
Depression is sex biased not only in its rate, but also in precipitating factors and symptoms. For example,
women report a lack of social support, while men report stressful events as major contributors to depression.
Understanding the mechanisms that drive these sex differences involves isolating different molecular pathways
to identify the causes of divergent vulnerability and symptoms. Sex chromosomes (XX vs. XY) are a major
source of sex bias within any type of cell, but this category has been difficult to discriminate from gonadal
hormone effects that often co-vary with sex chromosome complement. Sex chromosome effects on disease
mechanisms can now be studied in newly engineered XX and XY rats that have the same type of gonad, either
with testes or with ovaries. In these Four Core Genotypes (FCG)-like rats, sex chromosome effects (XX vs. XY)
will be discriminated from gonadal hormone effects that differentiate the brains of gonadal males from those of
gonadal females. Here we focus on the origins of sex differences in the septohippocampal circuit, which
consists of the medial septum (MS) projection to the hippocampus. The septohippocampal circuit mediates
memory and its dysregulation is implicated in the cognitive deficits that characterize several disorders,
including depression. We previously found that administering the stress neuropeptide, corticotropin releasing
factor (CRF), into the MS impairs hippocampal-dependent object location memory in rats. However, males are
more sensitive to this effect than females. Ovarian hormones do not confer resilience in females, and structural
sex differences in the MS of mice are causes by sex chromosome effects (SCEs). We aim to discriminate
SCEs from gonadal hormone effects that cause sex differences in the septohippocampal circuit that mediates
cognitive deficits in major depression, and to understand where these factors act and what molecular
mechanisms they control. Aim 1 will use the FCG-like rats to test the hypothesis that sex differences in CRF
receptor regulation of MS-mediated memory are due to SCEs. The beauty of the design is that even if the
hypothesis is not supported, the origin of sex difference in this stress effect on memory will be identified. To
determine molecular mechanisms that can underlie sex differences in the septohippocampal circuit, Aim 2 will
use single-cell RNAseq to differentiate neuronal and glial subtypes of the MS and hippocampus, identify sex
differences therein, and determine whether sex differences are caused by SCEs or gonadal hormones. Cell-
cell communications will be modeled within and between cell types and brain regions to retrieve cellular circuits
affected by SCEs vs. gonadal hormones. Collectively, the integration of sophisticated behavioral and molecular
analysis will uncover cell-specific mechanisms by which diverse sex-biasing factors influence stress regulation
of memory. These results will have important implications for developing novel treatments for depression that
work well in males and females.
项目摘要
抑郁症不仅在发病率上有性别偏见,而且在诱发因素和症状上也有性别偏见。比如说,
妇女报告说,缺乏社会支持,而男子报告说,压力事件是抑郁症的主要原因。
要了解驱动这些性别差异的机制,需要分离不同的分子途径
找出不同脆弱性和症状的原因。性染色体(XX与XY)是一个主要的
任何类型的细胞内的性别偏见的来源,但这一类一直难以区分从性腺
激素的影响,往往与性染色体互补变化。性染色体对疾病的影响
现在可以在具有相同类型性腺的新工程XX和XY大鼠中研究其机制,
有睾丸或卵巢。在这些四个核心基因型(FCG)样大鼠中,性染色体效应(XX与XY)
将被区别于性腺激素的影响,区分性腺男性的大脑从那些
雌性生殖腺在这里,我们集中在隔海马电路的性别差异的起源,
由内侧隔(MS)到海马的投射组成。隔海马回路介导
记忆及其失调与表征几种疾病的认知缺陷有关,
包括抑郁症我们之前发现,给予应激神经肽,促肾上腺皮质激素释放
因子(CRF)进入MS损害大鼠的海马依赖性物体位置记忆。然而,男性
对这种影响比女性更敏感。卵巢激素并不赋予女性弹性,
小鼠MS的性别差异是由性染色体效应(SCE)引起的。我们的目标是区别对待
性腺激素效应引起的SCE导致介导
认知缺陷,并了解这些因素在哪里起作用,
他们控制的机制。目的1:利用FCG样大鼠来验证CRF性别差异的假说
MS介导的记忆的受体调节是由于SCE。设计的美妙之处在于,即使
假设不被支持,这种应激对记忆影响的性别差异的起源将被确定。到
确定分子机制,可以在隔海马电路性别差异的基础上,目标2将
使用单细胞RNAseq来区分MS和海马的神经元和神经胶质亚型,
其中的差异,并确定性别差异是由SCE或性腺激素引起的。细胞-
将在细胞类型和大脑区域内以及细胞类型和大脑区域之间建立细胞通信模型,以检索细胞回路
受SCE和性腺激素的影响。总的来说,复杂的行为和分子的整合
分析将揭示不同性别偏向因素影响压力调节的细胞特异性机制
记忆。这些结果将对开发新的抑郁症治疗方法具有重要意义,
在男性和女性中效果良好。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Debra A Bangasser其他文献
Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats
κ-阿片受体拮抗剂在 Wistar Kyoto 大鼠中的抗抑郁样作用
- DOI:
10.1038/npp.2009.183 - 发表时间:
2009-11-18 - 期刊:
- 影响因子:7.100
- 作者:
Gregory V Carr;Debra A Bangasser;Thelma Bethea;Matthew Young;Rita J Valentino;Irwin Lucki - 通讯作者:
Irwin Lucki
Debra A Bangasser的其他文献
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{{ truncateString('Debra A Bangasser', 18)}}的其他基金
Determining the effect of early resource scarcity on adolescent addiction-related behavior and cell-type specific transcription
确定早期资源稀缺对青少年成瘾相关行为和细胞类型特异性转录的影响
- 批准号:
10825012 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Sex differences in stress inoculation of addiction-like phenotypes
成瘾样表型应激接种的性别差异
- 批准号:
10757580 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Cell-specific epigenetic and transcriptomic signatures of impulsivity and its regulation by stress in the nucleus accumbens
冲动的细胞特异性表观遗传和转录组特征及其受伏隔核应激的调节
- 批准号:
10592511 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Delineating the epigenetic and neural mechanisms by which early life scarcity alters motivated behavior
描述早期生命匮乏改变动机行为的表观遗传和神经机制
- 批准号:
10508379 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discriminating hormonal and sex chromosomal origins of sex differences in the septohippocampal circuit
区分隔海马回路中性别差异的激素和性染色体起源
- 批准号:
10618821 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Delineating the epigenetic and neural mechanisms by which early life scarcity alters motivated behavior
描述早期生命匮乏改变动机行为的表观遗传和神经机制
- 批准号:
10631152 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discriminating hormonal and sex chromosomal origins of sex differences in the septohippocampal circuit
区分隔海马回路中性别差异的激素和性染色体起源
- 批准号:
10757579 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Sex differences in stress inoculation of addiction-like phenotypes
成瘾样表型应激接种的性别差异
- 批准号:
10213001 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Sex differences in stress inoculation of addiction-like phenotypes
成瘾样表型应激接种的性别差异
- 批准号:
10392452 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Sex differences in stress inoculation of addiction-like phenotypes
成瘾样表型应激接种的性别差异
- 批准号:
10609158 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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