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: 10389770
• 负责人: Debra A Bangasser
• 金额: --
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10389770
• 关键词: Affect; Affective; Atlases; Beauty; Behavioral; Brain; Brain region; Categories; Cell Communication; Cell model; Cells; Cognitive deficits; Communities; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Disease; Dose; Elements; Engineering; Female; Four Core Genotypes; Genes; Genetic Transcription; Genomics; Gonadal Hormones; Gonadal structure; Hippocampus (Brain); Hormonal; Hormones; Impairment; Individual; Inferior; Libido; Link; Location; Magnetic Resonance Imaging; Major Depressive Disorder; Medial; Mediating; Memory; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Analysis; Mood Disorders; Mus; Neuroglia; Neuronal Differentiation; Neurons; Neuropeptides; Neurosciences; Outcome; Ovarian hormone; Ovary; Paired-Associate Learning; Pathway interactions; Play; Ploidies; Population; Precipitating Factors; Rattus; Regulation; Reporting; Reproduction; Resources; Rodent Model; Role; Sex Bias; Sex Chromosomes; Sex Differences; Sex Differentiation; Social support; Source; Stress; Stressful Event; Structure; Symptoms; Testing; Testis; Woman; Work; Yang; base; biological adaptation to stress; brain behavior; cell type; design; experimental study; genotypic sex; imaging study; insight; male; men; mouse model; neuronal circuitry; novel; programs; resilience; septohippocampal; sexual dimorphism; single-cell RNA sequencing; spatial memory; theories; tool

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.

项目总结 抑郁症不仅在患病率上存在性别偏见，而且在诱发因素和症状方面也存在性别偏见。例如, 女性报告缺乏社会支持，而男性报告压力事件是导致抑郁的主要原因。 要了解导致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对XY)是一个主要的 任何类型细胞内性别偏见的来源，但这一类别一直很难与性腺区分 荷尔蒙效应通常与性染色体互补共同变化。性染色体对疾病的影响 现在可以在具有相同性腺类型的新工程XX和XY大鼠身上研究机制 有睾丸或卵巢。在这四种核心基因(FCG)样鼠中，性染色体效应(XX与XY) 将与性腺激素效应相区别，性腺激素效应将性腺男性的大脑与 性腺雌性。在这里，我们关注隔区-海马区回路中性别差异的起源，这是 由内侧隔(MS)向海马体的投射组成。隔-海马区回路调节 记忆及其失调与认知缺陷有关，认知缺陷是几种障碍的特征， 包括抑郁症。我们先前发现，给予应激神经肽，促肾上腺皮质激素释放 因子(CRF)进入MS可损害大鼠的海马区依赖的物体位置记忆。然而，男性是 对这种影响比女性更敏感。卵巢激素不会增强女性的弹性，而且结构性 小鼠多发性硬化的性别差异是由性染色体效应(SCES)引起的。我们的目标是歧视 性腺激素对SCES的影响导致隔区-海马区环路中的性别差异 严重抑郁症的认知缺陷，并了解这些因素在哪里起作用，以及哪些分子 它们控制的机制。目标1将使用类似FCG的大鼠来检验CRF性别差异的假设 受体对MS介导的记忆的调节是由于SCES。设计的美妙之处在于，即使 假设不被支持，性别差异在这种应激对记忆的影响中的起源将被识别出来。至 确定隔区-海马区环路性别差异的分子机制，目标2将 使用单细胞RNAseq区分MS和海马区的神经元和神经胶质亚型，鉴定性别 其中的差异，并确定性别差异是由SCES还是性腺激素引起的。牢房- 细胞通信将在细胞类型和大脑区域内和之间建模，以检索细胞电路 受SCES和性腺激素的影响。总体而言，复杂的行为和分子的整合 分析将揭示不同性别偏见因素影响压力调节的特定细胞机制 对记忆的记忆。这些结果将对开发治疗抑郁症的新疗法具有重要意义 在男性和女性身上都能很好地发挥作用。