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.

项目概要 抑郁症不仅在发病率上存在性别偏见，而且在诱发因素和症状上也存在性别偏见。例如， 女性表示缺乏社会支持，而男性则表示压力事件是导致抑郁的主要原因。 了解驱动这些性别差异的机制涉及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）是主要的 任何类型细胞内性别偏见的来源，但这一类别很难与性腺区分开来 激素效应通常与性染色体补体共同变化。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 大鼠中研究机制 与睾丸或卵巢。在这些四种核心基因型 (FCG) 样大鼠中，性染色体效应（XX 与 XY） 会因性腺激素的影响而被区别对待，这种影响将性腺男性的大脑与男性的大脑区分开来。 性腺女性。在这里，我们重点关注隔海马环路性别差异的起源， 由内侧隔膜（MS）投射到海马体组成。隔海马环路介导 记忆及其失调与认知缺陷有关，而认知缺陷是多种疾病的特征， 包括抑郁症。我们之前发现，施用应激神经肽，会释放促肾上腺皮质激素 MS 中的因子（CRF）会损害大鼠海马依赖性物体位置记忆。然而，男性是 与女性相比，女性对这种影响更为敏感。卵巢激素不会赋予女性弹性，结构性的 小鼠 MS 的性别差异是由性染色体效应 (SCE) 引起的。我们的目标是歧视 来自性腺激素影响的 SCE，导致介导的隔海马回路中的性别差异 重度抑郁症的认知缺陷，并了解这些因素的作用以及分子机制 他们控制的机制。目标 1 将使用 FCG 样大鼠来检验 CRF 性别差异的假设 MS 介导的记忆的受体调节是由 SCE 引起的。设计之美在于，即使 如果假设不被支持，那么压力对记忆的影响中性别差异的根源将被确定。到 确定导致隔海马环路性别差异的分子机制，目标 2 将 使用单细胞 RNAseq 区分 MS 和海马的神经元和神经胶质亚型，识别性别 分析其中的差异，并确定性别差异是由 SCE 还是性腺激素引起。细胞- 细胞通信将在细胞类型和大脑区域内部和之间进行建模，以检索细胞回路 受 SCE 与性腺激素的影响。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见因素影响压力调节的细胞特异性机制 的记忆。这些结果将对开发治疗抑郁症的新疗法产生重要影响 对男性和女性都有效。