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
• 负责人: Debra A Bangasser
• 金额: $ 24.8万
• 依托单位: GEORGIA STATE UNIVERSITY
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10757579
• 关键词: Discriminating; hormonal; sex; chromosomal; origins

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 抑郁症不仅偏向于其速度，而且在降水因素和症状上也偏见。例如， 妇女报告缺乏社会支持，而男性则报告了压力大的事件是抑郁症的主要贡献者。 了解驱动这些性别差异的机制涉及隔离不同的分子途径 确定脆弱性和症状不同的原因。性染色体（XX与XY）是主要的 任何类型的细胞内的性偏见来源，但是此类别很难与性腺区分开 激素作用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的性腺的新工程XX和XY大鼠中研究机制 睾丸或卵巢。在这四种核心基因型（FCG）类似大鼠中，性别染色体效应（xx vs. xy） 将与性腺激素作用区分开来，使性腺雄性的大脑与 性腺女性。在这里，我们关注Septohappocampal电路中性别差异的起源， 由对海马的内侧隔膜（MS）投影组成。 septohappocampal电路介导 记忆及其失调与表征多种疾病的认知缺陷有关， 包括抑郁症。我们先前发现，施用应力神经肽，皮质激素释放 因子（CRF）进入MS，会损害大鼠海马依赖对象位置存储器。但是，男性是 对这种影响比女性更敏感。卵巢激素不赋予女性和结构性的弹性 小鼠MS的性别差异是性别染色体效应（SCE）的原因。我们旨在区分 性腺激素效应的SCE在介导的Septohappocampal电路中引起性别差异 严重抑郁症的认知缺陷，并了解这些因素在哪里起作用和分子 他们控制的机制。 AIM 1将使用类似FCG的大鼠来检验CRF性别差异的假设 MS介导的记忆的受体调节是由于SCES引起的。设计的美丽是，即使 不支持假设，将确定这种压力对记忆力影响的性别差异的起源。到 确定可以在septohampampal电路中的性别差异基础的分子机制，AIM 2 Will 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 其中的差异，并确定性别差异是由SCES还是由性腺激素引起的。细胞- 细胞通信将在细胞类型和大脑区域之间建模，以检索细胞电路 受SCES与性腺激素的影响。总体而言，复杂的行为和分子的整合 分析将揭示细胞特异性机制，通过这种机制，各种性别偏见因素会影响压力调节 记忆。这些结果将对为抑郁症开发新的疗法具有重要意义 在男性和女性中工作得很好。