Discriminating hormonal and sex chromosomal origins of sex differences in the septohippocampal circuit

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 激素的影响通常与性染色体的互补性共同变化。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， 包括抑郁症我们以前发现，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。该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。

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.