Molecular and spatial mapping of hypothalamic cell-types using the Xenium analyzer

使用 Xenium 分析仪绘制下丘脑细胞类型的分子和空间图谱

基本信息

批准号：
10852612
负责人：
Beau Alward
金额：
$ 25万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10852612
关键词：
AR gene Address Aggressive behavior Anatomy Androgen Receptor Androgens Animals Aromatase Atlases Bar Codes Behavior Control Behavioral Brain Brain region Candidate Disease Gene Cell physiology Cells Censuses Cichlids Complex Cues Data Set ENG gene Equipment Estradiol Estrogen Receptors Evolution Exhibits Female Formalin Foundations Freezing Funding Future Gene Conversion Gene Expression Gene Expression Profile Gene Expression Profiling Generations Genes Genetic Genetic Markers Genomics Glucocorticoid Receptor Goals Human Hypothalamic structure In Situ Knowledge Label Laboratories Link Location Maps Molecular Molecular Profiling Mus Neuronal Plasticity Neurophysiology - biologic function Organism Partner in relationship Physiological Population Preoptic Areas Process Progesterone Receptors Research Resolution Role Site Social Behavior Social Controls Social Environment Social Hierarchy Social Interaction Steroids Subcellular Anatomy System Testosterone Tissues Vertebrates Work behavioral response behavioral study cell type cost effectiveness design genetic signature hormonal signals infancy insight interest male mating behavior mind control neuroregulation novel programs response single-cell RNA sequencing social social influence spatial relationship steroid hormone teleost transcriptome whole genome

项目摘要

PROJECT SUMMARY Steroid hormones in humans and other animals coordinate physiological and behavioral processes underlying optimal responses to the social environment. The brain is a major site of steroid hormone action; however, our knowledge of the role of steroid hormones in regulating gene expression and neuroplasticity in the brain is in its infancy. My research program aims to uncover the connections between steroid hormones, gene expression in the brain, and specific cellular functions using Astatotilapia burtoni, a cichlid fish that exhibits sophisticated social hierarchies. In the wild as in the laboratory, male A. burtoni stratify along a social hierarchy where dominant males possess bright coloration, aggressively defend a territory, and mate with females, while non- dominant males do not. Female A. burtoni do not form a social hierarchy but behave aggressively towards one another for mating opportunities. Social rank is in flux, as dominant and non-dominant males can change their status depending on the social milieu. These complex social interactions are tightly linked to levels of a class of steroid hormones called androgens. My research program leverages the social dynamics of A. burtoni in the laboratory to discover the role of androgens in controlling genes in the brain and neuroplasticity. In our ongoing work, we have generated a cell-type specific molecular atlas of the A. burtoni hypothalamus using single-cell RNA-sequencing (scRNAseq). The hypothalamus is a conserved brain region that coordinates adaptive social behaviors across vertebrates. While scRNAseq provides cell-type resolution of specific gene expression patterns, it does not tell you where the specific cells are anatomically within the region of interest. The current proposal aims to address this issue using the 10X Genomics Xenium in situ analyzer, an end-to-end gene expression analysis platform that can label hundreds of genes simultaneously in fresh-frozen or formalin-fixed, sectioned tissue. Using the Xenium will allow for the spatial resolution of the distinct cell-types we have identified in our current scRNAseq dataset. We will combine genetic markers of all cell-types with candidate genes such as distinct androgen receptor (AR) genes present in our Xenium analysis, revealing precisely which cells and where are AR+, providing a precise road-map for testable hypotheses related to the molecular and cellular control of social behavior. Our hypothalamic spatial transcriptome will be compared to the currently only available hypothalamic spatial transcriptome in mice to reveal novel insights into the genetic signatures of AR+ cell types and other cell populations in two species used heavily in social behavior studies. With the generation of a molecular and spatial map of the A. burtoni hypothalamus, we will be able to address fundamental questions regarding the molecular and neural control of the brain and social behavior. Indeed, these questions may connect naturally to those on the control of social behavior in other species such as humans and how social systems emerge throughout evolution.

项目摘要人类和其他动物的类固醇激素协调生理和行为过程对社会环境的最佳反应。大脑是类固醇激素作用的主要部位。但是，我们的了解类固醇激素在调节大脑中基因表达和神经可塑性中的作用它的婴儿期。我的研究计划旨在发现类固醇激素，基因表达之间的联系在大脑中，使用Astatotilapia burtoni的特定细胞功能，这是一种表现出精致的酸毛鱼。社会等级。在野外，就像在实验室一样，雄性A. Burtoni沿着社会等级制度分层占主导地位的男性具有鲜明的色彩，积极地捍卫领土，并与女性交配，而不是主要的男性没有。雌性A. Burtoni不是形成社会等级的，而是对一个社会等级交配机会的另一个。社会等级处于不断变化的状态，因为占主导地位和非主导男性可以改变他们的地位取决于社会环境。这些复杂的社交互动与一类的水平紧密相关类固醇激素称为雄激素。我的研究计划利用A. Burtoni的社会动态实验室发现雄激素在控制脑和神经塑性中的基因中的作用。在我们正在进行的中工作，我们使用单细胞产生了burtoni下丘脑的细胞类型特异性分子图。 RNA-sequencing（SCRNASEQ）。下丘脑是一个保守的大脑区域，可协调适应性社会跨脊椎动物的行为。而SCRNASEQ提供了特定基因表达的细胞类型分辨率模式，它不会告诉您特定的细胞在解剖学上在感兴趣的区域内。电流提案旨在使用10倍基因组xenium situ Analyzer解决此问题，端到端基因表达分析平台可以同时标记数百个基因以新鲜固定或福尔马林固定的标记切片组织。使用Xenium将允许我们拥有的不同细胞类型的空间分辨率在我们当前的scrnaseq数据集中识别。我们将将所有细胞类型的遗传标记与候选者结合在一起我们的Xenium分析中存在的不同基因（例如不同的雄激素受体（AR）基因），揭示了精确的哪些细胞和AR+的位置，为与分子有关的可检验的假设提供了精确的路线图和对社会行为的蜂窝控制。我们的下丘脑空间转录组将被比较仅在小鼠中可用的下丘脑空间转录组来揭示对遗传特征的新见解在社会行为研究中，AR+细胞类型和其他细胞种群在社会行为研究中大量使用。与生成A. burtoni下丘脑的分子图和空间图，我们将能够解决关于大脑和社会行为的分子和神经控制的基本问题。的确，这些问题可能与控制其他物种（例如人类以及社会系统如何在整个演变中出现。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic dissection of steroid-hormone modulated social behavior: Novel paralogous genes are a boon for discovery

DOI：
10.1016/j.yhbeh.2022.105295
发表时间：
2022-12
期刊：
Hormones and Behavior
影响因子：
3.5
作者：
Beau A. Alward;Andrew P. Hoadley;Lillian R. Jackson;Mariana S. Lopez
通讯作者：
Beau A. Alward;Andrew P. Hoadley;Lillian R. Jackson;Mariana S. Lopez

Female cichlids attack and avoid-but will still mate with-androgen receptor mutant males that lack male-typical body coloration.

雌性丽鱼会攻击并避开缺乏雄性典型体色的雄激素受体突变雄性，但仍会与之交配。

DOI：
10.1101/2023.11.02.565323
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Howard,MeganR;Ramsaroop,MaxximusG;Hoadley,AndrewP;Jackson,LillianR;Lopez,MarianaS;Saenz,LaurenA;Alward,Beau
通讯作者：
Alward,Beau

Breaking through the bottleneck: Krogh's principle in behavioral neuroendocrinology and the potential of gene editing.