Mapping the human hypothalamic functional architecture underlying food intake control

绘制食物摄入控制背后的人类下丘脑功能结构

• 批准号: BB/S017593/1
• 负责人: Giles Yeo
• 金额: $ 79.65万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS017593%2F1
• 关键词: Mapping; human; hypothalamic; functional; architecture

Obesity is a growing public health problem. While our changing lifestyle and environment have undoubtedly driven this increase, there is a powerful genetic component that underlies the large variation in human body shape and size in this modern environment. Understanding the mechanisms controlling feeding behaviour that lead to this variability in body-weight will be important in informing any strategy to improve our health in this current food environment. While the preferred model in which to study food intake is clearly in humans, the fact that genetic studies point to a region in the brain called the hypothalamus as having a crucial role in modulating appetite has limited the mechanistic insights achievable through human research. The inaccessibility of the human hypothalamus has, to date, meant our understanding of brain circuits controlling food intake has emerged primarily from mouse studies. Now, an important collaboration with the Cambridge Brain Bank, is allowing us access to fresh human donor brain samples. This, coupled with recent developments in single-cell sequencing and in technologies allowing us to visualize single-molecules using fluorescence, provides us with a timely opportunity to map the functional architecture of the human hypothalamus, with a focus on appetitive behaviour. A functioning map requires two key elements; we first need to know the components of the map, and then we need to know where these components sit on the map, with respect to each other. Thus our two objectives are: A) using single-cell technologies, we will sequence 500,000 individual hypothalamic cells, in order to perform a molecular census of cell populations to identify components of the neuro-circuitry controlling food intake; B) using an approach called single-molecule fluorescent in-situ hybridization (smFISH), we will map the different components identified onto both mouse and human brains. We will examine the spatial expression of these genes in the human hypothalamus and compare this to the pattern seen in the mouse brain. Detailed mechanistic studies on the brain using modern genetic manipulation tools will, for obvious reasons, still require mouse models. Our rationale however, is that if a certain neuronal population is ONLY found in mice, then studying it makes little 'translatable' sense. It would be far better to focus finite resources on generating sophisticated mouse models once we can determine that a particular pathway or neuronal type actually exists in the human brain. Our goal of a comprehensive human hypothalamic atlas will be of utility to basic scientists and clinical researchers attempting to better understand the fundamental nature of energy balance regulation by the hypothalamus. This will hopefully allow us to manipulate these systems to improve the health of the population.

肥胖是日益增长的公共卫生问题。尽管我们不断变化的生活方式和环境无疑驱动了这一增长，但在这种现代环境中，有一个强大的遗传成分是人体形状和大小的巨大变化。了解控制喂养行为的机制，导致体重变异性对于在当前食品环境中改善我们的健康策略的任何策略都很重要。尽管在人类中显然是研究食物摄入量的首选模型，但遗传学研究表明大脑中一个称为下丘脑的区域在调节食欲中起着至关重要的作用，因此限制了通过人类研究获得的机械洞察力。迄今为止，人类下丘脑的无法获得的能力意味着我们对控制食物摄入的脑电路的理解主要来自小鼠研究。现在，与剑桥大脑银行进行的重要合作是使我们可以访问新鲜的人类供体脑样本。加上单细胞测序和技术的最新发展，使我们能够使用荧光可视化单分子，为我们提供了及时的机会，可以绘制人类下丘脑的功能性结构，重点是食用性行为。功能地图需要两个关键元素。我们首先需要了解地图的组件，然后我们需要知道这些组件相对于彼此而言位于地图上的位置。因此，我们的两个目标是：a）使用单细胞技术，我们将对500,000个单个下丘脑细胞进行序列，以进行细胞群体的分子普查，以鉴定控制食物摄入的神经循环的成分； b）使用一种称为单分子荧光内杂交（Smfish）的方法，我们将绘制在小鼠和人类大脑上识别的不同组件。我们将检查这些基因在人下丘脑中的空间表达，并将其与小鼠脑中看到的模式进行比较。出于明显的原因，使用现代基因操纵工具对大脑的详细机械研究仍然需要小鼠模型。但是，我们的理由是，如果仅在小鼠中发现某个神经元种群，那么研究它几乎没有“可翻译”的意义。一旦我们确定特定的途径或神经元类型实际上存在于人的大脑中，将有限资源集中在生成复杂的小鼠模型上。我们全面的人类下丘脑地图集的目标将是基础科学家和临床研究人员实用的，试图更好地了解下丘脑能量平衡调节的基本性质。希望这将使我们能够操纵这些系统以改善人口的健康。

项目成果

A program of successive gene expression in mouse one-cell embryos

• DOI: 10.1016/j.celrep.2023.112023
• 发表时间: 2023-01-31
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Asami, Maki;Lam, Brian Y. H.;Perry, Anthony C. F.
• 通讯作者: Perry, Anthony C. F.

The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

迷走神经介导 PYY3-36 对食物摄入的生理作用，但不介导药理作用。

• DOI: 10.1016/j.molmet.2024.101895
• 发表时间: 2024
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Alonso AM

Human embryonic genome activation initiates at the one-cell stage.

• DOI: 10.1016/j.stem.2021.11.012
• 发表时间: 2022-02-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Asami M;Lam BYH;Ma MK;Rainbow K;Braun S;VerMilyea MD;Yeo GSH;Perry ACF
• 通讯作者: Perry ACF