Mapping the human hypothalamic functional architecture underlying food intake control

肥胖是一个日益严重的公共健康问题。虽然我们不断变化的生活方式和环境无疑推动了这种增长，但在现代环境中，人体形状和大小的巨大变化背后有一个强大的遗传因素。了解控制进食行为的机制，从而导致体重的这种变化，对于在当前的食物环境中提供任何改善我们健康的策略都是重要的。虽然研究食物摄入的首选模型显然是在人类身上，但基因研究指出，大脑中一个名为下丘脑的区域在调节食欲方面起着至关重要的作用，这一事实限制了通过人类研究获得的机制见解。到目前为止，人类下丘脑的不可接近性意味着我们对控制食物摄入的大脑回路的理解主要来自于对老鼠的研究。现在，我们与剑桥脑库的一项重要合作，使我们能够获得新鲜的人类捐赠大脑样本。这一点，再加上单细胞测序的最新发展和利用荧光可视化单分子的技术，为我们提供了一个及时的机会来绘制人类下丘脑的功能结构，重点是食欲行为。一张有效的地图需要两个关键要素；我们首先需要知道地图的分量，然后我们需要知道这些分量在地图上的位置，相对于彼此的位置。因此，我们的两个目标是：A)使用单细胞技术，我们将对50万个下丘脑细胞进行测序，以便对细胞群进行分子普查，以确定控制食物摄入的神经回路的组成部分；B)使用一种称为单分子荧光原位杂交（smFISH）的方法，我们将把鉴定出的不同成分映射到小鼠和人类大脑上。我们将研究这些基因在人类下丘脑中的空间表达，并将其与小鼠大脑中的模式进行比较。由于显而易见的原因，使用现代基因操作工具对大脑进行详细的机制研究仍然需要小鼠模型。然而，我们的基本原理是，如果某种神经元群只在老鼠身上发现，那么研究它就没有什么“可翻译”的意义。一旦我们能够确定人类大脑中确实存在特定的通路或神经元类型，那么将有限的资源集中在制造复杂的小鼠模型上会好得多。我们的目标是建立一个全面的人类下丘脑图谱，这将有助于基础科学家和临床研究人员更好地理解下丘脑能量平衡调节的基本性质。这将使我们有希望操纵这些系统来改善人们的健康。

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.