The molecular and cellular mechanisms of human brain expansion.

人类大脑，特别是大脑新皮质的快速进化扩张，是我们独特智力的结构基础。人类大脑非同寻常的大小和广泛折叠的形状使其有别于其他哺乳动物的大脑，包括我们的灵长类亲属。在胎儿发育过程中，神经干细胞经历了高度受控的增殖和分化过程，以生成构成出生后大脑的神经元和胶质细胞。有人假设，人类神经干细胞行为的改变可能直接导致人脑的扩张和折叠。特别是，在灵长类动物大脑中丰富但在小鼠大脑中缺乏的不同亚型的神经干细胞可能有助于灵长类动物脑部的扩张。然而，这些假设在很大程度上是未经检验的，因为人类胎儿和非人类灵长类动物的大脑无法接触到。因此，我们对人类大脑扩张背后的分子和细胞机制的了解仍然极其有限。我之前的研究表明，可以在培养皿中模拟人脑形成的关键步骤，从而绕过对人类胎儿组织的需要。我们通过从人类皮肤细胞中提取多能干细胞，然后将这些干细胞分化为神经元和脑器官来实现这一目标。在拟议的研究中，我的团队将应用这一策略创建一个创新的多物种干细胞平台，以研究人类、非人类灵长类动物和小鼠的大脑发育。我们预计，对人类(具有大的折叠大脑的灵长类动物)、猕猴(具有中间折叠大脑的灵长类动物)、猕猴(大脑小而光滑的灵长类动物)和小鼠(大脑非常小而光滑的啮齿动物)的神经细胞和脑器官的直接比较将为调节大脑扩张和折叠的分子、细胞和解剖学机制提供前所未有的见解。我的研究计划中使用的策略、技术和基础设施将为HQP提供干细胞工程、基因编辑、基因组分析和高通量分析方面的尖端培训。了解人脑是如何形成的，以及是什么让它变得独特，是了解我们是谁的基石。这项工作的发现将推动干细胞生物学和神经生物学领域的发展，并对人类生物学的研究产生广泛影响。

The rapid evolutionary expansion of the human brain, in particular the cerebral neocortex, is the structural foundation of our unique intellectual abilities. The extraordinary size and extensively folded shape of the human brain makes it distinct from the brains of other mammals, including our primate relatives. During fetal development, neural stem cells undergo highly controlled proliferation and differentiation processes to generate the neurons and glia that make up the postnatal brain. It has been hypothesized that changes in the behaviours of human neural stem cells may be directly responsible for the expansion and folding of the human brain. In particular, distinct subtypes of neural stem cells that are abundant in the primate brains but absent in the mouse brains may contribute to brain expansion in the primate lineage. However, these hypotheses are largely untested, due to the inaccessible nature of the fetal human and non-human primate brains. As a result, our knowledge of the molecular and cellular mechanism that underlies human brain expansion remains extremely limited. My previous research has shown that crucial steps of human brain formation can be mimicked in the dish, thereby circumventing the need of human fetal tissues. We achieved this by deriving pluripotent stem cells from human skin cells, and then differentiating these stem cells into neurons and brain organoids. In the proposed research, my team will apply this strategy to create an innovative multi-species stem cell platform to study brain development in human, non-human primates, and mouse. We anticipate that the direct comparison of neural cells and brain organoids from human (a primate with large, folded brain), macaque (a primate with intermediate, folded brain), marmoset (a primate with small, smooth brain), and mouse (a rodent with very small, smooth brain) will provide unprecedented insights into the molecular, cellular, and anatomical mechanisms that regulate brain expansion and folding. The strategies, techniques, and infrastructure used in my research program will provide HQPs with cutting-edge training in stem cell engineering, gene editing, genomics analysis and high throughput assays. Understanding how the human brain forms and what makes it unique is the cornerstone for understanding who we are. Discoveries made in this work will advance the fields of stem cell biology and neurobiology, as well as have broad impact on studies of human biology.