An Astrocytic Basis for Humanity

描述(申请人提供)：我们将测试这样一种假设，即与啮齿动物相比，人类优越的认知能力至少部分是人类星形胶质细胞控制突触形成和功能的进化增强的结果，与啮齿动物星形胶质细胞相比。星形胶质细胞是大脑中的一种主要细胞类型，至少占啮齿动物和人类脑细胞的三分之一。长期以来，星形胶质细胞一直被认为是被动的支持细胞，在过去的15年里，许多实验室的研究表明，星形胶质细胞强大地控制着中枢神经系统(CNS)突触的形成、功能和可塑性。人类的卓越认知能力是否源于星形细胞对突触形成和/或功能的控制的进化进步？我们开发了新的方法来纯化啮齿动物和人类星形胶质细胞。这些新方法将使我们能够直接检验我们的假设。为了解决这一假设，我们将采取三种不同的方法。首先，我们将使用下一代RNA-Seq测序来确定和比较鼠和人星形胶质细胞的转录。我们假设的一个预测是，人类星形胶质细胞可能会分泌与啮齿动物星形胶质细胞分泌的突触信号在数量或质量上不同的信号。因此，在方法2中，将进一步评估已确定的人类特定基因的功能，以确定潜在的突触功能。第二，我们将直接比较小鼠和人类星形胶质细胞刺激突触形成和功能的能力。我们还将确定在方法1中发现的编码分泌蛋白的新的人类星形胶质细胞基因是否可以刺激突触的形成或功能。然后，强烈控制突触形成或功能的人类基因将在转基因小鼠的小鼠星形胶质细胞中表达，以确定它们是否具有增强的认知能力。在我们最后的第三个方法中，我们将使用现代代谢组学方法来阐明小鼠和人类星形胶质细胞分泌的小化学信号分子，重点是识别控制突触功能的新的星形胶质细胞分泌的化学物质。这些研究提供的关于人类星形胶质细胞的新的分子洞察力也将为研究人类神经疾病中星形胶质细胞的病理变化提供基础，并揭示星形胶质细胞功能障碍如何导致神经发育障碍(如自闭症)和在人类情绪和行为中具有独特表现的神经精神障碍，如自闭症、焦虑症和抑郁症。

DESCRIPTION (provided by applicant): We will test the hypothesis that the superior cognitive abilities of humans compared to rodents is, at least in part, the result of an evolutionary increas in the ability of human astrocytes to control synapse formation and function compared to rodent astrocytes. Astrocytes are a major cell type in the brain that constitute at least one third of rodent and human brain cells. Long thought to be passive support cells, studies from many labs over the past 15 years have shown that astrocytes powerfully control the formation, function, and plasticity of synapses in the central nervous system (CNS). Could the superior cognitive abilities of humans be due to an evolutionary advance in astrocytic control of synaptic formation and/or function? We have developed new methods to purify both rodent and human astrocytes. These new methods will enable us to directly test our hypothesis. To address this hypothesis, we will take three different approaches. First we will use next generation RNA-Seq sequencing to determine and compare the transcriptomes of mouse and human astrocytes. A prediction of our hypothesis is that human astrocytes may secrete synaptic signals that are quantitatively or qualititavely different than those secreted by rodent astrocytes. The function of the human specific genes identified will therefore be further assessed for potential synaptic functions in Approach 2. Second, we will directly compare the ability of mouse and human astrocytes to stimulate synapse formation and function. We will also determine whether novel human astrocyte genes identified in approach 1 that encode for secreted proteins can stimulate synapse formation or function. Human genes that strongly control synapse formation or function will then be expressed in mouse astrocytes in transgenic mice to determine if they have enhanced cognitive abilities. In our final third approach, we will use modern metabolomics methods to elucidate the small chemical signaling molecules secreted by mouse and human astrocytes, with a focus on identifying novel astrocyte secreted chemicals that control synaptic function. The new molecular insight these studies provide about human astrocytes will also provide the foundation for investigations of pathological changes of astrocytes in human neurological disorders and reveal how malfunction of astrocytes leads to neurodevelopmental disorders such as autism and neuropsychiatric disorders with unique manifestations in human emotion and behavior, such as autism, anxiety disorder, and depression.