Developmental origins of mental illness: evolution and reversibility

总体摘要 大多数精神疾病出现在大脑发育的脆弱窗口期， 人类虽然有数百种基因和/或环境因素与精神疾病有关， 单个基因上的相邻点突变（例如，Shank 3）可能导致“早期”疾病，如自闭症或“晚期”疾病， 精神分裂症这对了解其病因和潜在治疗提出了双重挑战-如何 跟踪电路脱轨的轨迹以及这些研究在小鼠等动物中的相关性， 技能的特征可能不那么明确。我们提议的Conte中心更新将直接解决这些问题 通过联合四位先驱神经生物学家，专注于两个神经回路的形成和完善， 发育阶段，胎儿和青春期前的关键时期。我们的核心假设是， 诱发环境因素或遗传基础，认知行为异常的近因， 将在改变的神经元连接的不同模式中发现病症。首先，检查兴奋性- 抑制平衡是建立在胎儿的生活，阿洛塔结合尖端干细胞，基因组，成像和 生理记录技术在人脑类器官特异性基因纵向研究中的应用 突变第二，在我们中心的第一阶段，Hensch的关键概念见解确定了 小清蛋白（PV+）细胞在决定出生后关键期时间中的作用。因为它们的高代谢 活动，PV+细胞在精神疾病中容易受到氧化应激的影响，因为它们是γ振荡， 产生（与认知有关）。改变PV+电池成熟曲线的操作有力地改变了 感觉皮层的塑料窗，表明关键时期本身的可塑性可能有助于 也有认知障碍第三，Hensch和Feng证实了在老年人中存在多感觉整合障碍。 在Shank 3和Mecp 2中携带自闭症风险突变的小鼠的岛叶皮质。值得注意的是，它们位于相反的两端， PV+回路发育不足或过度成熟。在这里，我们将利用可逆和条件遗传 这些基因的突变，以映射其他更高的相关功能的关键时期：注意力，认知， 灵活性和社会偏好--所有这些都是在亨施实验室里建立的。此外，为了与他的小鼠进行直接比较， Feng将使用CRISPR在PV+细胞中产生携带Cre重组酶或Shank 3缺失的绒猴 技术.他独特的基础设施将使操纵和分析相同的电路在这个灵长类动物 有着更好的额叶皮层和行为。第四，我们利用成熟的平台， Lichtman在我们中心的第一阶段建立了三维电子显微镜电路重建， 比较和对比人类类器官与小鼠和绒猴的“连接病”的出现。 最终，通过最先进的神经科学来减少精神疾病的耻辱感， 通过我们强有力的、积极的外展计划生成和传达这些知识是我们的主要使命 在哈佛的康特中心。

Overall abstract Most mental illnesses emerge during vulnerable windows of brain development to impact cognitive function in humans. While hundreds of genes and/or environmental factors have been linked to mental illnesses, even neighboring point mutations on a single gene (eg. Shank3) can lead to `early' disorders such as autism or `late' schizophrenia. This poses a double challenge to understanding their etiology and potential treatment – how to track the trajectory of circuit derailment and the relevance of such studies in animals like mice whose cognitive skills may be less well-characterized. Our proposed Conte Center renewal will tackle these problems directly by uniting four pioneering neurobiologists focused on the formation and refinement of neuronal circuits in two stages of development, fetal and pre-adolescent critical periods. Our central hypothesis is that whatever the predisposing environmental factors or genetic bases, the proximate cause of aberrant behavior in cognitive disorders will be found in distinct patterns of altered neuronal connectivity. First, to examine how excitatory- inhibitory balance is established in fetal life, Arlotta combines cutting edge stem cell, genomic, imaging and physiological recording technology for the longitudinal study of human brain organoids carrying specific gene mutation. Second, key conceptual insights from Hensch in the first phase of our Center identified the pivotal role of parvalbumin (PV+) cells in determining postnatal critical period timing. Because of their high metabolic activity, PV+ cells are vulnerable to oxidative stress in mental illness, as are the gamma oscillations which they generate (in association with cognition). Manipulations altering PV+ cell maturational profiles powerfully shift plastic windows in sensory cortex, indicating that malleability of critical periods themselves may contribute to cognitive disorders as well. Third, Hensch and Feng confirmed an impairment of multisensory integration in the insular cortex of mice carrying autism risk mutations in Shank3 and Mecp2. Notably, these lie on opposite ends of PV+ circuit hypo- or hyper-maturation. Here, we will take advantage of reversible and conditional genetic mutations in these genes to map critical periods for other higher functions of relevance: attention, cognitive flexibility, and social preference– all established in the Hensch lab. Moreover, for direct comparison to his mice, Feng will produce marmosets carrying Cre recombinase in PV+ cells or Shank3 deletion using CRISPR technology. His unique infrastructure will enable manipulation and analysis of the same circuits in this primate with better evolved frontal cortex and behaviors. Fourth, we capitalize on a sophisticated platform for complete 3D electron microscopic circuit reconstruction established by Lichtman during the first phase of our Center to compare and contrast the emergence of `connectopathies' from human organoids to mice and marmosets. Ultimately, reducing the stigma of mental illness through state-of-the-art neuroscience to train the next generation and conveying this knowledge through our strong, active Outreach program is the primary mission of the Conte Center at Harvard.