Developmental origins of mental illness: evolution and reversibility

精神疾病的发育起源：进化和可逆性

• 批准号: 10386838
• 负责人: Takao K Hensch
• 金额: $ 198.33万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386838
• 关键词: 3-Dimensional; Address; Affect; Anatomy; Animals; Attention; Awareness; Behavior; Behavioral; Biological; Brain; CRISPR/Cas technology; Callithrix; Cell Maturation; Cells; Cognition; Cognition Disorders; Cognitive; Complex; DNA Sequence Alteration; Data Set; Development; Disease; Electrons; Enterobacteria phage P1 Cre recombinase; Environmental Risk Factor; Equilibrium; Etiology; Evolution; Fetal Development; Future; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Risk; Genomics; Growth; Human; Image; Immersion; Impaired cognition; Impairment; Infrastructure; Intervention; Knowledge; Laboratories; Lead; Life; Link; Maps; Measures; Mechanics; Mental disorders; Metabolic; Methyl-CpG-Binding Protein 2; Microscopic; Mission; Modeling; Molecular; Monkeys; Mus; Mutant Strains Mice; Mutation; Neurons; Neurosciences; Organoids; Oxidative Stress; Parvalbumins; Pattern; Phase; Phenotype; Physiological; Point Mutation; Prefrontal Cortex; Prevention; Primates; Production; Research; Research Personnel; Resolution; Risk; Rodent; Role; Schizophrenia; Symptoms; Synapses; System; Technology; Testing; Tissues; Training; Transgenic Organisms; Virus; autism spectrum disorder; base; cognitive development; cognitive function; cognitive skill; collaborative environment; critical period; fetal; flexibility; frontal lobe; genetic manipulation; human fetus tissue; improved; in vivo; innovation; insight; longitudinal human study; mouse model; multisensory; mutant; neuronal circuitry; next generation; outreach; outreach program; postnatal; preadolescence; preference; reconstruction; sensory cortex; sensory system; social; social stigma; stem cells; tool; undergraduate student

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.

总体摘要 大多数精神疾病出现在大脑发育的脆弱时期，影响认知功能 尽管数百种基因和/或环境因素与精神疾病有关，但甚至与精神疾病有关。 单个基因（例如 Shank3）上的相邻点突变可能导致“早期”疾病，例如自闭症或“晚期”疾病 这对了解其病因和潜在的治疗方法提出了双重挑战——如何治疗。 追踪电路脱轨的轨迹以及此类研究在小鼠等动物中的相关性，这些动物的认知能力 我们提出的孔蒂中心更新计划可能会直接解决这些问题。 通过联合四位先驱神经生物学家，专注于两个领域神经元回路的形成和完善 我们的中心假设是，无论是发育阶段、胎儿期还是青春期前的关键期。 诱发环境因素或遗传基础，认知异常行为的直接原因 首先，要检查兴奋性如何改变。 抑制平衡是在胎儿生命中建立的，Arlotta 结合了尖端干细胞、基因组、成像和 用于纵向研究携带特定基因的人脑类器官的生理记录技术 其次，亨施在我们中心第一阶段的关键概念见解确定了关键的点。 小清蛋白 (PV+) 细胞由于其高代谢，在确定产后关键期时间中的作用。 PV+ 细胞在精神疾病中很容易受到氧化应激的影响，它们产生的伽马振荡也是如此。 产生（与认知相关）。 感觉皮层中的塑料窗口，表明关键时期本身的可塑性可能有助于 第三，Hensch 和 Feng 证实了多感觉整合障碍。 携带自闭症风险突变的小鼠的岛叶皮层 Shank3 和 Mecp2 值得注意的是，它们位于相反的两端。 在这里，我们将利用可逆和条件遗传。 这些基因的突变可绘制其他相关高级功能的关键时期：注意力、认知能力 灵活性和社会偏好——所有这些都是在亨施实验室中建立的，为了与他的老鼠进行直接比较， Feng将利用CRISPR在PV+细胞中生产携带Cre重组酶或Shank3缺失的狨猴 他独特的基础设施将能够操纵和分析这种灵长类动物的相同电路。 第四，我们利用先进的平台来实现完整的功能。 Lichtman 在我们中心第一阶段建立的 3D 电子显微电路重建 比较和对比从人类类器官到小鼠和狨猴的“连接病”的出现。 最终，通过最先进的神经科学来培训下一代，减少精神疾病的耻辱 通过我们强大、积极的外展计划生成和传播这些知识是我们的首要任务 哈佛大学康特中心。

项目成果

Critical period for acoustic preference in mice.

小鼠声学偏好的关键期。

• 发表时间: 2012-10-16
• 影响因子: 11.1
• 作者: Yang, Eun;Lin, Eric W;Hensch, Takao K
• 通讯作者: Hensch, Takao K

The Fuzzy Logic of Network Connectivity in Mouse Visual Thalamus.

小鼠视觉丘脑网络连接的模糊逻辑。

• 发表时间: 2016-03-24
• 影响因子: 64.5
• 作者: Morgan, Josh Lyskowski;Berger, Daniel Raimund;Wetzel, Arthur Willis;Lichtman, Jeff William
• 通讯作者: Lichtman, Jeff William

Mapping Synaptic Input Fields of Neurons with Super-Resolution Imaging.

用超分辨率成像映射神经元的突触输入场。

• 发表时间: 2015-10-08
• 影响因子: 64.5
• 作者: Sigal, Yaron M;Speer, Colenso M;Babcock, Hazen P;Zhuang, Xiaowei
• 通讯作者: Zhuang, Xiaowei

Multiplexed volumetric CLEM enabled by antibody derivatives provides new insights into the cytology of the mouse cerebellar cortex.

由抗体衍生物实现的多重体积 CLEM 为小鼠小脑皮质的细胞学提供了新的见解。

• 发表时间: 2023-07-06
• 作者: Han, Xiaomeng;Lu, Xiaotang;Li, Peter H;Wang, Shuohong;Schalek, Richard;Meirovitch, Yaron;Lin, Zudi;Adhinarta, Jason;Berger, Daniel;Wu, Yuelong;Fang, Tao;Meral, Elif Sevde;Asraf, Shadnan;Ploegh, Hidde;Pfister, Hanspeter;Wei, Donglai;Jain, V
• 通讯作者: Jain, V

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia.

针对精神分裂症发展轨迹中的氧化应激和异常关键期可塑性。

• DOI: 10.1093/schbul/sbv065
• 发表时间: 2015-07-01
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: K. Do;M. Cuénod;T. Hensch
• 通讯作者: T. Hensch