Gene expression changes during postnatal development of the marmoset, mouse, and human brain: a pilot study with focus on prefrontal cortex,adolescence, and psychiatric risk genetics

狨猴、小鼠和人脑出生后发育过程中的基因表达变化：一项重点研究前额皮质、青春期和精神风险遗传学的初步研究

• 批准号: 10373197
• 负责人: Matthew Bonser Johnson
• 金额: $ 17.37万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373197
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Age; Animal Model; Area; Atlases; Behavioral; Bioinformatics; Bipolar Disorder; Brain; Brain region; Callithrix; Callithrix jacchus jacchus; Cells; Cerebral cortex; Childhood; Cognition; Cognitive; Complex; Data; Development; Developmental Process; Diagnosis; Disease; Disease model; Dissection; Down Syndrome; Elements; Environmental Risk Factor; Event; Foundations; Future; Gene Expression; Gene Expression Profile; Genetic; Genetic Code; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic study; Goals; Histologic; Human; Image; Impaired cognition; In Situ; Incidence; Individual; International; Investigation; Life; Maps; Mental disorders; Modeling; Molecular; Mood Disorders; Mus; Neuroanatomy; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurologic; Neurosciences Research; Pathologic; Pathology; Pathway interactions; Pilot Projects; Prefrontal Cortex; Pregnancy; Primates; Regulator Genes; Regulatory Element; Reproducibility; Research; Risk; Risk Factors; Schizophrenia; Sensory; Site; Structure; Synapses; Testing; Therapeutic Human Experimentation; Validation; Viral; adolescent brain development; association cortex; autism spectrum disorder; cell type; clinically relevant; cognitive development; cognitive function; comparative; critical period; density; design; early childhood; experimental study; frontier; genetic risk factor; gray matter; human disease; human imaging; insight; mouse model; neuropsychiatric disorder; neuropsychiatry; nonhuman primate; postnatal; postnatal development; programs; psychiatric symptom; risk variant; sensory cortex; spatiotemporal; therapeutic target; transcriptome; transcriptomics; vulnerable adolescent

PROJECT SUMMARY The adolescent brain undergoes dramatic changes in both structure and function. Human imaging, structural, and genetic data suggest a developmental trajectory that extends through the second into the third decades of human life. Neuropsychiatric conditions such as schizophrenia and mood disorders typically emerge during this period and are believed to arise due to the interplay of genetic predispositions, environmental insults, and the long-term maturation of the adolescent brain. The prefrontal cortex undergoes a particularly extended maturation through adolescence, is critical for higher cognitive functions disrupted in psychiatric disorders, and is the primary site of proposed pathological hallmarks of schizophrenia, including decreased synaptic density and gray matter volume. To test mechanistic hypotheses of genetic and environmental factors impacting prefrontal development, we must invest in tractable animal models with the highest potential for clinical relevance. The common marmoset, a platyrrhine non-human primate, represents the next frontier in neurological therapeutics research. Their small stature, short gestation period, ease of handling and ability to be genetically modified have put them at the forefront of neuropsychiatric disease modeling. In this proposal, we aim to produce a comprehensive genetic dissection of the marmoset prefrontal cortex across childhood through adolescence to adulthood. Furthermore, we will take a major step to validate and enable the use of marmoset in neuropsychiatric research by integrating our findings across species and with identified genetic risk factors for schizophrenia and other neurodevelopmental disorders. Combining expertise in comparative neuroanatomy, single-cell and spatial transcriptomics, and bioinformatics, our collaborative team will identify developmental changes across all frontal cortical areas, cell types, and molecular pathways. Together, these experiments will provide a foundation to understand the vulnerabilities of adolescent prefrontal cortex and the specific impacts of genetic and environmental perturbations. 1

项目概要 青春期的大脑在结构和功能上都会发生巨大的变化。人体成像、结构、 遗传数据表明，发展轨迹从第二个十年一直延伸到第三个十年。 人类的生活。精神分裂症和情绪障碍等神经精神疾病通常在此期间出现 据信，这种现象是由于遗传倾向、环境损害和环境因素的相互作用而产生的。 青少年大脑的长期成熟。前额皮质经历了特别长时间的成熟 在整个青春期，对于精神疾病中破坏的高级认知功能至关重要，并且是主要的 拟议的精神分裂症病理特征的部位，包括突触密度和灰质减少 体积。为了测试影响前额叶发育的遗传和环境因素的机制假设， 我们必须投资于具有最高临床相关潜力的易驯化动物模型。常见的 狨猴是一种阔鼻非人类灵长类动物，代表了神经治疗研究的下一个前沿领域。 它们身材矮小，妊娠期短，易于操作，并且能够进行基因改造，这使得它们 处于神经精神疾病模型的前沿。在本提案中，我们的目标是制定一份全面的 对狨猴前额叶皮层从童年期到青春期到成年期的基因解剖。 此外，我们将采取重大步骤来验证狨猴并使其能够在神经精神病学研究中使用 通过整合我们跨物种的发现以及已确定的精神分裂症和其他疾病的遗传风险因素 神经发育障碍。结合比较神经解剖学、单细胞和空间方面的专业知识 转录组学和生物信息学，我们的协作团队将识别所有额叶的发育变化 皮质区域、细胞类型和分子途径。总之，这些实验将为 了解青少年前额皮质的脆弱性以及遗传和遗传因素的具体影响 环境扰动。 1