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: 10656162
• 负责人: Matthew Bonser Johnson
• 金额: $ 21.27万
• 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/10656162
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Age; Animal Model; Area; Atlases; Behavior; 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; Investments; 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; Site; Structure; Synapses; Testing; Therapeutic Research; Validation; Viral; adolescent brain development; association cortex; autism spectrum disorder; cell type; clinically relevant; cognitive development; cognitive function; comparative; critical period; data integration; density; design; early childhood; experimental study; frontal lobe; 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

项目摘要 青少年的大脑在结构和功能上都发生了巨大的变化。人体成像，结构， 基因数据表明，从20世纪20年代到30年代， 人类生活神经精神疾病，如精神分裂症和情绪障碍，通常出现在这个过程中， 期间，被认为是由于遗传易感性，环境侮辱， 青少年大脑的长期成熟。前额叶皮层经历了一个特别长的成熟期 通过青春期，是关键的较高的认知功能中断的精神疾病，是主要的 精神分裂症的病理学特征，包括突触密度和灰质的减少 音量.为了检验遗传和环境因素影响前额发育的机制假说， 我们必须投资于具有最大临床相关性潜力的易处理的动物模型。共同 绒猴是一种宽鼻非人灵长类动物，代表了神经治疗学研究的下一个前沿。 他们身材矮小，怀孕期短，易于处理和转基因能力使他们 在神经精神疾病建模的最前沿。在本建议中，我们的目标是制定一个全面的 从童年到青春期到成年期对绒猴前额皮质的遗传解剖。 此外，我们将采取重大步骤，以验证和使绒猴在神经精神病学研究中的使用 通过整合我们在不同物种中的发现，并与精神分裂症和其他疾病的遗传风险因素相结合， 神经发育障碍结合比较神经解剖学、单细胞和空间 转录组学和生物信息学，我们的合作团队将确定所有额叶的发育变化， 皮质区、细胞类型和分子通路。总之，这些实验将提供一个基础， 了解青少年前额叶皮层的脆弱性以及遗传和 环境扰动。 1