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

项目总结 青春期的大脑在结构和功能上都经历了戏剧性的变化。人体成像，结构， 基因数据表明，从第二年到第三个十年的发展轨迹 人类的生命。在此期间，通常会出现精神分裂症和情绪障碍等神经精神疾病 这被认为是由于遗传易感性、环境侮辱和 青春期大脑的长期成熟。前额叶皮质经历了特别长时间的成熟。 在青春期，是精神障碍中高级认知功能障碍的关键，也是主要的 提出的精神分裂症病理特征的位置，包括突触密度和灰质减少 音量。为了检验遗传和环境因素影响前额叶发育的机制假说， 我们必须投资于具有最高临床相关性潜力的易驯服的动物模型。平凡的 绒猴是一种非人类灵长类动物，代表着神经治疗学研究的下一个前沿。 它们身材矮小，妊娠期短，易于操作，能够被转基因，这些都使它们 处于神经精神病学疾病模型的前沿。在这项提案中，我们的目标是产生一个全面的 从童年到青春期到成年的绒猴前额叶皮质的基因解剖。 此外，我们将迈出重要的一步，验证和启用绒猴在神经精神病学研究中的使用 通过将我们的跨物种发现与精神分裂症和其他疾病的已识别遗传风险因素相结合 神经发育障碍。结合比较神经解剖学、单细胞和空间学的专业知识 转录学和生物信息学，我们的协作团队将识别所有前额叶的发育变化 皮质区域、细胞类型和分子通路。总而言之，这些实验将为 了解青少年前额叶皮质的脆弱性以及遗传和 环境扰动。 1

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