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

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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