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Brain-region-specific humanized cortical interneuron mice

脑区域特异性人源化皮质中间神经元小鼠

基本信息

批准号：
10735991
负责人：
SANGMI CHUNG
金额：
$ 66.05万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735991
关键词：
Ablation Address Area Astrocytes Behavior Behavioral Behavioral Assay Biological Models Blood Vessels Brain Brain Diseases Brain region Cell Culture Techniques Central Nervous System Chimera organism Complex Data Development Disease Dorsal Dose Electrodes Electrophysiology (science)Environment Failure Future Genetic Graft Survival Hippocampus Histologic Human Immunohistochemistry In Vitro Injections Interneuron function Interneurons Medial Methods Microglia Modeling Mus Neurons Oligodendroglia Pathogenesis Patients Phenotype Physiological Play Pluripotent Stem Cells Population Prefrontal Cortex Qualifying Regulation Rodent Rodent Model Role Schizophrenia Slice Source Synapses System Testing Therapeutic Titrations Transplantation Untranslated RNA Viral Vector autism spectrum disorder cell type cognitive function cognitive task cognitive testing disease mechanisms study experimental study human disease human fetal brain tissue in vivo in vivo Model induced pluripotent stem cell neuropsychiatric disorder novel novel therapeutics optogenetics physiologic model restoration risk variant stem cells

项目摘要

Abstract GABAergic cortical interneurons (cINs) play critical roles in balancing, synchronizing, and gating brain activity by inhibiting other neurons. Their malfunction, especially those of medial ganglionic eminence (MGE)-derived cINs, has been associated with various neurodevelopmental brain disorders, such as schizophrenia (SCZ) and autism spectrum disorders (ASD). Considering the fact that the divergence between human brains and rodent brains has resulted in the failure of many central nervous system (CNS) therapeutics validated in rodent models, it is critical to study human neurons to better understand the mechanisms of these cIN-associated brain disorders. Human fetal brain tissues are not accessible for mechanistic studies, but we have developed a method to efficiently generate homogeneous populations of MGE-type human cINs from pluripotent stem cells (PSCs) of healthy or diseased subjects. We have extensively characterized them and demonstrated their authenticity and functionality, making it possible to study the converging functional consequences of complex genetics in real patient neurons, which cannot be studied in mouse neurons due to a lack of conservation of non-coding regions, where most of risk loci are present. However, in vitro cultured neurons lack other critical components of the brain environment, such as astrocytes, oligodendrocytes, microglia and blood vessels, which can significantly impact their function. There have been efforts to optimize in vitro culture systems to better recapitulate in vivo physiological environments by adding other brain cellular components, but there are still limitations as to how closely they can simulate in vivo situations. To resolve this issue, in our previous study, we pioneered human neuron-mouse brain chimeras to study the function of human SCZ neurons in physiological environments. Although we were able to successfully identify SCZ cIN-intrinsic connectivity deficits in mouse brains, we were not able to analyze the impacts of grafted neurons on brain circuits and behaviors due to the presence of healthy mouse neurons in the grafted mice. Thus, in this proposed study, we will perform brain-region-specific cIN-ablation in NodScid gamma (NSG) mice, followed by the replacement of ablated host cINs with human cINs to generate region-specific humanized cIN chimeras. Based on previous studies, including ours, that show successful restoration of compromised mouse inhibition by grafted human cINs, these mice will allow us to analyze the functional impacts of grafted human cINs on the brain circuits and behaviors in physiological in vivo environments. This novel physiological model system will help us tease apart cell-type- and brain-region-specific disease mechanisms for complex brain disorders, and aid in developing novel therapeutics.

摘要