Human brain organoids are 3-dimensional brain-like tissues derived from human pluripotent stem cells and hold promising potential for modeling neurological,psychiatric,and developmental disorders.While the molecular a...Human brain organoids are 3-dimensional brain-like tissues derived from human pluripotent stem cells and hold promising potential for modeling neurological,psychiatric,and developmental disorders.While the molecular and cellular aspects of human brain organoids have been intensively studied,their functional properties such as organoid neural networks(ONNs)are largely understudied.Here,we summarize recent research advances in understanding,characterization,and application of functional ONNs in human brain organoids.We first discuss the formation of ONNs and follow up with characterization strategies including microelectrode array(MEA)technology and calcium imaging.Moreover,we highlight recent studies utilizing ONNs to investigate neurological diseases such as Rett syndrome and Alzheimer’s disease.Finally,we provide our perspectives on the future challenges and opportunities for using ONNs in basic research and translational applications.展开更多
pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hypera...pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied,in part,because current models cannot fully recapitulate human pathology.Here,we engineered novel human spinal microphysiological systems(MPSs)integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance.Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement.We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids,but also promotes their neuron maturation,neural activity,and functional development.We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia,as measured by altered neural activity,and downregulation ofμ-opioid receptor expression of human spinal MPSs.The MPSs are scalable,cost-effective,easy-to-use,and compatible with commonly-used well-plates,thus allowing plug-and-play measurements of neural activity.We believe the MPSs hold a promising translational potential for studying human pain etiology,screening new treatments,and validating novel therapeutics for human pain medicine.展开更多
基金supported by the National Institutes of Health(awards DP2AI160242 and U01DA056242).
文摘Human brain organoids are 3-dimensional brain-like tissues derived from human pluripotent stem cells and hold promising potential for modeling neurological,psychiatric,and developmental disorders.While the molecular and cellular aspects of human brain organoids have been intensively studied,their functional properties such as organoid neural networks(ONNs)are largely understudied.Here,we summarize recent research advances in understanding,characterization,and application of functional ONNs in human brain organoids.We first discuss the formation of ONNs and follow up with characterization strategies including microelectrode array(MEA)technology and calcium imaging.Moreover,we highlight recent studies utilizing ONNs to investigate neurological diseases such as Rett syndrome and Alzheimer’s disease.Finally,we provide our perspectives on the future challenges and opportunities for using ONNs in basic research and translational applications.
基金The project was supported by the departmental start-up funds of Indiana University Bloomington,and in part by NSF grants(CCF-1909509,and CMMI-2025434)NIH awards(DP2AI160242,DA056242,and DA047858).
文摘pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied,in part,because current models cannot fully recapitulate human pathology.Here,we engineered novel human spinal microphysiological systems(MPSs)integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance.Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement.We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids,but also promotes their neuron maturation,neural activity,and functional development.We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia,as measured by altered neural activity,and downregulation ofμ-opioid receptor expression of human spinal MPSs.The MPSs are scalable,cost-effective,easy-to-use,and compatible with commonly-used well-plates,thus allowing plug-and-play measurements of neural activity.We believe the MPSs hold a promising translational potential for studying human pain etiology,screening new treatments,and validating novel therapeutics for human pain medicine.
