The development of integrated human thalamocortical assembloid that produces the thalamocortical oscillation

About This Grant

Human brain rhythms serve as representations of inner states of the brain for vigilance and behavior. Dysregulation of brain rhythms is implicated in most neuropsychiatric and neurodegenerative disorders. The molecular, cellular, and circuit mechanisms underlying mammal brain rhythms have been mainly elucidated in animal models. However, the lack of tractable model has challenged the investigation in human system. We have developed methods to produce the 3D structures representing the human cortical (hCO, human cortical organoids) and thalamic (hThO, human thalamic organoids) areas by applying stem cell technologies. These organoids reproduce the developing and functional human brain. Most recently, we generated ventralized thalamic organoids (vThOs) that contain interneurons that are specifically present in thalamic reticular nucleus (TRN). The fusion or assembly of two or more neural organoids have shown the possibilities to study the interaction of the brain domains. While many previous studies have successfully demonstrated the utility of human brain organoids in modeling diseases, no studies have developed human brain organoids that reproduce human brain rhythms. The neuronal connection between thalamus and cortex are crucial for the formation of human cortical oscillations commonly observed in scalp EEG. Thus, our established hCOs and ThOs are essential elements to produce the cortical oscillations. Here, we will assemble the organoids to test the hypothesis that assembloid of hThO and vThO together with hCO generate thalamocortical oscillations via a synaptic interaction among these functionally distinct organoids. In Aim 1, we will develop hThO-vThO assembloids to produce intrinsic thalamic network oscillations. We will examine the role of TRN GABAergic cells in intrinsic thalamic network oscillations. In Aim 2. we will develop methods to produce hCOs assembled with hThO-vThO thalamic assembloid to generate thalamocortical network oscillations. Here, we will develop a thalamocortical network oscillation that reproduces human cortical rhythms. In Aim 3, we will test effect of the noradrenaline and acetylcholine on thalamocortical oscillation formation by examining the neural gene regulation, cellular and synaptic properties of thalamic neurons, and development of thalamocortical network activity. The results will define molecular, cellular, and circuit mechanisms of how neuromodulators promote proper thalamocortical network oscillation development. Overall, our project will generate the assembloids of cortical and thalamic organoids to reproduce the human corticothalamic oscillation, and will offer a highly innovative platform to define the molecular and cellular underpinnings of human cortical oscillation and its associated diseases.