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Though animal models are still the gold standard for fundamental biological studies and drug evaluation for brain diseases, concerns arise from an apparent lack of reflecting the human genetics and pathophysiology. Recently, human avatars such as brain‐on‐a‐chip and brain organoids which are generated in a 3D manner using multiple types of human‐originated cells have risen as alternative testing models. Particularly in monitoring the functional neuronal cells that express action potentials in brain‐on‐a‐chip or brain organoids, various methods of measuring their electrophysiological function have been suggested for the study of brain‐related disease. Recent methodologies for analyzing the electrophysiology of different types of cells in brain‐on‐a‐chip and brain organoids are summarized in this review. We first emphasize the inherent features of brain‐on‐a‐chip and brain organoids from the perspective of the cell culture environment and accessibility to cells in the deep layer. The applicable monitoring techniques are then overviewed based on these features. Finally, we discuss the unmet needs for electrophysiology monitoring in advanced human brain avatar models. [ABSTRACT FROM AUTHOR]

Understanding the impact of long‐term opioid exposure on the embryonic brain is critical due to the surging number of pregnant mothers with opioid dependency. However, this has been limited by human brain inaccessibility and cross‐species differences in animal models. Here, a human midbrain model is established that uses hiPSC‐derived midbrain organoids to assess cell‐type‐specific responses to acute and chronic fentanyl treatment and fentanyl withdrawal. Single‐cell mRNA sequencing of 25,510 cells from organoids in different treatment groups reveals that chronic fentanyl treatment arrests neuronal subtype specification during early midbrain development and alters synaptic activity and neuron projection. In contrast, acute fentanyl treatment increases dopamine release but does not significantly alter gene expression related to cell lineage development. These results provide the first examination of the effects of opioid exposure on human midbrain development at the single‐cell level. [ABSTRACT FROM AUTHOR]

Recent advances in human brain organoid systems have raised serious worries about the possibility that these in vitro 'mini‐brains' could develop sentience, and thus, moral status. This article considers the relative moral status of sentient human brain organoids and research animals, examining whether we have moral reasons to prefer using one over the other. It argues that, contrary to common intuitions, the wellbeing of sentient human brain organoids should not be granted greater moral consideration than the wellbeing of nonhuman research animals. It does so not by denying that typical humans have higher moral status than animals, but instead by arguing that none of the leading justifications for granting humans higher moral status than nonhuman animals apply to brain organoids. Additionally, it argues that there are no good reasons to be more concerned about the well‐being of human brain organoids compared to those generated from other species. [ABSTRACT FROM AUTHOR]

Biohybrid robots have been developed for biomedical applications and industrial robotics. However, the biohybrid robots have limitations to be applied in neurodegenerative disease research due to the absence of a central nervous system. In addition, the organoids‐on‐a‐chip has not yet been able to replicate the physiological function of muscle movement in the human motor system, which is essential for evaluating the accuracy of the drugs used for treating neurodegenerative diseases. Here, a human motor system‐based biohybrid robot‐on‐a‐chip composed of a brain organoid, multi‐motor neuron spheroids, and muscle bundle on solid substrateis proposed to evaluate the drug effect on neurodegenerative diseases for the first time. The electrophysiological signals from the cerebral organoid induced the muscle bundle movement through motor neuron spheroids. To evaluate the drug effect on Parkinson's disease (PD), a patient‐derived midbrain organoid is generated and incorporated into a biohybrid robot‐on‐a‐chip. The drug effect on PD is successfully evaluated by measuring muscle bundle movement. The muscle bundle movement of PD patient‐derived midbrain organoid‐based biohybrid robot‐on‐a‐chip is increased from 4.5 ± 0.99 µm to 18.67 ± 2.25 µm in response to levodopa. The proposed human motor system‐based biohybrid robot‐on‐a‐chip can serve as a standard biohybrid robot model for drug evaluation. [ABSTRACT FROM AUTHOR]

The electrophysiological technology having a high spatiotemporal resolution at the single‐cell level and noninvasive measurements of large areas provide insights on underlying neuronal function. Here, a complementary metal‐oxide semiconductor (CMOS)‐microelectrode array (MEA) is used that uses 236 880 electrodes each with an electrode size of 11.22 × 11.22 µm and 236 880 covering a wide area of 5.5 × 5.9 mm in presenting a detailed and single‐cell‐level neural activity analysis platform for brain slices, human iPS cell‐derived cortical networks, peripheral neurons, and human brain organoids. Propagation pattern characteristics between brain regions changes the synaptic propagation into compounds based on single‐cell time‐series patterns, classification based on single DRG neuron firing patterns and compound responses, axonal conduction characteristics and changes to anticancer drugs, and network activities and transition to compounds in brain organoids are extracted. This detailed analysis of neural activity at the single‐cell level using the CMOS‐MEA provides a new understanding of the basic mechanisms of brain circuits in vitro and ex vivo, on human neurological diseases for drug discovery, and compound toxicity assessment. [ABSTRACT FROM AUTHOR]

The aging of the immune system drives systemic aging and the pathogenesis of age‐related diseases. However, a significant knowledge gap remains in understanding immune‐driven aging, especially in brain aging, due to the limited current in vitro models of neuroimmune interaction. Here, the authors report the development of a human brain organoid microphysiological analysis platform (MAP) to discover the dynamic process of immune‐driven brain aging. The organoid MAP is created by 3D printing that confines organoid growth and facilitates cell and nutrition perfusion, promoting organoid maturation and their committment to forebrain identity. Dynamic rocking flow is incorporated into the platform that allows to perfuse primary monocytes from young (20 to 30‐year‐old) and aged (>60‐year‐old) donors and culture human cortical organoids to model neuroimmune interaction. The authors find that the aged monocytes increase infiltration and promote the expression of aging‐related markers (e.g., higher expression of p16) within the human cortical organoids, indicating that aged monocytes may drive brain aging. The authors believe that the organoid MAP may provide promising solutions for basic research and translational applications in aging, neural immunological diseases, autoimmune disorders, and cancer. [ABSTRACT FROM AUTHOR]

Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells, provide a powerful platform for mechanistic studies of disorders of neurodevelopment and neural networks. hPSC models of autism, epilepsy, and other neurological disorders are also advancing the path toward designing and testing precision therapies. The field is evolving rapidly with the addition of genome‐editing approaches, expanding protocols for the two‐dimensional (2D) differentiation of different neuronal subtypes, and three‐dimensional (3D) human brain organoid cultures. However, the application of these techniques to study complex neurological disorders, including the epilepsies, remains a challenge. Here, we review previous work using both 2D and 3D hPSC models of genetic epilepsies, as well as recent advances in the field. We also describe new strategies for applying these technologies to disease modeling of genetic epilepsies, and discuss current challenges and future directions. [ABSTRACT FROM AUTHOR]

Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics. [ABSTRACT FROM AUTHOR]