scholarly journals Complex Activity and Short-term Memories in Reciprocally Connected Cerebral Organoids

2021 ◽  
Author(s):  
Tatsuya Osaki ◽  
Yoshiho Ikeuchi

AbstractMacroscopic axonal connections in the human brain distribute information and neuronal activity across the brain. Although this complexity previously hindered elucidation of functional connectivity mechanisms, brain organoid technologies have recently provided novel avenues to investigate human brain function by constructing small segments of the brain in vitro. Here, we describe the neural activity of human cerebral organoids reciprocally connected by a bundle of axons. Compared to conventional organoids, connected organoids produced significantly more intense and complex oscillatory activity. Optogenetic manipulations revealed that the connected organoids could re-play and recapitulate over time temporal patterns found in external stimuli, indicating that the connected organoids were able to form and retain temporal memories. Our findings suggest that connected organoids may serve as powerful tools for investigating the roles of macroscopic circuits in the human brain – allowing researchers to dissect cellular functions in three-dimensional in vitro nervous system models in unprecedented ways.

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yi-Fan Wang ◽  
Cong Liu ◽  
Peng-Fei Xu

AbstractOrganoid has become a novel in vitro model to research human development and relevant disorders in recent years. With many improvements on the culture protocols, current brain organoids could self-organize into a complicated three-dimensional organization that mimics most of the features of the real human brain at the molecular, cellular, and further physiological level. However, lacking positional information, an important characteristic conveyed by gradients of signaling molecules called morphogens, leads to the deficiency of spatiotemporally regulated cell arrangements and cell–cell interactions in the brain organoid development. In this review, we will overview the role of morphogen both in the vertebrate neural development in vivo as well as the brain organoid culture in vitro, the strategies to apply morphogen concentration gradients in the organoid system and future perspectives of the brain organoid technology.


2020 ◽  
Vol 14 ◽  
Author(s):  
Takeshi K. Matsui ◽  
Yuichiro Tsuru ◽  
Ken-ichiro Kuwako

Human brain organoids are three-dimensional self-organizing tissues induced from pluripotent cells that recapitulate some aspects of early development and some of the early structure of the human brain in vitro. Brain organoids consist of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes and oligodendrocytes. Additionally, brain organoids contain fluid-filled ventricle-like structures surrounded by a ventricular/subventricular (VZ/SVZ) zone-like layer of neural stem cells (NSCs). These NSCs give rise to neurons, which form multiple outer layers. Since these structures resemble some aspects of structural arrangements in the developing human brain, organoid technology has attracted great interest in the research fields of human brain development and disease modeling. Developmental brain disorders have been intensely studied through the use of human brain organoids. Relatively early steps in human brain development, such as differentiation and migration, have also been studied. However, research on neural circuit formation with brain organoids has just recently began. In this review, we summarize the current challenges in studying neural circuit formation with organoids and discuss future perspectives.


2021 ◽  
Author(s):  
Nguyen-Vi Mohamed ◽  
Paula Lepine ◽  
Maria Lacalle-Aurioles ◽  
Julien Sirois ◽  
Meghna Mathur ◽  
...  

By providing a three-dimensional in vitro culture system with key features of the substantia nigra region in the brain, 3D neuronal organoids derived from human induced pluripotent stem cells (iPSCs) provide living neuronal tissue resembling the midbrain region of the brain. However, a major limitation of conventional brain organoid culture is that it is often labor-intensive, requiring highly specialized personnel for moderate throughput. Additionally, the methods published for long-term cultures require time-consuming maintenance to generate brain organoids in large numbers. With the increasing need for human midbrain organoids (hMOs) to better understand and model Parkinson′s disease (PD) in a dish, there is a need to implement new workflows and methods to both generate and maintain hMOs, while minimizing batch to batch variation. In this study, we developed a method with microfabricated disks to scale up the generation of hMOs. This opens up the possibility to generate larger numbers of hMOs, in a manner that minimizes the amount of labor required, while decreasing variability and maintaining the viability of these hMOs over time. Taken together, producing hMOs in this manner opens up the potential for these to be used to further PD studies.


2019 ◽  
Vol 6 (1) ◽  
pp. 9 ◽  
Author(s):  
Eyal Karzbrun ◽  
Orly Reiner

Brain organoids have recently emerged as a three-dimensional tissue culture platform to study the principles of neurodevelopment and morphogenesis. Importantly, brain organoids can be derived from human stem cells, and thus offer a model system for early human brain development and human specific disorders. However, there are still major differences between the in vitro systems and in vivo development. This is in part due to the challenge of engineering a suitable culture platform that will support proper development. In this review, we discuss the similarities and differences of human brain organoid systems in comparison to embryonic development. We then describe how organoids are used to model neurodevelopmental diseases. Finally, we describe challenges in organoid systems and how to approach these challenges using complementary bioengineering techniques.


2018 ◽  
Author(s):  
Cleber A. Trujillo ◽  
Richard Gao ◽  
Priscilla D. Negraes ◽  
Isaac A. Chaim ◽  
Alain Domissy ◽  
...  

SUMMARYStructural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed cortical organoids that spontaneously display periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. These nested oscillations exhibit cross-frequency coupling, proposed to coordinate neuronal computation and communication. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in preterm human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our approach provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex.HIGHLIGHTSEarly development of human functional neural networks and oscillatory activity can be modeled in vitro.Cortical organoids exhibit phase-amplitude coupling between delta oscillation (2 Hz) and high-frequency activity (100-400 Hz) during network-synchronous events.Differential role of glutamate and GABA in initiating and maintaining oscillatory network activity.Developmental impairment of MECP2-KO cortical organoids impacts the emergence of oscillatory activity.Cortical organoid network electrophysiological signatures correlate with human preterm neonatal EEG features.eTOCBrain oscillations are a candidate mechanism for how neural populations are temporally organized to instantiate cognition and behavior. Cortical organoids initially exhibit periodic and highly regular nested oscillatory network events that eventually transition to more spatiotemporally complex activity, capturing features of late-stage preterm infant electroencephalography. Functional neural circuitry in cortical organoids exhibits emergence and development of oscillatory network dynamics similar to those found in the developing human brain.


2021 ◽  
Author(s):  
Juan Eduardo Rodriguez-Gatica ◽  
Vira Iefremova ◽  
Liubov Sokhranyaeva ◽  
Si Wah Christina Au Yeung ◽  
Yannik Breitkreuz ◽  
...  

AbstractOrganoids are human stem cell-derived three-dimensional cultures offering a new avenue to model human development and disease. Brain organoids allow studying various aspects of human brain development in the finest details in vitro in a tissue-like context. However, spatial relationships of subcellular structures such as synaptic contacts between distant neurons are hardly accessible by conventional light microscopy. This limitation can be overcome by systems that quickly image the entire organoid in three dimensions and in super-resolution. To that end we have developed a setup combining tissue expansion and light sheet fluorescence microscopy for imaging and quantifying diverse spatial parameters during organoid development. This technique enables zooming from a mesoscopic perspective into super-resolution within a single imaging session, thus revealing cellular and subcellular structural details in three spatial dimensions, including unequivocal delineation of mitotic cleavage planes as well as the alignment of pre- and postsynaptic proteins. We expect light sheet fluorescence expansion microscopy (LSFEM) to facilitate qualitative and quantitative assessment of organoids in developmental and disease-related studies.Summary statementThe combination of light sheet fluorescence and expansion microscopy enables imaging of mature human brain organoids in toto and down to synaptic resolution


2021 ◽  
Vol 22 (5) ◽  
pp. 2491
Author(s):  
Yujin Park ◽  
Kang Moo Huh ◽  
Sun-Woong Kang

The process of evaluating the efficacy and toxicity of drugs is important in the production of new drugs to treat diseases. Testing in humans is the most accurate method, but there are technical and ethical limitations. To overcome these limitations, various models have been developed in which responses to various external stimuli can be observed to help guide future trials. In particular, three-dimensional (3D) cell culture has a great advantage in simulating the physical and biological functions of tissues in the human body. This article reviews the biomaterials currently used to improve cellular functions in 3D culture and the contributions of 3D culture to cancer research, stem cell culture and drug and toxicity screening.


2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.


PEDIATRICS ◽  
1951 ◽  
Vol 7 (2) ◽  
pp. 269-293
Author(s):  
CHARLES C. CHAPPLE

A study has been made of the known phenomena which affect the biologic organism. Certain correlations have been found and other correlations are logically inferred. The common grounds of anatomic structures, the anatomic responses to endocrine stimuli, the interrelationships and interdependencies of the endocrines and external stimuli have been followed and have been related to cellular permeability and hyaluronic acid. Cellular phases, including the rhythmic alternations in physiologic functions, have been delineated and their importance stressed. Further, the probability is advanced that this rhythmicity originates physiologically in the brain but that the brain itself is capable of receiving transmissions from within and without the body, and disseminating them, again rhythmically, in normal or altered amplitude and frequency. Further experimental evidence of these correlations and their practical extrapolations into drug actions and the therapy of infections and metabolic disease will be reported and will include clinical, animal and in vitro studies. At present, the following conclusions seem justified: 1. No component of the body is capable of independent action. 2. Action in any component is reflected, according to its magnitude and directness of application, upon all the body. 3. All such actions are mediated by the brain. 4. There is a dynamic, rhythmic cyclicity in physiologic action which can be altered in amplitude and frequency. 5. These rhythms are alternations of cellular tenseness and relaxation. 6. The concomitants of the tense phase are compactness, impermeability, electric conductivity and contraction of all cells, and these characteristics might be described collectively as the factors operative in maturing the cell. The concomitants of the relaxed phase are laxness, permeability, electric resistance and expansion of all cells and are factors of growth. 7. The phase of tenseness is accompanied by an increase in certain hormonal activities and that of relaxation by an increase in others. 8. The hormones may be causes of the phase or the results of it. 9. Infectious disease cannot act as an extraneous agent capable of bringing its own engine into such a highly integrated mechanism but must act on the body through its ability to affect one of the body's mechanisms. 10. Drugs must act through the same channels available to disease. 11. Foods may contain, in addition to their caloric content, components capable of stimulating either the phase of cellular expansion or cellular compaction, particularly foods from the reproductive systems of plants or animals (milk, eggs, cereal, for example). 12. Vitamins each stimulate one phase and should be evaluated in terms of positive actions. 13. Inherent growth and maturation factors are not of fixed capacity in an individual but beyond certain limits must be supplied him or applied to him constantly. 14. The hormone most manifest in the tense phase is estrogen and so may be considered the maturation factor, and the one most manifest in the phase of relaxation or cell division is progesterone, which may be considered the growth factor.


2006 ◽  
Vol 396 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Andreas G. Glaser ◽  
Andreas Limacher ◽  
Sabine Flückiger ◽  
Annika Scheynius ◽  
Leonardo Scapozza ◽  
...  

Cyclophilins constitute a family of proteins involved in many essential cellular functions. They have also been identified as a panallergen family able to elicit IgE-mediated hypersensitivity reactions. Moreover, it has been shown that human cyclophilins are recognized by serum IgE from patients sensitized to environmental cyclophilins. IgE-mediated autoreactivity to self-antigens that have similarity to environmental allergens is often observed in atopic disorders. Therefore comparison of the crystal structure of human proteins with similarity to allergens should allow the identification of structural similarities to rationally explain autoreactivity. A new cyclophilin from Aspergillus fumigatus (Asp f 27) has been cloned, expressed and showed to exhibit cross-reactivity in vitro and in vivo. The three-dimensional structure of cyclophilin from the yeast Malassezia sympodialis (Mala s 6) has been determined at 1.5 Å (1 Å=0.1 nm) by X-ray diffraction. Crystals belong to space group P41212 with unit cell dimensions of a=b=71.99 Å and c=106.18 Å. The structure was solved by molecular replacement using the structure of human cyclophilin A as the search model. The refined structure includes all 162 amino acids of Mala s 6, an active-site-bound Ala-Pro dipeptide and 173 water molecules, with a crystallographic R- and free R-factor of 14.3% and 14.9% respectively. The overall structure consists of an eight-stranded antiparallel β-barrel and two α-helices covering the top and bottom of the barrel, typical for cyclophilins. We identified conserved solvent-exposed residues in the fungal and human structures that are potentially involved in the IgE-mediated cross-reactivity.


Sign in / Sign up

Export Citation Format

Share Document