scholarly journals Methodologies for Generating Brain Organoids to Model Viral Pathogenesis in the CNS

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1510
Author(s):  
Hannah K. Hopkins ◽  
Elizabeth M. Traverse ◽  
Kelli L. Barr
Keyword(s):  
Viral Pathogenesis ◽  
Neural Progenitors ◽  
Fine Tuning ◽  
Mechanistic Studies ◽  
Search Terms ◽  
Multiple Regions ◽  
Research Goal ◽  
Brain Organoid ◽  
Neurological Infections ◽  
The Brain

(1) Background: The human brain is of interest in viral research because it is often the target of viruses. Neurological infections can result in consequences in the CNS, which can result in death or lifelong sequelae. Organoids modeling the CNS are notable because they are derived from stem cells that differentiate into specific brain cells such as neural progenitors, neurons, astrocytes, and glial cells. Numerous protocols have been developed for the generation of CNS organoids, and our goal was to describe the various CNS organoid models available for viral pathogenesis research to serve as a guide to determine which protocol might be appropriate based on research goal, timeframe, and budget. (2) Methods: Articles for this review were found in Pubmed, Scopus and EMBASE. The search terms used were “brain + organoid” and “CNS + organoid” (3) Results: There are two main methods for organoid generation, and the length of time for organoid generation varied from 28 days to over 2 months. The costs for generating a population of organoids ranged from USD 1000 to 5000. (4) Conclusions: There are numerous methods for generating organoids representing multiple regions of the brain, with several types of modifications for fine-tuning the model to a researcher’s specifications. Organoid models of the CNS can serve as a platform for characterization and mechanistic studies that can reduce or eliminate the use of animals, especially for viruses that only cause disease in the human CNS.

scholarly journals MiR-7 in Cancer Development

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 325
Author(s):  
Petra Korać ◽  
Mariastefania Antica ◽  
Maja Matulić
Keyword(s):  
Cell Fate ◽  
Dominant Role ◽  
Tumor Development ◽  
Mrna Translation ◽  
Cell Types ◽  
Fine Tuning ◽  
Non Coding Rna ◽  
Tumor Types ◽  
Different Cell Types ◽  
The Brain

MicroRNAs (miRNAs) are short non-coding RNA involved in the regulation of specific mRNA translation. They participate in cellular signaling circuits and can act as oncogenes in tumor development, so-called oncomirs, as well as tumor suppressors. miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of different cell types, protection from stress and chromatin remodulation. One of the most investigated tissues is the brain, where its downregulation is linked with glioblastoma cell proliferation. Its deregulation is found also in other tumor types, such as in liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be discovered, as well as the possibilities of its use as a specific biotherapeutic.

scholarly journals Imaging Implicit Morphological Processing: Evidence from Hebrew

2010 ◽  
Vol 22 (9) ◽  
pp. 1955-1969 ◽  
Author(s):  
Atira S. Bick ◽  
Ram Frost ◽  
Gadi Goelman
Keyword(s):  
Masked Priming ◽  
Statistical Correlation ◽  
Morphological Processing ◽  
Fine Tuning ◽  
Semantic Transparency ◽  
Lexical Structure ◽  
The Neural Networks ◽  
Distinct Aspect ◽  
The Brain

Is morphology a discrete and independent element of lexical structure or does it simply reflect a fine-tuning of the system to the statistical correlation that exists among orthographic and semantic properties of words? Hebrew provides a unique opportunity to examine morphological processing in the brain because of its rich morphological system. In an fMRI masked priming experiment, we investigated the neural networks involved in implicit morphological processing in Hebrew. In the lMFG and lIFG, activation was found to be significantly reduced when the primes were morphologically related to the targets. This effect was not influenced by the semantic transparency of the morphological prime, and was not found in the semantic or orthographic condition. Additional morphologically related decrease in activation was found in the lIPL, where activation was significantly modulated by semantic transparency. Our findings regarding implicit morphological processing suggest that morphology is an automatic and distinct aspect of visually processing words. These results also coincide with the behavioral data previously obtained demonstrating the central role of morphological processing in reading Hebrew.

scholarly journals Generation of Vascularized Brain Organoids to Study Neurovascular Interactions

2022 ◽  
Author(s):  
Zhen-Ge Luo ◽  
Xin-Yao Sun ◽  
Xiang-Chun Ju ◽  
Yang Li ◽  
Peng-Ming Zeng ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Development ◽  
Immune Cells ◽  
Aging Process ◽  
Neural Progenitors ◽  
Brain Disorders ◽  
Specific Population ◽  
Neurovascular Interactions ◽  
The Brain

The recently developed brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis, brain disorders, and aging process, limits the utility of brain organoids. In this study, we induced vessel and brain organoids respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures, and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood-brain-barrier (BBB)-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, in particular the vasculature and microglia niche.

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

2021 ◽  
Author(s):  
Tatsuya Osaki ◽  
Yoshiho Ikeuchi
Keyword(s):  
Human Brain ◽  
Three Dimensional ◽  
Oscillatory Activity ◽  
Cellular Functions ◽  
Complex Activity ◽  
Axonal Connections ◽  
Brain Organoid ◽  
External Stimuli ◽  
The Brain

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.

scholarly journals Robust and distributed neural representation of action values

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Eun Ju Shin ◽  
Yunsil Jang ◽  
Soyoun Kim ◽  
Hoseok Kim ◽  
Xinying Cai ◽  
...  
Keyword(s):  
Neural Activity ◽  
Statistical Tests ◽  
Brain Structures ◽  
Surrogate Data ◽  
Neural Representation ◽  
Decision Variables ◽  
Multiple Regions ◽  
Serial Correlations ◽  
Action Value ◽  
The Brain

Studies in rats, monkeys, and humans have found action-value signals in multiple regions of the brain. These findings suggest that action-value signals encoded in these brain structures bias choices toward higher expected rewards. However, previous estimates of action-value signals might have been inflated by serial correlations in neural activity and also by activity related to other decision variables. Here, we applied several statistical tests based on permutation and surrogate data to analyze neural activity recorded from the striatum, frontal cortex, and hippocampus. The results show that previously identified action-value signals in these brain areas cannot be entirely accounted for by concurrent serial correlations in neural activity and action value. We also found that neural activity related to action value is intermixed with signals related to other decision variables. Our findings provide strong evidence for broadly distributed neural signals related to action value throughout the brain.

scholarly journals 19-Hydroxy steroids in the aromatase reaction: Review on expression and potential functions

2021 ◽  
Author(s):  
Tatjana Abaffy ◽  
Hiroaki Matsunami
Keyword(s):  
Adrenal Glands ◽  
Ovarian Function ◽  
Scientific Evidence ◽  
Future Research ◽  
Analytical Sensitivity ◽  
Biological Processes ◽  
Search Terms ◽  
Pathological Conditions ◽  
Pubmed Database ◽  
The Brain

Abstract Scientific evidence related to the aromatase reaction in various biological processes spanning from mid-1960 is abundant, however, as our analytical sensitivity increases, a new look at the old chemical reaction is necessary. Here, we review an irreversible aromatase reaction from the substrate androstenedione. It proceeds in 3 consecutive steps. In the first two steps, 19-hydroxy steroids are produced. They can dissociate from the enzyme complex and either accumulate in tissues or enter the blood.In this review, we want to highlight the potential importance of these 19-hydroxy steroids in various physiological and pathological conditions. We focus primarily on 19-hydroxy steroids, and in particular on the 19-hydroxyandrostenedione produced by the incomplete aromatase reaction. Using a PubMed database and search terms aromatase reaction,19-hydroxylation of androgens and steroid measurements, we detail the chemistry of the aromatase reaction and list previous and current methods used to measure 19-hydroxy steroids. We present the evidence of the existence of 19-hydroxy steroids in the brain tissue, ovaries, testes, adrenal glands, prostate cancer and also during pregnancy and parturition and in Cushing’s disease. Based on the available literature, a potential involvement of 19-hydroxy steroids in the brain differentiation process, sperm motility, ovarian function, and hypertension is suggested and warrant future research.We hope that with the advancement of highly specific and sensitive analytical methods, future research into 19-hydroxy steroids will be encouraged, as much remains to be learned and discovered.

scholarly journals P11.57 A 3D brain organoid coculture system delineates the invasive cell components in glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii56-iii57
Author(s):  
W Zhou ◽  
B Klink ◽  
G Dittmar ◽  
P Nazarov ◽  
E M Garcia ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Cell Invasion ◽  
Ex Vivo ◽  
Normal Brain ◽  
Rna Seq ◽  
Normal Brain Tissue ◽  
Coculture System ◽  
Mature Brain ◽  
Brain Organoid ◽  
The Brain

Abstract BACKGROUND Glioblastoma (GBM) cell infiltration into the surrounding normal brain tissue where the blood brain barrier is intact, represents a major problem for clinical management and therapy. There is a vital need to understand the molecular mechanism that drives tumor cell invasion into the surrounding brain. We have previously developed a 3D coculture model where mature brain organoids are confronted with patient-derived glioblastoma stem-like cells (GSCs). In such a coculture system, single cell invasion into the normal brain tissue can be studied in detail. Here, we first describe in detail, by RNA-seq and proteomics, the differentiation of various neural cell lineages into mature brain organoids as well as their cellular organization. By real-time confocal microscopy and imaging analyses we also determine the speed of tumor cell invasion into the brain. Finally, we used this coculture system to delineate in detail the cellular heterogeneity within the invasive compartment and their gene expression. MATERIAL AND METHODS Immunohistochemistry and immunofluorescence were used to determine the expression and distribution of mature neurons, astrocytes, oligodendrocytes, and microglia within the brain organoids. Proteomics and RNA-seq were used to determine brain development ex-vivo. To assess the clonal composition of the GBM-invasive compartment, we used cellular (RGB) barcoding technology. By advanced imaging, we tracked in real time the invasion of barcoded cells into the brain organoids. Finally, we isolated invasive cells and non-invasive cells from our coculture system and used single cell sequencing to analyze their gene expression profiles and molecular phenotypes. RESULTS Immunohistochemistry and immunofluorescence showed that brain organoids, after 21 days of differentiation, display a highly cellular and structural organization. RNA-seq and proteomics, performed at different time points of organoid differentiation, revealed that the brain organoids develop into mature brain structures after 21 days as verified by a comparative analysis to normal rat brain development in vivo. Imaging analyses showed that multiple clones within the GBMs have the capacity to invade into the brain tissue with an average speed of ~ 20 μm/h. RNA-sec analysis of the invasive compartment revealed a strong up-regulation of genes and pathways associated with anaerobic respiration (glycolysis). CONCLUSION We describe a highly standardized brain organoid coculture system that can be used to delineate GBM invasion ex-vivo. We demonstrate that this platform can be used to unravel the mechanisms that drive GBM invasion into the normal brain.

scholarly journals Associations of Vitamin D and Vitamin K and Their Metabolites Across Four Regions of the Human Brain: The Memory and Aging Project (MAP) (FS05-02-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Xueyan Fu ◽  
Will Patterson ◽  
Gregory Dolnikowski ◽  
Bess Dawson-Hughes ◽  
Martha Morris ◽  
...  
Keyword(s):  
Vitamin D ◽  
Human Brain ◽  
Vitamin K ◽  
Vitamin D3 ◽  
Rank Order ◽  
Temporal Cortex ◽  
Correlation Coefficients ◽  
Brain Regions ◽  
Multiple Regions ◽  
The Brain

Abstract Objectives Very little is known about the forms of vitamin D and vitamin K in the human brain. The objective of this study is to evaluate concentrations of vitamin D and vitamin K forms in human brain and their correlations across four human brain regions. Methods Vitamin D [D3, 25(OH)D and 1,25(OH)2D] and vitamin K [phylloquinone and menaquinone-4 (MK4)] concentrations were measured by LC/MS/MS and HPLC, respectively, in four brain regions from post-mortem samples obtained from participants in the Rush Memory and Aging Project (n = 130, mean age 82 yrs, 81% female). The brain regions analyzed were the mid-frontal cortex (MF) and mid-temporal cortex (MT) [two regions important for memory in Alzheimer's Disease (AD)], the cerebellum (CR, a region not affected by AD), and the anterior watershed white matter (AWS, a region associated with vascular disease). The correlations among the vitamin forms across brain regions were calculated using Spearman rank order correlation coefficients. Significance was set at P < 0.001. Results The average concentrations of vitamin D3, 25(OH)D and MK4 were 604 pg/g, 535 pg/g, and 3.4 pmol/g, respectively. 25(OH)D and MK4 were detected in >95% of the brain samples. Nearly 92% of 1,25(OH)2D and 80% of phylloquinone samples had concentrations below the limit of assay detection (LOD) 1,25(OH)2D = 20 ng/g, phylloquinone = 0.1 pmol/g). Vitamin D3 and 25(OH)D concentrations were positively correlated across all four regions (all Spearman r ≥ 0.78, P < 0.0001). The 1,25(OH)2D was significantly correlated between the MF and CR regions only (Spearman r = 0.30, P < 0.001, all other P ≥ 0.002). MK4 and PK were positively correlated across the four regions studied (MK4 all Spearman r ≥ 0.78, phylloquinone r ≥ 0.49, all P < 0.001). Conclusions To the best of our knowledge, this study is the first evaluation of the concentrations of vitamin D and vitamin K forms in multiple regions of the human brain. Overall, the vitamin D and vitamin K forms were each positively correlated across the four brain regions studied. Future studies are needed to clarify the roles of these nutrients in AD and dementia. Funding Sources National Institute of Aging.

scholarly journals Robust parallel decision-making in neural circuits with nonlinear inhibition

2020 ◽  
Vol 117 (41) ◽  
pp. 25505-25516
Author(s):  
Birgit Kriener ◽  
Rishidev Chaudhuri ◽  
Ila R. Fiete
Keyword(s):  
Decision Making ◽  
Neural Circuits ◽  
Fine Tuning ◽  
Neural Computing ◽  
Hick’S Law ◽  
Noisy Input ◽  
Finite Memory ◽  
Winner Take All ◽  
The Brain ◽  
Take All

An elemental computation in the brain is to identify the best in a set of options and report its value. It is required for inference, decision-making, optimization, action selection, consensus, and foraging. Neural computing is considered powerful because of its parallelism; however, it is unclear whether neurons can perform this max-finding operation in a way that improves upon the prohibitively slow optimal serial max-finding computation (which takes∼N⁡log(N)time for N noisy candidate options) by a factor of N, the benchmark for parallel computation. Biologically plausible architectures for this task are winner-take-all (WTA) networks, where individual neurons inhibit each other so only those with the largest input remain active. We show that conventional WTA networks fail the parallelism benchmark and, worse, in the presence of noise, altogether fail to produce a winner when N is large. We introduce the nWTA network, in which neurons are equipped with a second nonlinearity that prevents weakly active neurons from contributing inhibition. Without parameter fine-tuning or rescaling as N varies, the nWTA network achieves the parallelism benchmark. The network reproduces experimentally observed phenomena like Hick’s law without needing an additional readout stage or adaptive N-dependent thresholds. Our work bridges scales by linking cellular nonlinearities to circuit-level decision-making, establishes that distributed computation saturating the parallelism benchmark is possible in networks of noisy, finite-memory neurons, and shows that Hick’s law may be a symptom of near-optimal parallel decision-making with noisy input.

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