scholarly journals Nested oscillatory dynamics in cortical organoids model early human brain network development

2018 ◽  
Author(s):  
Cleber A. Trujillo ◽  
Richard Gao ◽  
Priscilla D. Negraes ◽  
Isaac A. Chaim ◽  
Alain Domissy ◽  
...  
Keyword(s):  
Human Brain ◽  
Network Activity ◽  
Brain Maturation ◽  
Oscillatory Activity ◽  
List Type ◽  
Complex Activity ◽  
Neuronal Computation ◽  
Oscillatory Network

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.

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 STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

2018 ◽  
Vol 96 (10) ◽  
pp. 1061-1079 ◽  
Author(s):  
Carlos Pascual-Caro ◽  
Maria Berrocal ◽  
Aida M. Lopez-Guerrero ◽  
Alberto Alvarez-Barrientos ◽  
Eulalia Pozo-Guisado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Protein Expression ◽  
Transmembrane Domain ◽  
Neuroblastoma Cell ◽  
Disease Patient ◽  
List Type

Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

scholarly journals Identification of neural oscillations and epileptiform changes in human brain organoids

2019 ◽  
Author(s):  
Ranmal A. Samarasinghe ◽  
Osvaldo A. Miranda ◽  
Simon Mitchell ◽  
Isabella Ferando ◽  
Momoko Watanabe ◽  
...  
Keyword(s):  
Neural Network ◽  
Human Brain ◽  
Network Architecture ◽  
Network Formation ◽  
Neurological Diseases ◽  
Extracellular Recording ◽  
Brain Network ◽  
Network Activity ◽  
Intact Brain ◽  
Oscillatory Network

ABSTRACTHuman brain organoids represent a powerful tool for the study of human neurological diseases particularly those that impact brain growth and structure. However, many neurological diseases lack obvious anatomical abnormalities, yet significantly impact neural network functions, raising the question of whether organoids possess sufficient neural network architecture and complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex oscillatory network behaviors reminiscent of intact brain preparations. We further demonstrate strikingly abnormal epileptiform network activity in organoids derived from a Rett Syndrome patient despite only modest anatomical differences from isogenically matched controls, and rescue with an unconventional neuromodulatory drug Pifithrin-α. Together, these findings provide an essential foundation for the utilization of human brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

scholarly journals The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

2020 ◽  
Author(s):  
Linda Scaramuzza ◽  
Giuseppina De Rocco ◽  
Genni Desiato ◽  
Clementina Cobolli Gigli ◽  
Martina Chiacchiaretta ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neuronal Activity ◽  
Time Window ◽  
Early Time ◽  
Brain Maturation ◽  
Transcriptional Program ◽  
Brain Functions ◽  
Reduced Activity

AbstractMecp2 deficiency, the gene responsible for Rett syndrome (RTT), affects brain maturation by impairing neuronal activity, transcription and morphology. These three elements are physiologically linked in a feed-forward cycle where neuronal activity modulates transcription and morphology to further increase network maturity. We hypothesized that the reduced activity displayed by maturing Mecp2 null neurons during development could perturb such cycle, sustaining an improper transcriptional program that, ultimately, impairs neuronal maturation. Accordingly, we show that by enhancing activity within an early time window, Ampakine redirects, in vitro, the development of null neuronal networks towards more physiological routes. Similarly, the administration of the drug to newborn null offspring delays the progression of symptoms, significantly prolonging life span. Our data highlights the role of altered neuronal activity during the establishment of Mecp2 null networks and the importance of such early defects to the typically poor maturity of RTT brain functions in adulthood. We propose the existence of an “early molecular phase” of Rett syndrome, a detailed description of which might disclose relevant targets for new rescue treatments.

scholarly journals Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex

2008 ◽  
Vol 2008 ◽  
pp. 1-12 ◽  
Author(s):  
Nicola H. Morgan ◽  
Ian M. Stanford ◽  
Gavin L. Woodhall
Keyword(s):  
Synaptic Transmission ◽  
Cannabinoid Receptors ◽  
Brain Regions ◽  
Synaptic Activity ◽  
Network Activity ◽  
Oscillatory Activity ◽  
Gabaergic Neurotransmission ◽  
Network Oscillations ◽  
Gabaergic Synaptic Transmission

Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs) at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M), an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC) neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM), increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

scholarly journals Circ_0026416 downregulation blocks the development of colorectal cancer through depleting MYO6 expression by enriching miR-545-3p

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lei Zhang ◽  
Ranran Yu ◽  
Chunhua Li ◽  
Yu Dang ◽  
Xiaoyu Yi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Colony Formation ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
List Type ◽  
Mesenchymal Transition

Abstract Background Emerging evidence reveals that the initiation and development of human cancers, including colorectal cancer (CRC), are associated with the deregulation of circular RNAs (circRNAs). Our study intended to disclose the role of circ_0026416 in the malignant behaviors of CRC. Methods The detection for circ_0026416 expression, miR-545-3p expression, and myosin VI (MYO6) mRNA expression was performed using quantitative real-time PCR (qPCR). CCK-8 assay, colony formation assay, transwell assay, and flow cytometry assay were applied for functional analysis to monitor cell proliferation, migration, invasion, and apoptosis. The protein levels of MYO6 and epithelial mesenchymal-transition (EMT) markers were detected by western blot. Mouse models were used to determine the role of circ_0026416 in vivo. The potential relationship between miR-545-3p and circ_0026416 or MYO6 was verified by dual-luciferase reporter assay and RIP assay. Results The expression of circ_0026416 was increased in CRC tumor tissues and cell lines. Circ_0026416 downregulation inhibited CRC cell proliferation, colony formation, migration, invasion, and EMT but induced cell apoptosis in vitro, and circ_0026416 knockdown also blocked tumor growth in vivo. MiR-545-3p was a target of circ_0026416, and rescue experiments indicated that circ_0026416 knockdown blocked CRC development by enriching miR-545-3p. In addition, miR-545-3p targeted MYO6 and inhibited MYO6 expression. MiR-545-3p enrichment suppressed CRC cell malignant behaviors by sequestering MYO6. Importantly, circ_0026416 knockdown depleted MYO6 expression by enriching miR-545-3p. Conclusion Circ_0026416 downregulation blocked the development of CRC through depleting MYO6 expression by enriching miR-545-3p. Highlights Circ_0026416 downregulation inhibits CRC development in vitro and in vivo. Circ_0026416 regulates the expression of MYO6 by targeting miR-545-3p. Circ_0026416 governs the miR-545-3p/MYO6 axis to regulate CRC progression.

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