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 Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Austin Ferro ◽  
Yohan S. S. Auguste ◽  
Lucas Cheadle
Keyword(s):  
Brain Development ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Neural Activity ◽  
Signaling Molecules ◽  
Evolutionary Strategy ◽  
Inflammatory Signaling ◽  
Peripheral Tissues ◽  
And Function ◽  
The Brain

Intercellular signaling molecules such as cytokines and their receptors enable immune cells to communicate with one another and their surrounding microenvironments. Emerging evidence suggests that the same signaling pathways that regulate inflammatory responses to injury and disease outside of the brain also play powerful roles in brain development, plasticity, and function. These observations raise the question of how the same signaling molecules can play such distinct roles in peripheral tissues compared to the central nervous system, a system previously thought to be largely protected from inflammatory signaling. Here, we review evidence that the specialized roles of immune signaling molecules such as cytokines in the brain are to a large extent shaped by neural activity, a key feature of the brain that reflects active communication between neurons at synapses. We discuss the known mechanisms through which microglia, the resident immune cells of the brain, respond to increases and decreases in activity by engaging classical inflammatory signaling cascades to assemble, remodel, and eliminate synapses across the lifespan. We integrate evidence from (1) in vivo imaging studies of microglia-neuron interactions, (2) developmental studies across multiple neural circuits, and (3) molecular studies of activity-dependent gene expression in microglia and neurons to highlight the specific roles of activity in defining immune pathway function in the brain. Given that the repurposing of signaling pathways across different tissues may be an important evolutionary strategy to overcome the limited size of the genome, understanding how cytokine function is established and maintained in the brain could lead to key insights into neurological health and disease.

scholarly journals Tuberin levels during cellular differentiation in brain development

2021 ◽  
Author(s):  
Bashaer Abu Khatir ◽  
Gordon Omar Davis ◽  
Mariam Sameem ◽  
Rutu Patel ◽  
Jackie Fong ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Development ◽  
Cell Lines ◽  
Neural Development ◽  
Time Course ◽  
Embryonic Mouse ◽  
Organ Systems ◽  
The Central Nervous System

Tuberin is a member of a large protein complex, Tuberous Sclerosis Complex, and acts as a sensor for nutrient status regulating protein synthesis and cell cycle progression. Mutations in the Tuberin gene, TSC2, lead to the formation of tumors and developmental defects in many organ systems, including the central nervous system. Tuberin is expressed in the brain throughout development and levels of Tuberin have been found to decrease during neuronal differentiation in cell lines in vitro. Our current work investigates the levels of Tuberin at two stages of embryonic development in vivo, and we study the mRNA and protein levels during a time course using immortalized cell lines in vitro. Our results show that Tuberin levels remain stable in the olfactory bulb but decrease in the Purkinje cell layer during embryonic mouse brain development. We show here that Tuberin levels are higher when cells are cultured as neurospheres, and knockdown of Tuberin results in a reduction in the number of neurospheres. These data provide support for the hypothesis that Tuberin is an important regulator of stemness and the reduction of Tuberin levels might support functional differentiation in the central nervous system. Understanding how Tuberin expression is regulated throughout neural development is essential to fully comprehend the role of this protein in several developmental and neural pathologies.

MRI Characteristic of Cerebral White Matter Maturation Patterns in Normal Infants of Assisted Reproductive

2020 ◽  
Author(s):  
Xiaoming Wu ◽  
Junfeng Wang ◽  
Libo Zou ◽  
Xiaojian Cui ◽  
Youcheng Wang ◽  
...  
Keyword(s):  
Brain Development ◽  
Cerebral White Matter ◽  
Vitro Fertilization ◽  
Brain Scans ◽  
Number Of Children ◽  
Significant Difference ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Abstract Background Assisted reproductive technology (ART) such as in-vitro fertilization (IVF) and embryo transfer (ET) has been essential in the treatment of infertility, and the number of children born after these procedures has now passed 5 million worldwide. Children born after medically assisted reproduction are at higher risk of adverse birth outcomes than are children conceived naturally. In this study, we leveraged MRI technology to investigate whether ART pregnancy methods: intracytoplasmic sperm injection (ICSI) and ET have any effect on the brain development of offspring by comparing with the NAT pregnancy method. Methods A total of 75 infants were recruited in the study from 3 conception groups: 25 children born after ICSI, 25 children born after IVF-ET and 25 children born after natural pregnancy. Magnetic resonance imaging (MRI) scans provide exceptionally detailed information on how the human brain changes throughout childhood, adolescence, and old age. The use of MRI in the evaluation of the developing brain is well established. Results The results of routine brain scans on T1WI and T2WI showed that there was no significant difference among the 5-7, 11-13, and 23-25 months of infants among ET, ICSI, and NAT groups. The MRI values fluctuate at different time points indicating that they may change with the development of the brain. However, they are on a similar level for different conception groups supporting our previous statistical analysis that MRI values of ICSI and ET groups are not significantly different from NAT. Conclusions The results showed that there was no significant difference in brain development patterns between different modes of conception, which proved that ART does not affect the development of brain myelin in fetuses and infants.

scholarly journals Polysialic Acid-Directed Migration and Differentiation of Neural Precursors Are Essential for Mouse Brain Development

2007 ◽  
Vol 27 (19) ◽  
pp. 6659-6668 ◽  
Author(s):  
Kiyohiko Angata ◽  
Valerie Huckaby ◽  
Barbara Ranscht ◽  
Alexey Terskikh ◽  
Jamey D. Marth ◽  
...  
Keyword(s):  
Cell Migration ◽  
Brain Development ◽  
Glial Cell ◽  
Neural Development ◽  
Apoptotic Cell ◽  
Polysialic Acid ◽  
Neural Cell ◽  
Neural Precursors

ABSTRACT Polysialic acid, which is synthesized by two polysialyltransferases, ST8SiaII and ST8SiaIV, plays an essential role in brain development by modifying the neural cell adhesion molecule (NCAM). It is currently unclear how polysialic acid functions in different processes of neural development. Here we generated mice doubly mutant in both ST8SiaII and ST8SiaIV to determine the effects of loss of polysialic acid on brain development. In contrast to NCAM-deficient, ST8SiaII-deficient, or ST8SiaIV-deficient single mutant mice, ST8SiaII and ST8SiaIV double mutants displayed severe defects in anatomical organization of the forebrain associated with apoptotic cell death. Loss of polysialic acid affected both tangential and radial migration of neural precursors during cortical development, resulting in aberrant positioning of neuronal and glial cells. Glial cell differentiation was aberrantly increased in vivo and in vitro in the absence of polysialic acid. Consistent with these findings, polysialic acid-deficient mice exhibited increased expression of the glial cell marker glial fibrillary acidic protein and a decrease in expression of Pax6, a transcription factor regulating neural cell migration. These results indicate that polysialic acid regulates cell migration and differentiation of neural precursors crucial for brain development.

scholarly journals Probing the VIPR2 Microduplication Linkage to Schizophrenia in Animal and Cellular Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Yukio Ago ◽  
Satoshi Asano ◽  
Hitoshi Hashimoto ◽  
James A. Waschek
Keyword(s):  
Synaptic Plasticity ◽  
Brain Development ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Autism Spectrum ◽  
Cellular Models ◽  
Pituitary Adenylate Cyclase ◽  
Innervation Patterns ◽  
The Brain

Pituitary adenylate cyclase-activating polypeptide (PACAP, gene name ADCYAP1) is a multifunctional neuropeptide involved in brain development and synaptic plasticity. With respect to PACAP function, most attention has been given to that mediated by its specific receptor PAC1 (ADCYAP1R1). However, PACAP also binds tightly to the high affinity receptors for vasoactive intestinal peptide (VIP, VIP), called VPAC1 and VPAC2 (VIPR1 and VIPR2, respectively). Depending on innervation patterns, PACAP can thus interact physiologically with any of these receptors. VPAC2 receptors, the focus of this review, are known to have a pivotal role in regulating circadian rhythms and to affect multiple other processes in the brain, including those involved in fear cognition. Accumulating evidence in human genetics indicates that microduplications at 7q36.3, containing VIPR2 gene, are linked to schizophrenia and possibly autism spectrum disorder. Although detailed molecular mechanisms have not been fully elucidated, recent studies in animal models suggest that overactivation of the VPAC2 receptor disrupts cortical circuit maturation. The VIPR2 linkage can thus be potentially explained by inappropriate control of receptor signaling at a time when neural circuits involved in cognition and social behavior are being established. Alternatively, or in addition, VPAC2 receptor overactivity may disrupt ongoing synaptic plasticity during processes of learning and memory. Finally, in vitro data indicate that PACAP and VIP have differential activities on the maturation of neurons via their distinct signaling pathways. Thus perturbations in the balance of VPAC2, VPAC1, and PAC1 receptors and their ligands may have important consequences in brain development and plasticity.

Microbiota-immune interactions: from gut to brain

2020 ◽  
Vol 7 (1) ◽  
pp. 1-23 ◽  
Author(s):  
Eloisa Salvo-Romero ◽  
Patricia Stokes ◽  
Mélanie G. Gareau
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune System ◽  
Gut Microbiota ◽  
Brain Development ◽  
Immune Cells ◽  
Autism Spectrum ◽  
Immune System Development ◽  
And Function ◽  
The Brain

The vast diversity of bacteria that inhabit the gastrointestinal tract strongly influence host physiology, not only nutrient metabolism but also immune system development and function. The complexity of the microbiota is matched by the complexity of the host immune system, where they have coevolved to maintain homeostasis ensuring the mutualistic host-microbial relationship. Numerous studies in recent years investigating the gut-brain axis have demonstrated an important role for the gut microbiota in modulating brain development and function, with the immune system serving as an important coordinator of these interactions. Gut bacteria can modulate not only gut-resident immune cells but also brain-resident immune cells. Activation of the immune system in the gut and in the brain are implicated in responses to neuroinflammation, brain injury, as well as changes in neurogenesis and plasticity. Impairments in this bidirectional communication are implicated in the etiopathogenesis of psychiatric and neurodevelopmental diseases and disorders, including autism spectrum disorders, or comorbidities associated with Gastrointestinal diseases, including inflammatory bowel diseases, where dysbiosis is commonly seen. Consequently, probiotics, or beneficial microbes, are being recognized as promising therapeutic targets to modulate behavior and brain development by modulating the gut microbiota. Here we review the role of microbiota-immune interactions in the gut and the brain during homeostasis and disease and their impact on gut-brain communication, brain function, and behavior as well as the use of probiotics in central nervous system alterations. Statement of novelty: The microbiota-gut-brain axis is increasingly recognized as an important physiological pathway for maintaining health and impacting the brain and central nervous system. Increasing evidence suggests that the immune system is crucial for gut-brain signaling. In this review, we highlight the critical studies in the literature that identify the key immune pathways involved.

Postnatal Brain Development

2013 ◽  
pp. 128-163 ◽  
Author(s):  
Julie C. Markant ◽  
Kathleen M. Thomas
Keyword(s):  
Brain Development ◽  
Neural Development ◽  
Developmental Change ◽  
Childhood And Adolescence ◽  
Postnatal Brain ◽  
Significant Development ◽  
Key Aspects ◽  
The Brain ◽  
Synaptic Pruning ◽  
New Discovery

While key aspects of neural development occur prenatally in humans, the brain continues to show significant development postnatally. In this chapter, we review several aspects of brain development that continue well into childhood and adolescence. First, we discuss the continued sculpting of synaptic connections, including the extension of axons and dendrites, neurotransmitter function, synaptic pruning, and myelination. Second, we examine noninvasive indices of structural brain development, including regional volume and connectivity in the brain that may be more easily linked to changes in child behavior across development. Third, we briefly discuss broad developmental changes in functional activity of the brain and connectivity across regions. Finally, we discuss the evidence for postnatal neurogenesis, a relatively new discovery in postnatal brain development. We conclude that although prenatal events of brain development are critical, postnatal sculpting of the brain continues to play a central role in individual differences in behavior and developmental change.

scholarly journals EDITING THE BEHAVIOR OF EXPERIMENTAL ANIMALS MODULATED IN VITRO BY IMMUNE CELLS

2019 ◽  
Vol 19 (1S) ◽  
pp. 149-151
Author(s):  
M A Knyazheva ◽  
E V Serenko ◽  
G S Karpovich
Keyword(s):  
Field Test ◽  
Immune Cells ◽  
Functional Activity ◽  
Open Field Test ◽  
Test Tube ◽  
Male Mice ◽  
Experimental Animals ◽  
Hyperactive Behavior ◽  
The Brain

The aim of the study is to edit the hyperactive behavior in experiments using immunocyte transplantation using in vitro modules with neuroleptic functional activity. Materials and methods. Experimental model: male mice (CBAxC57Bl/6) F1 of three months of age with hyperactive behavior. Immune cells were treated with chlorpromazine in a test tube, injected intravenously into the recipient, in which the behavior parameters in the open field test and the cytokine content in the brain were determined by ELISA. Results. Transplantation of precision and neuroleptic components contained in recipient mice is accompanied by a decrease in the indices of research and motor components, as well as the levels of IL-1β, IL-6 and TNFα cytokines in the brain.

scholarly journals Altered expression of Armet and Mrlp51 in the oocyte, preimplantation embryo, and brain of mice following oocyte in vitro maturation but postnatal brain development and cognitive function are normal

Reproduction ◽  
2011 ◽  
Vol 142 (3) ◽  
pp. 401-408 ◽  
Author(s):  
Ning Wang ◽  
Liya Wang ◽  
Fang Le ◽  
Qitao Zhan ◽  
Yingming Zheng ◽  
...  
Keyword(s):  
Brain Development ◽  
Early Stage ◽  
Suppressive Subtractive Hybridization ◽  
Control Group ◽  
Newborn Mice ◽  
Altered Expression ◽  
Developmental Potential ◽  
The Brain

Despite the efforts to recapitulate the follicle environment, oocytes from in vitro maturation (IVM) have poorer developmental potential than those matured in vivo and the effects on the resultant offspring are of concern. The aim of this study was to determine altered gene expression in oocytes following IVM and to evaluate the expression of the arginine rich, mutated in early stage of tumors gene (Armet) and mitochondrial ribosomal protein L51 (Mrpl51) in embryos and brains of fetal/postnatal mice and the brain development of IVM offspring. An IVM mouse model was established while oocytes matured in vivo were used as the controls. Suppressive subtractive hybridization (SSH) and RT-PCR/western blot were used to analyze the differential expression of genes/proteins between IVM and the control group. HE staining and water maze were used to assess the histological changes in brain tissue and cognition of the offspring. The rates of fertilization, cleavage, and live birth were significantly decreased in IVM group. Thirteen genes were upregulated in IVM oocytes compared with the control, including Armet and Mrpl51. The higher level of Armet in IVM oocytes was retained in brain of newborn mice, which could be related to the upregulation of activating transcription factor 6 (Atf6) and X-box binding protein 1 (Xbp1), while Mrpl51 was expressed normally in brain of postnatal mice. No significant differences were detected in brain weight, neuronal counts, and the cognition in the offspring between the two groups. The present results suggested that IVM could affect the pregnancy outcome and the Armet and Mrpl51 gene/protein expression. The change in Armet expression lasted while the change of Mrpl51 disappeared after birth. However, the brain development of the offspring seemed to be unaffected by IVM.

Neuroleptic effect in aggressive mice after the transplantation of immune cells treated in vitro with chlorpromazine

2016 ◽  
Vol 33 (S1) ◽  
pp. s221-s221
Author(s):  
E. Markova ◽  
M. Knyazheva ◽  
T. Shushpanova
Keyword(s):  
Immune Cells ◽  
Social Stress ◽  
Nervous Activity ◽  
Mononuclear Phagocyte ◽  
T Helper 1 ◽  
Immune Systems ◽  
Research Results ◽  
Before And After ◽  
The Brain

IntroductionExistence of integration, mutual relations of nervous and immune systems, which cellular elements are characterized by expressed phenotype and functional similarity, means the possibility of immune cells participation in the regulation of higher nervous activity.ObjectivesPreviously, we demonstrated the possibility of targeted regulation of animal's behavior by the transplantation of immune cells with definite functional characteristics. Based on the our previous research results in the present study, we investigated the modulating effect of the immune cells, treated in vitro with chlorpromazine on the nervous and immune systems functional activity in aggressive mice.Methods(CBA × C57Bl/6) F1 aggressive mice, exposed to 10-days chronic social stress, were undergoing the transplantation of immune cells in vitro treated with chlorpromazine. Animal's behavioral parameters, cytokines synthesis in the brain and immune cells before and after transplantation were estimated.ResultsIt was shown that aggression is associated with the increased production of spleen T-helper 1 cell-derived cytokines IL-2 and IFNγ, as well as decreased TNFα production by the spleen mononuclear phagocyte cells. These alterations were more pronounced following mitogen stimulation. Spleen cells, obtaining from aggressive mice, were treated in vitro with chlorpromazine and then injected intravenously into syngeneic aggressive recipients. The cell's transplantation led to the reduction of the recipient's motor activity in the “open field” and Porsolt swimming tests and normalized cytokines synthesis in the brain and immune cells.ConclusionResearch results demonstrated the neuroleptic effect in aggressive mice, obtained by the transplantation of immune cells treated in vitro with chlorpromazine.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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