scholarly journals Development of schemas revealed by prior experience and NMDA receptor knock-out

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
George Dragoi ◽  
Susumu Tonegawa
Keyword(s):  
De Novo ◽  
Prior Experience ◽  
Anterograde Amnesia ◽  
Network Activity ◽  
Knock Out ◽  
Related Information ◽  
Neuronal Mechanisms ◽  
Hippocampal Ca3 ◽  
Mental Schemas ◽  
Neuronal Encoding

Prior experience accelerates acquisition of novel, related information through processes like assimilation into mental schemas, but the underlying neuronal mechanisms are poorly understood. We investigated the roles that prior experience and hippocampal CA3 N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity play in CA1 place cell sequence encoding and learning during novel spatial experiences. We found that specific representations of de novo experiences on linear environments were formed on a framework of pre configured network activity expressed in the preceding sleep and were rapidly, flexibly adjusted via NMDAR-dependent activity. This prior experience accelerated encoding of subsequent experiences on contiguous or isolated novel tracks, significantly decreasing their NMDAR-dependence. Similarly, de novo learning of an alternation task was facilitated by CA3 NMDARs; this experience accelerated subsequent learning of related tasks, independent of CA3 NMDARs, consistent with a schema-based learning. These results reveal the existence of distinct neuronal encoding schemes which could explain why hippocampal dysfunction results in anterograde amnesia while sparing recollection of old, schema-based memories.

TAMI-37. STEAROYL-COA DESATURASE 1 IS ESSENTIAL FOR THE GROWTH OF IDH MUTANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi206-vi206
Author(s):  
Tomohiro Yamasaki ◽  
Lumin Zhang ◽  
Tyrone Dowdy ◽  
Adrian Lita ◽  
Mark Gilbert ◽  
...  
Keyword(s):  
Glioma Cell ◽  
De Novo ◽  
Glioma Cells ◽  
Model Systems ◽  
De Novo Lipogenesis ◽  
Wild Type ◽  
Knock Out ◽  
Stearoyl Coa Desaturase ◽  
Scd1 Expression

Abstract BACKGROUND Increased de novo lipogenesis is a hallmark of cancer metabolism. In this study, we interrogated the role of de novo lipogenesis in IDH1 mutated glioma’s growth and identified the key enzyme, Stearoyl-CoA desaturase 1 (SCD1) that provides this growth advantage. MATERIALS ANDMETHODS We prepared genetically engineered glioma cell lines (U251 wild-type: U251WT and U251 IDHR132H mutant: U251RH) and normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH). Lipid metabolic analysis was conducted by using LC-MS and Raman imaging microscopy. SCD1 expression was investigated by The Cancer Genome Atlas (TCGA) data analysis and Western-blotting method. Knock-out of SCD1 was conducted by using CRISPR/Cas9 and shRNA. RESULTS Previously, we showed that IDH1 mut glioma cells have increased monounsaturated fatty acids (MUFAs). TCGA data revealed IDH mut glioma shows significantly higher SCD1 mRNA expression than wild-type glioma. Our model systems of IDH1 mut (U251RH, NHARH) showed increased expression of this enzyme compared with their wild-type counterpart. Moreover, addition of D-2HG to U251WT increased SCD1 expression. Herein, we showed that inhibition of SCD1 with CAY10566 decreased relative cell number and sphere forming capacity in a dose-dependent manner. Furthermore, addition of MUFAs were able to rescue the SCD1 inhibitor induced-cell death and sphere forming capacity. Knock out of SCD1 revealed decreased cell proliferation and sphere forming ability. Decreasing lipid content from the media did not alter the growth of these cells, suggesting that glioma cells rely on de novo lipid synthesis rather than scavenging them from the microenvironment. CONCLUSION Overexpression of IDH mutant gene altered lipid composition in U251 cells to enrich MUFA levels and we confirmed that D-2HG caused SCD1 upregulation in U251WT. We demonstrated the glioma cell growth requires SCD1 expression and the results of the present study may provide novel insights into the role of SCD1 in IDH mut gliomas growth.

scholarly journals α 2 Adrenergic Modulation of Hippocampal CA3 Network Activity

2006 ◽  
Vol 20 (4) ◽  
Author(s):  
Chris W.D. Jurgens ◽  
Jacob King ◽  
Sarah Boese ◽  
Jessica Lichter ◽  
Brian Nelson ◽  
...  
Keyword(s):  
Network Activity ◽  
Adrenergic Modulation ◽  
Hippocampal Ca3

scholarly journals CRISPR/Cas9-mediated knock-out of dUTPase in mice leads to early embryonic lethality

2018 ◽  
Author(s):  
Hajnalka Laura Pálinkás ◽  
Gergely Rácz ◽  
Zoltán Gál ◽  
Orsolya Hoffmann ◽  
Gergely Tihanyi ◽  
...  
Keyword(s):  
De Novo ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Blastocyst Stage ◽  
Genome Maintenance ◽  
Inorganic Pyrophosphate ◽  
Knock Out ◽  
Early Embryonic Lethality ◽  
Unicellular Organisms ◽  
Post Implantation

AbstractSanitization of nucleotide pools is essential for genome maintenance. Among the enzymes significant in this mechanism, deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) performs cleavage of dUTP into dUMP and inorganic pyrophosphate. By this reaction the enzyme efficiently prevents uracil incorporation into DNA and provides dUMP, the substrate for de novo thymidylate biosynthesis. Despite its physiological significance, knock-out models of dUTPase have not yet been investigated in mammals, only in unicellular organisms, such as bacteria and yeast. Here we generate CRISPR/Cas9-mediated dUTPase knock-out in mice. We find that heterozygous dut +/-animals are viable while the decreased dUTPase level is clearly observable. We also show that the enzyme is essential for embryonic development. Based on the present results, early dut -/-embryos can still reach the blastocyst stage, however, they die shortly after implantation. Analysis of preimplantion embryos indicate perturbed growth of both inner cell mass (ICM) and trophectoderm (TE). We conclude that dUTPase is indispensable for post-implantation development in mice. The gene targeting model generated in the present study will allow further detailed studies in combination with additional gene knock-outs.

scholarly journals A central role for the retrosplenial cortex in de novo environmental learning

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Stephen D Auger ◽  
Peter Zeidman ◽  
Eleanor A Maguire
Keyword(s):  
Virtual Reality ◽  
Information Processing ◽  
Navigation System ◽  
De Novo ◽  
Prior Experience ◽  
Brain Regions ◽  
Retrosplenial Cortex ◽  
Environmental Learning ◽  
Fundamental Knowledge ◽  
The World

With experience we become accustomed to the types of environments that we normally encounter as we navigate in the world. But how does this fundamental knowledge develop in the first place and what brain regions are involved? To examine de novo environmental learning, we created an ‘alien’ virtual reality world populated with landmarks of which participants had no prior experience. They learned about this environment by moving within it during functional MRI (fMRI) scanning while we tracked their evolving knowledge. Retrosplenial cortex (RSC) played a central and highly selective role by representing only the most stable, permanent features in this world. Subsequently, increased coupling was noted between RSC and hippocampus, with hippocampus then expressing knowledge of permanent landmark locations and overall environmental layout. Studying how environmental representations emerge from scratch provided a new window into the information processing underpinning the brain's navigation system, highlighting the key influence of the RSC.

scholarly journals Phytophthora capsici sterol reductase PcDHCR7 has a role in mycelium development and pathogenicity

2021 ◽  
Author(s):  
Weizhen Wang ◽  
Fan Zhang ◽  
Sicong Zhang ◽  
Zhaolin Xue ◽  
Linfang Xie ◽  
...  
Keyword(s):  
De Novo ◽  
Reductase Activity ◽  
Phytophthora Capsici ◽  
Biosynthesis Pathway ◽  
Wild Type ◽  
Knock Out ◽  
Type Isolate ◽  
De Novo Biosynthesis ◽  
Phytophthora Spp ◽  
Genes Encoding

The de novo biosynthesis of sterols is critical for eukaryotes, however, some organisms lack this pathway including most oomycetes. Phytophthora spp. are sterol auxotroph but remarkably, have retained a few genes encoding enzymes in the sterol biosynthesis pathway. Here we investigated the function of PcDHCR7, a gene in Phytophthora capsici predicted to encode the Δ7-sterol reductase. When expressed in Saccharomyces cerevisiae, PcDHCR7 showed a Δ7-sterol reductase activity. Knocking out PcDHCR7 in P. capsici resulted in loss of the capacity to transform ergosterol into brassicasterol, which means PcDHCR7 has a Δ7-sterol reductase activity in P. capsici itself. This enables P. capsici to transform sterols recruited from the environment for better use. Biological characteristics were compared between wild-type isolate and PcDHCR7 knock-out transformants. The results indicated that PcDHCR7 plays a key role in mycelium development and pathogenicity of zoospores in P. capsici.

The midbrain-hindbrain boundary genetic cascade is activated ectopically in the diencephalon in response to the widespread expression of one of its components, the medaka gene Ol-eng2

Development ◽  
1999 ◽  
Vol 126 (17) ◽  
pp. 3769-3779 ◽  
Author(s):  
F. Ristoratore ◽  
M. Carl ◽  
K. Deschet ◽  
L. Richard-Parpaillon ◽  
D. Boujard ◽  
...  
Keyword(s):  
Optic Tectum ◽  
De Novo ◽  
Ectopic Expression ◽  
Vertebrate Development ◽  
Medaka Fish ◽  
Knock Out ◽  
Essential Components ◽  
Engrailed Genes ◽  
Narrow Stripe ◽  
Neurula Stage

In vertebrates, the engrailed genes are expressed at early neurula stage in a narrow stripe encompassing the midbrain-hindbrain boundary (MHB), a region from which a peculiar structure, the isthmus, is formed. Knock-out experiments in mice demonstrated that these genes are essential for the development of this structure and of its derivatives. In contrast, little is known about the effect of an overexpression of engrailed genes in vertebrate development. Here we report the isolation of Ol-eng2, a medaka fish (Oryzias latipes) engrailed gene. We have monitored the effects of its widespread expression following mRNA injections in 1- and 2-cell medaka and Xenopus embryos. We found that the ectopic expression of Ol-eng2 predominantly results in an altered development of the anterior brain, including an inhibition of optic vesicle formation. No change in the patterns of mesencephalic and telencephalic markers were observed. In contrast, expressions of markers of the diencephalon were strongly repressed in injected embryos. Furthermore, the endogenous Ol-eng2, Pax2, Wnt1 and Fgf8, which are essential components of the MHB genetic cascade, were ectopically expressed in this region. Therefore, we propose that Ol-eng2 induces de novo formation of an isthmus-like structure, which correlates with the development of ectopic midbrain structures, including optic tectum. A competence of the diencephalon to change to a midbrain fate has been demonstrated in isthmic graft experiments. Our data demonstrate that this change can be mimicked by ectopic engrailed expression alone.

Activation of Ih is necessary for patterning of mGluR and mAChR induced network activity in the hippocampal CA3 region

2003 ◽  
Vol 44 (3) ◽  
pp. 293-303 ◽  
Author(s):  
S.R. Cobb ◽  
P.M. Larkman ◽  
D.O. Bulters ◽  
L. Oliver ◽  
C.H. Gill ◽  
...  
Keyword(s):  
Network Activity ◽  
Hippocampal Ca3 ◽  
Ca3 Region

scholarly journals CRISPR/Cas9-Mediated Knock-Out of dUTPase in Mice Leads to Early Embryonic Lethality

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 136 ◽  
Author(s):  
Hajnalka Pálinkás ◽  
Gergely Rácz ◽  
Zoltán Gál ◽  
Orsolya Hoffmann ◽  
Gergely Tihanyi ◽  
...  
Keyword(s):  
De Novo ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Blastocyst Stage ◽  
Genome Maintenance ◽  
Inorganic Pyrophosphate ◽  
Knock Out ◽  
Early Embryonic Lethality ◽  
Key Enzyme ◽  
Unicellular Organisms

Sanitization of nucleotide pools is essential for genome maintenance. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is a key enzyme in this pathway since it catalyzes the cleavage of 2′-deoxyuridine 5′-triphosphate (dUTP) into 2′-deoxyuridine 5′-monophosphate (dUMP) and inorganic pyrophosphate. Through its action dUTPase efficiently prevents uracil misincorporation into DNA and at the same time provides dUMP, the substrate for de novo thymidylate biosynthesis. Despite its physiological significance, knock-out models of dUTPase have not yet been investigated in mammals, but only in unicellular organisms, such as bacteria and yeast. Here we generate CRISPR/Cas9-mediated dUTPase knock-out in mice. We find that heterozygous dut +/– animals are viable while having decreased dUTPase levels. Importantly, we show that dUTPase is essential for embryonic development since early dut −/− embryos reach the blastocyst stage, however, they die shortly after implantation. Analysis of pre-implantation embryos indicates perturbed growth of both inner cell mass (ICM) and trophectoderm (TE). We conclude that dUTPase is indispensable for post-implantation development in mice.

Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 122-129 ◽  
Author(s):  
Markus Lucerna ◽  
Alma Zernecke ◽  
Ramon de Nooijer ◽  
Saskia C. de Jager ◽  
Ilze Bot ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
De Novo ◽  
Atherosclerotic Plaques ◽  
Vascular Endothelial ◽  
Bystander Effects ◽  
Knock Out ◽  
Knock Out Mice ◽  
Endothelial Growth Factor ◽  
Dependent Pathway

Abstract Vascular endothelial growth factor-A is widely used in clinical trials for the treatment of cardiac ischemia. VEGF-A was recently suggested to act in a proinflammatory manner, which could aggravate adjacent atherogenesis in VEGF-A–based therapy. To assess potential bystander effects, VEGF-A was focally overexpressed in advanced atherosclerotic plaques in ApoE−/− mice. Sheer-induced carotid artery plaques were transluminally incubated with Ad.hVEGF-A leading to neointimal overexpression of VEGF-A. Ad.hVEGF-A treatment of pre-existing lesions was seen to promote plaque expansion, with a concomitant increase in macrophage and lipid content, whereas it lowered collagen content. In general, Ad.hVEGF-A–treated plaques displayed a more vulnerable phenotype. VEGF-A overexpression was not accompanied by increased microvessel development in the neointima, suggesting that VEGF-A destabilizes atherosclerotic plaques through an angiogenesis-independent mechanism. Intravital microscopy confirmed that treatment with Ad.hVEGF-A led to an increased monocyte adhesion, which was mediated by a VCAM-1/PECAM-1–dependent pathway. VEGF-A indeed induced a differential expression of VCAM-1 and PECAM-1 in endothelial cells. Our data underline the importance of regular monitoring of stenotic vessels adjacent to the site of VEGF-A application. We propose that VCAM-1/PECAM-1–directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.

scholarly journals Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Carlo Brighi ◽  
Federico Salaris ◽  
Alessandro Soloperto ◽  
Federica Cordella ◽  
Silvia Ghirga ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cortical Neurons ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Functional Characterization ◽  
Model Systems ◽  
Network Activity ◽  
Knock Out ◽  
2D And 3D

AbstractFragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

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