91 results on '"Michela Fagiolini"'
Search Results
2. The Stage of the Estrus Cycle Is Critical for Interpretation of Female Mouse Social Interaction Behavior
- Author
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Trishala Chari, Sophie Griswold, Nick A. Andrews, and Michela Fagiolini
- Subjects
social behavior ,estrus cycle ,learning and memory ,anxiety ,sex differences ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Female animals in biomedical research have traditionally been excluded from research studies due to the perceived added complexity caused by the estrus cycle. However, given the importance of sex differences in a variety of neurological disorders, testing female mice is critical to identifying sex-linked effects in diseases. To determine the susceptibility of simple behaviors to hormonal fluctuations in the estrus cycle, we studied the effects of sex and the estrus cycle on a variety of behavioral tasks commonly used in mouse phenotyping laboratories. Male and female C57BL/6J mice were tested in a small battery of short duration tests and, immediately on completion of each test, females were classified using cytology of vaginal lavages as sexually-receptive (proestrus and estrus) or non-receptive (NR; metestrus and diestrus). We showed that there was a significant difference in 3-chamber social interaction (SI) between female mice at different stages of their estrus cycle, with sexually-receptive mice showing no preferential interest in a novel female mouse compared with an empty chamber. NR female mice showed the same level of preference for a novel female mouse as male mice did for a novel male mouse. No differences between or within sexes were found for tests of anxiety elevated plus maze (EPM; Hole board), working memory [Novel object recognition (NOR)], and motor learning (repeated tests on rotarod). We conclude that the stage of the estrus cycle may impact SI between same-sex conspecifics, and does not impact performance in the elevated plus-maze, hole board, NOR, and rotarod.
- Published
- 2020
- Full Text
- View/download PDF
3. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome
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Silvio Alessandro Di Gioia, Samantha Connors, Norisada Matsunami, Jessica Cannavino, Matthew F. Rose, Nicole M. Gilette, Pietro Artoni, Nara Lygia de Macena Sobreira, Wai-Man Chan, Bryn D. Webb, Caroline D. Robson, Long Cheng, Carol Van Ryzin, Andres Ramirez-Martinez, Payam Mohassel, Mark Leppert, Mary Beth Scholand, Christopher Grunseich, Carlos R. Ferreira, Tyler Hartman, Ian M. Hayes, Tim Morgan, David M. Markie, Michela Fagiolini, Amy Swift, Peter S. Chines, Carlos E. Speck-Martins, Francis S. Collins, Ethylin Wang Jabs, Carsten G. Bönnemann, Eric N. Olson, Moebius Syndrome Research Consortium, John C. Carey, Stephen P. Robertson, Irini Manoli, and Elizabeth C. Engle
- Subjects
Science - Abstract
During embryogenesis, the cytoplasmic protein Myomarker (MYMK) mediates muscle fibre formation by fusion of myoblasts. Here, the authors identify autosomal recessive mutations in MYMK that cause Carey-Fineman-Ziter syndrome in humans, and model the disease variants in zebrafish.
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- 2017
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4. A Diet With Docosahexaenoic and Arachidonic Acids as the Sole Source of Polyunsaturated Fatty Acids Is Sufficient to Support Visual, Cognitive, Motor, and Social Development in Mice
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Sarah J. Carlson, Alison A. O’Loughlin, Lorenzo Anez-Bustillos, Meredith A. Baker, Nicholas A. Andrews, Georgia Gunner, Duy T. Dao, Amy Pan, Prathima Nandivada, Melissa Chang, Eileen Cowan, Paul D. Mitchell, Kathleen M. Gura, Michela Fagiolini, and Mark Puder
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polyunsaturated fatty acid (PUFA) ,omega-3 fatty acids ,diet ,neurocognition ,docosahexaenoic acid (DHA) ,arachidonic acid (AA) ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Polyunsaturated fatty acids serve multiple functions in neurodevelopment and neurocognitive function. Intravenous lipid emulsions are administered to children that are dependent on parenteral nutrition to provide the essential fatty acids needed to sustain growth and development. One of these emulsions, derived from fish-oil, is particularly poor in the traditional essential fatty acids, linoleic and alpha-linolenic acids. However, it does contain adequate amounts of its main derivatives, arachidonic acid (ARA) and docosahexaenoic acid (DHA), respectively. This skewed composition has raised concern about the sole use of fish-oil based lipid emulsions in children and how its administration can be detrimental to their neurodevelopment. Using a custom-made diet that contains ARA and DHA as a sole source of polyunsaturated fatty acids, we bred and fed mice for multiple generations. Compared to adult, chow-fed mice, animals maintained on this special diet showed similar outcomes in a battery of neurocognitive tests performed under controlled conditions. Chow-fed mice did perform better in the rotarod test for ataxia and balance, although both experimental groups showed a conserved motor learning capacity. Conversely, mice fed the custom diet rich in DHA and ARA showed less neophobia than the chow-fed animals. Results from these experiments suggest that providing a diet where ARA and DHA are the sole source of polyunsaturated fatty acids is sufficient to support gross visual, cognitive, motor, and social development in mice.
- Published
- 2019
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5. RNA extraction from sorted neuronal subtypes
- Author
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Alka Saxena, Akiko Wagatsuma, Yukihiko Noro, Takenobu Kuji, Atsuko Asaka-Oba, Akira Watahiki, Cecile Gurnot, Michela Fagiolini, Takao K. Hensch, and Piero Carninci
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Biology (General) ,QH301-705.5 - Abstract
Protocol Summary Efficient isolation of specific, intact, living neurons from the adult brain is problematic due to the complex nature of the extracellular matrix consolidating the neuronal network. Here, we present significant improvements to the protocol for isolation of pure populations of neurons from mature postnatal mouse brain using fluorescence activated cell sorting (FACS). The 10-fold increase in cell yield enables cell-specific transcriptome analysis by protocols such as nanoCAGE and RNA seq.
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- 2017
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6. MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit.
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Robert A Volkmann, Christopher M Fanger, David R Anderson, Venkata Ramana Sirivolu, Kathy Paschetto, Earl Gordon, Caterina Virginio, Melanie Gleyzes, Bruno Buisson, Esther Steidl, Susanna B Mierau, Michela Fagiolini, and Frank S Menniti
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Medicine ,Science - Abstract
GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders.
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- 2016
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7. Trehalose-enhanced isolation of neuronal sub-types from adult mouse brain
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Alka Saxena, Akiko Wagatsuma, Yukihiko Noro, Takenobu Kuji, Atsuko Asaka-Oba, Akira Watahiki, Cecile Gurnot, Michela Fagiolini, Takao K. Hensch, and Piero Carninci
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FACS ,parvalbumin ,pyramidal ,nanoCAGE ,RNA seq ,Biology (General) ,QH301-705.5 - Abstract
Efficient isolation of specific, intact, living neurons from the adult brain is problematic due to the complex nature of the extracellular matrix consolidating the neuronal network. Here, we present significant improvements to the protocol for isolation of pure populations of neurons from mature postnatal mouse brain using fluorescence activated cell sorting (FACS). The 10-fold increase in cell yield enables cell-specific transcriptome analysis by protocols such as nanoCAGE and RNA seq.
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- 2012
- Full Text
- View/download PDF
8. Subtraction of cap-trapped full-length cDNA libraries to select rare transcripts
- Author
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Tomoko Hirozane-Kishikawa, Toshiyuki Shiraki, Kazunori Waki, Mari Nakamura, Takahiro Arakawa, Jun Kawai, Michela Fagiolini, Takao K. Hensch, Yoshihide Hayashizaki, and Piero Carninci
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Biology (General) ,QH301-705.5 - Abstract
The normalization and subtraction of highly expressed cDNAs from relatively large tissues before cloning dramatically enhanced the gene discovery by sequencing for the mouse fulllength cDNA encyclopedia, but these methods have not been suitable for limited RNA materials. To normalize and subtract full-length cDNA libraries derived from limited quantities of total RNA, here we report a method to subtract plasmid libraries excised from size-unbiased amplified λ phage cDNA libraries that avoids heavily biasing steps such as PCR and plasmid library amplification. The proportion of full-length cDNAs and the gene discovery rate are high, and library diversity can be validated by in silico randomization.
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- 2003
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9. Autism: A 'Critical Period' Disorder?
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Jocelyn J. LeBlanc and Michela Fagiolini
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely unknown and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits.
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- 2011
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10. A resource for transcriptomic analysis in the mouse brain.
- Author
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Charles Plessy, Michela Fagiolini, Akiko Wagatsuma, Norihiro Harasawa, Takenobu Kuji, Atsuko Asaka-Oba, Yukari Kanzaki, Sayaka Fujishima, Kazunori Waki, Hiroyuki Nakahara, Takao K Hensch, and Piero Carninci
- Subjects
Medicine ,Science - Abstract
BackgroundThe transcriptome of the cerebral cortex is remarkably homogeneous, with variations being stronger between individuals than between areas. It is thought that due to the presence of many distinct cell types, differences within one cell population will be averaged with the noise from others. Studies of sorted cells expressing the same transgene have shown that cell populations can be distinguished according to their transcriptional profile.MethodologyWe have prepared a low-redundancy set of 16,209 full-length cDNA clones which represents the transcriptome of the mouse visual cortex in its coding and non-coding aspects. Using an independent tag-based approach, CAGE, we confirmed the cortical expression of 72% of the clones. Clones were amplified by PCR and spotted on glass slides, and we interrogated the microarrays with RNA from flow-sorted fluorescent cells from the cerebral cortex of parvalbumin-egfp transgenic mice.ConclusionsWe provide an annotated cDNA clone collection which is particularly suitable for transcriptomic analysis in the mouse brain. Spotting it on microarrays, we compared the transcriptome of EGFP positive and negative cells in a parvalbumin-egfp transgenic background and showed that more than 30% of clones are differentially expressed. Our clone collection will be a useful resource for the study of the transcriptome of single cell types in the cerebral cortex.
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- 2008
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11. Dynamical Characteristics of Wild-Type Mouse Spontaneous Pupillary Fluctuations*.
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Nina Sviridova, Pietro Artoni, Michela Fagiolini, Takao K. Hensch, and Kazuyuki Aihara
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- 2021
- Full Text
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12. Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes
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Michela Fagiolini, Fritjof Helmchen, Jason P. Lerch, Davide Pozzi, Michela Matteoli, Alberto Galbusera, Marco Pagani, Giovanni Provenzano, Abhishek Banerjee, J. Ellegood, Maria Luisa Scattoni, Marija Markicevic, Markus Rudin, Nicole Wenderoth, Valerio Zerbi, Alessandro Gozzi, M. Albert Basson, Yuri Bozzi, University of Zurich, and Gozzi, A
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Autism Spectrum Disorder ,Personalized treatment ,Population ,2804 Cellular and Molecular Neuroscience ,610 Medicine & health ,Biology ,Brain mapping ,2738 Psychiatry and Mental Health ,Mice ,Cellular and Molecular Neuroscience ,Functional brain ,Neural Pathways ,mental disorders ,1312 Molecular Biology ,medicine ,Animals ,10064 Neuroscience Center Zurich ,Autistic Disorder ,education ,Molecular Biology ,Brain Mapping ,education.field_of_study ,10242 Brain Research Institute ,Functional connectivity ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Autism spectrum disorder ,570 Life sciences ,biology ,Autism ,Identification (biology) ,Neuroscience - Abstract
Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches., Molecular Psychiatry, 26 (12), ISSN:1359-4184, ISSN:1476-5578
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- 2021
13. A promoter-level mammalian expression atlas.
- Author
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The Fantom Consortium, RIKEN PMII, RIKEN CLST (DGT), Alistair R. R. Forrest, Hideya Kawaji, Michael Rehli, J. Kenneth Baillie, Michiel J. L. de Hoon, Vanja Haberle, Timo Lassmann, Ivan V. Kulakovskiy, Marina Lizio, Masayoshi Itoh, Robin Andersson, Christopher J. Mungall, Terrence F. Meehan, Sebastian Schmeier, Nicolas Bertin, Mette Jørgensen, Emmanuel Dimont, Erik Arner, Christian Schmidl, Ulf Schaefer, Yulia A. Medvedeva, Charles Plessy, Morana Vitezic, Jessica Severin, Colin A. M. Semple, Yuri Ishizu, Robert S. Young, Margherita Francescatto, Intikhab Alam, Davide Albanese, Gabriel M. Altschuler, Takahiro Arakawa, John A. C. Archer, Peter Arner, Magda Babina, Sarah Rennie, Piotr J. Balwierz, Anthony G. Beckhouse, Swati Pradhan-Bhatt, Judith A. Blake, Antje Blumenthal, Beatrice Bodega, Alessandro Bonetti, James Briggs, Frank Brombacher, A. Maxwell Burroughs, Andrea Califano, Carlo V. Cannistraci, Daniel Carbajo, Yun Chen, Marco Chierici, Yari Ciani, Hans Clevers, Emiliano Dalla, Carrie A. Davis, Michael Detmar, Alexander D. Diehl, Taeko Dohi, Finn Drabløs, Albert S. B. Edge, Matthias Edinger, Karl Ekwall, Mitsuhiro Endoh, Hideki Enomoto, Michela Fagiolini, Lynsey Fairbairn, Hai Fang, Mary C. Farach-Carson, Geoffrey J. Faulkner, Alexander V. Favorov, Malcolm E. Fisher, Martin C. Frith, Rie Fujita, Shiro Fukuda, Cesare Furlanello, Masaaki Furuno, Jun-ichi Furusawa, Teunis B. Geijtenbeek, Andrew P. Gibson, Thomas R. Gingeras, Daniel Goldowitz, Julian Gough, Sven Guhl, Reto Guler, Stefano Gustincich, Thomas J. Ha, Masahide Hamaguchi, Mitsuko Hara, Matthias Harbers, Jayson Harshbarger, Akira Hasegawa, Yuki Hasegawa, Takehiro Hashimoto, Meenhard Herlyn, Kelly J. Hitchens, Shannan J. Ho Sui, Oliver M. Hofmann, Ilka Hoof, Fumi Hori, Lukasz Huminiecki, Kei Iida, Tomokatsu Ikawa, Boris R. Jankovic, Hui Jia, Anagha Joshi, Giuseppe Jurman, Bogumil Kaczkowski, Chieko Kai, Kaoru Kaida, Ai Kaiho, Kazuhiro Kajiyama, Mutsumi Kanamori-Katayama, Artem S. Kasianov, Takeya Kasukawa, Shintaro Katayama, Sachi Kato, Shuji Kawaguchi, Hiroshi Kawamoto, Yuki I. Kawamura, Tsugumi Kawashima, Judith S. Kempfle, Tony J. Kenna, Juha Kere, Levon M. Khachigian, Toshio Kitamura, S. Peter Klinken, Alan J. Knox, Miki Kojima, Soichi Kojima, Naoto Kondo, Haruhiko Koseki, Shigeo Koyasu, Sarah Krampitz, Atsutaka Kubosaki, Andrew T. Kwon, Jeroen F. J. Laros, Weonju Lee, Andreas Lennartsson, Kang Li, Berit Lilje, Leonard Lipovich, Alan Mackay-Sim, Ri-ichiroh Manabe, Jessica Cara Mar, Benoit Marchand, Anthony Mathelier, Niklas Mejhert, Alison M. Meynert, Yosuke Mizuno, David A. de Lima Morais, Hiromasa Morikawa, Mitsuru Morimoto, Kazuyo Moro, Efthymios Motakis, Hozumi Motohashi, Christine Mummery, Mitsuyoshi Murata, Sayaka Nagao-Sato, Yutaka Nakachi, Fumio Nakahara, Toshiyuki Nakamura, Yukio Nakamura, Kenichi Nakazato, Erik van Nimwegen, Noriko Ninomiya, Hiromi Nishiyori, Shohei Noma, Tadasuke Nozaki, Soichi Ogishima, Naganari Ohkura, Hiroko Ohmiya, Hiroshi Ohno, Mitsuhiro Ohshima, Mariko Okada-Hatakeyama, Yasushi Okazaki, Valerio Orlando, Dmitry A. Ovchinnikov, Arnab Pain, Robert Passier, Margaret Patrikakis, Helena Persson, Silvano Piazza, James G. D. Prendergast, Owen J. L. Rackham, Jordan A. Ramilowski, Mamoon Rashid, Timothy Ravasi, Patrizia Rizzu, Marco Roncador, Sugata Roy, Morten B. Rye, Eri Saijyo, Antti Sajantila, Akiko Saka, Shimon Sakaguchi, Mizuho Sakai, Hiroki Sato, Hironori Sato, Suzana Savvi, Alka Saxena, Claudio Schneider, Erik A. Schultes, Gundula G. Schulze-Tanzil, Anita Schwegmann, Thierry Sengstag, Guojun Sheng, Hisashi Shimoji, Yishai Shimoni, Jay W. Shin, Christophe Simon, Daisuke Sugiyama, Takaaki Sugiyama, Masanori Suzuki, Naoko Suzuki, Rolf K. Swoboda, Peter A. C. 't Hoen, Michihira Tagami, Naoko Takahashi, Jun Takai, Hiroshi Tanaka, Hideki Tatsukawa, Zuotian Tatum, Mark Thompson 0002, Hiroo Toyoda, Tetsuro Toyoda, Eivind Valen, Marc van de Wetering, Linda M. van den Berg, Roberto Verardo, Dipti Vijayan, Ilya E. Vorontsov, Wyeth W. Wasserman, Shoko Watanabe, Christine A. Wells, Louise N. Winteringham, Ernst Wolvetang, Emily J. Wood, Yoko Yamaguchi, Masayuki Yamamoto, Misako Yoneda, Yohei Yonekura, Shigehiro Yoshida, Susan E. Zabierowski, Peter G. Zhang, Xiaobei Zhao, Silvia Zucchelli, Kim M. Summers, Harukazu Suzuki, Carsten O. Daub, Jun Kawai, Peter Heutink, Winston Hide, Tom C. Freeman, Boris Lenhard, Vladimir B. Bajic, Martin S. Taylor, Vsevolod J. Makeev, Albin Sandelin, David A. Hume, Piero Carninci, and Yoshihide Hayashizaki
- Published
- 2014
- Full Text
- View/download PDF
14. Phenotypic characterization of Cdkl5-knockdown neurons establishes elongated cilia as a functional assay for CDKL5 Deficiency Disorder
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Michela Fagiolini, Alina Rühmkorf, Ashton Brennecke, Mustafa Sahin, Patricia Award, and Alessia Di Nardo
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Neurons ,Gene knockdown ,General Neuroscience ,Cilium ,Encephalopathy ,CDKL5 ,General Medicine ,Biology ,Protein Serine-Threonine Kinases ,medicine.disease ,Phenotype ,Cell biology ,Mice ,Neurodevelopmental disorder ,In vivo ,Knockout mouse ,medicine ,Animals ,Cilia ,Epileptic Syndromes - Abstract
CDKL5 Deficiency Disorder (CDD) is a severe encephalopathy characterized by intractable epilepsy, infantile spasms, and cognitive disabilities. The detrimental CNS manifestations and lack of therapeutic interventions represent unmet needs, necessitating identification of CDD-dependent phenotypes for in vitro disease modeling and therapeutic testing. Here, we optimized a high-content assay to quantify cilia in CDKL5-deficient neurons. Our work shows that Cdkl5-knockdown neurons have elongated cilia and uncovers cilium lengthening in hippocampi of Cdkl5 knockout mice. Collectively, our findings identify cilia length alterations under CDKL5 activity loss in vitro and in vivo and reveal elongated cilia as a robust functional phenotype for CDD.
- Published
- 2021
15. Animal Models of Neurodevelopmental Disorders
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Michela Fagiolini and Yuri Bozzi
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Medical education ,Disease Models, Animal ,Text mining ,business.industry ,Neurodevelopmental Disorders ,General Neuroscience ,MEDLINE ,Medicine ,Animals ,business ,Introductory Journal Article - Published
- 2020
16. The Stage of the Estrus Cycle Is Critical for Interpretation of Female Mouse Social Interaction Behavior
- Author
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Michela Fagiolini, Sophie Griswold, Trishala Chari, and Nick Andrews
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sex differences ,Elevated plus maze ,Cognitive Neuroscience ,Male mice ,Physiology ,Biology ,lcsh:RC321-571 ,social behavior ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,medicine ,estrus cycle ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,030304 developmental biology ,Estrous cycle ,0303 health sciences ,Working memory ,Brief Research Report ,anxiety ,Social relation ,Neuropsychology and Physiological Psychology ,Anxiety ,learning and memory ,medicine.symptom ,Motor learning ,030217 neurology & neurosurgery ,Hormone - Abstract
Female animals in biomedical research have traditionally been excluded from research studies due to the perceived added complexity caused by the estrus cycle. However, given the importance of sex differences in a variety of neurological disorders, testing female mice is critical to identifying sex-linked effects in diseases. To determine the susceptibility of simple behaviors to hormonal fluctuations in the estrus cycle, we studied the effects of sex and the estrus cycle on a variety of behavioral tasks commonly used in mouse phenotyping laboratories. Male and female C57BL/6J mice were tested in a small battery of short duration tests and, immediately on completion of each test, females were classified using cytology of vaginal lavages as sexually-receptive (proestrus and estrus) or non-receptive (NR; metestrus and diestrus). We showed that there was a significant difference in 3-chamber social interaction (SI) between female mice at different stages of their estrus cycle, with sexually-receptive mice showing no preferential interest in a novel female mouse compared with an empty chamber. NR female mice showed the same level of preference for a novel female mouse as male mice did for a novel male mouse. No differences between or within sexes were found for tests of anxiety elevated plus maze (EPM; Hole board), working memory [Novel object recognition (NOR)], and motor learning (repeated tests on rotarod). We conclude that the stage of the estrus cycle may impact SI between same-sex conspecifics, and does not impact performance in the elevated plus-maze, hole board, NOR, and rotarod.
- Published
- 2020
17. Intellectual and Developmental Disabilities Research Centers: A Multidisciplinary Approach to Understand the Pathogenesis of Methyl-CpG Binding Protein 2-related Disorders
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Ahamed Hossain, Quiang Chang, Michela Fagiolini, Shilpa D. Kadam, Annarita Patrizi, Steven J. Gray, Jocelyn LeBlanc, Lee-Way Jin, Huda Y. Zoghbi, Zhaolan Zhou, Michael V. Johnston, Sakkubai Naidu, Xinyu Zhao, Mary E. Blue, Sarah E. Sinnett, John J. Foxe, Sophie Molholm, and Izumi Maezawa
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,Intellectual and Developmental Disabilities (IDD) ,Developmental Disabilities ,Rett syndrome ,Neurodegenerative ,Article ,MECP2 ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Multidisciplinary approach ,mental disorders ,Genetics ,medicine ,Rett Syndrome ,Psychology ,Humans ,Epigenetics ,Child ,Pediatric ,Neurology & Neurosurgery ,business.industry ,neurodevelopmental disorders ,translational ,General Neuroscience ,Neurosciences ,Outcome measures ,biomarkers ,Reproducibility of Results ,medicine.disease ,animal models ,signaling pathways ,Brain Disorders ,Mental Health ,030104 developmental biology ,Neuronal circuits ,METHYL-CpG-BINDING PROTEIN 2 ,Mutation ,Autism ,Cognitive Sciences ,business ,Carrier Proteins ,Neuroscience ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Disruptions in the gene encoding methyl-CpG binding protein 2 (MECP2) underlie complex neurodevelopmental disorders including Rett Syndrome (RTT), MECP2 duplication disorder, intellectual disabilities, and autism. Significant progress has been made on the molecular and cellular basis of MECP2-related disorders providing a new framework for understanding how altered epigenetic landscape can derail the formation and refinement of neuronal circuits in early postnatal life and proper neurological function. This review will summarize selected major findings from the past years and particularly highlight the integrated and multidisciplinary work done at eight NIH-funded Intellectual and Developmental Disabilities Research Centers (IDDRC) across the US. Finally, we will outline a path forward with identification of reliable biomarkers and outcome measures, longitudinal preclinical and clinical studies, reproducibility of results across centers as a synergistic effort to decode and treat the pathogenesis of the complex MeCP2 disorders.
- Published
- 2020
18. Rigor and reproducibility in rodent behavioral research
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Maria Gulinello, Heather A. Mitchell, Rodney C. Samaco, Michela Fagiolini, Jacqueline N. Crawley, Surabi Veeraragavan, Thomas M. Burbacher, Ted Abel, Qiang Chang, Li Wang, Toby B. Cole, Joshua G. Corbin, W. Timothy O'Brien, Nick Andrews, and Zhaolan Zhou
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0301 basic medicine ,Best practices ,Cognitive ,Computer science ,Cognitive Neuroscience ,Best practice ,Novel object recognition ,Replication ,Rigor ,Experimental and Cognitive Psychology ,Behavioral neuroscience ,Behavioral assays ,Behavioral Science & Comparative Psychology ,Medical and Health Sciences ,Article ,03 medical and health sciences ,Behavioral Neuroscience ,Mice ,0302 clinical medicine ,Behavioral and Social Science ,Animals ,Statistical analysis ,Scientific disciplines ,Behavior ,Management science ,Psychology and Cognitive Sciences ,Neurosciences ,Reproducibility of Results ,Cognition ,Experimental design ,Reproducibility ,Variety (cybernetics) ,Rats ,030104 developmental biology ,Behavioral test ,Mental Health ,Research Design ,Neuroscience ,030217 neurology & neurosurgery ,Behavioral Research - Abstract
Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.
- Published
- 2019
19. Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients
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Jocelyn LeBlanc, Michela Fagiolini, Viviana Vinci, Arianna Piffer, Charles A. Nelson, Takao K. Hensch, and Pietro Artoni
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0301 basic medicine ,Male ,Methyl-CpG-Binding Protein 2 ,CDKL5 ,Rett syndrome ,Protein Serine-Threonine Kinases ,MECP2 ,Arousal ,Cohort Studies ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Deep Learning ,Neuromodulation ,medicine ,Rett Syndrome ,Animals ,Humans ,Autistic Disorder ,Multidisciplinary ,business.industry ,Pupil ,medicine.disease ,Acetylcholine ,Biological Embedding Across Timescales Special Feature ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Biomarker (medicine) ,Autism ,Cholinergic ,Female ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Neurodevelopmental spectrum disorders like autism (ASD) are diagnosed, on average, beyond age 4 y, after multiple critical periods of brain development close and behavioral intervention becomes less effective. This raises the urgent need for quantitative, noninvasive, and translational biomarkers for their early detection and tracking. We found that both idiopathic (BTBR) and genetic (CDKL5- and MeCP2-deficient) mouse models of ASD display an early, impaired cholinergic neuromodulation as reflected in altered spontaneous pupil fluctuations. Abnormalities were already present before the onset of symptoms and were rescued by the selective expression of MeCP2 in cholinergic circuits. Hence, we trained a neural network (ConvNetACh) to recognize, with 97% accuracy, patterns of these arousal fluctuations in mice with enhanced cholinergic sensitivity (LYNX1-deficient). ConvNetACh then successfully detected impairments in all ASD mouse models tested except in MeCP2-rescued mice. By retraining only the last layers of ConvNetACh with heart rate variation data (a similar proxy of arousal) directly from Rett syndrome patients, we generated ConvNetPatients, a neural network capable of distinguishing them from typically developing subjects. Even with small cohorts of rare patients, our approach exhibited significant accuracy before (80% in the first and second year of life) and into regression (88% in stage III patients). Thus, transfer learning across species and modalities establishes spontaneous arousal fluctuations combined with deep learning as a robust noninvasive, quantitative, and sensitive translational biomarker for the rapid and early detection of neurodevelopmental disorders before major symptom onset.
- Published
- 2019
20. MeCP2: an epigenetic regulator of critical periods
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Michela Fagiolini and Nathalie Picard
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0301 basic medicine ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,General Neuroscience ,Regulator ,Biology ,MECP2 ,Epigenesis, Genetic ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Gene expression ,Rett Syndrome ,Animals ,Humans ,Epigenetics ,Gene ,Neuroscience ,030217 neurology & neurosurgery ,DNA - Abstract
Complex adult behaviors arise from the integration of sequential and often overlapping critical periods (CPs) early in life and adolescence. These processes rely on a subtle interplay between the set of genes inherited from the parents, the surrounding environment and epigenetic regulation. Methyl-CpG-binding protein 2 (MeCP2) has been shown to recognize epigenetic states and regulate gene expression by reading methylated DNA. Here, we will review the recent findings revealing the role of MeCP2 during postnatal CPs of development using mouse models of Rett (RTT) syndrome.
- Published
- 2019
21. Cortical Feedback Regulates Feedforward Retinogeniculate Refinement
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Michela Fagiolini, Chinfei Chen, Andrew Thompson, Lia Min, and Nathalie Picard
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Retinal Ganglion Cells ,0301 basic medicine ,Thalamus ,Sensory system ,Visual system ,Retinal ganglion ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cortex (anatomy) ,medicine ,Animals ,Visual Pathways ,Clozapine ,Visual Cortex ,Feedback, Physiological ,Muscimol ,Critical Period, Psychological ,General Neuroscience ,Geniculate Bodies ,030104 developmental biology ,medicine.anatomical_structure ,Visual cortex ,Neuron ,Psychology ,Neuroscience ,Neural development ,030217 neurology & neurosurgery - Abstract
According to the prevailing view of neural development, sensory pathways develop sequentially in a feedforward manner, whereby each local microcircuit refines and stabilizes before directing the wiring of its downstream target. In the visual system, retinal circuits are thought to mature first and direct refinement in the thalamus, after which cortical circuits refine with experience-dependent plasticity. In contrast, we now show that feedback from cortex to thalamus critically regulates refinement of the retinogeniculate projection during a discrete window in development, beginning at postnatal day 20 in mice. Disrupting cortical activity during this window, pharmacologically or chemogenetically, increases the number of retinal ganglion cells innervating each thalamic relay neuron. These results suggest that primary sensory structures develop through the concurrent and interdependent remodeling of subcortical and cortical circuits in response to sensory experience, rather than through a simple feedforward process. Our findings also highlight an unexpected function for the corticothalamic projection.
- Published
- 2016
22. Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype
- Author
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Nathalie Picard, Annarita Patrizi, Eleonora Centofante, Alex Joseph Simon, Michela Fagiolini, Georgia Gunner, and Nick Andrews
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,medicine.drug_class ,Visual Acuity ,Rett syndrome ,Neurological disorder ,Pharmacology ,Receptors, N-Methyl-D-Aspartate ,Article ,MECP2 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Rett Syndrome ,medicine ,Animals ,Ketamine ,GABAergic Neurons ,Receptor ,Biological Psychiatry ,Visual Cortex ,Mice, Knockout ,Neurons ,Pyramidal Cells ,Respiration ,Antagonist ,medicine.disease ,Receptor antagonist ,Survival Analysis ,Mice, Inbred C57BL ,Disease Models, Animal ,Parvalbumins ,Phenotype ,030104 developmental biology ,Anesthesia ,NMDA receptor ,Psychology ,Photic Stimulation ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Rett syndrome (RTT) is a neurological disorder caused by mutation of the X-linked MECP2 gene, which results in the progressive disruption of excitatory and inhibitory neuronal circuits. To date, there is no effective treatment available for the disorder. Studies conducted in RTT patients and murine models have shown altered expression of N -methyl-D-aspartate receptors (NMDARs). Genetic deletion of the NMDAR subunit, GluN2A, in mice lacking Mecp2 is sufficient to prevent RTT phenotypes, including regression of vision. Methods We performed a systematic, randomized preclinical trial of chronic administration of low-dose (8 mg/kg, intraperitoneal) ketamine, an NMDAR antagonist, starting either early in development or at the onset of RTT phenotype in Mecp2 -null mice. Results Daily exposure to ketamine ameliorated RTT symptoms and extended the life span of treated Mecp2 -null mice without adverse side effects. Furthermore, significant improvement was observed in cortical processing and connectivity, which were fully restored to a wild-type level, particularly when treatment was started at the onset of regression. Conclusions Our findings provide strong evidence that targeting NMDA receptors can be a safe and effective treatment for RTT.
- Published
- 2016
23. Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits
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Michela Fagiolini, Annarita Patrizi, Takao K. Hensch, and Susanna B. Mierau
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0301 basic medicine ,biology ,musculoskeletal, neural, and ocular physiology ,Protein subunit ,Inhibitory postsynaptic potential ,MECP2 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,nervous system ,mental disorders ,biology.protein ,Excitatory postsynaptic potential ,NMDA receptor ,Patch clamp ,Cognitive decline ,Neuroscience ,030217 neurology & neurosurgery ,Biological Psychiatry ,Parvalbumin - Abstract
Background Early postnatal experience shapes N -methyl-D-aspartate receptor (NMDAR) subunit composition and kinetics at excitatory synapses onto pyramidal cells; however, little is known about NMDAR maturation onto inhibitory interneurons. Methods We combined whole-cell patch clamp recordings ( n = 440) of NMDAR-mediated currents from layer-4-to-layer-2/3 synapses onto pyramidal and green fluorescent protein labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30, and 45 postnatal days) with array tomography three-dimensional reconstructions of NMDAR subunits GluN2A- and GluN2B-positive synapses onto PV cells. Results We show that the trajectory of the NMDAR subunit switch is slower in PV interneurons than in excitatory pyramidal cells in visual cortex. Notably, this differential time course is reversed in the absence of methyl-CpG-binding protein, MECP2, the molecular basis for cognitive decline in Rett syndrome and some cases of autism. Additional genetic reduction of GluN2A subunits, which prevents regression of vision in Mecp2 -knockout mice, specifically rescues the accelerated NMDAR maturation in PV cells. Conclusions We demonstrate 1) the time course of NMDAR maturation is cell-type specific, and 2) a new cell-type specific role for Mecp2 in the development of NMDAR subunit composition. Reducing GluN2A expression in Mecp2 -knockout mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus, circuit-based therapies targeting NMDAR subunit composition on PV cells may provide novel treatments for Rett syndrome.
- Published
- 2016
24. Transparent, Flexible, Penetrating Microelectrode Arrays with Capabilities of Single-Unit Electrophysiology
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Yi Qiang, Wenhao Yao, Xun Han, Yiding Zhong, Michela Fagiolini, Pietro Artoni, Kyung Jin Seo, Hui Fang, and Zhan Shi
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Materials science ,Biomedical Engineering ,Bending ,Brain mapping ,General Biochemistry, Genetics and Molecular Biology ,Biomaterials ,chemistry.chemical_compound ,Mice ,Materials Testing ,medicine ,Premovement neuronal activity ,Animals ,Pliability ,Visual Cortex ,Neurons ,Equipment Design ,Electrodes, Implanted ,Electrophysiology ,Mice, Inbred C57BL ,Microelectrode ,Nanomesh ,Visual cortex ,medicine.anatomical_structure ,chemistry ,Electrode ,Microelectrodes ,Biomedical engineering - Abstract
Accurately mapping neuronal activity across brain networks is critical to understand behaviors, yet it is very challenging due to the need of tools with both high spatial and temporal resolutions. Here, penetrating arrays of flexible microelectrodes made of low-impedance nanomeshes are presented, which are capable of recording single-unit electrophysiological neuronal activity and at the same time, transparent, allowing to bridge electrical and optical brain mapping modalities. These 32 transparent penetrating electrodes with site area, 225 µm2 , have a low impedance of ≈149 kΩ at 1 kHz, an adequate charge injection limit of ≈0.76 mC cm-2 , and up to 100% yield. Mechanical bending tests reveal that the array is robust up to 1000 bending cycles, and its high transmittance of 67% at 550 nm makes it suitable for combining with various optical methods. A temporary stiffening using polyethylene glycol allows the penetrating nanomesh arrays to be inserted into the brain minimally invasively, with in vivo validation of recordings of spontaneous and evoked single-unit activity of neurons across layers of the mouse visual cortex. Together, these results establish a novel neurotechnology-transparent, flexible, penetrating microelectrode arrays-which possesses great potential for brain research.
- Published
- 2018
25. Transparent arrays of bilayer-nanomesh microelectrodes for simultaneous electrophysiology and two-photon imaging in the brain
- Author
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Victoria Hogan, Po-Min Wang, Michela Fagiolini, Xun Han, Wentai Liu, Kyung Jin Seo, Yiding Zhong, Hui Fang, Yi Qiang, Jung Soo V. Chu, Stanislav Culaclii, Yi-Kai Lo, Abhijeet Sambangi, Pietro Artoni, Yueming Li, Yifu Huang, Henil A. Patel, and Xuanyi Zhao
- Subjects
Male ,Materials science ,Capacitive sensing ,Thiophenes ,02 engineering and technology ,03 medical and health sciences ,chemistry.chemical_compound ,Engineering ,0302 clinical medicine ,Two-photon excitation microscopy ,Animals ,Research Articles ,Visual Cortex ,Transparent conducting film ,Photons ,Multidisciplinary ,business.industry ,Brain ,SciAdv r-articles ,021001 nanoscience & nanotechnology ,Electrodes, Implanted ,Molecular Imaging ,Nanostructures ,Electrophysiology ,Mice, Inbred C57BL ,Coupling (electronics) ,Microelectrode ,Nanomesh ,chemistry ,Dielectric Spectroscopy ,Electrode ,Polystyrenes ,Optoelectronics ,Calcium ,Gold ,0210 nano-technology ,business ,Microelectrodes ,Wireless Technology ,Layer (electronics) ,Photic Stimulation ,030217 neurology & neurosurgery ,Research Article ,Neuroscience - Abstract
We report a transparent, bilayer-nanomesh microelectrode array for concurrent electrophysiology recording and two-photon imaging., Transparent microelectrode arrays have emerged as increasingly important tools for neuroscience by allowing simultaneous coupling of big and time-resolved electrophysiology data with optically measured, spatially and type resolved single neuron activity. Scaling down transparent electrodes to the length scale of a single neuron is challenging since conventional transparent conductors are limited by their capacitive electrode/electrolyte interface. In this study, we establish transparent microelectrode arrays with high performance, great biocompatibility, and comprehensive in vivo validations from a recently developed, bilayer-nanomesh material composite, where a metal layer and a low-impedance faradaic interfacial layer are stacked reliably together in a same transparent nanomesh pattern. Specifically, flexible arrays from 32 bilayer-nanomesh microelectrodes demonstrated near-unity yield with high uniformity, excellent biocompatibility, and great compatibility with state-of-the-art wireless recording and real-time artifact rejection system. The electrodes are highly scalable, with 130 kilohms at 1 kHz at 20 μm in diameter, comparable to the performance of microelectrodes in nontransparent Michigan arrays. The highly transparent, bilayer-nanomesh microelectrode arrays allowed in vivo two-photon imaging of single neurons in layer 2/3 of the visual cortex of awake mice, along with high-fidelity, simultaneous electrical recordings of visual-evoked activity, both in the multi-unit activity band and at lower frequencies by measuring the visual-evoked potential in the time domain. Together, these advances reveal the great potential of transparent arrays from bilayer-nanomesh microelectrodes for a broad range of utility in neuroscience and medical practices.
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- 2018
26. Behavioral analyses of animal models of intellectual and developmental disabilities
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Michela Fagiolini, Rodney C. Samaco, Michael B. Robinson, Jacqueline N. Crawley, David F. Wozniak, and Fiona E. Harrison
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Developmental Disabilities ,Cognitive Neuroscience ,media_common.quotation_subject ,Experimental and Cognitive Psychology ,050105 experimental psychology ,Developmental psychology ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Intellectual Disability ,medicine ,Animals ,Humans ,0501 psychology and cognitive sciences ,Function (engineering) ,media_common ,05 social sciences ,Genetic variants ,Foundation (evidence) ,Cognition ,Disease Models, Animal ,Anxiety ,Degree of confidence ,medicine.symptom ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Primary research - Abstract
Intellectual and developmental disabilities (IDDs) are a common group of disorders that frequently share overlapping symptoms, including cognitive deficits, altered attention, seizures, impaired social interactions, and anxiety. The causes of these disorders are varied ranging from early prenatal/postnatal insults to genetic variants that either cause or are associated with an increased likelihood of an IDD. As many of the symptoms observed in individuals with IDDs are a manifestation of altered nervous system function resulting in altered behaviors, it should not be surprising that the field is very dependent upon in vivo model systems. This special issue of Neurobiology of Learning and Memory is focused on the methods and approaches that are being used to model and understand these disorders in mammals. While surveys by the Pew Foundation continue to find a high degree of confidence/trust in scientists by the public, several recent studies have documented issues with reproducibility in scientific publications. This special issue includes both primary research articles and review articles in which careful attention has been made to transparently report methods and use rigorous approaches to ensure reproducibility. Although there have been and will continue to be remarkable advances for treatment of subset of IDDs, it is clear that this field is still in its early stages. There is no doubt that the strategies being used to model IDDs will continue to evolve. We hope this special issue will support this evolution so that we can maintain the trust of the public and elected officials, and continue developing evidence-based approaches to new therapeutics.
- Published
- 2019
27. Accelerated Hyper-Maturation of Parvalbumin Circuits in the Absence of MeCP2
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Annarita Patrizi, Patricia N. Awad, Graziella Di Cristo, Bidisha Chattopadhyaya, Chloe Li, and Michela Fagiolini
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,Cognitive Neuroscience ,Biology ,Cell Maturation ,Inhibitory postsynaptic potential ,medicine.disease_cause ,MECP2 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Interneurons ,mental disorders ,Neural Pathways ,medicine ,Animals ,GABAergic Neurons ,030304 developmental biology ,Visual Cortex ,Mice, Knockout ,0303 health sciences ,Mutation ,Perineuronal net ,nervous system diseases ,Mice, Inbred C57BL ,Visual cortex ,medicine.anatomical_structure ,Parvalbumins ,biology.protein ,GABAergic ,Original Article ,Neuroscience ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
Methyl-CpG-binding protein 2 (MeCP2) mutations are the primary cause of Rett syndrome, a severe neurodevelopmental disorder. Cortical parvalbumin GABAergic interneurons (PV) make exuberant somatic connections onto pyramidal cells in the visual cortex of Mecp2-deficient mice, which contributes to silencing neuronal cortical circuits. This phenotype can be rescued independently of Mecp2 by environmental, pharmacological, and genetic manipulation. It remains unknown how Mecp2 mutation can result in abnormal inhibitory circuit refinement. In the present manuscript, we examined the development of GABAergic circuits in the primary visual cortex of Mecp2-deficient mice. We identified that PV circuits were the only GABAergic interneurons to be upregulated, while other interneurons were downregulated. Acceleration of PV cell maturation was accompanied by increased PV cells engulfment by perineuronal nets (PNNs) and by an increase of PV cellular and PNN structural complexity. Interestingly, selective deletion of Mecp2 from PV cells was sufficient to drive increased structure complexity of PNN. Moreover, the accelerated PV and PNN maturation was recapitulated in organotypic cultures. Our results identify a specific timeline of disruption of GABAergic circuits in the absence of Mecp2, indicating a possible cell-autonomous role of MeCP2 in the formation of PV cellular arbors and PNN structures in the visual cortex.
- Published
- 2018
28. Deep Learning of spontaneous arousal fluctuation detects early impairments in Rett Syndrome and CDKL5 disorder
- Author
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Michela Fagiolini
- Subjects
medicine.medical_specialty ,CDKL5 Disorder ,General Neuroscience ,medicine ,Rett syndrome ,Audiology ,medicine.disease ,Psychology ,Arousal - Published
- 2019
29. Visual evoked potentials detect cortical processing deficits in Rett syndrome
- Author
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Walter E. Kaufmann, Geneva DeGregorio, Eleonora Centofante, Charles A. Nelson, Jocelyn LeBlanc, Vanessa Vogel-Farley, Michela Fagiolini, and Katherine Barnes
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Visual acuity ,genetic structures ,medicine.diagnostic_test ,Rett syndrome ,Electroencephalography ,medicine.disease ,MECP2 ,Neurodevelopmental disorder ,Visual cortex ,medicine.anatomical_structure ,Neurology ,medicine ,Neurology (clinical) ,Evoked potential ,medicine.symptom ,Psychology ,Neuroscience ,Developmental regression - Abstract
Objective Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X-linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT. Methods We recorded pattern-reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli. Results Mecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT. Interpretation VEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatment. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
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- 2015
30. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells
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Christine L. Mummery, Hiroshi Kawamoto, Mitsuru Morimoto, Hiroki Sato, Misako Yoneda, Kim M. Summers, Haruhiko Koseki, Carsten O. Daub, Imad Abugessaisa, Olga Hrydziuszko, Akira Hasegawa, Afsaneh Eslami, J Kenneth Baillie, Dan Goldowitz, Frank Brombacher, Piero Carninci, Thomas J. Ha, Tomokatsu Ikawa, Peter G. Zhang, Andru Tomoiu, Erik Arner, Robin Andersson, Soichi Kojima, Margaret Patrikakis, Andreas Lennartsson, Christine A. Wells, Valerio Orlando, Miki Kojima, Lesley M. Forrester, Peter Arner, Marina Lizio, Christopher J. Mungall, Geoffrey J. Faulkner, Berit Lilje, David A. Hume, Takeya Kasukawa, Hideya Kawaji, Louise N. Winteringham, Soichi Ogishima, Kristoffer Vitting-Seerup, Jayson Harshbarger, Michael Detmar, Anita Schwegmann, Yasushi Okazaki, Rolf Swoboda, Alka Saxena, Jun Kawai, Hiromi Nishiyori-Sueki, Mitsuko Hara, Yoshihide Hayashizaki, Ernst J. Wolvetang, Chieko Kai, Naoto Kondo, Richard A Axton, Albin Sandelin, James Briggs, Yutaka Nakachi, Dmitry A. Ovchinnikov, Carmelo Ferrai, Mitsuyoshi Murata, Masayoshi Itoh, Finn Drabløs, Anthony G Beckhouse, Lynsey Fairbairn, Meenhard Herlyn, Mariko Okada-Hatakeyama, Beatrice Bodega, Susan E. Zabierowski, Morana Vitezic, Michiel J. L. de Hoon, Masaaki Furuno, Ana Pombo, Reto Guler, Hiroshi Tanaka, Alistair R. R. Forrest, Serkan Sahin, Timo Lassmann, Robert Passier, S. Peter Klinken, Tom C. Freeman, Alexander D. Diehl, Niklas Mejhert, Anna Ehrlund, Ken Miyaguchi, Michela Fagiolini, Nicolas Bertin, Michelle Rönnerblad, Sayaka Nagao-Sato, Levon M. Khachigian, Mitsuhiro Endoh, Margaret B. Davis, Shiro Fukuda, Daisuke Sugiyama, Xian-Yang Qin, Malcolm E. Fisher, Yosuke Mizuno, Jessica Severin, Sarah Klein, Suzana Savvi, Kelly J. Morris, Terrence F. Meehan, Yuri Ishizu, Fumi Hori, Ahmad M. N. Alhendi, Sachi Ishikawa-Kato, Tsugumi Kawashima, Harukazu Suzuki, Sugata Roy, and Chiyo Yanagi-Mizuochi
- Subjects
Transcription, Genetic ,Cellular differentiation ,Enhancer RNAs ,Biology ,Article ,Mice ,Dogs ,Transcription (biology) ,Animals ,RNA, Messenger ,Enhancer ,Gene ,Transcription factor ,Genetics ,Regulation of gene expression ,Multidisciplinary ,Binding Sites ,Stem Cells ,Gene Expression Regulation, Developmental ,Promoter ,Cell Differentiation ,Cell biology ,Rats ,Enhancer Elements, Genetic ,Cattle ,Transcription Factors - Abstract
Uncaging promoter and enhancer dynamics In order to understand cellular differentiation, it is important to understand the timing of the regulation of gene expression. Arner et al. used cap analysis of gene expression (CAGE) to analyze gene enhancer and promoter activities in a number of human and mouse cell types. The RNA of enhancers was transcribed first, followed by that of transcription factors, and finally by genes that are not transcription factors. Science , this issue p. 1010
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- 2015
31. FANTOM5 CAGE profiles of human and mouse samples
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Jun Kawai, Anthony G Beckhouse, Dipti Vijayan, Michael Rehli, Toshiyuki Nakamura, Yuki Hasegawa, Timothy C. Barnett, Hisashi Shimoji, Erik Arner, Masayoshi Itoh, Masahide Hamaguchi, Sarah Klein, Reto Guler, Patrizia Rizzu, Atsutaka Kubosaki, Soichi Kojima, Timo Lassmann, Kelly J. Morris, Mutsumi Kanamori-Katayama, Ri Ichiroh Manabe, Hiromasa Morikawa, Kelly J Hitchens, Fumi Hori, Linda M. van den Berg, Yasushi Okazaki, Andru Tomoiu, Antti Sajantila, Akiko Saka, Thierry Sengstag, Alessandro Bonetti, Haruhiko Koseki, Matthias Edinger, Mitsuhiro Ohshima, Carsten O. Daub, Jayson Harshbarger, Sachi Ishikawa-Kato, Tsugumi Kawashima, Christine L. Mummery, Niklas Mejhert, Jun Takai, Dan Goldowitz, Naoko Suzuki, Guojun Sheng, David A. Hume, Hiroshi Kawamoto, Ai Kaiho, Jun Ichi Furusawa, Ailsa J Carlisle, Tomokatsu Ikawa, Shiro Fukuda, Peter G. Zhang, Akira Hasegawa, James Briggs, Toshio Kitamura, Alistair R. R. Forrest, Takahiro Arakawa, Marcvande Wetering, Shohei Noma, Fumio Nakahara, Jessica Severin, Sven Guhl, Atsushi Kondo, Mary C. Farach-Carson, Hans Clevers, Afsaneh Eslami, Christian Schmidl, Peter Heutink, Hideki Tatsukawa, Anita Schwegmann, Noriko Ninomiya, Antje Blumenthal, Yoshihide Hayashizaki, Suzana Savvi, Thomas J. Ha, Claudio Schneider, Daisuke Sugiyama, Hironori Satoh, Mitsuru Morimoto, Hiroki Sato, Yosuke Mizuno, Meenhard Herlyn, Hozumi Motohashi, Shigehiro Yoshida, Hiroo Toyoda, Christophe Simon, Piero Carninci, Tadasuke Nozaki, Hideya Kawaji, Louise N. Winteringham, Swati Pradhan-Bhatt, Imad Abugessaisa, Michihira Tagami, Tony J. Kenna, Yoko Yamaguchi, Geoffrey J. Faulkner, Alka Saxena, Naoto Kondo, Dmitry A. Ovchinnikov, Rie Fujita, Ernst J. Wolvetang, Michael Detmar, Miki Kojima, Peter Arner, Mitsuko Hara, Stefano Gustincich, Carrie A. Davis, Judith S. Kempfle, Margaret Patrikakis, Alan Mackay-Sim, Carmelo Ferrai, Yutaka Nakachi, Juha Kere, Mitsuyoshi Murata, Shimon Sakaguchi, Soichi Ogishima, Silvia Zucchelli, Andreas Lennartsson, Thomas R. Gingeras, Masanori Suzuki, Beatrice Bodega, Sugata Roy, Sayaka Nagao-Sato, Mitsuhiro Endoh, Anna Ehrlund, J Kenneth Baillie, Mizuho Sakai, Michela Fagiolini, Taeko Dohi, Christine A. Wells, Frank Brombacher, Masayuki Yamamoto, Robert Passier, Lynsey Fairbairn, Teunis B. H. Geijtenbeek, Shigeo Koyasu, Hiromi Nishiyori-Sueki, Yuri Ishizu, Yuki I. Kawamura, Chiyo Yanagi-Mizuochi, Roberto Verardo, Misako Yoneda, Mariko Okada-Hatakeyama, Kaoru Kaida, Ana Pombo, Gundula Schulze-Tanzil, Lesley M. Forrester, Kim M. Summers, Harukazu Suzuki, Naganari Ohkura, Weon Ju Lee, Hiroshi Tanaka, Alan J. Knox, Karl Ekwall, Yukio Nakamura, Serkan Sahin, Shuhei Noguchi, Hiroshi Ohno, Yohei Yonekura, Richard A Axton, Marina Lizio, S. Peter Klinken, Malcolm E. Fisher, Shoko Watanabe, Magda Babina, Xian-Yang Qin, Takaaki Sugiyama, B. Albert S. Edge, Eri Saijyo, Valerio Orlando, Takeya Kasukawa, Kazuyo Moro, Kenichi Nakazato, Naoko Takahashi, Levon M. Khachigian, Chieko Kai, Masaaki Furuno, Jay W. Shin, Hideki Enomoto, Hubrecht Institute for Developmental Biology and Stem Cell Research, AII - Infectious diseases, Infectious diseases, and AII - Amsterdam institute for Infection and Immunity
- Subjects
0301 basic medicine ,500 Naturwissenschaften und Mathematik::570 Biowissenschaften ,Biologie ,Data Descriptor ,Molecular biology ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit ,Genome ,Mice ,0302 clinical medicine ,Transcription (biology) ,Promoter Regions, Genetic ,Non-U.S. Gov't ,Regulation of gene expression ,Research Support, Non-U.S. Gov't ,Statistics ,Computer Science Applications1707 Computer Vision and Pattern Recognition ,Computer Science Applications ,Library and Information Sciences ,Information Systems ,Statistics, Probability and Uncertainty ,Statistics and Probability ,ddc:500 ,Cell activation ,Systems biology ,Cell biology ,Computational biology ,Biology ,Research Support ,Education ,03 medical and health sciences ,Species Specificity ,Developmental biology ,Journal Article ,Animals ,Humans ,Enhancer ,Gene Expression Profiling ,Promoter ,Cap analysis gene expression ,Computational biology and bioinformatics ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,Cardiovascular and Metabolic Diseases ,Probability and Uncertainty ,030217 neurology & neurosurgery - Abstract
Scientific Data, 4, ISSN:2052-4463
- Published
- 2017
- Full Text
- View/download PDF
32. NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity
- Author
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Michela Fagiolini, Anne E. Takesian, Takao K. Hensch, and Nathalie Picard
- Subjects
0301 basic medicine ,Male ,N-Methylaspartate ,Receptor expression ,Prefrontal Cortex ,Estrous Cycle ,Inhibitory postsynaptic potential ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Sex Factors ,Interneurons ,medicine ,Animals ,Ketamine ,Receptor ,Molecular Biology ,Estrous cycle ,biology ,Depression ,Receptors, GABA-A ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,Parvalbumins ,nervous system ,biology.protein ,GRIN2A ,NMDA receptor ,Female ,Immediate Communication ,Neuroscience ,030217 neurology & neurosurgery ,Parvalbumin ,medicine.drug - Abstract
Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2A mRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.
- Published
- 2017
33. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome
- Author
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Bryn D. Webb, Speck-Martins Ce, Peter S. Chines, Pietro Artoni, Wai-Man Chan, Mary Beth Scholand, Nori Matsunami, Irini Manoli, John C. Carey, Jessica Cannavino, Michela Fagiolini, Mark Leppert, Carlos Ferreira, Connors S, Hartman T, de Macena Sobreira Nl, Eric N. Olson, Frank H. Collins, Di Gioia Sa, Matthew F. Rose, Elizabeth C. Engle, Payam Mohassel, Carsten G. Bönnemann, Andres Ramirez-Martinez, Long Cheng, Van Ryzin C, Ethylin Wang Jabs, Amy J. Swift, Nicole M. Gilette, Stephen P. Robertson, Caroline D. Robson, Timothy R. Morgan, Ian Hayes, Christopher Grunseich, and David Markie
- Subjects
Male ,0301 basic medicine ,Embryo, Nonmammalian ,Gene Expression ,Muscle Proteins ,General Physics and Astronomy ,Cell Fusion ,Myoblasts ,Myoblast fusion ,0302 clinical medicine ,Morphogenesis ,Myocyte ,Child ,Zebrafish ,Genetics ,Multidisciplinary ,Cell fusion ,Pierre Robin Syndrome ,biology ,Myogenesis ,musculoskeletal system ,Mobius Syndrome ,Pedigree ,3. Good health ,Cell biology ,medicine.anatomical_structure ,Female ,Adult ,Science ,Genes, Recessive ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Muscular Diseases ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Muscle, Skeletal ,Sequence Homology, Amino Acid ,Genetic Complementation Test ,Wild type ,Infant ,Membrane Proteins ,Skeletal muscle ,General Chemistry ,Zebrafish Proteins ,medicine.disease ,biology.organism_classification ,Congenital myopathy ,Disease Models, Animal ,030104 developmental biology ,Mutation ,Sequence Alignment ,030217 neurology & neurosurgery - Abstract
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits., During embryogenesis, the cytoplasmic protein Myomarker (MYMK) mediates muscle fibre formation by fusion of myoblasts. Here, the authors identify autosomal recessive mutations in MYMK that cause Carey-Fineman-Ziter syndrome in humans, and model the disease variants in zebrafish.
- Published
- 2017
34. Microelectrode Arrays: Transparent, Flexible, Penetrating Microelectrode Arrays with Capabilities of Single‐Unit Electrophysiology (Adv. Biosys. 3/2019)
- Author
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Zhan Shi, Michela Fagiolini, Kyung Jin Seo, Yiding Zhong, Hui Fang, Pietro Artoni, Xun Han, Yi Qiang, and Wenhao Yao
- Subjects
Biomaterials ,Microelectrode ,Electrophysiology ,Materials science ,Biomedical Engineering ,General Biochemistry, Genetics and Molecular Biology ,Biomedical engineering - Published
- 2019
35. NMDA Receptor Regulation Prevents Regression of Visual Cortical Function in the Absence of Mecp2
- Author
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Lea Hachigian, Roman Pavlyuk, Michela Fagiolini, Alka Saxena, Severine Durand, Piero Carninci, Annarita Patrizi, Takao K. Hensch, and Kathleen B. Quast
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,Neuroscience(all) ,Visual Acuity ,Gating ,Visual system ,Biology ,Inhibitory postsynaptic potential ,Receptors, N-Methyl-D-Aspartate ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Rett Syndrome ,medicine ,Animals ,Visual Pathways ,Sensory deprivation ,Vision test ,Visual Cortex ,030304 developmental biology ,Mice, Knockout ,Neurons ,0303 health sciences ,Vision Tests ,General Neuroscience ,Disease Models, Animal ,Parvalbumins ,Visual cortex ,medicine.anatomical_structure ,Nerve Degeneration ,Excitatory postsynaptic potential ,NMDA receptor ,Female ,Neuroscience ,030217 neurology & neurosurgery - Abstract
SummaryBrain function is shaped by postnatal experience and vulnerable to disruption of Methyl-CpG-binding protein, Mecp2, in multiple neurodevelopmental disorders. How Mecp2 contributes to the experience-dependent refinement of specific cortical circuits and their impairment remains unknown. We analyzed vision in gene-targeted mice and observed an initial normal development in the absence of Mecp2. Visual acuity then rapidly regressed after postnatal day P35–40 and cortical circuits largely fell silent by P55-60. Enhanced inhibitory gating and an excess of parvalbumin-positive, perisomatic input preceded the loss of vision. Both cortical function and inhibitory hyperconnectivity were strikingly rescued independent of Mecp2 by early sensory deprivation or genetic deletion of the excitatory NMDA receptor subunit, NR2A. Thus, vision is a sensitive biomarker of progressive cortical dysfunction and may guide novel, circuit-based therapies for Mecp2 deficiency.
- Published
- 2012
36. MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit
- Author
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Frank S. Menniti, Esther Steidl, Earl Gordon, Michela Fagiolini, Bruno Buisson, Caterina Virginio, Kathy Paschetto, Volkmann Robert A, Melanie Gleyzes, Christopher Fanger, David E. Anderson, Susanna B. Mierau, and Venkata Ramana Sirivolu
- Subjects
0301 basic medicine ,Xenopus ,Physiology ,lcsh:Medicine ,Pharmacology ,Biochemistry ,0302 clinical medicine ,Animal Cells ,Electrochemistry ,Amino Acids ,Receptor ,lcsh:Science ,Neurons ,Multidisciplinary ,biology ,Organic Compounds ,Glutamate receptor ,Neurochemistry ,Animal Models ,Neurotransmitters ,Chemistry ,Physical Sciences ,Xenopus Oocytes ,Vertebrates ,Excitatory postsynaptic potential ,NMDA receptor ,Frogs ,Cell lines ,Cellular Types ,Glutamate ,Biological cultures ,Receptor Physiology ,Research Article ,Cell Physiology ,Materials Science ,Material Properties ,Glycine ,Research and Analysis Methods ,Amphibians ,03 medical and health sciences ,Model Organisms ,Animals ,Electrode Potentials ,HEK 293 cells ,Organic Chemistry ,lcsh:R ,Chemical Compounds ,Organisms ,Biology and Life Sciences ,Proteins ,Glutamic acid ,Cell Biology ,biology.organism_classification ,030104 developmental biology ,Aliphatic Amino Acids ,Solubility ,biology.protein ,GRIN2A ,lcsh:Q ,030217 neurology & neurosurgery ,Neuroscience - Abstract
GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders.
- Published
- 2016
37. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors
- Author
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Ana Maria Blanco Martinez, Michela Fagiolini, Hui-ya Gilbert, Takuji Kurimoto, Yiqing Li, Larry I. Benowitz, Yuqin Yin, Silmara de Lima, Yoshiki Koriyama, and Júlia Teixeira Oliveira
- Subjects
Retinal Ganglion Cells ,Superior Colliculi ,genetic structures ,Genetic Vectors ,Glaucoma ,Biology ,Lateral geniculate nucleus ,Retinal ganglion ,Mice ,Cyclic AMP ,medicine ,Animals ,Regeneration ,Axon ,Multidisciplinary ,Integrases ,Superior colliculus ,Regeneration (biology) ,Calcium-Binding Proteins ,PTEN Phosphohydrolase ,Zymosan ,Geniculate Bodies ,Optic Nerve ,Dependovirus ,medicine.disease ,Axons ,eye diseases ,Circadian Rhythm ,medicine.anatomical_structure ,Optic Nerve Injuries ,Optomotor response ,Optic nerve ,sense organs ,Neuroscience ,Gene Deletion - Abstract
The mature optic nerve cannot regenerate when injured, leaving victims of traumatic nerve damage or diseases such as glaucoma with irreversible visual losses. Recent studies have identified ways to stimulate retinal ganglion cells to regenerate axons part-way through the optic nerve, but it remains unknown whether mature axons can reenter the brain, navigate to appropriate target areas, or restore vision. We show here that with adequate stimulation, retinal ganglion cells are able to regenerate axons the full length of the visual pathway and on into the lateral geniculate nucleus, superior colliculus, and other visual centers. Regeneration partially restores the optomotor response, depth perception, and circadian photoentrainment, demonstrating the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals.
- Published
- 2012
38. Bilayer Nanomesh Structures for Transparent Recording and Stimulating Microelectrodes
- Author
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Po-Min Wang, Pietro Artoni, Wentai Liu, Katherine S. Ziemer, Michela Fagiolini, Yi Qiang, Kyung Jin Seo, Negar H. Golshan, Hui Fang, Stanislav Culaclii, and Xuanyi Zhao
- Subjects
Bioelectronics ,Materials science ,Bilayer ,Nanotechnology ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,0104 chemical sciences ,Electronic, Optical and Magnetic Materials ,Biomaterials ,Microelectrode ,chemistry.chemical_compound ,Nanomesh ,PEDOT:PSS ,chemistry ,Electrode ,Electrochemistry ,Transmittance ,0210 nano-technology ,Electroplating - Abstract
Nanomeshed forms of metal have emerged as a promising biocompatible electrode material for future soft bioelectronics. However, metal/electrolyte interfaces are intrinsically capacitive, severely limiting their electrochemical performance, especially for scaled electrodes, which are essential for high-resolution brain mapping. Here, an innovative bilayer nanomesh approach is demonstrated to address this limitation while preserving the nanomesh advantage. Electroplating low-impedance coatings on a gold nanomesh template achieves an impedance < 30 kΩ at 1 kHz and a charge injection limit of 1 mC cm−2 for 80 × 80 µm2 microelectrodes, a 4.3× and 12.8× improvement over uncoated electrodes, respectively, while maintaining a transparency of ≈70% at 550 nm. Systematic characterization of transmittance, impedance, charge injection limits, cyclic charge injection, and light-induced artifacts reveal an encouraging performance of the bilayer nanomesh microelectrodes. The bilayer nanomesh approach presented here is expected to enable next-generation large-scale transparent bioelectronics with broad utility in biology.
- Published
- 2017
39. FADC signal reconstruction for the MAGIC telescope
- Author
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H. Anderhub, K. Shinozaki, Stefano Ciprini, M. Camara, R. Mirzoyan, E. Carmona, Roberta Zanin, Florian Goebel, M. V. Fonseca, P. Jacon, Jorge Andres Lopez Lopez, D. Hakobyan, F. Zandanel, E. Domingo-Santamaría, J. Hose, Jelena Ninkovic, Michela Fagiolini, Oriana Mansutti, Francesco Dazzi, M. Rissi, S. Mizobuchi, Tadeusz Wibig, V. Scalzotto, M. A. Lopez, T. Schweizer, Francesco Longo, W. Wittek, Marc Ribó, J. Zapatero, D. Tescaro, Pol Bordas, Dorota Sobczyńska, M. T. Costado, V. Vitale, C. C. Hsu, Miriam Lucio Martinez, Justin Albert, M. Asensio, Steven N. Shore, V. Curtef, R. Schmitt, Riccardo Paoletti, Takashi Saito, Masahiro Teshima, Igor Oya, Jose Flix, G. Maneva, Daniel Nieto, Daniel Kranich, C. Merck, E. Aliu, E. Prandini, P. Antoranz, Elina Lindfors, Ll. Font, R. K. Bock, C. Baixeras, A. Sillanpää, A. Herrero, A. Saggion, L. O. Takalo, Adrian Biland, S. Rügamer, C. Delgado, V. Danielyan, Masaaki Hayashida, Antonio Stamerra, Juan Abel Barrio, Diego F. Torres, Ciro Bigongiari, M. Pasanen, R. G. Pegna, Markus Gaug, K. Berger, A. Armada, J. Rico, Jose Luis Contreras, Mosè Mariotti, M. Garczarczyk, Josep M. Paredes, M. Shayduk, T. Jogler, Ashot Chilingarian, Juan Cortina, E. Oña-Wilhelmi, R. Kritzer, A. Raymers, A. De Angelis, R. Firpo, B. De Lotto, D. Höhne, L. S. Stark, R. J. García-López, N. Puchades, A. Piccioli, Nicola Galante, R. Kosyra, Robert Wagner, Saverio Lombardi, H. Bartko, E. Fernandez, E. Lorenz, I. Britvitch, Daniel Ferenc, Maria Giller, Thomas Bretz, H. Vankov, Abelardo Moralejo, Michele Doro, N. Otte, M. Panniello, P. Sartori, D. Mazin, Manel Errando, Kari Nilsson, Wolfgang Rhode, Julia Becker, S. Commichau, Wlodek Bednarek, Jose Miguel Miranda, Daniela Dorner, A. Laille, Petar Temnikov, M. Fuchs, Massimo Persic, Mario Meucci, J. A. Coarasa, Valentí Bosch-Ramon, L. Peruzzo, V. Scapin, R. de los Reyes, Nicola Turini, P. Majumdar, N. Sidro, M. Meyer, D. Pascoli, A. Robert, Felicitas Pauss, T. Hengstebeck, Denis Bastieri, Alvaro Sanchez, Karl Mannheim, J., Albert, E., Aliu, H., Anderhub, P., Antoranz, A., Armada, M., Asensio, C., Baixera, J. A., Barrio, H., Bartko, D., Bastieri, J., Becker, W., Bednarek, K., Berger, C., Bigongiari, A., Biland, R. K., Bock, P., Borda, V., Bosch Ramon, T., Bretz, I., Britvitch, M., Camara, E., Carmona, A., Chilingarian, S., Ciprini, J. A., Coarasa, S., Commichau, J. L., Contrera, J., Cortina, M. T., Costado, V., Curtef, V., Danielyan, F., Dazzi, A. D., Angeli, C., Delgado, R. d., los Reye, B. D., Lotto, E., Domingo Santamaria, D., Dorner, M., Doro, M., Errando, M., Fagiolini, D., Ferenc, E., Fernandez, R., Firpo, J., Flix, M. V., Fonseca, L., Font, M., Fuch, N., Galante, R. J., Garcia Lopez, M., Garczarczyk, M., Gaug, M., Giller, F., Goebel, D., Hakobyan, M., Hayashida, T., Hengstebeck, A., Herrero, D., Hohne, J., Hose, C. C., Hsu, P., Jacon, T., Jogler, R., Kosyra, D., Kranich, R., Kritzer, A., Laille, E., Lindfor, S., Lombardi, Longo, Francesco, J., Lopez, M., Lopez, E., Lorenz, P., Majumdar, G., Maneva, K., Mannheim, O., Mansutti, M., Mariotti, M., Martinez, D., Mazin, C., Merck, M., Meucci, M., Meyer, J. M., Miranda, R., Mirzoyan, S., Mizobuchi, A., Moralejo, D., Nieto, K., Nilsson, J., Ninkovic, E., Ona Wilhelmi, N., Otte, I., Oya, M., Panniello, R., Paoletti, J. M., Parede, M., Pasanen, D., Pascoli, F., Pau, R., Pegna, M., Persic, L., Peruzzo, A., Piccioli, N., Puchade, E., Prandini, A., Raymer, W., Rhode, M., Ribo, J., Rico, M., Rissi, A., Robert, S., Rugamer, A., Saggion, T., Saito, A., Sanchez, P., Sartori, V., Scalzotto, V., Scapin, R., Schmitt, T., Schweizer, M., Shayduk, K., Shinozaki, S. N., Shore, N., Sidro, A., Sillanpaa, D., Sobczynska, A., Stamerra, L. S., Stark, L., Takalo, P., Temnikov, D., Tescaro, M., Teshima, D. F., Torre, N., Turini, H., Vankov, V., Vitale, R. M., Wagner, T., Wibig, W., Wittek, F., Zandanel, R., Zanin, and J., Zapatero
- Subjects
signal sampling ,Nuclear and High Energy Physics ,Photomultiplier ,Physics::Instrumentation and Detectors ,Very High Energy Gamma Ray Astronomy ,Detectors ,MAGIC telescope ,Astrophysics::High Energy Astrophysical Phenomena ,FOS: Physical sciences ,Astrophysics ,Signal ,law.invention ,Telescope ,Optics ,IMAGING CHERENKOV DETECTOR ,law ,Calibration ,MAGIC (telescope) ,Instrumentation ,Cherenkov radiation ,CALIBRATION ,Physics ,Signal reconstruction ,business.industry ,GAMMA-RAY ASTRONOMY ,SYSTEM ,TESTS ,Astrophysics (astro-ph) ,Astrophysics::Instrumentation and Methods for Astrophysics ,Gamma ray ,Detector ,business - Abstract
Until April 2007 the MAGIC telescope used a 300 MSamples/s FADC system to sample the shaped PMT signals produced by the captured Cherenkov photons of air showers. Different algorithms to reconstruct the signal from the read-out samples (extractors) have been implemented and are described and compared. Criteria based on the obtained charge and time resolution/bias are defined and used to judge the different extractors, by applying them to calibration, cosmic and pedestal signals. The achievable charge and time resolution have been derived as functions of the incident number of photo-electrons., Accepted for publication in NIM A
- Published
- 2008
40. Unfolding of differential energy spectra in the MAGIC experiment
- Author
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E. Fernandez, M. I. Martínez, K. Shinozaki, V. Danielyan, R. K. Bock, N. Sidro, A. Laille, J. M. Paredes, Antonio Stamerra, Francesco Longo, W. Wittek, D. Pascoli, Roberta Zanin, M. Fuchs, Massimo Persic, F. Pauss, E. Lorenz, T. Hengstebeck, E. Domingo-Santamaría, Michela Fagiolini, Oriana Mansutti, M. Pasanen, Abelardo Moralejo, R. de los Reyes, Stefano Ciprini, D. Hakobyan, S. Mizobuchi, Denis Bastieri, A. Robert, Nicola Turini, Jelena Ninkovic, R. Firpo, Alvaro Sanchez, Marc Ribó, K. Nilsson, M. T. Costado, C. Baixeras, H. Anderhub, Julia Becker, Francesco Dazzi, S. Commichau, J. A. Coarasa, D. Tescaro, Tadeusz Wibig, Dorota Sobczyńska, P. Antoranz, J. Zapatero, Justin Albert, Jose Miguel Miranda, Juan Abel Barrio, V. Vitale, I. Oya, J. Rico, G. Maneva, A. Saggion, F. Zandanel, Daniel Nieto, Adrian Biland, Mario Meucci, E. Carmona, Markus Gaug, N. Otte, C. Merck, C. Delgado, K. Berger, L. Peruzzo, K. Mannheim, E. Aliu, Elina Lindfors, L. S. Stark, M. Meyer, Daniel Mazin, Riccardo Paoletti, Michele Doro, M. V. Fonseca, M. Garczarczyk, S. Rügamer, Elisa Prandini, V. Curtef, M. Camara, Ashot Chilingarian, Maria Giller, M. Shayduk, Diego F. Torres, Ciro Bigongiari, Manel Errando, L. O. Takalo, A. Raymers, Pol Bordas, A. Herrero, Mosè Mariotti, A. De Angelis, A. Piccioli, Nicola Galante, P. Sartori, Saverio Lombardi, R. Kritzer, M. Asensio, B. De Lotto, M. López, R. Schmitt, R. Kosyra, Robert Wagner, H. Bartko, E. Oña-Wilhelmi, N. Puchades, P. Jacon, C. C. Hsu, A. Armada, Thomas Bretz, S. N. Shore, R. Mirzoyan, M. Panniello, Masahiro Teshima, Wolfgang Rhode, T. Schweizer, I. Britvitch, A. Sillanpää, W. Bednarek, Jose Flix, Ll. Font, Takashi Saito, Daniela Dorner, J. Hose, Petar Temnikov, Valentí Bosch-Ramon, V. Scapin, Florian Goebel, Masaaki Hayashida, Jose Luis Contreras, Juan Cortina, R. Pegna, Daniel Ferenc, H. Vankov, P. Majumdar, Jorge Andres Lopez Lopez, V. Scalzotto, M. Rissi, D. Kranich, T. Jogler, D. Höhne, R. J. García-López, J., Albert, E., Aliu, H., Anderhub, P., Antoranz, A., Armada, M., Asensio, C., Baixera, J. A., Barrio, H., Bartko, D., Bastieri, J., Becker, W., Bednarek, K., Berger, C., Bigongiari, A., Biland, R. K., Bock, P., Borda, V., Bosch Ramon, T., Bretz, I., Britvitch, M., Camara, E., Carmona, A., Chilingarian, S., Ciprini, J. A., Coarasa, S., Commichau, J. L., Contrera, J., Cortina, M. T., Costado, V., Curtef, V., Danielyan, F., Dazzi, Angelis, A., C., Delgado, Los, R., Lotto, B., E., Domingo Santamar\ia, D., Dorner, M., Doro, M., Errando, M., Fagiolini, D., Ferenc, E., Fernandez, R., Firpo, J., Flix, M. V., Fonseca, L., Font, M., Fuch, N., Galante, R. J., Garc\ia Lopez, M., Garczarczyk, M., Gaug, M., Giller, F., Goebel, D., Hakobyan, M., Hayashida, T., Hengstebeck, A., Herrero, D., H\ohne, J., Hose, C. C., Hsu, P., Jacon, T., Jogler, R., Kosyra, D., Kranich, R., Kritzer, A., Laille, E., Lindfor, S., Lombardi, Longo, Francesco, J., Lopez, M., Lopez, E., Lorenz, P., Majumdar, G., Maneva, K., Mannheim, O., Mansutti, M., Mariotti, M., Mart\inez, D., Mazin, C., Merck, M., Meucci, M., Meyer, J. M., Miranda, R., Mirzoyan, S., Mizobuchi, A., Moralejo, D., Nieto, K., Nilsson, J., Ninkovic, E., O\~na Wilhelmi, N., Otte, I., Oya, M., Panniello, R., Paoletti, J. M., Parede, M., Pasanen, D., Pascoli, F., Pau, R., Pegna, M., Persic, L., Peruzzo, A., Piccioli, N., Puchade, E., Prandini, A., Raymer, W., Rhode, M., Ribo, J., Rico, M., Rissi, A., Robert, S., R\ugamer, A., Saggion, T., Saito, A., Sanchez, P., Sartori, V., Scalzotto, V., Scapin, R., Schmitt, T., Schweizer, M., Shayduk, K., Shinozaki, S. N., Shore, N., Sidro, A., Sillanp\a\a, D., Sobczynska, A., Stamerra, L. S., Stark, L., Takalo, P., Temnikov, D., Tescaro, M., Teshima, D. F., Torre, N., Turini, H., Vankov, V., Vitale, R. M., Wagner, T., Wibig, W., Wittek, F., Zandanel, R., Zanin, and J., Zapatero
- Subjects
Nuclear and High Energy Physics ,statistics techniques ,DISTRIBUTIONS ,ENTROPY ,regularization ,unfolding ,Very High Energy Gamma-ray Astronomy ,Calibrations ,Astrophysics::High Energy Astrophysical Phenomena ,FOS: Physical sciences ,Astrophysics ,Spectral line ,Nuclear physics ,Software ,gamma ray astronomy ,Statistical analysis ,Statistical physics ,Instrumentation ,Physics ,Quantitative Biology::Biomolecules ,business.industry ,Astrophysics (astro-ph) ,Very high energy gamma ray astronomy ,Electrónica ,Física nuclear ,Electricidad ,business - Abstract
The paper describes the different methods, used in the MAGIC experiment, to unfold experimental energy distributions of cosmic ray particles (gamma-rays). Questions and problems related to the unfolding are discussed. Various procedures are proposed which can help to make the unfolding robust and reliable. The different methods and procedures are implemented in the MAGIC software and are used in most of the analyses., Comment: Submitted to NIM A
- Published
- 2007
41. Restoration of Visual Function by Enhancing Conduction in Regenerated Axons
- Author
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Henry H.C. Lee, Michela Fagiolini, lijun Hou, Zhigang He, Eric Frank, Xuefeng Liu, Chinfei Chen, Takao K. Hensch, Chen Wang, Fengfeng Bei, Long Ma, Hai Jin, Joshua R. Sanes, and Georgia Gunner
- Subjects
0301 basic medicine ,Superior Colliculi ,medicine.medical_treatment ,Suppressor of Cytokine Signaling Proteins ,Ciliary neurotrophic factor ,Eye ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,medicine ,Potassium Channel Blockers ,Animals ,Regeneration ,Ciliary Neurotrophic Factor ,Axon ,4-Aminopyridine ,Insulin-Like Growth Factor I ,Myelin Sheath ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,Regeneration (biology) ,Growth factor ,Superior colliculus ,PTEN Phosphohydrolase ,Potassium channel blocker ,Retinal ,Optic Nerve ,Anatomy ,Axons ,Electrophysiological Phenomena ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,nervous system ,Suppressor of Cytokine Signaling 3 Protein ,Synapses ,Optic nerve ,biology.protein ,Osteopontin ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian central nervous system, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC), but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after optic nerve injury.
- Published
- 2015
42. Visual evoked potentials detect cortical processing deficits in Rett syndrome
- Author
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Jocelyn J, LeBlanc, Geneva, DeGregorio, Eleonora, Centofante, Vanessa K, Vogel-Farley, Katherine, Barnes, Walter E, Kaufmann, Michela, Fagiolini, and Charles A, Nelson
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,mice ,genetic structures ,visual acuity ,evoked potentials ,aging ,animals ,biomarkers ,child ,child, preschool ,disease progression ,electroencephalography ,evoked potentials, visual ,female ,humans ,infant ,methyl-cpg-binding protein 2 ,mice, inbred c57bl ,mutation ,photic stimulation ,rett syndrome ,visual cortex ,neurology ,neurology (clinical) ,medicine (all) ,Article ,preschool ,Mice, Inbred C57BL ,Child, Preschool ,Evoked Potentials, Visual ,visual ,inbred c57bl - Abstract
OBJECTIVE: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X-linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT. METHODS: We recorded pattern-reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli. RESULTS: Mecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT. INTERPRETATION: VEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatment.
- Published
- 2015
43. Rapid Critical Period Induction by Tonic Inhibition in Visual Cortex
- Author
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Kunihiko Obata, Michela Fagiolini, Takao K. Hensch, and Youichi Iwai
- Subjects
Time Factors ,genetic structures ,Development/Plasticity/Repair ,Glutamate decarboxylase ,Biology ,Inhibitory postsynaptic potential ,Synaptic Transmission ,Tonic (physiology) ,Ocular dominance ,Mice ,medicine ,Animals ,GABA Modulators ,Visual Cortex ,Mice, Knockout ,Diazepam ,Neuronal Plasticity ,Neocortex ,Glutamate Decarboxylase ,Critical Period, Psychological ,General Neuroscience ,Neural Inhibition ,Darkness ,Receptors, GABA-A ,Isoenzymes ,Mice, Inbred C57BL ,Monocular deprivation ,Visual cortex ,medicine.anatomical_structure ,Sensory Deprivation ,Neuroscience ,Photic Stimulation - Abstract
Mice lacking a synaptic isoform of glutamic acid decarboxylase (GAD65) do not exhibit ocular dominance plasticity unless an appropriate level of GABAergic transmission is restored by direct infusion of benzodiazepines into the brain. To better understand how intracortical inhibition triggers experience-dependent changes, we dissected the precise timing requirement for GABA function in the monocular deprivation (MD) paradigm.Diazepam (DZ) or vehicle solution was infused daily before and/or during 4 d of MD in GAD65 knock-out mice. Extracellular single-unit recordings from the binocular zone of visual cortex were performed at the end of deprivation. We found that a minimum treatment of 2 d near the beginning of MD was sufficient to fully activate plasticity but did not need to overlap the deprivation per se. Extended delay after DZ infusion eventually led to loss of plasticity accompanied by improved intrinsic inhibitory circuit function. Two day DZ treatment just after eye opening similarly closed the critical period prematurely in wild-type mice.Raising wild-type mice in complete darkness from birth delayed the peak sensitivity to MD as in other mammals. Interestingly, 2 d DZ infusion in the dark also closed the critical period, whereas equally brief light exposure during dark-rearing had no such effect. Thus, enhanced tonic signaling through GABAAreceptors rapidly creates a milieu for plasticity within neocortex capable of triggering a critical period for ocular dominance independent of visual experience itself.
- Published
- 2003
44. RNA extraction from sorted neuronal subtypes
- Author
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Michela Fagiolini, Akira Watahiki, Alka Saxena, Cecile Gurnot, Piero Carninci, Atsuko Asaka-Oba, Akiko Wagatsuma, Takenobu Kuji, Yukihiko Noro, and Takao K. Hensch
- Subjects
Extracellular matrix ,Biological neural network ,RNA extraction ,Biology ,Protocol Summary ,General Biochemistry, Genetics and Molecular Biology ,Biotechnology ,Cell biology - Abstract
Protocol Summary Efficient isolation of specific, intact, living neurons from the adult brain is problematic due to the complex nature of the extracellular matrix consolidating the neuronal network. Here, we present significant improvements to the protocol for isolation of pure populations of neurons from mature postnatal mouse brain using fluorescence activated cell sorting (FACS). The 10-fold increase in cell yield enables cell-specific transcriptome analysis by protocols such as nanoCAGE and RNA seq.
- Published
- 2017
45. Sensory integration in mouse insular cortex reflects GABA circuit maturation
- Author
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Guoping Feng, Anne E. Takesian, Takao K. Hensch, Nadine Gogolla, Michela Fagiolini, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at MIT, and Feng, Guoping
- Subjects
Male ,Methyl-CpG-Binding Protein 2 ,Neuroscience(all) ,Glutamate decarboxylase ,Sensation ,Sensory system ,Nerve Tissue Proteins ,Insular cortex ,Article ,MECP2 ,Mice ,Species Specificity ,Neural Pathways ,medicine ,Animals ,Autistic Disorder ,GABAergic Neurons ,Cerebral Cortex ,Mice, Knockout ,Diazepam ,Glutamate Decarboxylase ,General Neuroscience ,Microfilament Proteins ,Multisensory integration ,medicine.disease ,Disease Models, Animal ,medicine.anatomical_structure ,Cerebral cortex ,Knockout mouse ,Autism ,Psychology ,Neuroscience - Abstract
SummaryInsular cortex (IC) contributes to a variety of complex brain functions, such as communication, social behavior, and self-awareness through the integration of sensory, emotional, and cognitive content. How the IC acquires its integrative properties remains unexplored. We compared the emergence of multisensory integration (MSI) in the IC of behaviorally distinct mouse strains. While adult C57BL/6 mice exhibited robust MSI, this capacity was impaired in the inbred BTBR T+tf/J mouse model of idiopathic autism. The deficit reflected weakened γ-aminobutyric acid (GABA) circuits and compromised postnatal pruning of cross-modal input. Transient pharmacological enhancement by diazepam in BTBR mice during an early sensitive period rescued inhibition and integration in the adult IC. Moreover, impaired MSI was common across three other monogenic models (GAD65, Shank3, and Mecp2 knockout mice) displaying behavioral phenotypes and parvalbumin-circuit abnormalities. Our findings offer developmental insight into a key neural circuit relevant to neuropsychiatric conditions like schizophrenia and autism.
- Published
- 2014
46. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons
- Author
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Alan R. Mardinly, Michela Fagiolini, Jeremy E. Bazinet, Annarita Patrizi, David A. Harmin, Ivo Spiegel, Caleigh Mandel-Brehm, Hillel Adesnik, Eleonora Centofante, Christopher P. Tzeng, and Michael E. Greenberg
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Vasoactive intestinal peptide ,Neural Inhibition ,Biology ,Inhibitory postsynaptic potential ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cellular neuroscience ,Neurotrophic factors ,Internal medicine ,Neural Pathways ,medicine ,Biological neural network ,Animals ,Insulin-Like Growth Factor I ,Vision, Ocular ,Visual Cortex ,Neurons ,Multidisciplinary ,Neuronal Plasticity ,Pyramidal Cells ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,nervous system ,Synaptic plasticity ,Synapses ,Female ,Neuroscience ,Non-spiking neuron ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Vasoactive Intestinal Peptide - Abstract
Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.
- Published
- 2014
47. CAGE-defined promoter regions of the genes implicated in Rett Syndrome
- Author
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Michela Fagiolini, Timo Lassmann, Dan Goldowitz, Alka Saxena, Nicolas Bertin, Peter Heutink, Thomas J. Ha, Peter G. Zhang, Piero Carninci, Hideya Kawaji, Annarita Patrizi, Leonard Lipovich, Morana Vitezic, Robin Andersson, Alistair R. R. Forrest, and Albin Sandelin
- Subjects
Methyl-CpG-Binding Protein 2 ,CDKL5 ,Histones ,Mice ,pathology [Brain] ,Promoter Regions, Genetic ,genetics [Nerve Tissue Proteins] ,Genetics ,Neurons ,genetics [Methyl-CpG-Binding Protein 2] ,Brain ,Forkhead Transcription Factors ,Genomics ,genetics [Histones] ,Protein-Serine-Threonine Kinases ,TATA Box ,FOXG1 ,Regulatory sequence ,CAGE ,metabolism [Neurons] ,genetics [Forkhead Transcription Factors] ,Transcription Initiation Site ,Biotechnology ,Research Article ,Rett syndrome ,genetics [Protein Serine-Threonine Kinases] ,Nerve Tissue Proteins ,Biology ,Protein Serine-Threonine Kinases ,genetics [Protein-Serine-Threonine Kinases] ,MECP2 ,Cell Line, Tumor ,medicine ,Rett Syndrome ,genetics [TATA Box] ,Animals ,Humans ,FOXG1 protein, human ,ddc:610 ,CDKL5 protein, human ,Enhancer ,Transcriptomics ,Gene ,Transcription factor ,Gene Expression Profiling ,medicine.disease ,metabolism [Brain] ,genetics [Promoter Regions, Genetic] ,genetics [Rett Syndrome] ,CpG Islands ,Promoter architecture ,pathology [Rett Syndrome] ,genetics [CpG Islands] - Abstract
Background Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes. Results Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum. Conclusions Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1177) contains supplementary material, which is available to authorized users.
- Published
- 2014
48. Visual Acuity Development and Plasticity in the Absence of Sensory Experience
- Author
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Severine Durand, Chinfei Chen, Jocelyn LeBlanc, Michela Fagiolini, Erin Kang, and Takao K. Hensch
- Subjects
Male ,Visual acuity ,genetic structures ,Visual Acuity ,Sensory system ,Plasticity ,Ocular dominance ,Mice ,Vision, Monocular ,Neuroplasticity ,medicine ,Animals ,Sensory deprivation ,Visual Cortex ,Neurons ,Neuronal Plasticity ,General Neuroscience ,Articles ,eye diseases ,Mice, Inbred C57BL ,Monocular deprivation ,Visual cortex ,medicine.anatomical_structure ,medicine.symptom ,Sensory Deprivation ,Psychology ,Neuroscience - Abstract
Visual circuits mature and are refined by sensory experience. However, significant gaps remain in our understanding how deprivation influences the development of visual acuity in mice. Here, we perform a longitudinal study assessing the effects of chronic deprivation on the development of the mouse subcortical and cortical visual circuits using a combination of behavioral optomotor testing,in vivovisual evoked responses (VEP) and single-unit cortical recordings. As previously reported, orientation tuning was degraded and onset of ocular dominance plasticity was delayed and remained open in chronically deprived mice. Surprisingly, we found that the development of optomotor threshold and VEP acuity can occur in an experience-independent manner, although at a significantly slower rate. Moreover, monocular deprivation elicited amblyopia only during a discrete period of development in the dark. The rate of recovery of optomotor threshold upon exposure of deprived mice to light confirmed a maturational transition regardless of visual input. Together our results revealed a dissociable developmental trajectory for visual receptive-field properties in dark-reared mice suggesting a differential role for spontaneous activity within thalamocortical and intracortical circuits.
- Published
- 2013
49. Excitatory-Inhibitory Balance : Synapses, Circuits, Systems
- Author
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Takao K. Hensch, Michela Fagiolini, Takao K. Hensch, and Michela Fagiolini
- Subjects
- Neurosciences, Medical genetics
- Abstract
A new perspective on brain function depends upon an understanding of the interaction and integration of excitation and inhibition. A recent surge in research activity focused on inhibitory interneurons now makes a more balanced view possible. Technological advances such as improved imaging methods, visualized patch-clamp recording, multiplex single-cell PCR, and gene-targeted deletion or knock-in mice are some of the novel tools featured in this book. This book will provide an integrated view of neuron function, operating in a balanced regime of excitation and inhibition. It is a timely contribution emphasizing how this balance is established, maintained, and modified from the molecular to system levels. The broad spectrum of topics from molecular to cellular and system/computational neuroscience will appeal to a wide audience of advanced graduate students, post-docs, and faculty. Moreover, this book this book features active young researchers from around the world, who are currently educating the brain scientists of tomorrow.
- Published
- 2012
50. Specific GABA A Circuits for Visual Cortical Plasticity
- Author
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Takao K. Hensch, Uwe Rudolph, Joan Marc Fritschy, Karin Löw, Michela Fagiolini, and Hanns Möhler
- Subjects
medicine.medical_specialty ,Zolpidem ,Multidisciplinary ,GABAA receptor ,Central nervous system ,Neural Inhibition ,Neurotransmission ,Biology ,Inhibitory postsynaptic potential ,Visual cortex ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Neuroplasticity ,medicine ,Neuroscience ,medicine.drug - Abstract
Weak inhibition within visual cortex early in life prevents experience-dependent plasticity. Loss of responsiveness to an eye deprived of vision can be initiated prematurely by enhancing γ-aminobutyric acid (GABA)–mediated transmission with benzodiazepines. Here, we use a mouse “knockin” mutation to α subunits that renders individual GABA type A (GABA A ) receptors insensitive to diazepam to show that a particular inhibitory network controls expression of the critical period. Only α1-containing circuits were found to drive cortical plasticity, whereas α2-enriched connections separately regulated neuronal firing. This dissociation carries implications for models of brain development and the safe design of benzodiazepines for use in infants.
- Published
- 2004
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