152 results on '"Corfas G"'
Search Results
2. Treating small fiber neuropathy by topical application of a small molecule GFRα/RET modulator: S14-02
- Author
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Corfas, G., Hedstrom, K. L., Murtie, J. C., Albers, K. M., and Calcutt, N.
- Published
- 2015
3. Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene
- Author
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Buxbaum, J D, Georgieva, L, Young, J J, Plescia, C, Kajiwara, Y, Jiang, Y, Moskvina, V, Norton, N, Peirce, T, Williams, H, Craddock, N J, Carroll, L, Corfas, G, Davis, K L, Owen, M J, Harroch, S, Sakurai, T, and O'Donovan, M C
- Published
- 2008
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4. Adhesion G protein-coupled receptor GPR56 in CNS myelination: PSM08–19
- Author
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Giera, S., Deng, Y., Makinodan, M., Mogha, A., Monk, K. R., Corfas, G., and Piao, X.
- Published
- 2013
5. γ-SECRETASE-DEPENDENT ERBB4 NUCLEAR SIGNALING REGULATES ASTROGENESIS AND DENDRITIC FORMATION: S04-03
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Corfas, G.
- Published
- 2009
6. NRG-erbB signaling in neuron-glia interactions: Sym07-2
- Author
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CORFAS, G.
- Published
- 2006
7. PlexinA2 forward signaling through Rap1 GTPasesregulates dentate gyrus development andSchizophrenia-like behaviors
- Author
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Zhao, XF, Kohen, R, Parent, R, Duan, Y, Fisher, GL, Korn, MJ, Ji, L, Wan, G, Jin, J, Püschel, AW, Dolan, DF, Parent, JM, Corfas, G, Murphy, GG, and Giger, RJ
- Subjects
Rap1 ,fear memory ,sensorimotor gating ,GAP ,Nerve Tissue Proteins ,Receptors, Cell Surface ,GTP Phosphohydrolases ,adult neurogenesis ,schizophrenia ,Mice ,mossy fiber ,Dentate Gyrus ,PlexinA2 ,Animals ,Humans ,semaphoring ,Signal Transduction - Abstract
Dentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We identify the Plexin family members Plxna2 and Plxna4 as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP) domain and Rap1 small GTPases. In adult Plxna2−/− but not Plxna2-GAP-deficient mice, the dentate GC layer is severely malformed, neurogenesis is compromised, and mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with Plxna2−/− mice revealed deficits in associative learning, sociability, and sensorimotor gating—traits commonly observed in neuropsychiatric disorder. Remarkably, while morphological defects are minimal in Plxna2-GAP-deficient brains, defects in fear memory and sensorimotor gating persist. Since allelic variants of human PLXNA2 and RAP1 associate with schizophrenia, our studies identify a biochemical pathway important for brain development and mental health. Zhao et al. find that Sema5A-PlexinA2 forward signaling through Rap1 GTPases is required for progenitor distribution in the developing mouse dentate gyrus. Adult Plxna2−/−, but not Plxna2-GAP-deficient, mice show defects in dentate morphology, neurogenesis, and mossy fiber connectivity. Plxna2−/− and Plxna2-GAP mice exhibit behavioral defects suggestive of neuropsychiatric illness.
- Published
- 2018
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8. Biological Function of Nuclear Receptor Tyrosine Kinase Action
- Author
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Song, S., primary, Rosen, K. M., additional, and Corfas, G., additional
- Published
- 2013
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9. Inner Hair Cells Are Not Required for Survival of Spiral Ganglion Neurons in the Adult Cochlea
- Author
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Zilberstein, Y., primary, Liberman, M. C., additional, and Corfas, G., additional
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- 2012
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10. GPR56-Regulated Granule Cell Adhesion Is Essential for Rostral Cerebellar Development
- Author
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Koirala, S., primary, Jin, Z., additional, Piao, X., additional, and Corfas, G., additional
- Published
- 2009
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11. Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene
- Author
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Buxbaum, J D, primary, Georgieva, L, additional, Young, J J, additional, Plescia, C, additional, Kajiwara, Y, additional, Jiang, Y, additional, Moskvina, V, additional, Norton, N, additional, Peirce, T, additional, Williams, H, additional, Craddock, N J, additional, Carroll, L, additional, Corfas, G, additional, Davis, K L, additional, Owen, M J, additional, Harroch, S, additional, Sakurai, T, additional, and O'Donovan, M C, additional
- Published
- 2007
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12. Mechanisms and Roles of Axon-Schwann Cell Interactions
- Author
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Corfas, G., primary
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- 2004
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13. ARIA is concentrated in the synaptic basal lamina of the developing chick neuromuscular junction.
- Author
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Goodearl, A D, primary, Yee, A G, additional, Sandrock, A W, additional, Corfas, G, additional, and Fischbach, G D, additional
- Published
- 1995
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14. A role for the acetylcholine receptor-inducing protein ARIA in oligodendrocyte development.
- Author
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Vartanian, T, primary, Corfas, G, additional, Li, Y, additional, Fischbach, G D, additional, and Stefansson, K, additional
- Published
- 1994
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15. The number of Na+ channels in cultured chick muscle is increased by ARIA, an acetylcholine receptor-inducing activity
- Author
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Corfas, G, primary and Fischbach, GD, additional
- Published
- 1993
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16. ARIA, a protein that stimulates acetylcholine receptor synthesis, also induces tyrosine phosphorylation of a 185-kDa muscle transmembrane protein.
- Author
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Corfas, G, primary, Falls, D L, additional, and Fischbach, G D, additional
- Published
- 1993
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17. Spinal anesthesia in infant rats: development of a model and assessment of neurologic outcomes.
- Author
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Yahalom B, Athiraman U, Soriano SG, Zurakowski D, Carpino EA, Corfas G, Berde CB, Yahalom, Barak, Athiraman, Umeshkumar, Soriano, Sulpicio G, Zurakowski, David, Carpino, Elizabeth A, Corfas, Gabriel, and Berde, Charles B
- Published
- 2011
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18. Morphology of a sensory neuron in Drosophila is abnormal in memory mutants and changes during aging.
- Author
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Corfas, G, primary and Dudai, Y, additional
- Published
- 1991
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19. Adaptation and fatigue of a mechanosensory neuron in wild-type Drosophila and in memory mutants
- Author
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Corfas, G, primary and Dudai, Y, additional
- Published
- 1990
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20. Mr 42,000 ARIA: A Protein That May Regulate the Accumulation of Acetylcholine Receptors at Developing Chick Neuromuscular Junctions
- Author
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Falls, D.L., primary, Harris, D.A., additional, Johnson, F.A., additional, Morgan, M.M., additional, Corfas, G., additional, and Fischbach, G.D., additional
- Published
- 1990
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21. Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4.
- Author
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Rio, C, Buxbaum, J D, Peschon, J J, and Corfas, G
- Abstract
HER4 is a member of the epidermal growth factor receptor family and has an essential function in heart and neural development. Identification of two HER4 isoforms, HER4 JM-a and JM-b, which differ in their extracellular juxtamembrane region and in their susceptibility to cleavage after phorbol ester stimulation, showed that the juxtamembrane region of the receptor is critical for proteolysis. We now demonstrate that phorbol ester and pervanadate are effective stimuli for HER4 JM-a processing and that the HER4 JM-b isoform does not undergo cleavage in response to any of the stimuli studied. We also show that HER4 JM-a is not cleaved in cells lacking the metalloprotease tumor necrosis factor-alpha-converting enzyme (TACE) and that reexpression of TACE in these cells restores constitutive and regulated processing of HER4 JM-a. Moreover, we show that the sequence specific to the HER4 JM-a juxtamembrane region is sufficient to confer susceptibility to phorbol 12-myristate 13-acetate-induced cleavage of the HER2 receptor. In conclusion, we provide evidence that TACE is essential for the regulated shedding of the HER4 JM-a receptor.
- Published
- 2000
22. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester.
- Author
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Elenius, K, Corfas, G, Paul, S, Choi, C J, Rio, C, Plowman, G D, and Klagsbrun, M
- Abstract
Human epidermal growth factor receptor 4 (HER4) is a member of the epidermal growth factor (EGF) receptor subfamily of receptor tyrosine kinases that is activated by neuregulins (NRG), betacellulin (BTC), and heparin-binding EGF-like growth factor. Sequencing of full-length human HER4 cDNAs revealed the existence of two HER4 isoforms that differed by insertion of either 23 or 13 alternative amino acids in the extracellular juxtamembrane (JM) region. The 23-amino acid form (HER4 JM-a) and the 13-amino acid form (HER4 JM-b) were expressed in a tissue-specific manner, as demonstrated by reverse transcriptase-polymerase chain reaction analysis of mouse and human tissues. Both isoforms were expressed in neural tissues such as cerebellum, whereas kidney expressed HER4 JM-a only and heart HER4 JM-b only. In situ hybridization using specific oligonucleotides demonstrated transcription of both JM-a and JM-b isoforms in the mouse cerebellum. Tyrosine phosphorylation analysis indicated that both receptor isoforms were activated to the same extent by NRG-beta1 and BTC, and to a lesser extent by NRG-alpha1 and heparin-binding EGF-like growth factor. A functional difference was found, however, in response to phorbol ester treatment. Stimulation of cells with phorbol ester resulted in a loss of 125I-NRG-beta1 binding and in a reduction of total cell-associated HER4 protein in HER4 JM-a transfectants but not in HER4 JM-b transfectants. It was concluded that novel alternatively spliced isoforms of HER4 exist, that they are distributed differentially in vivo in mouse and human tissues, that they are both activated by HER4 ligands, and that they may represent cleavable and noncleavable forms of HER4.
- Published
- 1997
23. Defective cAMP metabolism and defective memory in Drosophila
- Author
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Dudai, Y., Joseph Buxbaum, Corfas, G., Orgad, S., Segal, D., Sher, B., Uzzan, A., and Zvi, S.
24. Habituation and dishabituation of a cleaning reflex in normal and mutant Drosophila
- Author
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Corfas, G, primary and Dudai, Y, additional
- Published
- 1989
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25. Evidence for a Neural Activity Which Downregulates AChR Expression.
- Author
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Montgomery, J.M., Mills, R.G., and Corfas, G.
- Subjects
BRAIN research ,CHOLINERGIC receptors ,SYNAPSES - Abstract
Presents an abstract of a paper presented at the Sixteenth International Australasian Winter Conference on Brain Research, held in August 1998 in Queenstown, New Zealand. Focus on acetylcholine receptor (AChR) expression; Leading candidate in AChR upregulation at the synapse.
- Published
- 1999
26. Differential expression of ARIA isoforms in the rat brain
- Author
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CORFAS, G
- Published
- 1995
- Full Text
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27. Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model.
- Author
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Cassinotti LR, Ji L, Yuk MC, Desai AS, Cass ND, Amir ZA, and Corfas G
- Subjects
- Animals, Mice, Cochlear Nerve physiopathology, Hearing Loss physiopathology, Humans, Male, Female, Hair Cells, Auditory, Inner pathology, Auditory Threshold physiology, Hearing Loss, Central physiopathology, Hearing Loss, Hidden, Charcot-Marie-Tooth Disease physiopathology, Charcot-Marie-Tooth Disease genetics, Disease Models, Animal
- Abstract
Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds and has become a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the effect of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Furthermore, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in patients with CMT1A might help develop robust clinical tests for HHL, which are currently lacking.
- Published
- 2024
- Full Text
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28. Population coding of auditory space in the dorsal inferior colliculus persists with altered binaural cues.
- Author
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Rogalla MM, Quass GL, Yardley H, Martinez-Voigt C, Ford AN, Wallace G, Dileepkumar D, Corfas G, and Apostolides PF
- Abstract
Sound localization is critical for real-world hearing, such as segregating overlapping sound streams. For optimal flexibility, central representations of auditory space must adapt to peripheral changes in binaural cue availability, such as following asymmetric hearing loss in adulthood. However, whether the mature auditory system can reliably encode spatial auditory representations upon abrupt changes in binaural input is unclear. Here we use 2-photon Ca
2+ imaging in awake head-fixed mice to determine how the higher-order "shell" layers of the inferior colliculus (IC) encode sound source location in the frontal azimuth, under binaural conditions and after acute monaural hearing loss induced by an ear plug ipsilateral to the imaged hemisphere. Spatial receptive fields were typically broad and not exclusively contralateral: Neurons responded reliably to multiple positions in the contra- and ipsi-lateral hemifields, with preferred positions tiling the entire frontal azimuth. Ear plugging broadened receptive fields and reduced spatial selectivity in a subset of neurons, in agreement with an inhibitory influence of ipsilateral sounds. However ear plugging also enhanced spatial tuning and/or unmasked receptive fields in other neurons, shifting the distribution of preferred angles ipsilaterally with minimal impact on the neuronal population's overall spatial resolution; these effects occurred within 2 hours of ear plugging. Consequently, linear classifiers trained on fluorescence data from control and ear-plugged conditions had similar classification accuracy when tested on held out data from within, but not across hearing conditions. Spatially informative neuronal population codes therefore arise rapidly following monaural hearing loss, in absence of overt experience.- Published
- 2024
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29. From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density.
- Author
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Ji L, Borges BC, Martel DT, Wu C, Liberman MC, Shore SE, and Corfas G
- Subjects
- Animals, Mice, Auditory Threshold, Evoked Potentials, Auditory physiology, Reflex, Startle physiology, Auditory Perception physiology, Spiral Ganglion metabolism, Female, Male, Hearing Loss, Hidden, Hair Cells, Auditory, Inner metabolism, Hair Cells, Auditory, Inner pathology, Synapses metabolism, Synapses physiology, Neurotrophin 3 metabolism, Neurotrophin 3 genetics
- Abstract
Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies., Competing Interests: GC and MCL were scientific founders of Decibel Therapeutics, hadequity interest in the company and have received compensation for consulting. SES and DM are scientific founders of Auricle, Inc and have equity interest in the company. Neither company was involved in this study., (Copyright: © 2024 Ji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
- Full Text
- View/download PDF
30. Respiratory Virus-Induced PARP1 Alters DC Metabolism and Antiviral Immunity Inducing Pulmonary Immunopathology.
- Author
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Mire MM, Elesela S, Morris S, Corfas G, Rasky A, and Lukacs NW
- Subjects
- Animals, Mice, Mice, Knockout, Cytokines metabolism, Cytokines immunology, Immunity, Innate, Female, Poly (ADP-Ribose) Polymerase-1 metabolism, Poly (ADP-Ribose) Polymerase-1 genetics, Dendritic Cells immunology, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections virology, Lung immunology, Lung pathology, Lung virology, Respiratory Syncytial Viruses immunology
- Abstract
Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis of RSV-induced transcriptomic changes in RSV-infected DC revealed metabolic gene signatures suggestive of altered cellular metabolism. Reverse phase protein array (RPPA) data showed significantly increased PARP1 phosphorylation in RSV-infected DC. Real-time cell metabolic analysis demonstrated increased glycolysis in PARP1-/- DC after RSV infection, confirming a role for PARP1 in regulating DC metabolism. Our data show that enzymatic inhibition or genomic ablation of PARP1 resulted in increased ifnb1, il12, and il27 in RSV-infected DC which, together, promote a more appropriate anti-viral environment. PARP1-/- mice and PARP1-inhibitor-treated mice were protected against RSV-induced immunopathology including airway inflammation, Th2 cytokine production, and mucus hypersecretion. However, delayed treatment with PARP1 inhibitor in RSV-infected mice provided only partial protection, suggesting that PARP1 is most important during the earlier innate immune stage of RSV infection.
- Published
- 2024
- Full Text
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31. Ultrastructure of noise-induced cochlear synaptopathy.
- Author
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Moverman DJ, Liberman LD, Kraemer S, Corfas G, and Liberman MC
- Subjects
- Mice, Animals, Noise adverse effects, Hair Cells, Auditory, Hair Cells, Auditory, Inner physiology, Synapses ultrastructure, Cochlear Nerve, Auditory Threshold physiology, Cochlea physiology, Hearing Loss, Noise-Induced
- Abstract
Acoustic overexposure can eliminate synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs), even if hair-cell function recovers. This synaptopathy has been extensively studied by confocal microscopy, however, understanding the nature and sequence of damage requires ultrastructural analysis. Here, we used focused ion-beam scanning electron microscopy to mill, image, segment and reconstruct ANF terminals in mice, 1 day and 1 week after synaptopathic exposure (8-16 kHz, 98 dB SPL). At both survivals, ANF terminals were normal in number, but 62% and 53%, respectively, lacked normal synaptic specializations. Most non-synapsing fibers (57% and 48% at 1 day and 1 week) remained in contact with an IHC and contained healthy-looking organelles. ANFs showed a transient increase in mitochondrial content (51%) and efferent innervation (34%) at 1 day. Fibers maintaining synaptic connections showed hypertrophy of pre-synaptic ribbons at both 1 day and 1 week. Non-synaptic fibers were lower in mitochondrial content and typically on the modiolar side of the IHC, where ANFs with high-thresholds and low spontaneous rates are normally found. Even 1 week post-exposure, many ANF terminals remained in IHC contact despite loss of synaptic specializations, thus, regeneration efforts at early post-exposure times should concentrate on synaptogenesis rather than neurite extension., (© 2023. The Author(s).)
- Published
- 2023
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32. Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.
- Author
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Radyk MD, Nelson BS, Halbrook CJ, Wood A, Lavoie B, Salvatore L, Corfas G, Colacino JA, Shah YM, Crawford HC, and Lyssiotis CA
- Abstract
Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras
G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.- Published
- 2023
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33. Loss of oligodendrocyte ErbB receptor signaling leads to hypomyelination, reduced density of parvalbumin-expressing interneurons, and inhibitory function in the auditory cortex.
- Author
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Borges BC, Meng X, Long P, Kanold PO, and Corfas G
- Subjects
- Mice, Animals, ErbB Receptors metabolism, Interneurons metabolism, Oligodendroglia metabolism, Parvalbumins metabolism, Auditory Cortex metabolism
- Abstract
For a long time, myelin was thought to be restricted to excitatory neurons, and studies on dysmyelination focused primarily on excitatory cells. Recent evidence showed that axons of inhibitory neurons in the neocortex are also myelinated, but the role of myelin on inhibitory circuits remains unknown. Here we studied the impact of mild hypomyelination on both excitatory and inhibitory connectivity in the primary auditory cortex (A1) with well-characterized mouse models of hypomyelination due to loss of oligodendrocyte ErbB receptor signaling. Using laser-scanning photostimulation, we found that mice with mild hypomyelination have reduced functional inhibitory connections to A1 L2/3 neurons without changes in excitatory connections, resulting in altered excitatory/inhibitory balance. These effects are not associated with altered expression of GABAergic and glutamatergic synaptic components, but with reduced density of parvalbumin-positive (PV
+ ) neurons, axons, and synaptic terminals, which reflect reduced PV expression by interneurons rather than PV+ neuronal loss. While immunostaining shows that hypomyelination occurs in both PV+ and PV- axons, there is a strong correlation between MBP and PV expression, suggesting that myelination influences PV expression. Together, the results indicate that mild hypomyelination impacts A1 neuronal networks, reducing inhibitory activity, and shifting networks towards excitation., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)- Published
- 2023
- Full Text
- View/download PDF
34. The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.
- Author
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Zhao XF, Huffman LD, Hafner H, Athaiya M, Finneran MC, Kalinski AL, Kohen R, Flynn C, Passino R, Johnson CN, Kohrman D, Kawaguchi R, Yang LJS, Twiss JL, Geschwind DH, Corfas G, and Giger RJ
- Subjects
- Mice, Animals, Leukocytes, Mononuclear, Sciatic Nerve metabolism, Nerve Degeneration, Nerve Crush, Nerve Regeneration, Cytoskeletal Proteins metabolism, Armadillo Domain Proteins metabolism, Wallerian Degeneration metabolism, Wallerian Degeneration pathology, Peripheral Nerve Injuries metabolism
- Abstract
Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1
-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/., Competing Interests: XZ, LH, HH, MA, MF, AK, RK, CF, RP, CJ, DK, RK, LY, JT, DG, RG No competing interests declared, GC Except for Gabriel Corfas, the authors declare no competing financial or non-financial interests. Gabriel Corfas is a scientific founder of Decibel Therapeutics; he has an equity interest in and has received compensation for consulting. The company was not involved in this study, (© 2022, Zhao, Huffman, Hafner et al.)- Published
- 2022
- Full Text
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35. Author Correction: Identification of in vivo roles of ErbB4-JMa and its direct nuclear signaling using a novel isoform-specific knock out mouse.
- Author
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Doherty R, MacLeod BL, Nelson MM, Ibrahim MMH, Borges BC, Jaradat NW, Finneran MC, Giger RJ, and Corfas G
- Published
- 2022
- Full Text
- View/download PDF
36. Identification of in vivo roles of ErbB4-JMa and its direct nuclear signaling using a novel isoform-specific knock out mouse.
- Author
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Doherty R, MacLeod BL, Nelson MM, Ibrahim MMH, Borges BC, Jaradat NW, Finneran MC, Giger RJ, and Corfas G
- Subjects
- Animals, Mice, Mice, Knockout, Protein Isoforms genetics, Protein Isoforms metabolism, Receptor, ErbB-4 genetics, Receptor, ErbB-4 metabolism, Signal Transduction, Tyrosine metabolism
- Abstract
Like all receptor tyrosine kinases (RTKs), ErbB4 signals through a canonical signaling involving phosphorylation cascades. However, ErbB4 can also signal through a non-canonical mechanism whereby the intracellular domain is released into the cytoplasm by regulated intramembrane proteolysis (RIP) and translocates to the nucleus where it regulates transcription. These different signaling mechanisms depend on the generation of alternative spliced isoforms, a RIP cleavable ErbB4-JMa and an uncleavable ErbB4-JMb. Non-canonical signaling by ErbB4-JMa has been implicated in the regulation of brain, heart, mammary gland, lung, and immune cell development. However, most studies on non-canonical ErbB4 signaling have been performed in vitro due to the lack of an adequate mouse model. We created an ErbB4-JMa specific knock out mouse and demonstrate that RIP-dependent, non-canonical signaling by ErbB4-JMa is required for the regulation of GFAP expression during cortical development. We also show that ErbB4-JMa signaling is not required for the development of the heart, mammary glands, sensory ganglia. Furthermore, we identify genes whose expression during cortical development is regulated by ErbB4, and show that the expression of three of them, CRYM and DBi, depend on ErbB4-JMa whereas WDFY1 relies on ErbB4-JMb. Thus, we provide the first animal model to directly study the roles of ErbB4-JMa and non-canonical ErbB4 signaling in vivo., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
37. Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss.
- Author
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Cassinotti LR, Ji L, Borges BC, Cass ND, Desai AS, Kohrman DC, Liberman MC, and Corfas G
- Subjects
- Animals, Cochlea pathology, Evoked Potentials, Auditory, Brain Stem physiology, Mice, Spiral Ganglion pathology, Synapses pathology, Hair Cells, Auditory, Inner, Hearing Loss
- Abstract
Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age-related IHC synaptopathy can be prevented, and if this impacts the time-course of ARHL, we tested the effects of cochlear overexpression of neurotrophin-3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC-SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials compared with age-matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with larger sound-evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age-matched controls. Our results also provide evidence that an age-related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age-related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2022
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38. Binaural Processing Deficits Due to Synaptopathy and Myelin Defects.
- Author
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Budak M, Roberts MT, Grosh K, Corfas G, Booth V, and Zochowski M
- Subjects
- Acoustic Stimulation, Animals, Auditory Perception, Evoked Potentials, Auditory, Brain Stem physiology, Humans, Cochlea, Myelin Sheath
- Abstract
Hidden hearing loss (HHL) is a deficit in auditory perception and speech intelligibility that occurs despite normal audiometric thresholds and results from noise exposure, aging, or myelin defects. While mechanisms causing perceptual deficits in HHL patients are still unknown, results from animal models indicate a role for peripheral auditory neuropathies in HHL. In humans, sound localization is particularly important for comprehending speech, especially in noisy environments, and its disruption may contribute to HHL. In this study, we hypothesized that neuropathies of cochlear spiral ganglion neurons (SGNs) that are observed in animal models of HHL disrupt the activity of neurons in the medial superior olive (MSO), a nucleus in the brainstem responsible for locating low-frequency sound in the horizontal plane using binaural temporal cues, leading to sound localization deficits. To test our hypothesis, we constructed a network model of the auditory processing system that simulates peripheral responses to sound stimuli and propagation of responses via SGNs to cochlear nuclei and MSO populations. To simulate peripheral auditory neuropathies, we used a previously developed biophysical SGN model with myelin defects at SGN heminodes (myelinopathy) and with loss of inner hair cell-SGN synapses (synaptopathy). Model results indicate that myelinopathy and synaptopathy in SGNs give rise to decreased interaural time difference (ITD) sensitivity of MSO cells, suggesting a possible mechanism for perceptual deficits in HHL patients. This model may be useful to understand downstream impacts of SGN-mediated disruptions on auditory processing and to eventually discover possible treatments for various mechanisms of HHL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Budak, Roberts, Grosh, Corfas, Booth and Zochowski.)
- Published
- 2022
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39. GnRH neurons recruit astrocytes in infancy to facilitate network integration and sexual maturation.
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Pellegrino G, Martin M, Allet C, Lhomme T, Geller S, Franssen D, Mansuy V, Manfredi-Lozano M, Coutteau-Robles A, Delli V, Rasika S, Mazur D, Loyens A, Tena-Sempere M, Siepmann J, Pralong FP, Ciofi P, Corfas G, Parent AS, Ojeda SR, Sharif A, and Prevot V
- Subjects
- Astrocytes metabolism, Hypothalamus physiology, Neurons physiology, Gonadotropin-Releasing Hormone metabolism, Sexual Maturation physiology
- Abstract
Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D
2 receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that 'escort' them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A. Inhibition of DP1 signaling in the infantile preoptic region, where GnRH cell bodies reside, disrupts the correct wiring and firing of GnRH neurons, alters minipuberty or the first activation of the hypothalamic-pituitary-gonadal axis during infancy, and delays the timely acquisition of reproductive capacity. These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2021
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40. Poly (ADP-Ribose) Polymerase 1 Regulates Cajal-Retzius Cell Development and Neural Precursor Cell Adhesion.
- Author
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Nelson MM, Hoff JD, Zeese ML, and Corfas G
- Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) is a ubiquitously expressed enzyme that regulates DNA damage repair, cell death, inflammation, and transcription. PARP1 functions by adding ADP-ribose polymers (PAR) to proteins including itself, using NAD
+ as a donor. This post-translational modification known as PARylation results in changes in the activity of PARP1 and its substrate proteins and has been linked to the pathogenesis of various neurological diseases. PARP1 KO mice display schizophrenia-like behaviors, have impaired memory formation, and have defects in neuronal proliferation and survival, while mutations in genes that affect PARylation have been associated with intellectual disability, psychosis, neurodegeneration, and stroke in humans. Yet, the roles of PARP1 in brain development have not been extensively studied. We now find that loss of PARP1 leads to defects in brain development and increased neuronal density at birth. We further demonstrate that PARP1 loss increases the expression levels of genes associated with neuronal migration and adhesion in the E15.5 cerebral cortex, including Reln . This correlates with an increased number of Cajal-Retzius (CR) cells in vivo and in cultures of embryonic neural progenitor cells (NPCs) derived from the PARP1 KO cortex. Furthermore, PARP1 loss leads to increased NPC adhesion to N-cadherin, like that induced by experimental exposure to Reelin. Taken together, these results uncover a novel role for PARP1 in brain development, i.e., regulation of CR cells, neuronal density, and cell adhesion., Competing Interests: GC is a scientific founder of Decibel Therapeutics, has an equity interest in and has received compensation for consulting. The company was not involved in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nelson, Hoff, Zeese and Corfas.)- Published
- 2021
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41. Axon-glia interactions in the ascending auditory system.
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Kohrman DC, Borges BC, Cassinotti LR, Ji L, and Corfas G
- Subjects
- Acoustic Stimulation, Animals, Axons, Humans, Mammals, Neuroglia, Auditory Pathways physiology, Cochlea physiology
- Abstract
The auditory system detects and encodes sound information with high precision to provide a high-fidelity representation of the environment and communication. In mammals, detection occurs in the peripheral sensory organ (the cochlea) containing specialized mechanosensory cells (hair cells) that initiate the conversion of sound-generated vibrations into action potentials in the auditory nerve. Neural activity in the auditory nerve encodes information regarding the intensity and frequency of sound stimuli, which is transmitted to the auditory cortex through the ascending neural pathways. Glial cells are critical for precise control of neural conduction and synaptic transmission throughout the pathway, allowing for the precise detection of the timing, frequency, and intensity of sound signals, including the sub-millisecond temporal fidelity is necessary for tasks such as sound localization, and in humans, for processing complex sounds including speech and music. In this review, we focus on glia and glia-like cells that interact with hair cells and neurons in the ascending auditory pathway and contribute to the development, maintenance, and modulation of neural circuits and transmission in the auditory system. We also discuss the molecular mechanisms of these interactions, their impact on hearing and on auditory dysfunction associated with pathologies of each cell type., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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42. Correction: Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.
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Budak M, Grosh K, Sasmal A, Corfas G, Zochowski M, and Booth V
- Abstract
[This corrects the article DOI: 10.1371/journal.pcbi.1008499.].
- Published
- 2021
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43. An injectable PEG hydrogel controlling neurotrophin-3 release by affinity peptides.
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Wang J, Youngblood R, Cassinotti L, Skoumal M, Corfas G, and Shea L
- Subjects
- Biocompatible Materials, Poloxamer, Polyethylene Glycols, Proteins, Hydrogels, Peptides
- Abstract
Neurotrophin-3 growth factor can improve cochlear neuron survival, and localized delivery of this protein to the round window membrane in the middle ear may be able to reverse sensorineural hearing loss. Thus, the goal of this work was to develop an injectable hydrogel delivery system that can allow localized release of neurotrophin-3 in a controlled and sustained manner. We identified a PEG hydrogel formulation that uses thiol-vinyl sulfone Michael addition for crosslinking. This injectable formulation provides elastic hydrogels with higher mechanical rigidity, better bio-adhesion and longer residence time than Poloxamer hydrogels currently being investigated clinically for hearing loss. In vivo, PEG hydrogels induce local immune responses comparable to biocompatible Poloxamer hydrogels, yet they released payloads at a ~5-fold slower rate in the subcutaneous area. Based on this injectable hydrogel formulation, we designed an affinity-based protein release system by modifying PEG hydrogels with affinity peptides specific to neurotrophin-3 proteins. We verified the sustained release of neurotrophin-3 from peptide-conjugated PEG hydrogels resulting from the reversible interaction between peptides and proteins. The rate of affinity-controlled release depends on the polymer concentrations, the affinity of peptides and the peptide-to-protein ratios. Collectively, we developed an injectable hydrogel formulation for localized delivery of neurotrophin-3, which provides affinity-controlled release and longer delivery time compared to Poloxamer hydrogels., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
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- View/download PDF
44. Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.
- Author
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Budak M, Grosh K, Sasmal A, Corfas G, Zochowski M, and Booth V
- Subjects
- Animals, Cochlea physiopathology, Cochlear Nerve physiopathology, Disease Models, Animal, Hair Cells, Auditory, Inner pathology, Hair Cells, Auditory, Inner physiology, Mice, Models, Neurological, Spiral Ganglion cytology, Spiral Ganglion physiopathology, Hearing Loss physiopathology, Myelin Sheath pathology, Myelin Sheath physiology, Synapses pathology, Synapses physiology
- Abstract
Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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- View/download PDF
45. Hidden Hearing Loss: A Disorder with Multiple Etiologies and Mechanisms.
- Author
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C Kohrman D, Wan G, Cassinotti L, and Corfas G
- Subjects
- Animals, Cochlea physiopathology, Cochlear Nerve physiopathology, Diagnosis, Differential, Disease Models, Animal, Hair Cells, Auditory, Inner pathology, Hair Cells, Auditory, Inner physiology, Humans, Hearing Loss etiology, Hearing Loss physiopathology, Hearing Loss therapy
- Abstract
Hidden hearing loss (HHL), a recently described auditory disorder, has been proposed to affect auditory neural processing and hearing acuity in subjects with normal audiometric thresholds, particularly in noisy environments. In contrast to central auditory processing disorders, HHL is caused by defects in the cochlea, the peripheral auditory organ. Noise exposure, aging, ototoxic drugs, and peripheral neuropathies are some of the known risk factors for HHL. Our knowledge of the causes and mechanisms of HHL are based primarily on animal models. However, recent clinical studies have also shed light on the etiology and prevalence of this cochlear disorder and how it may affect auditory perception in humans. Here, we review the current knowledge regarding the causes and cellular mechanisms of HHL, summarize information on available noninvasive tests for differential diagnosis, and discuss potential therapeutic approaches for treatment of HHL., (Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
46. Protection from noise-induced cochlear synaptopathy by virally mediated overexpression of NT3.
- Author
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Hashimoto K, Hickman TT, Suzuki J, Ji L, Kohrman DC, Corfas G, and Liberman MC
- Subjects
- Animals, Auditory Threshold, Cochlea physiopathology, Evoked Potentials, Auditory, Brain Stem, Green Fluorescent Proteins metabolism, Hair Cells, Auditory, Inner metabolism, Hair Cells, Auditory, Inner pathology, Hair Cells, Auditory, Outer metabolism, Hair Cells, Auditory, Outer pathology, Male, Mice, Inbred C57BL, Mice, Inbred CBA, Neurotrophin 3 genetics, Otoacoustic Emissions, Spontaneous, RNA, Messenger genetics, RNA, Messenger metabolism, Synapses metabolism, Cochlea pathology, Dependovirus metabolism, Neurotrophin 3 metabolism, Noise, Synapses pathology
- Abstract
Noise exposures causing only transient threshold shifts can destroy auditory-nerve synapses without damaging hair cells. Here, we asked whether virally mediated neurotrophin3 (NT3) overexpression can repair this damage. CBA/CaJ mice at 6 wks were injected unilaterally with adeno-associated virus (AAV) containing either NT3 or GFP genes, via the posterior semicircular canal, 3 wks prior to, or 5 hrs after, noise exposure. Controls included exposed animals receiving vehicle only, and unexposed animals receiving virus. Thresholds were measured 2 wks post-exposure, just before cochleas were harvested for histological analysis. In separate virus-injected animals, unexposed cochleas were extracted for qRT-PCR. The GFP reporter showed that inner hair cells (IHCs) were transfected throughout the cochlea, and outer hair cells mainly in the apex. qRT-PCR showed 4- to 10-fold overexpression of NT3 from 1-21 days post-injection, and 1.7-fold overexpression at 40 days. AAV-NT3 delivered prior to noise exposure produced a dose-dependent reduction of synaptopathy, with nearly complete rescue at some cochlear locations. In unexposed ears, NT3 overexpression did not affect thresholds, however GFP overexpression caused IHC loss. In exposed ears, NT3 overexpression increased permanent threshold shifts. Thus, although NT3 overexpression can minimize noise-induced synaptic damage, the forced overexpression may be harmful to hair cells themselves during cochlear overstimulation.
- Published
- 2019
- Full Text
- View/download PDF
47. Synaptopathy as a Mechanism for Age-Related Vestibular Dysfunction in Mice.
- Author
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Wan G, Ji L, Schrepfer T, Gong S, Wang GP, and Corfas G
- Abstract
Age-related decline of inner ear function contributes to both hearing loss and balance disorders, which lead to impaired quality of life and falls that can result in injury and even death. The cellular mechanisms responsible for the ear's functional decline have been controversial, but hair cell loss has been considered the key cause for a long time. However, recent studies showed that in the cochlea, loss of inner hair cell (IHC) synapses precedes hair cell or neuronal loss, and this synaptopathy is an early step in the functional decline. Whether a similar process occurs in the vestibular organ, its timing and its relationship to organ dysfunction remained unknown. We compared the time course of age-related deterioration in vestibular and cochlear functions in mice as well as characterized the age-associated changes in their utricles at the histological level. We found that in the mouse, as in humans, age-related decline in vestibular evoked potentials (VsEPs) occurs later than hearing loss. As in the cochlea, deterioration of VsEPs correlates with the loss of utricular ribbon synapses but not hair cells or neuronal cell bodies. Furthermore, the age-related synaptic loss is restricted to calyceal innervations in the utricular extrastriolar region. Hence, our findings suggest that loss of extrastriolar calyceal synapses has a key role in age-related vestibular dysfunction (ARVD).
- Published
- 2019
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- View/download PDF
48. Auditory metabolomics, an approach to identify acute molecular effects of noise trauma.
- Author
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Ji L, Lee HJ, Wan G, Wang GP, Zhang L, Sajjakulnukit P, Schacht J, Lyssiotis CA, and Corfas G
- Subjects
- Animals, Auditory Threshold, Ear, Inner pathology, Hair Cells, Auditory pathology, Hearing Loss, Noise-Induced etiology, Hearing Loss, Noise-Induced pathology, Mice, Mice, Inbred CBA, Tandem Mass Spectrometry, Ear, Inner metabolism, Hair Cells, Auditory metabolism, Hearing Loss, Noise-Induced metabolism, Metabolome, Noise adverse effects
- Abstract
Animal-based studies have provided important insights into the structural and functional consequences of noise exposure on the cochlea. Yet, less is known about the molecular mechanisms by which noise induces cochlear damage, particularly at relatively low exposure levels. While there is ample evidence that noise exposure leads to changes in inner ear metabolism, the specific effects of noise exposure on the cochlear metabolome are poorly understood. In this study we applied liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS)-based metabolomics to analyze the effects of noise on the mouse inner ear. Mice were exposed to noise that induces temporary threshold shifts, synaptopathy and permanent hidden hearing loss. Inner ears were harvested immediately after exposure and analyzed by targeted metabolomics for the relative abundance of 220 metabolites across the major metabolic pathways in central carbon metabolism. We identified 40 metabolites differentially affected by noise. Our approach detected novel noise-modulated metabolites and pathways, as well as some already linked to noise exposure or cochlear function such as neurotransmission and oxidative stress. Furthermore, it showed that metabolic effects of noise on the inner ear depend on the intensity and duration of exposure. Collectively, our results illustrate that metabolomics provides a powerful approach for the characterization of inner ear metabolites affected by auditory trauma. This type of information could lead to the identification of drug targets and novel therapies for noise-induced hearing loss.
- Published
- 2019
- Full Text
- View/download PDF
49. Exposure to enriched environment rescues anxiety-like behavior and miRNA deregulated expression induced by perinatal malnutrition while altering oligodendrocyte morphology.
- Author
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Berardino BG, Chertoff M, Gianatiempo O, Alberca CD, Priegue R, Fiszbein A, Long P, Corfas G, and Cánepa ET
- Subjects
- Animals, Anxiety etiology, Anxiety pathology, Behavior, Animal physiology, Brain pathology, Cell Shape physiology, Disease Models, Animal, Exploratory Behavior physiology, Housing, Animal, Malnutrition complications, Malnutrition pathology, Mice, MicroRNAs genetics, Oligodendroglia pathology, Anxiety metabolism, Brain metabolism, Environment, Gene Expression Regulation, Malnutrition metabolism, MicroRNAs metabolism, Oligodendroglia metabolism
- Abstract
Maternal malnutrition is one of the major early-life adversities affecting the development of newborn's brain and is associated with an increased risk to acquire cognitive and emotional deficiencies later in life. Studies in rodents have demonstrated that exposure to an enriched environment (EE) can reverse the negative consequences of early adversities. However, rescue of emotional disorders caused by perinatal malnutrition and the mechanisms involved has not been determined. We hypothesized that exposure to an EE may attenuate the anxiety-like disorders observed in mice subjected to perinatal protein malnutrition and that this could be mediated by epigenetic mechanisms. Male CF-1 mice were subject to perinatal protein malnutrition until weaning and then exposed to an EE for 5 weeks after which small RNA-seq was performed. In parallel, dark-light box and elevated plus maze tests were conducted to evaluate anxiety traits. We found that exposure to an EE reverses the anxiety-like behavior in malnourished mice. This reversal is paralleled by the expression of three miRNAs that become dysregulated by perinatal malnutrition (miR-187-3p, miR-369-3p and miR-132-3p). The predicted mRNA targets of these miRNAs are mostly related to axon guidance pathway. Accordingly, we also found that perinatal malnutrition leads to reduction in the cingulum size and altered oligodendrocyte morphology. These results suggest that EE-rescue of anxiety disorders derived from perinatal malnutrition is mediated by the modulation of miRNAs associated with the regulation of genes involved in axonal guidance., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
50. Social Isolation During the Critical Period Reduces Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Cell in Mouse Prefrontal Cortex.
- Author
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Yamamuro K, Yoshino H, Ogawa Y, Makinodan M, Toritsuka M, Yamashita M, Corfas G, and Kishimoto T
- Subjects
- 6-Cyano-7-nitroquinoxaline-2,3-dione pharmacology, Action Potentials drug effects, Animals, Animals, Newborn, Electric Stimulation, Excitatory Amino Acid Antagonists pharmacology, Excitatory Postsynaptic Potentials drug effects, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Patch-Clamp Techniques, Pyramidal Cells classification, Pyramidal Cells drug effects, Receptors, AMPA metabolism, Synapses drug effects, Tetrodotoxin pharmacology, Action Potentials physiology, Critical Period, Psychological, Prefrontal Cortex cytology, Pyramidal Cells physiology, Social Isolation, Synapses physiology
- Abstract
Juvenile social experience is crucial for the functional development of forebrain regions, especially the prefrontal cortex (PFC). We previously reported that social isolation for 2 weeks after weaning induces prefrontal cortex dysfunction and hypomyelination. However, the effect of social isolation on physiological properties of PFC neuronal circuit remained unknown. Since hypomyelination due to isolation is prominent in deep-layer of medial PFC (mPFC), we focused on 2 types of Layer-5 pyramidal cells in the mPFC: prominent h-current (PH) cells and nonprominent h-current (non-PH) cells. We found that a 2-week social isolation after weaning leads to a specific deterioration in action potential properties and reduction in excitatory synaptic inputs in PH cells. The effects of social isolation on PH cells, which involve reduction in functional glutamatergic synapses and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate charge ratio, are specific to the 2 weeks after weaning and to the mPFC. We conclude that juvenile social experience plays crucial roles in the functional development in a subtype of Layer-5 pyramidal cells in the mPFC. Since these neurons project to subcortical structures, a deficit in social experience during the critical period may result in immature neural circuitry between mPFC and subcortical targets., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2018
- Full Text
- View/download PDF
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