Journal of Neuroscience

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Classification of NPY-Expressing Neocortical Interneurons
Journal of Neuroscience - Tập 29 Số 11 - Trang 3642-3659 - 2009
Anastassios Karagiannis, Thierry Gallopin, Csaba Dávid, Demian Battaglia, H Geoffroy, Jean Rossier, Elizabeth M. C. Hillman, Kathleen S. Rockland, Bruno Cauli
Neuropeptide Y (NPY) is an abundant neuropeptide of the neocortex involved in numerous physiological and pathological processes. Because of the large electrophysiological, molecular, and morphological diversity of NPY-expressing neurons their precise identity remains unclear. To define distinct populations of NPY neurons we characterized, in acute slices of rat barrel cortex, 200 cortical neurons of layers I–IV by means of whole-cell patch-clamp recordings, biocytin labeling, and single-cell reverse transcriptase-PCR designed to probe for the expression of well established molecular markers for cortical neurons. To classify reliably cortical NPY neurons, we used and compared different unsupervised clustering algorithms based on laminar location and electrophysiological and molecular properties. These classification schemes confirmed that NPY neurons are nearly exclusively GABAergic and consistently disclosed three main types of NPY-expressing interneurons. (1) Neurogliaform-like neurons exhibiting a dense axonal arbor, were the most frequent and superficial, and substantially expressed the neuronal isoform of nitric oxide synthase. (2) Martinotti-like cells characterized by an ascending axon ramifying in layer I coexpressed somatostatin and were the most excitable type. (3) Among fast-spiking and parvalbumin-positive basket cells, NPY expression was correlated with pronounced spike latency. By clarifying the diversity of cortical NPY neurons, this study establishes a basis for future investigations aiming at elucidating their physiological roles.
Remyelination of the Rat Spinal Cord by Transplantation of Identified Bone Marrow Stromal Cells
Journal of Neuroscience - Tập 22 Số 15 - Trang 6623-6630 - 2002
Yukinori Akiyama, Christine Radtke, Jeffery D. Kocsis
A Large-Scale Chemical Screen for Regulators of the Arginase 1 Promoter Identifies the Soy Isoflavone Daidzeinas a Clinically Approved Small Molecule That Can Promote Neuronal Protection or Regeneration via a cAMP-Independent Pathway
Journal of Neuroscience - Tập 30 Số 2 - Trang 739-748 - 2010
C. Thong, Aline Campana, Philipp S. Lange, Hsinhwa Lee, Kasturi Banerjee, J. Barney Bryson, Lata Mahishi, S. Munir Alam, Roman J. Giger, Stephen Barnes, Sidney M. Morris, Dianna E. Willis, Jeffrey L. Twiss, Marie T. Filbin, Rajiv R. Ratan
An ideal therapeutic for stroke or spinal cord injury should promote survival and regeneration in the CNS. Arginase 1 (Arg1) has been shown to protect motor neurons from trophic factor deprivation and allow sensory neurons to overcome neurite outgrowth inhibition by myelin proteins. To identify small molecules that capture Arg1's protective and regenerative properties, we screened a hippocampal cell line stably expressing the proximal promoter region of thearginase 1gene fused to a reporter gene against a library of compounds containing clinically approved drugs. This screen identified daidzein as a transcriptional inducer of Arg1. Both CNS and PNS neurons primedin vitrowith daidzein overcame neurite outgrowth inhibition from myelin-associated glycoprotein, which was mirrored by acutely dissociated and cultured sensory neurons primedin vivoby intrathecal or subcutaneous daidzein infusion. Further, daidzein was effective in promoting axonal regenerationin vivoin an optic nerve crush model when given intraocularly without lens damage, or most importantly, when given subcutaneously after injury. Mechanistically, daidzein requires transcription and induction of Arg1 activity for its ability to overcome myelin inhibition. In contrast to canonical Arg1 activators, daidzein increases Arg1 without increasing CREB phosphorylation, suggesting its effects are cAMP-independent. Accordingly, it may circumvent known CNS side effects of some cAMP modulators. Indeed, daidzein appears to be safe as it has been widely consumed in soy products, crosses the blood–brain barrier, and is effective without pretreatment, making it an ideal candidate for development as a therapeutic for spinal cord injury or stroke.
Glial Scar Borders Are Formed by Newly Proliferated, Elongated Astrocytes That Interact to Corral Inflammatory and Fibrotic Cells via STAT3-Dependent Mechanisms after Spinal Cord Injury
Journal of Neuroscience - Tập 33 Số 31 - Trang 12870-12886 - 2013
Ina B. Wanner, Mark A. Anderson, Bao‐Liang Song, Joel M. Levine, Ana Patricia Fernández, Zachary Thompson, Yan Ao, Michael V. Sofroniew
The Gigantocellular Reticular Nucleus Plays a Significant Role in Locomotor Recovery after Incomplete Spinal Cord Injury
Journal of Neuroscience - Tập 40 Số 43 - Trang 8292-8305 - 2020
Anne K. Engmann, Flavio Bizzozzero, Marc P. Schneider, Dario Pfyffer, Stefan Imobersteg, Regula Schneider, Anna‐Sophie Hofer, Adriano Aguzzi, Martin E. Schwab
Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.SIGNIFICANCE STATEMENTFollowing unilateral hemisection of the spinal cord, reticulospinal projections are destroyed on the injured side, resulting in impaired locomotion. Over time, a high degree of recovery can be observed in lesioned animals, like in human hemicord patients. In the rat, recovery is accompanied by pronounced spontaneous plasticity of axotomized and spared reticulospinal axons. We demonstrate the causative relevance of locally rewired as well as compensatory reticulospinal plasticity for the recovery of locomotor functions following spinal hemisection, using chemogenetic tools to selectively silence newly formed connections in behaviorally recovered animals. Moving from a correlative to a causative understanding of the role of neuroanatomical plasticity for functional recovery is fundamental for successful translation of treatment approaches from experimental studies to the clinics.
Rac1-Mediated Endocytosis during Ephrin-A2- and Semaphorin 3A-Induced Growth Cone Collapse
Journal of Neuroscience - Tập 22 Số 14 - Trang 6019-6028 - 2002
William M. Jurney, Gianluca Gallo, Paul C. Letourneau, Steven C. McLoon
Negative guidance molecules are important for guiding the growth of axons and ultimately for determining the wiring pattern in the developing nervous system. In tissue culture, growth cones at the tips of growing axons collapse in response to negative guidance molecules, such as ephrin-A2 and semaphorin 3A. The small GTPase Rac1 is involved in growth cone collapse, but the nature of its role is not clear. Rac1 activity assays showed that Rac1 is transiently inactivated after treatment with ephrin-A2. Ephrin-induced growth cone collapse, however, correlated with resumption of Rac1 activity. We demonstrate that Rac1 is required for endocytosis of the growth cone plasma membrane and reorganization of F-actin but not for the depolymerization of F-actin during growth cone collapse in response to ephrin-A2 and semaphorin 3A. Rac1, however, does not regulate constitutive endocytosis in growth cones. These findings show that in response to negative guidance molecules, the function of Rac1 changes from promoting actin polymerization associated with axon growth to driving endocytosis of the plasma membrane, resulting in growth cone collapse. Furthermore, Rac1 antisense injected into the embryonic chick eyein vivocaused the retinotectal projection to develop without normal topography in a manner consistent with Rac1 having an obligatory role in mediating ephrin signaling.
Aluminum effect on slow axonal transport: a novel impairment of neurofilament transport
Journal of Neuroscience - Tập 4 Số 3 - Trang 722-731 - 1984
Alberto Bizzi, R. Crane, L. Autilio‐Gambetti, Pierluigi Gambetti
Administration of aluminum (Al) produces accumulation of neurofilaments (NF), called neurofibrillary tangles (NFT), in neuronal cell bodies and proximal axonal segments. This study was undertaken to investigate whether these changes are associated with impairment of the slow axonal transport. Local administration of AlCl3 induced the formation of NFT in 90 to 100% of the rabbit hypoglossal neurons. [35S]Methionine was then administered to the hypoglossal nerve nuclei. The hypoglossal nerves were processed 18 or 28 days later for one- and two-dimensional SDS-polyacrylamide gel electrophoresis and fluorography. Labeled NF polypeptides and a polypeptide of 57 kilodaltons (Kd) were not detectable beyond the proximal 9-mm segment of the hypoglossal nerve in Al-treated rabbits 18 days after labeling, whereas they were present up to 27 mm from the medulla in controls. Tubulin and polypeptides migrating with slow component b were not significantly affected. In rabbits sacrificed 28 days after labeling, accumulation of NF subunits within the proximal 9 mm of hypoglossal nerve was less dramatic, and labeled NF were present up to 30 mm from the medulla whereas they were detectable up to 45 mm in controls. Morphological studies demonstrated the presence of enlarged axons filled with NF in the proximal 9 mm of the hypoglossal nerve. In nerve segments immediately distal, axons were markedly reduced in size and contained no NF but an apparently normal number of microtubules and other organelles. Transport of NF and of a 57-Kd polypeptide is markedly but reversibly slowed down or blocked within the proximal 9-mm segments of the hypoglossal nerve following Al administration to the hypoglossal nucleus. It is suggested that NF transport is maintained distally, resulting in lack of NF in axonal segments immediately distal to the block. Local Al intoxication provides a novel model of impairment of NF transport.
Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns
Journal of Neuroscience - Tập 34 Số 49 - Trang 16467-16481 - 2014
Dianer Yang, Yu Sun, Siddhartha Kumar Bhaumik, Yikun Li, Jessica M. Baumann, Xiaoyi Lin, Yujin Zhang, Shang-Hsuan Lin, Richard S. Dunn, Chia‐Yang Liu, Feng‐Shiun Shie, Yi‐Hsuan Lee, Marsha Wills‐Karp, Claire Chougnet, Suhas G. Kallapur, Ian Lewkowich, Diana M. Lindquist, Kaja Murali‐Krishna, Chia‐Yi Kuan
Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic–ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood–brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in bothin vivoandin vitromodels, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.
MSX3 Switches Microglia Polarization and Protects from Inflammation-Induced Demyelination
Journal of Neuroscience - Tập 35 Số 16 - Trang 6350-6365 - 2015
Zhongwang Yu, Dingya Sun, Jifeng Feng, Weixing Tan, Fang Xue, Ming Zhao, Xiaolin Zhao, Yingyan Pu, Aijun Huang, Zhenghua Xiang, Li Cao, Cheng He
The major challenge for progressive multiple sclerosis therapy is the promotion of remyelination from inflammation-induced demyelination. A switch from an M1- to an M2-dominant polarization of microglia is critical in these repair processes. In this study, we identified the homeobox gene msh-like homeobox-3 (Msx3) as a new pivotal regulator for microglial polarization. MSX3 was induced during microglia M2 polarization and repressed in M1 cells. The expression of MSX3 in microglia was dynamically regulated during experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. The overexpression of MSX3 in microglia promoted M2 but impeded M1 polarization. Interrupting MSX3 expression in microglia accelerated inflammation-induced demyelination and neurodegeneration. The conditioned medium from MSX3-transduced microglia promoted oligodendrocyte progenitor survival, differentiation, and neurite outgrowth. The adoptive transfer of MSX3-transduced microglia suppressed EAE and facilitated remyelination within the murine CNS in EAE and the LPC model. Mechanically, chromatin immunoprecipitation assays also indicated that MSX3 directly regulated three key genes associated with microglia M2 polarization, includingPparg,Stat6, andJak3. Importantly, we found that overexpression of MSX3 in human-derived microglia represents the M2 phenotype and ameliorated EAE after intraventricular injection. Our findings suggest a new homeobox protein-dependent mechanism for driving microglia M2 polarization and identify MSX3 as an attractive therapeutic approach for preventing inflammation-induced demyelination and promoting remyelination.
Activity-Dependent Degradation of Synaptic Vesicle Proteins Requires Rab35 and the ESCRT Pathway
Journal of Neuroscience - Tập 36 Số 33 - Trang 8668-8686 - 2016
Patricia Sheehan, Mei Zhu, Anne Beskow, Cyndel Vollmer, Clarissa L. Waites
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