Language：English   Publishing type：Research paper (scientific journal)  

The corticospinal tract (CST) is an essential neural pathway for reorganization that recovers motor functions after brain injuries such as stroke. CST comprises multiple pathways derived from different sensorimotor areas of the cerebral cortex; however, the patterns of reorganization in such complex pathways postinjury are largely unknown. Here we comprehensively examined the rewiring patterns of the CST pathways of multiple cerebral origins in a mouse stroke model that varied in size and location in the sensorimotor cortex. We found that spared contralesional motor and sensory CST axons crossed the midline and sprouted into the denervated side of the cervical spinal cord after stroke in a large cortical area. In contrast, the contralesional CST fibers did not sprout in a small stroke, whereas the ipsilesional axons from the spared motor area grew on the denervated side. We further showed that motor and sensory CST axons did not innervate the projecting areas mutually when either one was injured. The present results reveal the basic principles that generate the patterns of CST rewiring, which depend on stroke location and CST subtype. Our data indicate the importance of targeting different neural substrates to restore function among the types of injury.

DOI： 10.3389/fnins.2021.737034

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.

DOI： 10.1038/s41419-020-02897-w

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.

DOI： 10.1093/cercor/bhaa142

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background. Brain injury often causes severe motor dysfunction, leading to difficulties with living a self-reliant social life. Injured neural circuits must be reconstructed to restore functions, but the adult brain is limited in its ability to restore neuronal connections. The combination of molecular targeting, which enhances neural plasticity, and rehabilitative motor exercise is an important therapeutic approach to promote neuronal rewiring in the spared circuits and motor recovery. Objective. We tested whether genetic reduction of Src homology 2-containing phosphatase-1 (SHP-1), an inhibitor of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, has synergistic effects with rehabilitative training to promote reorganization of motor circuits and functional recovery in a mouse model of brain injury. Methods. Rewiring of the corticospinal circuit was examined using neuronal tracers following unilateral cortical injury in control mice and in Shp-1 mutant mice subjected to voluntary exercise. Recovery of motor functions was assessed using motor behavior tests. Results. We found that rehabilitative exercise decreased SHP-1 and increased BDNF and TrkB expression in the contralesional motor cortex after the injury. Genetic reduction of SHP-1 and voluntary exercise significantly increased sprouting of corticospinal tract axons and enhanced motor recovery in the impaired forelimb. Conclusions. Our data demonstrate that combining voluntary exercise and SHP-1 suppression promotes motor recovery and neural circuit reorganization after brain injury.

DOI： 10.1177/1545968320921827

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The correlation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with non-alcoholic fatty liver disease (NAFLD) has been reported in epidemiological studies. However, the mechanisms of molecular and inter-organ systems that render these factors to influence on NAFLD have not been elucidated. In this study, we examined the induction of ghrelin which is the GH-releasing hormone and IGF-1, and involvement of autonomic neural circuits, in the pathogenesis of NAFLD. METHODS: The expression of gastric and hypothalamic ghrelin, neural activation in the brain, and serum IGF-1 were examined in NAFLD models of choline-deficient defined l-amino-acid diet-fed, melanocortin 4 receptor knockout mice, and partial hepatectomy mice with or without the blockades of autonomic nerves to test the contribution of neural circuits connecting the brain, liver, and stomach. KEY RESULTS: The fatty changes in the liver increased the expression of gastric ghrelin through the autonomic pathways which sends the neural signals to the arcuate nucleus in the hypothalamus through the afferent vagal nerve which reached the pituitary gland to release GH and then stimulate the IGF-1 release from the liver. In addition, high levels of ghrelin expression in the arcuate nucleus were correlated with NAFLD progression regardless of the circuits. CONCLUSIONS: Our study demonstrated that the fatty liver stimulates the autonomic nervous signal circuits which suppress the progression of the disease by activating the gastric ghrelin expression, the neural signal transduction in the brain, and the release of IGF-1 from the liver.

DOI： 10.1111/nmo.13799

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Microglia, the resident immune cells of the central nervous system, accumulate along subcerebral projection axons and support neuronal survival during the early postnatal period. It remains unknown how microglia follow an axon-specific distribution pattern to maintain neural circuits. Here, we investigated the mechanisms of microglial accumulation along subcerebral projection axons that were necessary for microglial accumulation in the internal capsule. Screening of molecules involved in this accumulation of microglia to axons of layer V cortical neurons identified netrin-G1, a member of the netrin family of axon guidance molecules with a glycosyl-phosphatidylinositol anchor. Deletion or knockdown of the netrin-G1 gene Ntng1 reduced microglial accumulation and caused loss of cortical neurons. Netrin-G1 ligand-Ngl1 knockout-mice-derived microglia showed reduced accumulation along the axons compared with wild-type microglia. Thus, microglia accumulate around the subcerebral projection axons via NGL1-netrin-G1 signaling and support neuronal survival. Our observations unveil bidirectional neurotrophic interactions between neurons and microglia.

DOI： 10.1016/j.celrep.2020.107580

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Microglia colonize the central nervous system (CNS) parenchyma during embryogenesis and contribute to various developmental processes leading to the formation of refined neural circuits. In this review, we focus on the bidirectional function of microglia during normal CNS development and discuss recent perspectives on the functions of microglia in neural circuit formation. Microglia participate in neurogenesis, migration, axonal growth, and synapse formation and remodeling, all of which are fundamental for the establishment of neural networks, by secreting a variety of molecules toward neurons and phagocytosing both live and dying neurons or their debris. Intriguingly, microglia play dual roles in each of the neurodevelopmental processes that they affect. For instance, microglia modulate synapse numbers by both promoting the formation of new synapses and eliminating unnecessary synapses. The study of the developmental roles of microglia is essential not only for understanding normal CNS development but also for preventing developmental brain disorders caused by microglial dysfunction.

DOI： 10.1016/j.ijdevneu.2018.09.009

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

Corticospinal (CS) neurons in layer V of the sensorimotor cortex are essential for voluntary motor control. Those neurons project axons to specific segments along the rostro-caudal axis of the spinal cord, and reach their spinal targets by sending collateral branches interstitially along axon bundles. Currently, little is known how CS axon collaterals are formed in the proper spinal cord regions. Here, we show that the semaphorin3A (Sema3A)-neuropilin-1 (Npn-1) signaling pathway is an essential negative regulator of CS axon collateral formation in the spinal cord from mice of either sex. Sema3A is expressed in the ventral spinal cord, whereas CS neurons express Npn-1, suggesting that Sema3A might prevent CS axons from entering the ventral spinal cord. Indeed, the ectopic expression of Sema3A in the spinal cord <i>in vivo</i> inhibits CS axon collateral formation, whereas <i>Sema3A</i> or <i>Npn-1</i> mutant mice have ectopic CS axon collateral formation within the ventral spinal cord compared with littermate controls. Finally, <i>Npn-1</i> mutant mice exhibit impaired skilled movements, likely because of aberrantly formed CS connections in the ventral spinal cord. These genetic findings reveal that Sema3A-Npn-1 signaling-mediated inhibition of CS axon collateral formation is critical for proper CS circuit formation and the ability to perform skilled motor behaviors.<b>SIGNIFICANCE STATEMENT</b> CS neurons project axons to the spinal cord to control skilled movements in mammals. Previous studies revealed some of the molecular mechanisms underlying different phases of CS circuit development such as initial axon guidance in the brain, and midline crossing in the brainstem and spinal cord. However, the molecular mechanisms underlying CS axon collateral formation in the spinal gray matter has remained obscure. In this study, using <i>in vivo</i> gain-of- and loss-of-function experiments, we show that Sema3A-Npn-1 signaling functions to inhibit CS axon collateral formation in the ventral spinal cord, allowing for the development of proper skilled movements in mice.

DOI： 10.1523/jneurosci.2832-18.2019

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, we map the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects of skilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10+ interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3+ spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3+ interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in the motor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits. Ueno et al. generate a detailed connectivity map between corticospinal (CS) neurons in the motor and sensory cortices and spinal interneurons. The CS circuits originating from the motor and sensory cortices connect to distinct subpopulations of spinal interneurons to control discrete aspects of skilled movements.

DOI： 10.1016/j.celrep.2018.03.137

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Abnormalities in limbic neural circuits have been implicated in the onset of anxiety disorders. However, the molecular pathogenesis underlying anxiety disorders remains poorly elucidated. Here, we demonstrate that myristoylated alanine-rich C-kinase substrate like 1 (MARCKSL1) regulates amygdala circuitry to control the activity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as induces anxiety-like behaviors in mice. MARCKSL1 expression was predominantly localized in the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala of the adult mouse brain. MARCKSL1 transgenic (Tg) mice exhibited anxiety-like behaviors dependent on corticotropin-releasing hormone. MARCKSL1 increased spine formation in the central amygdala, and downregulation of MARCKSL1 in the amygdala normalized both increased HPA axis activity and elevated anxiety-like behaviors in Tg mice. Furthermore, MARCKSL1 expression was increased in the PFC and amygdala in a brain injury model associated with anxiety-like behaviors. Our findings suggest that MARCKSL1 expression in the amygdala plays an important role in anxiety-like behaviors.

DOI： 10.1016/j.ebiom.2018.03.018

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Superior manual dexterity in higher primates emerged together with the appearance of cortico-motoneuronal (CM) connections during the evolution of the mammalian corticospinal (CS) system. Previously thought to be specific to higher primates, we identified transient CM connections in early postnatal mice, which are eventually eliminated by Sema6D-PlexA1 signaling. PlexA1 mutant mice maintain CM connections into adulthood and exhibit superior manual dexterity as compared with that of controls. Last, differing PlexA1 expression in layer 5 of the motor cortex, which is strong in wild-type mice but weak in humans, may be explained by FEZF2-mediated cis-regulatory elements that are found only in higher primates. Thus, species-dependent regulation of PlexA1 expression may have been crucial in the evolution of mammalian CS systems that improved fine motor control in higher primates.

DOI： 10.1126/science.aan3721

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Early postnatal mammals, including human babies, can perform only basic motor tasks. The acquisition of skilled behaviors occurs later, requiring anatomical changes in neural circuitry to support the development of coordinated activation or suppression of functionally related muscle groups. How this circuit reorganization occurs during postnatal development remains poorly understood. Here we explore the connectivity between corticospinal (CS) neurons in the motor cortex and muscles in mice. Using trans-synaptic viral and electrophysiological assays, we identify the early postnatal reorganization of CS circuitry for antagonistic muscle pairs. We further show that this synaptic rearrangement requires the activity-dependent, non-apoptotic Bax/Bak-caspase signaling cascade. Adult Bax/Bak mutant mice exhibit aberrant co-activation of antagonistic muscle pairs and skilled grasping deficits but normal reaching and retrieval behaviors. Our findings reveal key cellular and molecular mechanisms driving postnatal motor circuit reorganization and the resulting impacts on muscle activation patterns and the execution of skilled movements.

DOI： 10.1016/j.neuron.2017.04.019

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Spinal cord injury (SCI) at high spinal levels (e.g., above thoracic level 5) causes systemic immune suppression; however, the underlying mechanisms are unknown. Here we show that profound plasticity develops within spinal autonomic circuitry below the injury, creating a sympathetic anti-inflammatory reflex, and that chemogenetic silencing of this reflex circuitry blocks post-SCI immune suppression. These data provide new insights and potential therapeutic options for limiting the devastating consequences of post-traumatic autonomic hyperreflexia and post-injury immune suppression.

DOI： 10.1038/nn.4289

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CURRENT BIOLOGY LTD  

The developing brain employs multi-step processes to construct neural circuitry. Recent studies have highlighted that microglia, traditionally known to be the resident immune cells in the brain, have essential roles in these processes, which range from neurogenesis to establishing synaptic connections. Microglia play bidirectional roles for maintaining proper circuitry: eliminating unnecessary cells, axons, and synapses, while supporting the neighboring ones. Although these processes are performed in different parts of the neuron, similar molecular mechanisms are possibly involved. This paper reviews recent progress on the knowledge of the roles of microglia in brain development, and further discusses the application of this knowledge in therapies for brain disorders and injuries.

DOI： 10.1016/j.conb.2014.02.004

Web of Science

PubMed

researchmap

Language：English   Publisher：NATURE PUBLISHING GROUP  

Molecular orchestration mediated by Fezf2, a master transcriptional regulator of a particular type of cortical neurons, directly determines both their identity and axonal routing, and thus their connectivity.

DOI： 10.1038/nn.3765

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Transfer of type-1 helper T-gamma onditioned (Th1-conditioned) cells promotes functional recovery with enhanced axonal remodeling after spinal cord injury (SCI). This study explored the molecular mechanisms underlying the beneficial effects of pro-inflammatory Th1-conditioned cells after SCI. The effect of Th1-conditioned cells from interferon-gamma (ifn-gamma) knockout mice (ifn-gamma(-/-) Th1 cells) on the recovery after SCI was reduced. Transfer of Th1-conditioned cells led to the activation of microglia (MG) and macrophages (MUs), with interleukin 10 (IL-10) upregulation. This upregulation of IL-10 was reduced when ifn-gamma(-/-) Th1 cells were transferred. Intrathecal neutralization of IL-10 in the spinal cord attenuated the effects of Th1-conditioned cells. Further, IL-10 is robustly secreted from Th1-conditioned cells in an ifn-gamma-dependent manner. Th1-conditioned cells from interleukin 10 knockout (il-10(-/-)) mice had no effects on recovery from SCI. These findings demonstrate that ifn-gamma-dependent secretion of IL-10 from Th1 cells, as well as native MG/MUs, is required for the promotion of motor recovery after SCI.

DOI： 10.1038/cddis.2013.234

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Neurons require trophic support during neural circuit formation
however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro. In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain. © 2013 Nature America, Inc. All rights reserved.

DOI： 10.1038/nn.3358

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Reorganization of spared neural network connections is one of the most important processes for restoring impaired function after brain injury. However, plasticity is quite limited in the adult brain due to the presence of inhibitory molecules and a lack of intrinsic neuronal signals for axonal growth. Src homology 2-containing phosphatase (SHP)-1 has been shown to have a role in axon growth inhibition. Here, we tested the hypothesis that SHP-1 negatively affects axonal reorganization. We observed that unilateral motor cortex injury led to increased expression and activity of SHP-1 in the contralesional cortex. In this model, corticospinal axons originating from the contralesional cortex sprouted into the denervated side of the cervical spinal cord after injury. We observed that the number of sprouting fibers was increased in SHP-1-deficient heterozygous viable motheaten (+/mev) mice, which show reduced SHP-1 activity, and in wild-type mice treated with an SHP inhibitor. Motor function recovery of impaired forelimb was enhanced in +/mev mice. Collectively, our results indicate that downregulation of SHP-1 activity promotes corticospinal tract sprouting and functional recovery after brain injury. © 2013 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/cddis.2013.102

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Traumatic brain injury (TBI) results in severe motor function impairment, and subsequent recovery is often incomplete. Rehabilitative training is considered to promote restoration of the injured neural network, thus facilitating functional recovery. However, no studies have assessed the effect of such trainings in the context of neural rewiring. Here, we investigated the effects of two types of rehabilitative training on corticospinal tract (CST) plasticity and motor recovery in mice. We injured the unilateral motor cortex with contusion, which induced hemiparesis on the contralesional side. After the injury, mice performed either a single pellet-reaching task (simple repetitive training) or a rotarod task (bilateral movement training). Multiple behavioral tests were then used to assess forelimb motor function recovery: staircase, ladder walk, capellini handling, single pellet, and rotarod tests. The TBI+rotarod group performed most forelimb motor tasks (staircase, ladder walk, and capellini handling tests) better than the TBI-only group did. In contrast, the TBI+reaching group did not perform better except in the single pellet test. After the injury, the contralateral CST, labeled by biotinylated dextran amine, formed sprouting fibers into the denervated side of the cervical spinal cord. The number of these fibers was significantly higher in the TBI+rotarod group, whereas it did not increase in the TBI+reaching group. These results indicate that bilateral movement training effectively promotes axonal rewiring and motor function recovery, whereas the effect of simple repetitive training is limited. Cell Death and Disease (2013) 4, e534; doi:10.1038/cddis.2013.62; published online 7 March 2013

DOI： 10.1038/cddis.2013.62

Web of Science

PubMed

researchmap

Language：English   Publisher：12  

BACKGROUND: The cleavage of β-amyloid precursor protein (APP) generates multiple proteins: Soluble β-amyloid Precursor Protein Alpha (sAPPα), sAPPβ, and amyloid β (Aβ). Previous studies have shown that sAPPα and sAPPβ possess neurotrophic properties, whereas Aβ is neurotoxic. However, the underlying mechanism of the opposing effects of APP fragments remains poorly understood. In this study, we have investigated the mechanism of sAPPα-mediated neurotrophic effects. sAPPα and sAPPβ interact with p75 neurotrophin receptor (p75(NTR)), and sAPPα promotes neurite outgrowth. METHODS AND FINDINGS: First, we investigated whether APP fragments interact with p75(NTR), because full-length APP and Aβ have been shown to interact with p75(NTR) in vitro. Both sAPPα and sAPPβ were co-immunoprecipitated with p75(NTR) and co-localized with p75(NTR) on COS-7 cells. The binding affinity of sAPPα and sAPPβ for p75(NTR) was confirmed by enzyme-linked immunosorbent assay (ELISA). Next, we investigated the effect of sAPPα on neurite outgrowth in mouse cortical neurons. Neurite outgrowth was promoted by sAPPα, but sAPPα was uneffective in a knockdown of p75(NTR). CONCLUSION: We conclude that p75(NTR) is the receptor for sAPPα to mediate neurotrophic effects.

DOI： 10.1371/journal.pone.0082321

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The role of T lymphocytes in central nervous system (CNS) injuries is controversial, with inconsistent results reported concerning the effects of T-lymphocyte transfer on spinal cord injury (SCI). Here, we demonstrate that a specific T-lymphocyte subset enhances functional recovery after contusion SCI in mice. Intraperitoneal adoptive transfer of type 1 helper T (Th1)-conditioned cells 4 days after SCI promoted recovery of locomotor activity and tactile sensation and concomitantly induced regrowth of corticospinal tract and serotonergic fibers. However, neither type 2 helper T (Th2)- nor IL-17-producing helper T (Th17)-conditioned cells had such effects. Activation of microglia and macrophages were observed in the spinal cords of Th1-transfered mice after SCI. Specifically, M2 subtype of microglia/macrophages was upregulated after Th1 cell transfer. Neutralization of interleukin 10 secreted by Th1-conditioned cells significantly attenuated the beneficial effects by Th1-conditioned lymphocytes after SCI. We also found that Th1-conditioned lymphocytes secreted significantly higher levels of neurotrophic factor, neurotrophin 3 (NT-3), than Th2- or Th17-conditioned cells. Thus, adoptive transfer of pro-inflammatory Th1-conditioned cells has neuroprotective effects after SCI, with prospective implications in immunomodulatory treatment of CNS injury. Cell Death and Disease (2012) 3, e363; doi:10.1038/cddis.2012.106; published online 9 August 2012

DOI： 10.1038/cddis.2012.106

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery of motor function following brain injury. After destruction of unilateral sensorimotor cortex, intact-side corticospinal tract formed sprouting fibres into the specific lamina of the denervated side of the cervical spinal cord, and made new contact with two types of spinal interneurons-segmental and propriospinal neurons. Anatomical and electrophysiological analyses revealed that this rewired corticospinal tract functionally linked to motor neurons and forelimb muscles. This newly formed corticospinal circuit was necessary for motor recovery, because transection of the circuit led to impairment of recovering forelimb function. Knockdown of brain-derived neurotrophic factor in the spinal neurons or its receptor in the intact corticospinal neurons diminished fibre sprouting of the corticospinal tract. Our findings establish the anatomical, functional and molecular basis for the intrinsic capacity of neurons to form compensatory neural network following injury.

DOI： 10.1093/brain/aws053

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：3  

c-Jun N-terminal kinase (JNK) mediates neuronal death in response to stress and injury in the CNS and peripheral nervous system. Here, we show that JNK also regulates retrograde axonal degeneration (axonal dieback) after spinal cord injury (SCI) in mice. Activated phospho-JNK was highly expressed in damaged corticospinal tract (CST) axons after thoracic SCI by hemisection. Local administration of SP600125, a JNK inhibitor, prevented accumulation of amyloid-β precursor protein and retraction of the severed CST axons as well as preserved the axonal arbors rostral to the injury site. The treatment with SP600125 also improved functional recovery of the hindlimbs, assessed by Basso mouse scale open-field scores and the grid-walking test. In Jnk1(-/-) and Jnk3(-/-) mice, we observed prevention of axonal degeneration and enhancement of motor recovery after SCI. These results indicate that both JNK1 and JNK3 induce axonal degeneration and limit motor recovery after SCI. Thus, a JNK inhibitor may be a suitable therapeutic agent for SCI.

DOI： 10.1016/j.neures.2011.07.1830

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Purpose: To study RhoA activation and the effect of the Rho-kinase inhibitor in the development of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).
Methods: C57BL/6 mice at postnatal day (P7) were exposed to hyper-oxygen for 5 days and returned to room air for 5 days to induce OIR. RhoA-GTP, an active form of RhoA, in retinas at P12, P13 and P17 was detected. Mice received a single intravitreal injection of Y27632 (5 mu M or 50 mu M), a Rho-kinase inhibitor, in one eye during the transition from oxygen to room air at P12. Contralateral eyes were used as the control. Fluorescein-conjugated dextran angiography of retinal whole mount was prepared to score features of neovascular retinopathy at P17. The preretinal neovascular nuclei quantification was performed in frozen sections as well to evaluate the neovascularization.
Results: The retinal RhoA-GTP in OIR mice significantly increased from 0.24 +/- 0.06 at P12 to 0.38 +/- 0.12 at P13 (p &lt; 0.05). The median total retinopathy score of 5.7 was significantly lower in eyes treated with Y27632 than controls (p &lt; 0.001). Significant improvement was found in the specific categories of vascular tufts (p &lt; 0.01) and extraretinal neovascularization (p &lt; 0.05) in treated eyes. Those treated eyes also had a significantly decreased number of neovascular nuclei (p &lt; 0.01).
Conclusions: These results suggest that Rho/Rho-kinase signaling pathways are involved in the early process of hypoxia-induced retinal neovascularization and Y27632 might have therapeutic potential for the treatment of retinal neovascularization.

DOI： 10.3109/02713683.2011.593110

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

By causing damage to neural networks, spinal cord injuries (SCI) often result in severe motor and sensory dysfunction. Functional recovery requires axonal regrowth and regeneration of neural network, processes that are quite limited in the adult central nervous system (CNS). Previous work has shown that SCI lesions contain an accumulation of activated microglia, which can have multiple pathophysiological influences. Here, we show that activated microglia inhibit axonal growth via repulsive guidance molecule a (RGMa). We found that microglia activated by lipopolysaccharide (LPS) inhibited neurite outgrowth and induced growth cone collapse of cortical neurons in vitro-a pattern that was only observed when there was direct contact between microglia and neurons. After microglia were activated by LPS, they increased expression of RGMa; however, treatment with RGMa-neutralizing antibodies or transfection of RGMa siRNA attenuated the inhibitory effects of microglia on axonal outgrowth. Furthermore, minocycline, an inhibitor of microglial activation, attenuated the effects of microglia and RGMa expression. Finally, we examined whether these in vitro patterns could also be observed in vivo. Indeed, in a mouse SCI model, minocycline treatment reduced the accumulation of microglia and decreased RGMa expression after SCI, leading to reduced dieback in injured corticospinal tracts. These results suggest that activated microglia play a major role in inhibiting axon regeneration via RGMa in the injured CNS.

DOI： 10.1371/journal.pone.0025234

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Brain injury in the motor cortex can result in deleterious functional deficits of skilled and fine motor functions. However, in contrast to humans, the destruction of cortex and its descending fibers has been thought not to cause remarkable deficits in simple locomotion in quadropedal animals. In the present study, we aimed to investigate in detail how lesion of the sensorimotor cortex affected locomotion ability in mice using the KinemaTracer system, a novel video-based kinematic analyzer. We found that traumatic injury to the left sensorimotor cortex induced several apparent deficits in the movement of contralesional right limbs during treadmill locomotion. The step length of right limbs decreased, and the speed in the forward direction was abrogated in the swing phase. The coordinates and angle of each joint were also changed after the injury. Some of the abnormal values in these parameters gradually recovered near the control level. The number of cFos-expressing neurons following locomotion significantly decreased in the right side of the spinal cord in injured mice, suggesting a role for cortex and descending fibers in locomotion. In contrast, interlimb coordination did not change remarkably even after the injury, supporting the notion that the basic locomotor pattern was determined by intraspinal neural circuits. These results indicate that the motor cortex and its descending fibers regulate several aspects of fine limb movement during locomotion. Our findings provide practical parameters to assess motor deficits and recovery following cortical injury in mice. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2011.05.006

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

The fibers of corticospinal tract (CST), which control fine motor function, predominantly project to the contralateral spinal cord, not recross to the ipsilateral side. Ephrin-B3, which is expressed in the midline of the spinal cord, and its receptor, EphA4, are crucial for preventing CST fibers from recrossing the midline in the developing spinal cord. However, these fibers can cross the midline to the denervated side after a unilateral CST or cortical injury. We determined the reason CST fibers can cross the midline after a cortical injury and the changes in ephrin-B3-EphA4 signaling associated with such a crossing. We first examined axonal sprouting from CST fibers after unilateral ablation of the motor cortex in postnatal and adult mice. CST fibers crossed the midline of the spinal cord after cortical ablation, especially when conducted during the early postnatal period. These fibers were well associated with functional recovery after the injury. We next assessed the mRNA expression of ephrin-B3 and EphA4 before and after the ablation. Surprisingly, no changes were detected in the expression patterns. We found, however, that ephrin-B3 expression in the ventral part of the midline disappeared after postnatal day 9 (P9), but was pronounced along the entire midline before P6. Most of the CST fibers crossed the midline through the ventral region, where ephrin-B3 expression was absent. Our results suggest that ephrin-B3 is not expressed along the entire midline of the spinal cord, and sprouting axons can cross the midline at ephrin-B3-negative areas. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2010.12.004

Web of Science

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Remodeling of the remnant neuronal network after brain injury possibly mediates spontaneous functional recovery; however, the mechanisms inducing axonal remodeling during spontaneous recovery remain unclear. Here, we show that altered gamma-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury. After injury to the sensorimotor cortex in mice, we found a significant decrease in the expression of GABA(A)R-alpha 1 subunits in the intact sensorimotor cortex for 2 weeks. Motor functions, assessed by grid walk and cylinder tests, spontaneously improved in 4 weeks after the injury to the sensorimotor cortex. With motor recovery, corticospinal tract (CST) axons from the contralesional cortex sprouted into the denervated side of the cervical spinal cord at 2 and 4 weeks after the injury. To determine the functional implications of the changes in the expression of GAB(A)AR-alpha 1 subunits, we infused muscimol, a GABA R agonist, into the contralesional cortex for a week after the injury. Compared with the vehicle-treated mice, we noted significantly inhibited recovery in the muscimol-treated mice. Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord. In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABA(A)R subunit expression and decreased GABAergic signaling. Cell Death and Disease (2011) 2, e133; doi: 10.1038/cddis.2011.16; published online 17 March 2011

DOI： 10.1038/cddis.2011.16

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

The anatomy of the mammalian thalamus is characterized by nuclei, which can be readily identified in postnatal animals. However, the molecular mechanisms that guide specification and differentiation of neurons in specific thalamic nuclei are still largely unknown, and few molecular markers are available for most of these thalamic subregions at early stages of development. We therefore searched for patterned gene expression restricted to specific mouse thalamic regions by in situ hybridization during the onset of thalamic neurogenesis (embryonic [E] days E10.5-E12.5). To obtain correct regional information, we used Shh as a landmark and compared spatial relationships with the zona limitans intrathalamica (Zli), the border of the p2 and p3 compartments of the diencephalon. We identified genes that are expressed specifically in the ventricular zone of the thalamic neuroepithelium and also identified a number of genes that already exhibited regional identity at E12.5. Although many genes expressed in the mantle regions of the thalamus at E12.5 showed regionally restricted patterns, none of these clearly corresponded to individual thalamic nuclei. We next examined gene expression at E15.5, when thalamocortical axons (TCAs) project from distinct regions of the thalamus and reach their targets in the cerebral cortex. Regionally restricted patterns of gene expression were again seen for many genes, but some regionally bounded expression patterns in the early postnatal thalamus had shifted substantially by E15.5. These findings reveal that nucleogenesis in the developing thalamus is associated with selective and complex changes in gene expression and provide a list of genes that may actively regulate the development of thalamic nuclei. J. Comp. Neurol. 519:528-543, 2011. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/cne.22531

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Myelin components that inhibit axonal regeneration are believed to contribute significantly to the lack of axonal regeneration noted in the adult central nervous system. Three proteins found in myelin, Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein, inhibit neurite outgrowth in vitro. All of these proteins interact with the same receptors, namely, the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PIR-B). As per previous reports, corticospinal tract (CST) regeneration is not enhanced in NgR-knock-out mice after spinal cord injury. Therefore, we assessed CST regeneration in PIR-B-knock-out mice. We found that hindlimb motor function, as assessed using the Basso mouse scale, footprint test, inclined plane test, and beam walking test, did not differ between the PIR-B-knock-out and wildtype mice after dorsal hemisection of the spinal cord. Further, tracing of the CST fibers after injury did not reveal enhanced axonal regeneration or sprouting in the CST of the PIR-B-knock-out mice. Systemic administration of NEP1-40, a NgR antagonist, to PIR-B knock-out mice did not enhance the regenerative response. These results indicate that PIR-B knockout is not sufficient to induce extensive axonal regeneration after spinal cord injury.

DOI： 10.1074/jbc.M110.163493

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

The rewiring of neural networks is a fundamental step in recovering behavioral functions after brain injury. However, there is limited potential for axonal plasticity in the adult CNS. The myelin-associated proteins Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are known to inhibit axonal plasticity, and thus targeting the inhibitory pathways they participate in is a potential means of promoting plasticity and functional recovery. Each of Nogo, MAG, and OMgp interacts with both the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Here, we determined whether blocking PirB activity enhances axonal reorganization and functional recovery after cortical injury. We found that axons of the contralesional corticospinal tract sprouted into the denervated side of the cervical spinal cord after unilateral injury of the motor cortex. The extent to which this axonal reorganization occurred was far greater in mice lesioned during early postnatal days than in mice lesioned at an age when myelin had begun to form. This suggests that myelin-associated proteins might limit axonal remodeling in vivo. However, the number of sprouting fibers within either the corticospinal or corticorubral tract was not enhanced in PirB(-/-) mice. Blocking PirB signaling also failed to enhance functional recovery with three motor tests. Our results suggest that blocking the function of PirB is not sufficient to promote axonal reorganization or functional recovery after cortical injury.

DOI： 10.1523/JNEUROSCI.3228-10.2010

Web of Science

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Purpose: Several recent studies showed that olfactory mucosal transplantation after spinal cord injury promotes extensive regeneration of the injured spinal cord. We examined the efficacy of olfactory mucosal transplantation for bladder dysfunction after spinal cord injury in rats.
Materials and Methods: In adult female rats the Th9-10 spinal cord was completely transected, followed by olfactory mucosal transplantation or gelatin sponge filling as the control. Each group was examined by cystometrogram and external urethral sphincter electromyogram. Calcitonin gene-related peptide and growth associated protein 43 double positive expression in the L6/S1 dorsal horn was evaluated by immunohistochemistry. Transplant sites were examined by immunohistochemistry with antibodies against neurofilament M and neuronal class III beta-tubulin.
Results: On cystometrogram voiding efficiency was significantly higher in the transplantation group than in controls. On external urethral sphincter electromyogram with simultaneous cystometrogram the transplantation group showed a larger ratio of interburst silent periods to burst activity duration and a greater number of high frequency oscillations. In the transplantation group calcitonin gene-related peptide and growth associated protein 43 double positive expression in the L6/S1 dorsal horn was less dense than in controls. The transplantation group showed strong neurofilament M and neuronal class III beta-tubulin expression at the transplant site.
Conclusions: Olfactory mucosal transplantation after spinal cord injury weakened external urethral sphincter excessive bursting and increased the urethral opening to improve voiding efficiency. Olfactory mucosal transplantation may modify emergence of the spinal micturition reflex after spinal cord injury. Transplantation resulted in new axons growing at the transplant site, implying the possible existence of interneuron bridging across the injured spinal cord.

DOI： 10.1016/j.juro.2010.03.105

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Galectin-1, a member of a family of beta-galactoside-binding proteins, is differentially expressed by various tissues and performs a wide range of biological functions. Galectin-1 has been shown to mediate inflammation and to be involved in axonal regeneration in the oxidized form and in axonal degeneration in the reduced form, however. its involvement in injury and the repair processes after spinal cord Injury have not been studied Therefore, we studied galectin-1 expression in injured spinal cords Immunostaining analysis of galectin-1 in injured spinal cords revealed that galectin-l-expressing cells assembled around the lesion site Galectin-1 was intensively expressed by neutrophils 1 day. by microglia/macrophages 3 days. and by astrocytes 7 days after spinal cord injury These results Suggest that galectin-1 may be associated with the pathogenesis of spinal cord Injury (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society All rights reserved.

DOI： 10.1016/j.neures.2009.11.008

Web of Science

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：2  

OBJECT: The olfactory mucosa (OM) consists of 2 layers, the epithelium and the lamina propria. Attempts have been made to restore motor function in rat models of spinal cord injury (SCI) by transplanting olfactory ensheathing cells from the lamina propria, but there has been no attempt to transplant the OM in animal models. To investigate the potential of the OM to restore motor function, the authors developed a rat model of SCI and delayed transplantation of syngenic OM. METHODS: Two weeks after complete transection of the spinal cord at the T-10 level in Wistar rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats that underwent respiratory mucosa transplantation were used as controls. The authors evaluated the locomotor activity according to the Basso-Beattie-Bresnahan scale for 8 weeks after transplantation. Obtained spinal cords were analyzed histologically. Results The OM transplantation rats showed significantly greater hindlimb locomotor recovery than the respiratory mucosa-transplanted rats. However, the recovery was limited according to the Basso-Beattie-Bresnahan scale. In the histological examination, the serotonergic raphespinal tract was regenerated. The pseudocyst cavity volume in the vicinity of the SCI lesion correlated negatively with the functional recovery. CONCLUSIONS: Transplantation of whole-layer OM in rats contributes to functional recovery from SCI, but the effect is limited. In addition to OM transplantation, other means would be necessary for better outcomes in clinical situations.

DOI： 10.3171/2009.9.SPINE09233

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The clearance of debris after injuries to the nervous system is a critical step for restoration of the injured neural network. Microglia are thought to be involved in elimination of degenerating neurons and axons in the central nervous system (CNS), presumably restoring a favorable environment after CNS injuries. However, the mechanism underlying debris clearance remains elusive. Here, we establish an in vitro assay system to estimate phagocytosis of axon debris. We employed a Wallerian degeneration model by cutting axons of the cortical explants. The cortical explants were co-cultured with primary microglia or the MG5 microglial cell line. The cortical neurites were then transected. MG5 cells efficiently phagocytosed the debris, whereas primary microglia showed phagocytic activity only when they were activated by lipopolysaccharide or interferon-beta. When MG5 cells or primary microglia were co-cultured with degenerated axons, p38 mitogen-activated protein kinase (MAPK) was activated in these cells. Engulfment of axon debris was blocked by the p38 MAPK inhibitor SB203580, indicating that p38 MAPK is required for phagocytic activity. Receptors that recognize dying cells appeared not to be involved in the process of phagocytosis of the axon debris. In addition, the axons undergoing Wallerian degeneration did not release lactate dehydrogenase, suggesting that degeneration of the severed axons and apoptosis may represent two distinct self-destruction programs. We observed regrowth of the severed neurites after axon debris was removed. This finding suggests that axon debris, in addition to myelin debris, is an inhibitory factor for axon regeneration.

DOI： 10.1074/jbc.M109.005603

Web of Science

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC STUDY REPRODUCTION  

Abnormal regulation of placental apoptosis and proliferation has been implicated in placental disorders. Recently, several DNA-damaging agents were reported to induce excessive apoptosis and reduce cell proliferation in the placenta; however, the molecular pathways of these toxic effects on the placenta are unclear. The aim of the present study was to determine the involvement of TRP53, a tumor suppressor that mediates cellular responses to DNA damage, in the induction of apoptosis and cell cycle arrest in the developing placenta. For this purpose, we treated pregnant mice on Day 12 of gestation with 10 mg/kg of etoposide and 5-Gy gamma irradiation, potent inducers of DNA damage. We found an increase in the number of trophoblastic apoptoses 8 and 24 h after etoposide injection and 6 and 24 h after irradiation in the placental labyrinth zone. The number of mitoses and DNA syntheses in trophoblasts decreased after treatment. The accumulation and phosphorylation of TRP53 protein were detected 8 and 6 h after etoposide injection and irradiation, respectively. In Trp53-deficient placentas, the induction of etoposide-induced trophoblastic apoptosis is abrogated, while the reduction of proliferation occurred similarly as in wild-type placentas. CDC2A, a regulator of G2/M progression, was inactivated by phosphorylation after etoposide injection and irradiation, suggesting that the cell cycle was arrested at the G2/M border by treatment. Our study demonstrated that etoposide injection induced TRP53-dependent apoptosis and TRP53-independent cell cycle arrest in labyrinthine trophoblasts, providing insights into the molecular pathway of placental disorders.

DOI： 10.1095/biolreprod.108.069419

Web of Science

PubMed

researchmap

Language：English   Publisher：IRCA-BSSA  

Injuries to the adult central nervous system (CNS), such as spinal cord injury and brain contusion, can cause permanent functional deficits if axonal connections are broken. Spontaneous functional recovery rarely occurs. It has been widely accepted that the extracellular environment of the CNS inhibits neuronal regeneration. However, it should be noted that another reason for injured neurons failing to regenerate is their weak intrinsic ability to do so. The regeneration of injured neurons is a process involving many intracellular phenomena, including cytoskeletal changes, gene and protein expression, and changes in the responsiveness to extracellular cues. The capacity of injured neurons to regenerate is modulated to some extent by changes in the expression of intracellular signaling molecules such as glycogen synthase kinase-3 beta and cyclic adenosine 3',5'-monophosphate. Knowledge of these effects has guided the development of animal models for regenerative therapies of CNS injury. Enhancing the intrinsic regenerative machinery of injured axons in the adult CNS is a potentially powerful strategy for treating patients with a CNS injury.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

During the early developmental stage, a neural circuit is established between the entorhinal cortex (EC) and the hippocampal dentate gyrus (DG) via the perforant pathway. However, the manner in which the perforant fibers are navigated has mostly remained a mystery. Here, we analyzed the functional role of a chemokine, namely, stromal cell-derived factor 1 alpha(SDF-1 alpha), in the navigation of the perforant fibers. SDF-1 alpha was observed to promote neurite growth, which is dependent on mDia1, in cultured entorhinal cortical neurons obtained from rats at postnatal day 0. We then used entorhino-hippocampal cocultures comprising green fluorescence-labeled EC and DG slices to assess the projection of the perforant fibers from the EC. Although the specific laminar termination of the entorhinal axons was observed with this system, the number of appropriately terminating entorhinal axons decreased significantly when the SDF-1 alpha signaling pathway was blocked by a neutralizing antibody against SDF-1 alpha or by the specific SDF-1 alpha receptor antagonist AMD3100 (1,1 alpha-[1,4-phenylenebis(methylene)] bis-1,4,8,11-tetra-azacyclotetradecane octahydrochloride). Furthermore, inhibition of the SDF-1 alpha signaling pathway resulted in a decrease in the immunoreactivity for PSD-95 (postsynaptic density protein-95) in the DG, possibly because of a reduction in the number of projecting perforant fibers. These results demonstrate that SDF-1 alpha plays a critical role in promoting the growth of perforant fibers from the EC to the DG.

DOI： 10.1523/JNEUROSCI.1670-08.2008

Web of Science

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：2  

Axonal regeneration does not occur easily after an adult central nervous system (CNS) injury. Various attempts have partially succeeded in promoting axonal regeneration after the spinal cord injury (SCI). Interestingly, several recent therapeutic concepts have emerged from or been tightly linked to the researches on brain development. In a developing brain, remarkable and dynamic axonal elongation and sprouting occur even after the injury; this finding is essential to the development of a therapy for SCI. In this review, we overview the revealed mechanism of axonal tract formation and plasticity in the developing brain and compare the differences between a developing brain and a lesion site in an adult brain. One of the differences is that mature glial cells participate in the repair process in the case of adult injuries. Interestingly, these cells express inhibitory molecules that impede axonal regeneration such as myelin-associated proteins and the repulsive guidance molecules found originally in the developing brain for navigating axons to specific routes. Some reports have clearly elucidated that any treatment designed to suppress these inhibitory cues is beneficial for promoting regeneration and plasticity after an injury. Thus, understanding the developmental process will provide us with an important clue for designing therapeutic strategies for recovery from SCI.

DOI： 10.2147/btt.s2715

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

A cDNA microarray analysis was conducted to examine hepatic gene expression profiles in pregnant and lactating F344 rats compared to a virgin control group using an Affymetrix GeneChip system. Of the approximately 16000 gene transcripts interrogated, more than 1000 were significantly modified in their expression when detected either in late pregnancy (19 days of gestation, GD 19, 513 genes upregulated and 579 downregulated) or on the day of delivery (Postpartum 0 day, PPD 0, 497 upregulated and 733 downregulated). Particular interest was paid to the gene expression of drug-metabolizing enzymes (DMEs) and nuclear receptors (NRs). Though the expression of a few genes, those forCYP7A1, CYP51 and Sultx3, increased, the expression of a number of genes encoding DMEs (Phase I and Phase II) and NRs decreased during pregnancy and lactation. Changes in the expression of 9 genes encoding DMEs and NRs were confirmed by quantitative real-time PCR. For all 9 genes tested, overall, the results of the microarray and real-time PCR analyses were in agreement. This is the first application of a microarray analysis to the expression profiling of genes encoding DMEs and NRs in the liver of pregnant and lactating rats. When combined with other studies, the present study may provide a basis for investigating the mechanism of toxicity of environmental or other nonphysiologic chemicals to the fetus and mother and drug safety during pregnancy and lactation. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexmp.2006.05.002

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Placental apoptosis plays important roles in both normal morphogenesis and pathogenesis. We previously reported that administration of cytosine arabinoside (Ara-C), a DNA-damaging agent, to pregnant rats induced apoptosis of trophoblasts in the placental labyrinth zone. Our aim here was to clarify the molecular pathway of DNA damage induced-trophoblastic apoptosis. We found the accumulation and phosphorylation of p53 protein, a tumor suppressor that mediates apoptosis under various cellular stresses, in Ara-C-treated rat placentas. Expression of the mRNAs of downstream targets of p53 was upregulated, suggesting that p53 exerts its function as a transcription factor. We also observed release of mitochondrial cytochrome c and activation of caspase-9, hallmarks of the intrinsic apoptotic pathway. Phosphorylation of Chk1 and H2A.X, target substrates of DNA damage transducers, was detected immediately after Ara-C treatment, suggesting activation of DNA damage cascades to phosphorylate p53. Ara-C-induced trophoblastic apoptosis was almost completely abrogated in placentas of Trp53 (coding p53)deficient mice, whereas the levels of physiological apoptosis in trophoblasts were similar among wild-type and Trp53-deficient mice. These results indicate that p53 is essential for DNA damage-induced trophoblastic apoptosis and suggest that the mechanisms that regulate the damage-induced apoptosis differ from those that regulate physiological apoptosis.

DOI： 10.1007/s10495-007-0099-z

Web of Science

PubMed

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

The fetal brain is susceptible to many extrinsic stresses. Some of these stresses induce excessive cell death in the prenatal stage, leading to anomalies in the neonatal brain. However, it is unclear how the developing brain responds to and repairs the prenatal tissue damage. We treated pregnant rats on day 13 of gestation with 5-azacytidine, one of the compounds that induces excessive cell death and inhibits proliferation in neural progenitor cells, to damage the fetal brain, and investigated the repair process up to 60 h after treatment. Histological analysis showed that 5-azacytidine induced strong apoptosis of neural cells. By 60 h, apoptotic cells disappeared and the tissue was repaired, although the telencephalic wall remained thinner than in controls. Flow cytometry analysis showed that the cell cycle distribution also returned to control levels at 60 h, suggesting that the repair process was completed around 60 h. During the repair period, amoeboid microglia infiltrated the brain and ingested the apoptotic cells. These microglial cells were positive for the multiple microglial markers, and mRNAs for the microglia-related cytokines tumor necrosis factor alpha, interleukin 1 beta and macrophage colony stimulating factor (M-CSF) were up-regulated. DNA microarray analysis showed the up-regulation of genes relevant to glial cells, inflammation, the extracellular matrix, glycolysis, proliferation and neural development. We show here that the developing brain has the capacity to respond to the damage induced by extrinsic chemical stresses, including changing the expression of numerous genes and the induction of microglia to aid the repair process.

DOI： 10.1111/j.1460-9568.2006.05161.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to create animal models of Parkinson disease. There is conflicting evidence on the occurrence of apoptosis induced by MPTP in the mouse substantia nigra pars compacta. We demonstrated that a single acute injection of MPTP induced apoptosis in the subventricular zone (SVZ) and rostral migratory stream (RMS) in the adult C57BL/6 mouse brain. The number of TUNEL-positive cells peaked at 24 hours after injection and decreased thereafter, paralleling the change in the number of cleaved caspase-3-positive cells after MPTP injection. Results of immunohistochemistry and ultrastructural analyses indicated that the majority of apoptotic cells in the SVZ and RMS were migrating neuroblasts (type A cells), whereas a few were astrocytes (type B cells). No apoptosis occurred in transit-amplifying progenitors (type C cells). The decrease in A cell numbers was most marked on day 2 and lasted to day 8 after the administration. A rapid and transient phagocytosis of apoptotic cells by microglial cells was demonstrated to parallel the MPTP-induced apoptosis. The present findings provide new insight into the extensive neurotoxicity of MPTP and may be valuable in reevaluating the MPTP mouse model of Parkinson disease.

DOI： 10.1097/01.jnen.0000235115.29440.ce

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

In the developing brain, neural progenitor cells in the ventricular zone (VZ) show a typical migration pattern-interkinetic nuclear migration, in which nuclear position within the VZ is correlated with the cell cycle. However, the mechanisms underlying this regulation remain unclear. To clarify whether the cell cycle progression controls nuclear migration of neural progenitor cells, we determined whether chemically induced cell cycle arrest affected nuclear migration patterns in the VZ. Administration of 5-azacytidine (5AzC) or cyclophosphamide (CP) to pregnant mice induced cell cycle arrest in the fetal neural progenitor cells of the telencephalon: 5AzC induced G2/M-phase arrest, and CP induced S-phase arrest. We used 5-bromo-2'-deoxyuridine (BrdU) labeling to determine the position of the cell in the cell cycle and the nuclei within the VZ at the same time. Cells arrested in G2/ M-phase stopped migrating in the inner area of the VZ. Cells arrested in S-phase stopped migrating in the outer area. These results indicate that nuclear position within the VZ was correlated with cell cycle phase, even when the cell cycle was disrupted, and that the nuclei of neural progenitor cells can migrate only when their cell cycle is going. Our results suggest that cell cycle regulators might control the machinery of migration through a common regulatory mechanism. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2006.03.042

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

In the developing brain, neural progenitor cells are susceptible to many extrinsic stresses, including DNA damage. We treated pregnant rats with 5-azacytidine (5AzC), a DNA demethylating and damaging agent, to investigate the cellular responses of the fetal brain, focusing on the regulation of proliferation and cell death. 5AzC first induced the accumulation of cells in abnormal mitosis, G2-phase accumulation, and then apoptosis of the neural progenitor cells. Most of the apoptotic cells were in G1 phase. Cell cycle transition studies suggested that G2/M progression was blocked, after which the cells moved to G I phase or underwent apoptosis. p53, a key factor for response to DNA damage, and some of its target genes showed increased expression in Western blot and DNA microarray analyses. In 5AzC-treated fetal brains of p53-deficient mice, apoptosis did not occur, although G2/M accumulation was induced. These results suggest that, in the developing brain, apoptosis is p53-dependent but that another mechanism governs the G2/M checkpoint. The G2/M regulator, Cdc:2, was activated by dephosphorylation through G2/M accumulation, suggesting accelerated entry into mitosis leading to accumulation of cells showing abnormal mitosis. Furthermore, some cells may have died due to mitotic catastrophe. Throughout brain development, various cell cycle and cell death regulation mechanisms provide neural progenitor cells with options for defense from DNA damage. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2005.11.024

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

BACKGROUND: Ethylnitrosourea (ENU), a monofunctional alkylating agent, induces apoptosis and cell cycle arrest in neuroepithelial cells, neural stem cells in the fetal central nervous system (CNS). These effects occur immediately after the administration of ENU to pregnant animals resulting in fetal brain anomalies and long-term effects include brain tumors in the offspring. METHODS: Changes in gene expression were investigated in the fetal CNS after ENU administration to pregnant rats using microarray to identify the genes involved in the injury and recovery of the fetal CNS. RESULTS: The up-regulation of 21 genes in injury and 15 genes in recovery phases and down-regulation of 5 genes in injury and 3 genes in recovery phases were identified. The genes up-regulated in the injury phase contained p53-target genes that mediate apoptosis and cell cycle arrest, and those in the recovery phase contained cell proliferation-promoting genes. The genes down-regulated in the injury phase contained cholesterol biosynthesis-related genes. In addition, there were some genes that have not been identified to be involved in the CNS injury and recovery. CONCLUSIONS: The present study will provide a better understanding of the mechanisms of development, regeneration and carcinogenesis of the CNS as well as the mechanisms of ENU-induced fetal CNS injury and recovery. (c) 2005 Wiley-Liss, Inc.

DOI： 10.1002/bdrb.20045

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Neural progenitor cells populate the ventricular zone of the fetal central nervous system. In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed. This event was caused by the inhibition or arrest of DNA replication rather than acceleration of the G1/S transition. Soon after this accumulation reached its peak, the number of cells in the G2/M phase decreased and the apoptotic cell count increased. In p53-deficient mice, both ENU-induced apoptosis and S-phase accumulation were almost completely abrogated. These findings indicate that ENU inhibits or arrests DNA replication in neural progenitor cells during the S phase and then evokes apoptosis before the cells enter the G2 phase. Furthermore, these data also demonstrate that both ENU-induced apoptosis and cell cycle perturbation in the S phase require p53. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.nbd.2004.09.015

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：URBAN & FISCHER VERLAG  

Hlydroxyurea (HU), a ribonucleotide reductase inhibitor, induces morphological anomalies in the central nervous system, craniofacial tissues and limb buds in animals, and neonatal respiratory distress in humans. The neonates and offspring of pregnant mice treated with 400 or 800 mg/kg of HU on day 13 of gestation were examined at 0 day and 10 weeks after birth to find a clue for clarifying the relationship between HU-induced apoptosis in the fetal tissues and teratogenicity. The offspring from dams treated with HU were retarded in growth compared with controls. But there was no significant difference in the body weight gain between the 400 and 800 mg/kg groups. In the teratologic changes, microencephaly, hydrocephalus and curved coccygeal vertebrae were observed in the offspring, and the incidence of these teratologic changes was similar but their degree was more severe in the 800 mg/kg group than in the 400 mg/kg group. Based on the above-mentioned previous and present studies of ours, we suggest that HU-induced apoptosis in fetal tissues may play an important role in the development of anomalies in the corresponding tissues of offspring. (C) 2004 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.etp.2004.04.011

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

1-beta-D-Arabiiioftiranosylcytosine (Ara-C), a cytidine analogue cytotoxic to proliferating cells, has a teratogenic effect in the brain of experimental animals and causes neural cell apoptosis in vitro and in vivo. In the present study, pregnant rats were injected with Ara-C on Day 13 of gestation and the fetal brain was collected from 1 to 48 It after treatment. Histopathological examinations revealed marked induction of apoptotic cell death and decrease of mitosis in neuroepithelial cells in the brain of Ara-C-treated fetus, and these changes were most prominent from 9 to 12 h. Expression of p53 protein, which mediates apoptosis and cell cycle arrest after DNA damage, was elevated remarkably and peaked at 3 h. p21, a cyclin-dependent kinase inhibitor responsible for p53-mediated cell cycle arrest, showed intense overexpression in protein and mRNA levels following the increase of p53 protein. The mRNA expressions of other p53 transcriptional target genes, bax, cyclinG1, and fas, also significantly increased and peaked at around 9 h. In conclusion, prenatal treatment of Ara-C is thought to induce apoptosis and inhibition of cell proliferation mediated by p53 and its target genes in the fetal brain. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ntt.2004.03.010

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC STUDY REPRODUCTION  

1-beta-D-Arabinofuranosyicytosine (Ara-C), a DNA-damaging agent, severely inhibits fetal growth and has teratogenicity. Recently, we reported that Ara-C also causes placental growth retardation and increases placental apoptosis. The aim of the present study is to elucidate the mechanisms of placental injury induced by genotoxic stress and involvement of p53, which mediates apoptosis and cell-cycle arrest after DNA damage. We injected Ara-C into pregnant rats on Day 13 of gestation and examined the placentas from 1 to 48 h after the administration. Terminal deoxynucleotidyltransferase-mediated dUTP end-labeling (TUNEL) revealed that the apoptosis of trophoblastic cells in the placental labyrinth zone increased from 3 h after the treatment and peaked at 6 h before returning to control levels at 48 h. An increase in cleaved caspase-3 immunoreactivity was also detected at 6 h. Proliferative activity as measured by immunohistochemistry for topoisomerase IIalpha and by mitotic index significantly decreased after the treatment in the labyrinth zone. Immunoreactivity for p53 protein in the placental labyrinth zone was remarkably enhanced and peaked at 3 h after treatment, although no increase in p53 mRNA expression was detected with a reverse transcription-polymerase chain reaction. Regarding p53 target genes, p21, cyclinG1, and fas mRNA levels increased significantly and peaked at around 9 h after the treatment. These results indicate that Ara-C would induce apoptosis and impair cell proliferation in the placental labyrinth zone, and p53 and its transcriptional target genes may play an important role in the pathogenesis of the Ara-C-induced placental toxicity.

DOI： 10.1095/biolreprod.103.026252

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The present study was designed to evaluate dopaminergic neuronal loss in the substantia nigra pars compact (SNpc) with immunohistochemical staining. C57BL/6 mice were intraperitoneally injected four times with 15 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at 2 h intervals on 10 and 21 days, and 6, 12, 24 and 48 weeks of age. Animals were sacrificed 48 hours after the last injection. No change in the number of tyrosine hydroxylase (TH)-positive neurons was observed in 10- and 21-day-old mice after MPTP treatment compared with their corresponding controls. In contrast, MPTP produced a loss of 20.3% of TH-positive neurons in 6 week-old mice, and further decreases with advancing age, i.e., 35.8%, 39.9% and 56.2% TH-positive neuronal loss at 12, 24 and 48 weeks of age, respectively. These results provide evidence of age-related susceptibility of C57BL/6 mice to MPTP using TH immunohistochemistry. However, we failed to observe apoptosis of neurons in SNpc of mice of all ages after a subacute protocol of MPTP treatment (30 mg/kg/day x 5days).

DOI： 10.1293/tox.17.239

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：URBAN & FISCHER VERLAG  

Ethylnitrosourea (ENU) is a simple alkylating agent. It induces gene mutations in fetal primordial germ cells (PGCs), and a high incidence of congenital malformations is also found in the offspring of male mice treated with ENU at the embryonic stage. It is also reported that decreases in the fertility rate and weights of the testis and ovary were found in the offspring from dams treated with ENU. In this study, we analyzed the occurrence of apoptotic cell death and the expression of p53 protein which is thought to play an important role in the DNA damage-induced apoptosis after administration of ENU to pregnant rats on day 13 of gestation to obtain a clue for clarifying the toxic effect of ENU on PGCs. Apoptotic cells increased in PGCs in fetal gonads from 3 h after treatment. The number of apoptotic PGCs peaked at 6 h and gradually decreased towards 24 h after treatment. On the other hand, p53-positive PGCs increased from 1 h after treatment, prior to the induction of apoptosis. The number of p53-positive PGCs peaked at 3 h and returned to the control level at 24 h after treatment. These results suggest that ENU induces apoptosis in rat fetal PGCs immediately after its administration to dams and excess cell death by apoptosis may have a close relation to the later occurrence of decreases in the fertility rate and gonadal weight. Moreover, a possible involvement of p53 is suggested in the ENU-induced apoptosis in PGCs.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：URBAN & FISCHER VERLAG  

5-Azacytidine (5AzC) is a cytidine analogue which possesses nitrogen atom instead of carbon atom at the position 5 of the pyrimidine ring. In this study, detailed histopathological changes were sequentially examined in the rat fetal brain obtained from dams treated with 5AzC (10 mg/kg) on day 13 of gestation (GD13). At 6 hours after treatment (HAT), a prominent accumulation of neuroepithelial cells showing pleomorphic mitotic figures were observed in the telencephalic wall. The mitosis-index peaked at 6 HAT, and decreased thereafter. Neuroepithelial cells positive for nick end labeling (TUNEL) method, which is widely used for the detection of apoptotic cells, prominently increased at 9 HAT, and the TUNEL-index peaked at 12 HAT. TUNEL-positive cells showed ultrastructural characteristics of apoptosis. At 24 HAT, the formation of rosette-like structures was observed in the fetal brain. From the results of the present study, it was evident that abnormal mitosis and neuronal apoptosis were induced in the rat fetal brain following 5AzC-administration to dams on GD13. In addition, it is suggested that 5AzC-induced apoptosis might occur mainly in the post mitotic phase of cell cycle.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC STUDY REPRODUCTION  

Ethyl nitrosourea (ENU), a well known alkylating agent, induces congenital anomalies in fetuses when it is administered to pregnant animals. In previous studies, we reported that ENU induced apoptosis and growth arrest in fetal tissues and organs immediately after its administration to pregnant rats. In the present study, we investigated the histopathological changes of the placenta after ENU administration to pregnant rats on Day 13 of gestation (GD13) to obtain a clue for clarifying the role of the placenta in the process of fetal developmental disability induced by genotoxic stress. Apoptotic cells increased and DNA-replicating cells decreased in the trophoblastic cells in the placental labyrinth zone of the ENU-treated group by 3 h after treatment. The number of apoptotic cells peaked at 6 h after treatment and returned to control levels at 48 h after treatment. The number of DNA-replicating cells reached minimum levels at 6 h after treatment and returned to control levels at 48 h after treatment. By immunohistochemistry, p53-positive signals were observed in trophoblastic cells in the labyrinth zone of the ENU-treated group from 3 to 6 h after treatment. Significant decreases in fetal and placental weights were observed in the ENU-treated group at 2 days (GD15) and 8 days (GD21) after treatment. A reduction in the thickness of the labyrinth zone was histopathologically significant in the ENU-treated group. These results indicate that ENU induces apoptosis and growth arrest not only in fetal tissues, but also in trophoblastic cells in the rat placental labyrinth zone, and these placental changes may have roles in the induction of fetotoxicity and teratogenicity of ENU. Moreover, a possible involvement of p53 in the induction of apoptosis and growth arrest is suggested.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING LTD  

Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain were investigated. 5AzC (10 mg/kg) was injected into pregnant rats on day 13 of gestation and the protein and mRNA expressions of p53 and its transcriptional target genes, p21 , bax , cyclin G1 , fas , and gadd45 , were examined in the foetal brain. The number of p53-positive cells peaked at 9 h after treatment (HAT) and those of apoptotic cells and p21-positive cells peaked at 12 HAT. The expressions of p21 , bax , cyclin G1 , and fas mRNAs were significantly elevated from 9 to 12 HAT. From the experiments using 5-bromo-2'-deoxyuridine (BrdU), as compared with controls, the migration of neuroepithelial cells significantly delayed and BrdU-positive signals were observed in many apoptotic cells from 9 to 24 HAT in the 5AzC-group. In addition, the number of S phase cells significantly decreased at 12 HAT. The present results indicate that 5AzC induced apoptosis and cell cycle arrest probably at G1 phase in the rat foetal brain and they might be mediated by p53 in response to DNA damage.

DOI： 10.1046/j.1365-2613.2002.00225.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

5-Azacytidine (5AzC) induces neuronal apoptosis in rat and mouse fetuses. 5AzC also induces apoptosis in undifferentiated PC12 cells, and ribosomal protein L4 (rpL4) mRNA expression increases prior to apoptosis. To clarify the roles of rpL4 during neurogenesis, we first examined the distribution of rpL4 mRNA in the developing rat brain by in situ hybridization and RT-PCR, and compared the results to the distribution of TUNEL- or PCNA-positive cells. rpL4 mRNA expression was strong in the ventricular zone (VZ), subventricular zone (SVZ), cortical plate (CP), cerebral cortex, granule cell layer (GCL), pyramidal cell layer (Py) and external granular layer (EGL) during embryonic and early postnatal days, and it was remarkably weakened thereafter. A lot of PCNA-positive cells were observed in VZ, SVZ, and EGL during embryonic and early postnatal days, and such distribution of PCNA-positive cells was almost identical to rpL4 mRNA distribution. Only few TUNEL-positive cells were observed in VZ, SVZ, cerebral cortex, EGL, and hippocampus during embryonic and early postnatal days, and the regions with TUNEL-positive cells were not identical to rpL4 mRNA distribution. Next, the changes of rpL4 mRNA expression in the brain of 5AzC-treated rat fetuses were examined by in situ hybridization and RT-PCR. Apoptotic cells appeared at 9 to 24 hours after treatment (HAT). However, the rpL4 mRNA expression was unchanged during the apoptotic process. From the results, it is suggested that rpL4 would have certain roles in cell proliferation and differentiation during neurogenesis, but have no roles in 5AzC-induced apoptosis in the fetal brain.

Scopus

PubMed

researchmap

Authorship：Last author   Language：Japanese   Publisher：Japanese Society of Physical Therapy Fundamentals  

Brain injury often causes severe motor dysfunction. Previously, we showed that the corticospinal tract (CST) axons are rewired to form an intraspinal circuit that contributes to motor recovery after brain injury in young adult mice. Although brain injury is often suffered by elderly individuals, little is known about the ability of rewiring and functional recovery in aged rodent model. In this study, we examined CST sprouting and functional recovery in aged mice after brain injury and further investigated whether voluntary running could promote them. We found that axon sprouting was limited and motor function was not recovered in aged mice. Contrastingly, voluntary running significantly increased sprouting and enhanced motor recovery. Moreover, we performed RNA sequencing to examine exercise-induced gene expression of motor area changes in aged mice. Expressions of 91 genes increased in exercised aged mice compared to non-exercised mice, in which a set of circadian rhythm-related genes was involved. Accordingly, a day-night activity rhythm was impaired in the aged mice, whereas it was gradually recovered by exercise, similar to the patterns of younger mice. Our study reveals that voluntary running restores circadian rhythms, CST sprouting, and motor recovery after brain injury in aged mice.

DOI： 10.24780/jjptf.jjptf_2023-06

researchmap

Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(株)ニュー・サイエンス社  

脳脊髄液接触ニューロン(Cerebrospinal Fluid-contacting Neurons:CSF-cNs)は,脊髄中心管に沿って存在し,樹状突起を脳脊髄液と接するユニークな神経細胞である。近年,ゼブラフィッシュやヤツメウナギでは,脳脊髄液のpHや構成成分を化学受容するとともに,脳脊髄液の流れや脊髄の動きを機械受容し,遊泳運動や姿勢を制御することが明らかになってきた。一方哺乳類では,CSF-cNsのもつ構造や接続,機能は多くが不明である。筆者らは,アデノ随伴ウイルスを脳室内投与すると,マウスのCSF-cNsを特異的に標識できることを偶然見出した。この手法は,遺伝学的な標識や活動操作を可能とする点で画期的であり,CSF-cNsが脊髄の前後軸に沿って回路網をつくり,歩行運動を制御することが明らかとなった。本稿では,この不思議な細胞の脳脊髄液/脊髄内センサーとしての役割を論じたい。(著者抄録)

researchmap

Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：日本神経心理学会  

皮質脊髄路は随意運動の制御に重要な役割を果たしており,脳卒中や脊髄損傷などで損傷を受けると重篤な運動障害が引き起こされる.一方で,脳や脊髄には可塑性があり,失われた機能は時間を経て回復あるいは増悪するなどしばしば変容することが知られる.近年の研究成果から,こうした機能の変容は,障害をのがれた回路網の代償的なはたらきや再編に起因することが明らかとなりつつある.本総説では,げっ歯類の基礎研究から明らかになってきた皮質脊髄路の構造や機能,障害パターンに応じた再編様式について概説し,中枢神経障害後の回路再編と機能回復を促進しうる有望な治療アプローチと今後の課題について述べていく.(著者抄録)

researchmap

Authorship：Last author   Language：Japanese   Publisher：(一社)日本基礎理学療法学会  

脳損傷はしばしば重篤な運動機能障害を引き起こし,自立した社会生活を困難にする。傷害された神経回路の再編は機能回復に重要であるが,成体の中枢神経における再編能力は限定的である。脳損傷後において,神経分子を標的とした治療やリハビリテーション等,様々なアプローチが試行されてきたが,未だ十分な機能回復は達成されていない。したがって,再編と機能回復を強化する新しいコンセプトの治療法が求められている。例えば我々は,神経軸索の伸長を阻害しているチロシン脱リン酸化酵素(src homology 2-containing phosphatase-1:以下,SHP-1)に着目し,遺伝学的なSHP-1の欠損と自発的運動の併用が脳損傷モデルマウスの神経回路の再編や機能回復を相乗的に高めることを報告してきた。本稿では,中枢神経損傷のモデル動物における神経回路の再編についての知見を整理し,リハビリテーションや分子標的がもたらす再編や機能回復への効果とその機序について概説する。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J07591&link_issn=&doc_id=20221220310006&doc_link_id=%2Fch1ufund%2F2022%2F002501%2F006%2F0043-0049%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fch1ufund%2F2022%2F002501%2F006%2F0043-0049%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (other)  

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Igaku-Shoin Ltd  

Microglia, traditionally known as resident immune cells in the brain, have been recently identified as one of the important cell types engaging in the formation and maintenance of neural circuitry, especially during the development. In this review, I describe the diversity of microglial functions revealed in different phases of development, ranging from neurogenesis to circuit formation. In particular, microglia possess dual functions in supporting the survival of neuronal structures or neural cells themselves, and removing excess neural components. Understanding these processes and underlying molecular mechanisms will provide important insights into the regulation of neural circuitry development. It further implicates the involvement of microglial dysfunction in neurodevelopmental disorders.

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

researchmap

researchmap

Language：English   Publisher：Springer Japan  

Diseases or injuries in the central nervous system (CNS) often cause robust immune responses, which significantly affect the recovery process. Here we review recent knowledge about brain-immune system interactions, which occur during degenerative and reparative processes, and focus mainly on spinal cord injury (SCI). Immune system-brain inflammatory responses involve multiple cell types that originate in the bloodstream and reside in the brain. Studies indicate that these cells have bidirectional destructive and supportive effects on the repair of damaged neural tissue after SCI. These opposing roles likely depend on the types of cells and their state of activation. Further detailed investigations on the mechanisms and function of their interactions are required to ultimately reduce the toxicity and enhance the trophic effects of the immune system. This would lead to the development of novel strategies to enhance recovery after SCI. The recent discovery of neural circuits that directly regulate immune responses has further highlighted brain-immune system communication. In this regard, signals from the brain to the immune system should also be considered to understand the whole pathology of SCI. In this review, we aim to emphasize that cell-cell and system-system interactions are important concepts for understanding the complex reactions that occur in the degenerating CNS.

DOI： 10.1007/978-4-431-54541-5_3

Scopus

researchmap

Language：English  

Neurons require trophic support during neural circuit formation
however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro. In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain. © 2013 Nature America, Inc. All rights reserved.

DOI： 10.1038/nn.3358

Scopus

PubMed

researchmap

Language：Japanese   Publisher：学研メディカル秀潤社 ; 1982-  

CiNii Article

CiNii Books

researchmap