bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calpain‐mediated cleavage of collapsin response mediator protein(CRMP)‐2 during neurite degeneration in mice
Authors: Touma Ekatherina , Kato Satoko , Fukui Koji , Koike Tatsuro 
Published: July 2010

AbstractAxon or dendrite degeneration involves activation of the ubiquitin–proteasome system, failure to maintain neuritic ATP levels, microtubule fragmentation and a mitochondrial permeability transition that occur independently of the somal death programs. To gain further insight into the neurite degeneration mechanims we have compared two‐dimensional gel electrophoresis patterns of neurite proteins from suprior cervical ganglia during degeneration caused by nerve growth factor (NGF) deprivation. We show here that collapsin response mediator protein (CRMP)‐2 and CMRP‐4 protein patterns were altered during beading formation, an early hallmark of neurite degeneration, prior to neurite fragmentation, the final stage of degeneration. Western blotting using a monoclonal antibody against CRMP‐2 shows that the native form (64 kDa) was cleaved to generate a truncated form (58 kDa). No cleavage of CRMP‐2 or ‐4 occurred in NGF‐deprived neurites from Wld s (Wallerian degeneration slow) mutant mice in which neurite degeneration is markedly delayed. Using different protease inhibitors, purified calpain 1 protein and calpain 1‐specific siRNA, we have demonstrated that CRMP‐2 is a substrate for calpain 1. Indeed, caplain activity was activated at an early phase of neuronal degeneration in cerebellar granule neurons, and down‐regulation of caplain 1 expression suppressed CRMP‐2 cleavage. Furthermore, this cleavage occurred after vinblastine treatment or in vitro Wallerian degeneration, suggesting that it represents a common step in the process of dying neurites. CRMP‐2 and ‐4 play a pivotal role in axonal growth and transport, and the C‐terminus region of CRMP‐2 is essential for its binding to kinesin‐1. Hence, this cleavage will render them dysfunctional and subject to autophagic processing associated with beading formation, as evidenced by the finding that the truncated form was localized in the beadings.
Monocular deprivation reduces reliability of visual cortical responses to binocular disparity stimuli
Authors: Vorobyov Vasily , Schwarzkopf D. Samuel , Mitchell Donald E. , Sengpiel Frank 
Published: July 2010

AbstractWhile continuous monocular deprivation (MD) of patterned vision causes severe loss of visual cortical responses and visual acuity in the affected eye, these effects can be avoided by providing brief daily periods of binocular exposure [BE; D.E. Mitchell et al. (2003) Curr. Biol., 8, 1179–1182; D.E. Mitchell et al. (2006) Eur. J. Neurosci., 23, 2458–2466; D.S. Schwarzkopf et al. (2007) Eur. J. Neurosci., 25, 270–280]. In order to analyse binocular mechanisms involved in this phenomenon, we studied neuronal responses in primary visual cortex to binocular disparity stimuli in cats that had experienced mixed daily visual exposure (i.e. different amounts of daily binocular and monocular exposure). To examine whether binocular responses are as reliable in MD as in normal animals, we analysed single‐trial responses to spatial phase disparity stimuli. In cats with various amounts of daily binocular experience (3.5 h, 7 h or 12 h) alone, about half of neurons (47.9%) showed reliable phase‐specific binocular responses in two consecutive trials. The percentage of phase‐selective cells was reduced in cats with mixed visual exposure with a decrease in the duration of daily BE. Within these neurons, a ‘stable’ cell population, i.e. with identical relative phases eliciting the strongest and weakest responses in two trials, was also reduced. In other words, the responses of neurons recorded from deprived animals were more likely to show different preferred phases on successive trials, although their amplitude ratios in both trials were about equal. We suggest that the detrimental effect of MD on binocular vision may begin, at least in part, with a subtle disruption of the mechanism involved in discrimination of binocular disparity signals.
X chromosome‐linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia‐ischemia through up‐regulation of mitochondrial antioxidants
Authors: Zhu Changlian , Xu Falin , Fukuda Aya , Wang Xiaoyang , Fukuda Hirotsugu , Korhonen Laura , Hagberg Henrik , Lannering Birgitta , Nilsson Michael , Eriksson Peter S. , Northington Frances J. , Björk‐Eriksson Thomas , Lindholm Dan , Blomgren Klas 
Published: July 2010

AbstractWe demonstrate that X chromosome‐linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease‐related models of brain injury, hypoxia‐ischemia and irradiation, as judged by lower expression of nitrotyrosine (5‐fold) and 4‐hydroxy‐2‐nonenal (10‐fold) in XIAP‐overexpressing compared with wild‐type mice. XIAP overexpression induced up‐regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP‐overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up‐regulation of mitochondrial antioxidants. XIAP‐induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia‐ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
The transcriptional corepressor TPA‐inducible sequence 7 regulates adult axon growth through cellular retinoic acid binding protein II expression
Authors: Dieplinger Benjamin , Schiefermeier Natalia , Juchum‐Pasquazzo Michaela , Gstir Ronald , Huber Lukas A. , Klimaschewski Lars , Vietor Ilja 
Published: July 2010

AbstractTPA‐inducible sequence 7 (TIS7) expression is regulated in epithelial cells and acts as a transcriptional corepressor. Using a TIS7 knock‐out mouse we demonstrated that TIS7 is involved in the process of muscle regeneration. In this study, we analysed the role of TIS7 in axon regeneration, applying primary neurone cultures derived from adult dorsal root ganglia (DRGs) of TIS7+/+ and TIS7–/– mice. TIS7–/– DRG neurones exhibited a significant decrease in axon initiation and maximal axon extension. In contrast, nerve growth factor‐induced axon initiation and branching were significantly enhanced in cultures obtained from TIS7–/– DRGs when compared with wildtype ganglia, suggesting an inhibitory effect of TIS7 on nerve growth factor‐stimulated axon growth. TIS7 overexpression in TIS7–/– DRG neurones caused their morphological appearance to revert back to the wildtype phenotype. Furthermore, the expression of cellular retinoic acid binding protein II (CRABP II), previously identified by us as a TIS7 target gene, was up‐regulated in adult DRG sensory neurones from TIS7–/– mice. Overexpression of CRABP II in TIS7+/+ neurones strongly increased the number of branch points, making them morphologically similar to TIS7–/– neurones. Based on these results we propose that TIS7 inhibits CRABP II expression during axonal regeneration, thereby modulating retinoic acid signalling. Hence, neurite initiation and branching are regulated by a negative feedback mechanism involving TIS7 and CRABP II.
Site‐specific effects of tau phosphorylation on its microtubule assembly activity and self‐aggregation
Authors: Liu Fei , Li Bin , Tung E‐Jan , Grundke‐Iqbal Inge , Iqbal Khalid , Gong Cheng‐Xin 
Published: July 2010

AbstractMicrotubule‐associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline‐rich (residues 172–251) and C‐terminal tail (residues 368–441) regions, which flank the microtubule‐binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self‐aggregation. We found that tau phosphorylation at the proline‐rich region by dual‐specificity tyrosine‐phosphorylated and ‐regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self‐aggregation slightly. Tau phosphorylation at the C‐terminal tail region by glycogen synthase kinase‐3β increased its activity and promoted its self‐aggregation markedly. Tau phosphorylation at both regions plus the microtubule‐binding region by cAMP‐dependent protein kinase diminished its activity (∼70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self‐aggregation by phosphorylation at various sites/regions.
Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation
Authors: Prosser Haydn M. , Bradley Allan , Caldwell Maeve A. 
Published: July 2010

AbstractNew neurons are added on a daily basis to the olfactory bulb (OB) of a mammal, and this phenomenon exists throughout its lifetime. These new cells are born in the subventricular zone and migrate to the OB via the rostral migratory stream (RMS). To examine the role of the prokineticin receptor 2 (Prokr2) in neurogenesis, we created a Prokr2 null mouse, and report a decrease in the volume of its OB and also a decrease in the number of bromodeoxyuridine (BrdU)‐positive cells. There is disrupted architecture of the OB, with the glomerular layer containing terminal dUTP nick‐end labeling (TUNEL) ‐positive nuclei and also a decrease in tyrosine hydroxylase‐positive neurons in this layer. In addition, there are increased numbers of doublecortin‐positive neuroblasts in the RMS and increased PSA‐NCAM (polysialylated form of the neural cell adhesion molecule) ‐positive neuronal progenitors around the olfactory ventricle, indicating their detachment from homotypic chains is compromised. Finally, in support of this, Prokr2‐deficient cells expanded in vitro as neurospheres are incapable of migrating towards a source of recombinant human prokineticin 2 (PROK2). Together, these findings suggest an important role for Prokr2 in OB neurogenesis.
Developmental changes in the BDNF‐induced modulation of inhibitory synaptic transmission in the Kölliker–Fuse nucleus of rat
Authors: Kron Miriam , Zhang Weiqi , Dutschmann Mathias 
Published: July 2010

AbstractThe Kölliker–Fuse nucleus (KF), part of the pontine respiratory group, is involved in the control of respiratory phase duration, and receives both excitatory and inhibitory afferent input from various other brain regions. There is evidence for developmental changes in the modulation of excitatory inputs to the KF by the neurotrophin brain‐derived neurotrophic factor (BDNF). In the present study we investigated if BDNF exerts developmental effects on inhibitory synaptic transmission in the KF.Recordings of inhibitory postsynaptic currents (IPSCs) in KF neurons in a pontine slice preparation revealed general developmental changes. Recording of spontaneous and evoked IPSCs (sIPSCs, eIPSCS) revealed that neonatally the γ‐aminobutyric acid (GABA)ergic fraction of IPSCs was predominant, while in later developmental stages glycinergic neurotransmission significantly increased. Bath‐application of BDNF significantly reduced sIPSC frequency in all developmental stages, while BDNF‐mediated modulation on eIPSCs showed developmental differences. The eIPSCs mean amplitude was uniformly and significantly reduced following BDNF application only in neurons from rats younger than postnatal day 10. At later postnatal stages the response pattern became heterogeneous, and both augmentations and reductions of eIPSC amplitudes occurred. All BDNF effects on eIPSCs and sIPSCs were reversed with the tyrosine kinase receptor‐B inhibitor K252a.We conclude that developmental changes in inhibitory neurotransmission, including the BDNF‐mediated modulation of eIPSCs, relate to the postnatal maturation of the KF. The changes in BDNF‐mediated modulation of IPSCs in the KF may have strong implications for developmental changes in synaptic plasticity and the adaptation of the breathing pattern to afferent inputs.
Short light–dark cycles affect sleep in mice
Authors: Deboer Tom , Ruijgrok Guido , Meijer Johanna H. 
Published: July 2010

AbstractEnvironmental light has a strong impact on human physiology and behaviour, including cognitive functioning and alertness. Previous studies have shown that short light–dark (LD) cycles influence sleep in the albino rat. Rapid eye movement (REM) sleep increases after the onset of darkness and increases after light onset. In the present study, we investigated whether light affects sleep in mice. To this purpose the electroencephalogram and electromyogram of nine adult male C57BL/6 mice was recorded under 12 : 12 h baseline LD conditions, followed by 24 h continuous darkness (DD) and 6 days with LD cycles of different durations (2 h, 30 min, 14 min, 10 min, 4 min and 2 min), presented in a randomized order. NREM sleep was evenly distributed over the light and dark intervals of all short LD cycles. REM sleep, however, was increased during the dark intervals of short (10–30 min) LD cycles. Analysis showed that in these LD cycles, the increment in REM sleep was maximal in the second minute after dark onset, where the percentage of epochs with REM sleep increased significantly to 175% of baseline values. This increase was attributable to an increase in REM sleep episode duration. The recorded responses show that sleep in mice is affected by photic stimulation. The results demonstrate that pigmented animals can show REM sleep induction after dark onset and indicate that light has significant effects on the regulation of sleep.
Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in rats
Authors: Li Man , Peake Philip W. , Charlesworth John A. , Tracey David J. , Moalem‐Taylor Gila 
Published: July 2010

AbstractComplement activation triggers inflammation and has been implicated in neurological diseases associated with pain. However, the role of complement in neuropathic pain has not been clearly defined. In this study, we tested whether complement is activated by partial ligation of the rat sciatic nerve, a widely used model of neuropathic pain, and whether complement activation or inhibition in peripheral nerve influences leukocyte recruitment and neuropathic pain. We found that C3 deposition significantly increased from 6 h to 7 days in the injured nerve and was associated with the extent of thermal hyperalgesia and mechanical allodynia. However, no deposition of the membrane attack complex was detected. Complement activation by endoneurial injection of aggregated rat immunoglobulin G into normal sciatic nerve produced significant thermal hyperalgesia and mechanical allodynia of the ipsilateral hindpaw at 2–7 days after injection. This was accompanied by increased deposition of C3 and recruitment of macrophages at 7 days following injection. Complement inhibition using systemic injections of soluble complement receptor 1 (AVANT Immunotherapeutics, Inc., Needham, USA) into rats markedly suppressed C3 deposition and T‐cell and macrophage recruitment to the injured nerve, and produced significant alleviation of thermal hyperalgesia and mechanical allodynia. These results demonstrate that C3 activation in the nerve contributes to increased infiltration of inflammatory cells and to neuropathic pain behaviors following peripheral nerve injury. Complement inhibition may be a potential therapeutic treatment for neuropathic pain.
Effect of minocycline on inflammation‐induced damage to the blood–brain barrier and white matter during development
Authors: Stolp H. B. , Ek C. J. , Johansson P. A. , Dziegielewska K. M. , Potter A. M. , Habgood M. D. , Saunders N. R. 
Published: July 2010

AbstractDamage to white matter in some premature infants exposed to intrauterine infections is thought to involve disruption of the blood–brain barrier. We have examined the effect of minocycline, an agent reported to reduce brain damage resulting from inflammation, on inflammation‐induced disruption of the blood–brain barrier and damage to white matter. Post‐natal marsupial opossums (Monodelphis domestica) were studied as most brain development in this species occurs after birth. Single intraperitoneal lipopolysaccharide (LPS) injection (0.2 mg/kg) with or without minocycline (45 mg/kg) at post‐natal day (P)35 caused short‐lasting barrier breakdown to plasma proteins but not to 14C‐sucrose. By P44, blood–brain barrier integrity was intact but a reduced volume of white matter was present. At P44 after prolonged inflammation (5 × 0.2 mg/kg LPS at 48 h intervals), proteins from blood were observed within brain white matter and permeability to 14C‐sucrose in the hindbrain increased by 31%. The volume of the external capsule and the proportion of myelin were 70 and 57%, respectively, of those in control animals. Minocycline administered during prolonged inflammation restored blood–brain barrier integrity but not LPS‐induced damage to white matter. These data suggest that long‐term changes in blood–brain barrier permeability occur only after a prolonged period of inflammation during development; however, damage to white matter can result from even a short‐lasting breakdown of the barrier. Manipulation of the inflammatory response may have implications for prevention of some developmentally induced neurological conditions.
Insulin and IGF‐1 enhance the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of the phosphoinositide 3‐kinase–Akt–mammalian target of rapamycin pathway
Authors: Chenal Julie , Pierre Karin , Pellerin Luc 
Published: July 2010

AbstractMCT2 is the main neuronal monocarboxylate transporter essential for facilitating lactate and ketone body utilization as energy substrates. Our study reveals that treatment of cultured cortical neurons with insulin and IGF‐1 led to a striking enhancement of MCT2 immunoreactivity in a time‐ and concentration‐dependent manner. Surprisingly, neither insulin nor IGF‐1 affected MCT2 mRNA expression, suggesting that regulation of MCT2 protein expression occurs at the translational rather than the transcriptional level. Investigation of the putative signalling pathways leading to translation activation revealed that insulin and IGF‐1 induced p44‐ and p42 MAPK, Akt and mTOR phosphorylation. S6 ribosomal protein, a component of the translational machinery, was also strongly activated by insulin and IGF‐1. Phosphorylation of p44‐ and p42 MAPK was blocked by the MEK inhibitor PD98058, while Akt phosphorylation was abolished by the PI3K inhibitor LY294002. Phosphorylation of mTOR and S6 was blocked by the mTOR inhibitor rapamycin. In parallel, it was observed that LY294002 and rapamycin almost completely blocked the effects of insulin and IGF‐1 on MCT2 protein expression, whereas PD98059 and SB202190 (a p38K inhibitor) had no effect on insulin‐induced MCT2 expression and only a slight effect on IGF‐1‐induced MCT2 expression. At the subcellular level, a significant increase in MCT2 protein expression within an intracellular pool was observed while no change at the cell surface was apparent. As insulin and IGF‐1 are involved in synaptic plasticity, their effect on MCT2 protein expression via an activation of the PI3K–Akt–mTOR–S6K pathway might contribute to the preparation of neurons for enhanced use of nonglucose energy substrates following altered synaptic efficacy.
Preoptic neuronal nitric oxide synthase induction by testosterone is consistent with a role in gating male copulatory behavior
Authors: Sanderson Nicholas S. R. , Le Brandon , Zhou Zifei , Crews David 
Published: July 2010

AbstractCopulatory behaviors are generally dependent on testicular androgens in male vertebrates, being eliminated by castration and re‐instated by testosterone administration. It is postulated that a critical factor in this hormonal gating is up‐regulation of neuronal nitric oxide synthase (nNOS) in the preoptic area, and consequent enhanced nitric oxide synthesis in response to stimuli associated with a receptive female. Previous studies have suggested that nNOS protein is more abundant in behaviorally relevant preoptic regions of testosterone‐exposed animals than in hormone‐deprived controls. This study sought to elucidate the molecular events underlying this apparent up‐regulation by examining preoptic nNOS mRNA abundance at several time points following testosterone administration in a castration and replacement paradigm. Castrated male whiptails (Cnemidophorus inornatus) were implanted with testosterone, and at four time points over the subsequent 18 days their sexual behavior was tested. A rostral periventricular area previously implicated in hormonal gating of male‐typical copulatory behavior was then excised by laser microdissection, and nNOS transcript abundance was assessed by quantitative PCR. As neither this technique nor nNOS mRNA measurements have previously been performed in this area of the brain, expression was concommitantly assayed on adjacent sections by in situ hybridization or NADPH diaphorase histochemistry. Results are consistent with transcriptional up‐regulation of nNOS by testosterone and a central role for the enzyme in mediating hormonal gating of copulatory behavior.
Reduced saccadic resilience and impaired saccadic adaptation due to cerebellar disease
Authors: Golla Heidrun , Tziridis Konstantin , Haarmeier Thomas , Catz Nicolas , Barash Shabtai , Thier Peter 
Published: July 2010

AbstractThe term short‐term saccadic adaptation (STSA) captures our ability to unconsciously move the endpoint of a saccade to the final position of a visual target that has jumped to a new location during the saccade. STSA depends on the integrity of the cerebellar vermis. We tested the hypothesis that STSA reflects the working of a cerebellar mechanism needed to avoid ‘fatigue’, a gradual drop in saccade amplitude during a long series of stereotypic saccades. To this end we compared the kinematics of saccades of 14 patients suffering from different forms of cerebellar disease with those of controls in two tests of STSA and a test of saccadic resilience. Controls showed an increase in saccade amplitude (SA) for outward adaptation, prompted by outward target shifts, due to an increase in saccade duration (SD) in the face of constant peak velocity (PV). The decrease in SA due to inward adaptation was, contrariwise, accompanied by a drop in PV and SD. Whereas patients with intact vermis did not differ from controls, those with vermal pathology lacked outward adaptation: SD remained constant, as did SA and PV. In contrast, vermal patients demonstrated a significant decrease in SA, paralleled by a decrease in PV but mostly unaltered SD in the inward adaptation experiment as well as in the resilience test. These findings support the notion that inward adaptation is at least partially based on uncompensated fatigue. On the other hand, outward adaptation reflects an active mechanism for the compensation of fatigue, residing in the cerebellum.