bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying loci for behavioral traits using genome‐tagged mice
Authors: Liu Dahai , Singh Ram Pyare , Khan Arshad H. , Bhavsar Kinnar , Lusis Aldons J. , Davis Richard C. , Smith Desmond J. 
Published: October 2003

AbstractIdentification of behavioral loci through complex trait mapping remains a widely employed approach but suffers from poor gene localization and low replicability. Genome‐tagged mice (GTMs) are overlapping sets of congenic strains spanning the whole genome and offer the possibilities of superior mapping power and reproducibility. In this study, three GTM strains each consisting of an average ∼27 cM DBA/2J genomic intervals introgressed onto a C57BL/6J background were employed for localization of behavioral traits. These GTMs were chosen because the corresponding chromosomal regions had been previously identified as containing loci for learning and memory. Analysis of the GTMs allowed confirmation of the learning and memory loci, and one on chromosome 3 was in addition fine mapped to an 8.8‐cM region of overlap between two of the GTMs. Moreover, loci for prepulse inhibition of the startle response, acoustic startle response, and spontaneous locomotor activity were also mapped. These results suggest that the GTMs should be a valuable resource for mapping and confirmation of loci contributing to complex behavioral traits in the mouse. © 2003 Wiley‐Liss, Inc.
Ethanol‐induced oxidative stress precedes mitochondrially mediated apoptotic death of cultured fetal cortical neurons
Authors: Ramachandran Vinitha , Watts Lora Talley , Maffi Shivani Kaushal , Chen Juanjuan , Schenker Steven , Henderson George 
Published: October 2003

AbstractIn utero ethanol exposure elicits apoptotic cell death in the fetal brain, and this may be mediated by oxidative stress. Our studies utilize cultured fetal rat cortical neurons and illustrate that ethanol elicits a rapid onset of oxidative stress, which culminates in mitochondrially mediated apoptotic cell death. Cells exposed to ethanol (2.5 mg/ml) remained attached to their polylysine matrix during a 24‐hr exposure, but they exhibited distinct signs of oxidative stress, decreased viability, and apoptosis. Confocal microscopy of live cortical neurons pretreated with dichlorodihydrofluorescein diacetate demonstrated an increase in reactive oxygen species (ROS) within 5 min of ethanol exposure. The levels of ROS further increased by 58% within 1 hr (P < .05) and by 82% within 2 hr (P < .05), accompanied by increases of mitochondrial 4‐hydroxynonenal (HNE). These early events were followed by decreased trypan blue exclusion of 10% to 32% (P < .05) at the 6‐ to 24‐hr time points, respectively. This culminates in apoptotic death, with increases of Annexin V binding of 43%, 89%, 123%, and 238%, at 2, 6, 12, and 24 hr of ethanol treatment, respectively, as well as DNA fragmentation increases of 50% and 65% by 12 and 24 hr, respectively. Release of cytochrome c by mitochondria increased by 53% at 6 hr of exposure (P < .05), concomitant with activation of caspase 3 (52% at 12 hr, P < .05). Pretreatment with N‐acetylcysteine increased cellular glutathione and prevented apoptosis. These studies provide a time line illustrating that oxidative stress and formation of a proapoptotic lipid peroxidation product, HNE, precede a cascade of mitochondrially mediated events in cultured fetal cortical neurons, culminating in apoptotic death. The prevention of apoptosis by augmentation of glutathione stores also strongly supports a role for oxidative stress in ethanol‐mediated apoptotic death of fetal cortical neurons. © 2003 Wiley‐Liss, Inc.
Isolation of neural stem cells from the forebrain of deceased early postnatal and adult rats with protracted post‐mortem intervals
Authors: Xu Yi , Kimura Kazushi , Matsumoto Naoya , Ide Chizuka 
Published: October 2003

AbstractNeural stem cells were isolated from deceased early postnatal and adult rats with varying post‐mortem intervals. Animals were killed by deep anesthesia and stored in a refrigerator at 4°C for 1–6 days before use. Neurospheres were obtained from the forebrain tissue, including the lateral ventricle in the early postnatal rats, and from the striatal wall of lateral ventricle, including the subventricular zone (SVZ) in adult rats. The number of neurospheres obtained in the primary culture from early postnatal animals was much larger than that from the adult rats. There was no significant difference in the population of neurospheres between the living and the deceased animals at least within 2 days after death. A few neurospheres were still obtainable at 6 days after death in early postnatal animals, but almost no neurospheres were obtained at 5 days after death in the adult rats. The differentiation capacity of neural stem cells in neurospheres was similar between the deceased and the living animals. The rich vascular bed in the SVZ of the lateral ventricle suggests that the vascular architecture might be in part responsible for the survival of the neural stem cells in the deceased animals. Neurosphere cells derived from deceased adult rats survived and differentiated mainly into glial cells in the host spinal cord tissue after transplantation into the injured spinal cord. Therefore, the neural stem cells from deceased animals express the same phenotypes as those from living animals in terms of neurosphere formation, proliferation, and differentiation at least 2 days after death. The neural stem cells from cadavers have great significance in terms of their clinical use as homografts for CNS regeneration. © 2003 Wiley‐Liss, Inc.
Plasmalemmal sealing of transected mammalian neurites is a gradual process mediated by Ca2+‐regulated proteins
Authors: Yoo Soonmoon , Nguyen Michael P. , Fukuda Mitsunori , Bittner George D. , Fishman Harvey M. 
Published: October 2003

AbstractCultured mammalian PC12 or B104 cells do not instantaneously restore a plasmalemmal barrier (seal) after neurite transection, as measured using fluorescent dye probes of various sizes and saline solutions with different [Ca2+]o. Rather, transected cells gradually (from 15 to 60 min postseverance) exclude probes (dye molecules) of progressively smaller size. Furthermore, an inhibitor (calpeptin) of a Ca2+‐activated cysteine protease (calpain) and antibodies or toxins to a Ca2+‐regulated protein (synaptotagmin) and other membrane fusion proteins (syntaxin and synaptobrevin) inhibit plasmalemmal sealing. These data obtained using molecular probes on mammalian cell lines are consistent with previous data on invertebrate giant axons indicating that Ca2+ plays many roles in the formation, accumulation, and fusion/interaction of vesicles gradually forming a seal at a site of plasmalemmal damage. © 2003 Wiley‐Liss, Inc.
Specific inhibitor of FGF receptor signaling: FGF‐2‐mediated effects on proliferation, differentiation, and MAPK activation are inhibited by PD173074 in oligodendrocyte‐lineage cells
Authors: Bansal Rashmi , Magge Suma , Winkler Susan 
Published: October 2003

AbstractMultiple studies have shown that migration, proliferation, and differentiation of oligodendrocyte (OL) lineage cells are influenced by fibroblast growth factor‐2 (FGF‐2) signaling through its receptors (FGFR) FGFR‐1, FGFR‐2, and FGFR‐3. We report the effectiveness and specificity of a unique inhibitor, PD173074, for inhibiting FGF receptor signaling in OL‐lineage cells. Three FGF‐mediated responses of OL progenitors and two of differentiated OLs were examined by immunofluorescence microscopy and immunoblotting. PD173074 effectively antagonized the effect of FGF‐2 on proliferation and differentiation of OL progenitors in culture. One dose of PD173074 at nanomolar concentrations was sufficient to inhibit ongoing FGF‐2 mediated proliferation for prolonged periods, in a non‐toxic, dose‐dependent manner. In contrast, platelet‐derived growth factor (PDGF)‐induced proliferation was unaffected by PD173074. Similarly, mitogen‐activated protein kinase (MAPK) activation, a downstream event after activation of either FGFR or PDGFR, was also blocked by PD173074 in OL progenitors stimulated with FGF‐2 but not PDGF. A general tyrosine kinase inhibitor (PD166285), however, antagonized both FGF‐2‐ and PDGF‐mediated responses. PD173074 also completely antagonized two phenotypic alterations of differentiated OLs, specifically downregulation of myelin proteins, and their re‐entry into the cell cycle. We conclude that PD173704 is an effective and specific inhibitor for multiple FGF‐2‐mediated responses of both OL progenitors and differentiated OLs. This inhibitor provides a direct approach for identifying the importance of FGF signaling, comparable in effect to a knockout of all FGF receptors and all FGF ligands, while leaving other pathways unaffected. Thus, PD173704 is an excellent tool for investigating the role of FGF signaling in vivo in the context of combinatorial interactions of other signals. © 2003 Wiley‐Liss, Inc.
Distinct presenilin‐dependent and presenilin‐independent γ‐secretases are responsible for total cellular Aβ production
Authors: Wilson Christina A. , Doms Robert W. , Lee Virginia M.‐Y. 
Published: October 2003

Abstractγ‐Secretase is the second of two proteolytic enzymes involved in the liberation of the β‐amyloid peptide (Aβ) from the amyloid precursor protein (APP). γ‐Secretase cleavage occurs at several intracellular sites, including the Golgi network and the endoplasmic reticulum/intermediate compartment (ER/IC) to produce multiple forms of the Aβ peptide that can be either secreted from the cell or remain intracellular. To date, most evidence has suggested that members of the presenilin protein family are required for γ‐secretase activity. Although it seems that presenilins are indeed necessary for the production of most secreted and intracellular Aβ particularly that generated in downstream organelles, it was shown recently that a presenilin‐independent γ‐secretase is active in the ER/IC and is responsible for the production of a portion of intracellular Aβ42. We discuss the implications of this finding for the understanding of presenilin biology and speculate on the putative identity of the presenilin‐independent cleavage activity. © 2003 Wiley‐Liss, Inc.
EP24.15 is associated with lipid rafts
Authors: Jeske Nathaniel A. , Glucksman Marc J. , Roberts James L. 
Published: October 2003

AbstractMetalloendopeptidase EC 3.4.24.15 (EP24.15, thimet oligopeptidase) is a neuropeptide‐metabolizing peptidase expressed throughout the body, but primarily in the brain, gonads, and pituitary. For EP24.15 to have its greatest effect upon peptides in the periphery, it must be targeted and released into the extracellular space. Western blot analysis of fractions taken from discontinuous sucrose density gradients carried out on crude plasma membrane fractions from AtT‐20 cells reveals colocalization of EP24.15 and flotillin‐1, a known lipid raft marker. Further analysis revealed that an intracellular membrane marker and non‐lipid raft, plasma membrane marker, failed to colocalize, supporting EP24.15/lipid raft association. Furthermore, EP24.15 immunoreactivity in lipid raft fractions generated from cells treated with methyl β‐cyclodextrin (MβCD) was greatly reduced. Finally, treatment with MβCD resulted in the accumulation of EP24.15 in the media of drug‐treated cells over vehicle‐treated cells, suggesting that a large percentage of EP24.15 associating with lipid rafts resides on the extracellular surface of the plasma membrane. With this exofacial localization, EP24.15 could have ample access to neuropeptides not only in the immediate microenvironment, but the ability to degrade or modify peptides bound for receptor interaction. © 2003 Wiley‐Liss, Inc.
Extracellular matrix and matrix metalloproteinases in sciatic nerve
Authors: Platt C.I. , Krekoski C.A. , Ward R.V. , Edwards D.R. , Gavrilovic J. 
Published: October 2003

AbstractAlthough matrix metalloproteinases (MMPs) are increasingly being implicated in several pathologies of the nervous system, it is not yet clear what role they play in normal neurobiological processes. We review the expression of extracellular matrix (ECM) components as well as MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the peripheral nervous system. We explore the expression of certain MMPs and the four TIMPs at the mRNA level in the postnatal mouse sciatic nerve. In addition, we have used substrate gel and in situ zymography to determine levels of MMP‐2 and ‐9 and TIMP activity in rat sciatic nerve after crush and during regeneration. A rapid and transient increase in MMP‐9 localised at and immediately distal to the site of injury was observed, whereas an increase in MMP‐2 activity was delayed, prolonged, and extended proximal and distal to the injury site. This activity coincides with periods of axonal elongation, suggesting that it could act to facilitate axonal extension along the nerve matrix. We also detected multiple species of gelatinolytic inhibitory activity, including TIMP‐1 and ‐3 in control and injured nerve. These activities probably act to prevent uncontrolled gelatinolytic activity, maintaining nerve integrity at the level essential for axonal regrowth. © 2003 Wiley‐Liss, Inc.
Cysteine proteases are the major β‐secretase in the regulated secretory pathway that provides most of the β‐amyloid in Alzheimer's disease: Role of BACE 1 in the constitutive secretory pathway
Authors: Hook Vivian Y.H. , Reisine Terry D. 
Published: October 2003

AbstractThis article focuses on β‐amyloid (Aβ) peptide production and secretion in the regulated secretory pathway and how this process relates to accumulation of toxic Aβ in Alzheimer's disease. New findings are presented demonstrating that most of the Aβ is produced and secreted, in an activity‐dependent manner, through the regulated secretory pathway in neurons. Only a minor portion of cellular Aβ is secreted via the basal, constitutive secretory pathway. Therefore, regulated secretory vesicles contain the primary β‐secretases that are responsible for producing the majority of secreted Aβ. Investigation of β‐secretase activity in regulated secretory vesicles of neuronal chromaffin cells demonstrated that cysteine proteases account for the majority of the β‐secretase activity. BACE 1 is present in regulated secretory vesicles but provides only a small percentage of the β‐secretase activity. Moreover, the cysteine protease activities prefer to cleave the wild‐type β‐secretase site, which is relevant to the majority of AD cases. In contrast, BACE 1 prefers to cleave the Swedish mutant β‐secretase site that is expressed in a minor percentage of the AD population. These new findings lead to a unifying hypothesis in which cysteine proteases are the major β‐secretases for the production of Aβ in the major regulated secretory pathway and BACE 1 is the β‐secretase responsible for Aβ production in the minor constitutive secretory pathway. These results indicate that inhibition of multiple proteases may be needed to decrease Aβ production as a therapeutic strategy for Alzheimer's disease. © 2003 Wiley‐Liss, Inc.
Effects of immunosuppression on regrowth of adult rat retinal ganglion cell axons into peripheral nerve allografts
Authors: Gillon Russell S. , Cui Qi , Dunlop Sarah A. , Harvey Alan R. 
Published: October 2003

AbstractAnalysis of the effectiveness of allografts and immunosuppression in the repair of nerve defects in the adult peripheral nervous system (PNS) has a long experimental and clinical history. There is little information, however, on the use of allografts in peripheral nerve (PN) transplantation into the injured central nervous system (CNS). We assessed the ability of PN allografts (from Dark‐Agouti rats) to support regeneration of adult rat retinal ganglion cell (RGC) axons in immunosuppressed host Lewis rats. PN allografts were sutured onto intraorbitally transected optic nerves. Three weeks after grafting, regenerating RGC axon numbers were determined using retrograde fluorescent labelling, and total axons within PN grafts were assessed using pan‐neurofilament immunohistochemistry. In the absence of immunosuppression, PN allografts contained few axons and there were very few labelled RGC. These degenerate grafts contained many T cells and macrophages. Systemic (intraperitoneal) application of the immunosuppressants cyclosporin‐A or FK506 reduced cellular infiltration into allografts and resulted in extensive axonal regrowth from surviving RGCs. The average number of RGCs regenerating axons into immunosuppressed allografts was not significantly different from that seen in PN autografts in rats sham‐injected with saline. Many pan‐neurofilament‐positive axons, a proportion of which were myelinated, were seen in immunosuppressed allografts, particularly in proximal regions of the grafts toward the optic nerve‐PN interface. This study demonstrates that PN allografts can support axonal regrowth in immunosuppressed adult hosts, and points to possible clinical use in CNS repair. © 2003 Wiley‐Liss, Inc.
Opposing effects of low and high‐dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice
Authors: Turner B.J. , Rembach A. , Spark R. , Lopes E.C. , Cheema S.S. 
Published: October 2003

AbstractClozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early‐diagnosed schizophrenia. Aside from well‐described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75NTR) and superoxide dismutase 1 (SOD1) expression. The death‐signalling activities of both p75NTR and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose‐dependently inhibited full‐length and cleaved p75NTR but not SOD1 protein expression in the motor neuron‐like (NSC‐34) cell line. Furthermore, low concentrations of clozapine protected NSC‐34 cells from paraquat‐mediated superoxide toxicity, nerve growth factor (NGF)‐induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice‐weekly administration of low and high‐dose clozapine to mutant superoxide dismutase 1 (SOD1G93A) mice produced differential effects on disease onset and survival. Low‐dose treatment was associated with delayed locomotor impairment and death, compared to high‐dose clozapine, which accelerated paralysis and mortality (P < 0.05). Increased death was not attributable to toxicity, as clozapine‐induced agranulocytosis was not detected from blood analysis. High‐dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75NTR levels overall. These results suggest that although clozapine may exert p75NTR‐mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice. © 2003 Wiley‐Liss, Inc.
Centrally administered norepinephrine modifies the behavior induced by corticotropin‐releasing factor in neonatal chicks
Authors: Zhang Rong , Tachibana Tetsuya , Takagi Tomo , Koutoku Tomoyuki , Denbow D. Michael , Furuse Mitsuhiro 
Published: October 2003

AbstractWe previously reported that glucagon‐like peptide‐1 decreased corticotropin‐releasing factor (CRF)‐induced behaviors in neonatal chicks, and such an effect is hypothesized to act through norepinephrine (NE). Experiments were designed to explore the effect of the NE on CRF‐induced behaviors. In experiment 1, the chicks were intracerebroventricularly (i.c.v.) administered saline, 0.1 μg of CRF, 50.0 μg of NE, or 0.1 μg of CRF with 50.0 μg of NE. Behavior was monitored for the 10 min immediately after i.c.v. injection, and plasma corticosterone was analyzed at the end of behavior tests. Compared with the control, chicks were excited by CRF as evidenced by increased spontaneous activity and distress vocalizations (DVs). NE decreased the spontaneous activity of chicks, and the differences diverged with time. DVs completely disappeared in the presence of NE, and sleep‐like (sitting with eyes closed) behavior was observed in the same birds. NE‐treated birds spent most of the time in a sleep‐like posture irrespective of CRF treatment. CRF‐treated chicks had increased plasma corticosterone, whereas NE injection caused a decrease in corticosterone. In experiment 2, the effect of NE was further studied using i.c.v. administration with either 0.1 μg of CRF alone or 0.1 μg of CRF plus 12.5, 25.0, or 50.0 μg of NE. NE dose dependently modified the CRF‐induced locomotor activity in the open field, and DVs disappeared when chicks were given any dose of NE with CRF. With these findings taken together, it is suggested that central NE interacts the CRF‐induced behaviors in neonatal chicks. © 2003 Wiley‐Liss, Inc.
Nonopioid receptor‐mediated effects of U‐50,488H on [Ca2+]i and extracellular dopamine in PC12 cells
Authors: Chudapongse Nuannoi , Kim Seong‐Youl , Sasaki Kenroh , Kramer Robert E. , Ho Ing K. 
Published: October 2003

AbstractThe present studies were carried out to determine the effects of a κ‐opioid receptor agonist on cytosolic Ca2+ concentration, [Ca2+]i, and extracellular dopamine in undifferentiated PC12 cells. The κ‐opioid receptor agonist U‐50,488H caused concentration‐dependent increases in [Ca2+]i and extracellular dopamine. Neither effect was blocked by the selective κ‐opioid receptor antagonist nor‐binaltorphimine. Increases in extracellular dopamine content and [Ca2+]i caused by U‐50,488H were correlated positively in the presence of extracellular Ca2+; however, reduction of extracellular Ca2+ abolished the increase in [Ca2+]i, but not that in dopamine. The latter observation suggests that stimulation of exocytotic release is not the primary mechanism involved in the increase in extracellular dopamine caused by U‐50,488H. Effects on dopamine synthesis or catabolism also seem unlikely because the enhancement of extracellular dopamine occurred rapidly, and the amount of a major metabolite of dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC), was not affected. In any event, neither the increase in [Ca2+]i nor the increase in extracellular dopamine caused by U‐50,488H is mediated by the κ‐opioid receptor. © 2003 Wiley‐Liss, Inc.
Myelin‐associated inhibitors of axon regeneration
Authors: Grados‐Munro Edith M. , Fournier Alyson E. 
Published: October 2003

AbstractTrauma in the adult mammalian central nervous system (CNS) has devastating clinical consequences due to the failure of injured axons to spontaneously regenerate. Over 20 years ago, pioneering work demonstrated that the non‐permissive nature of CNS myelin for axon outgrowth contributes to this regenerative failure. Over the past few years, tremendous progress has been made in our understanding of the inhibitory components of CNS myelin, the axonal receptors that respond to these cues, and the intracellular signaling cascades mediating axon outgrowth inhibition. Several approaches designed to antagonize molecular mediators of axon inhibition have been tested in an effort to promote regenerative growth after CNS injury. These studies have validated the role of many candidate proteins in axon outgrowth inhibition; however, other approaches such as the generation of knockout mice for myelin‐associated inhibitors have created new questions in the field. © 2003 Wiley‐Liss, Inc.