bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental regulation and overexpression of the transcription factor AP‐2, a potential regulator of the timing of Schwann cell generation
Authors: Stewart Helen J. S. , Brennan Angela , Rahman Mary , Zoidl Georg , Mitchell Pamela J. , Jessen Kristján R. , Mirsky Rhona 
Published: March 2003

AbstractThere is now evidence from in vivo and in vitro studies that the rate of Schwann cell generation is regulated by the balance of two opposing signals, β neuregulins and endothelins. The β neuregulins promote the development of precursors to Schwann cells whereas endothelins retard it through an action on endothelin‐B receptors. The present work has shown additional controls of this transition, and implicates AP‐2 transcription factors, in particular AP‐2α, as negative regulators of Schwann cell generation. We found that both AP‐2α and AP‐2γ are present in early embryonic nerves, whereas AP‐2β was not. Isoform‐specific analysis of AP‐2α showed that isoform 3 was most abundant with isoforms 1 and 2 present in lesser amounts; isoform 4 was absent. Maximal AP‐2α and AP‐2γ mRNA expression occurred at embryonic day (E) 12/13 in the mouse and at E14/15 in the rat, which correlates with the presence of Schwann cell precursors in the nerve. In both rats and in mice, in vivo and in vitro, downregulation of AP‐2α mRNA and protein coincided with one of the main steps in Schwann cell development, the precursor–Schwann cell transition. Moreover, Schwann cell generation was delayed if this downregulation was prevented by enforced expression of AP‐2α in precursors. These studies suggest that AP‐2 is involved in the control of the timing of Schwann cell development.
Bradykinin‐induced nociceptor sensitization to heat is mediated by cyclooxygenase products in isolated rat skin
Authors: Pethö Gabor , Derow Alexandra , Reeh Peter W. 
Published: March 2003

AbstractBradykinin can excite C‐polymodal nociceptors and sensitize them to heat and it can also enhance prostaglandin synthesis, but it is unclear whether these effects are causally related. The role of cyclooxygenase products was investigated using two enantiomers of the cyclooxygenase inhibitor flurbiprofen of which S(+)‐ is more potent than R(–)‐flurbiprofen. Single‐unit activity was recorded from mechano‐heat‐sensitive, polymodal C‐fibers in the isolated rat skin‐saphenous nerve preparation. Bradykinin pretreatment (10 µm, 5 min) induced a 219 ± 26% increase in the number of spikes evoked by noxious heat stimulation and a drop in the heat threshold by 5.2 ± 0.6 °C in a fully reproducible manner. S(+)‐flurbiprofen (1 µm) abolished the bradykinin‐induced heat sensitization but did not alter the unconditioned heat response itself. Under R(–)‐flurbiprofen (1 µm) bradykinin still induced a significant heat sensitization which was reduced by 33 ± 21% (P = 0.11) of its previous extent; this effect may be due to the limited purity of the enantiomer preparation or to a cyclooxygenase‐independent action of flurbiprofen. The heat sensitization suppressed by S(+)‐flurbiprofen could be significantly restored (to 43 ± 12%) by addition of PGE2 plus PGI2 (10 µm both) to bradykinin. Neither S(+)‐ nor R(–)‐flurbiprofen had an influence on the magnitude of the excitatory effect of bradykinin. It is concluded that (i) cyclooxygenase products are the main mediators of nociceptor sensitization to heat following bradykinin treatment in the isolated rat skin; (ii) PGE2/I2 are essential but perhaps not the only relevant cyclooxygenase products involved and (iii) neither S(+)‐ nor R(–)‐flurbiprofen inhibit the unconditioned noxious heat response and the excitatory bradykinin response of the polymodal C‐nociceptors.
Δ9‐tetrahydrocannabinol‐induced MAPK/ERK and Elk‐1 activation in vivo depends on dopaminergic transmission
Authors: Valjent Emmanuel , Pagès Christiane , Rogard Monique , Besson Marie‐Jo , Maldonado Rafael , Caboche Jocelyne 
Published: March 2003

AbstractIt is now well established that central effects of Δ9‐tetrahydrocannabinol (THC), the main psychoactive component of marijuana, are mediated by CB1 cannabinoid receptors. However, intraneuronal signalling pathways activated in vivo by THC remain poorly understood. We show that acute administration of THC induces a progressive and transient activation (i.e. phosphorylation) of the mitogen activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) in the dorsal striatum and the nucleus accumbens (NA). This activation, corresponding to both neuronal cell bodies and the surrounding neuropil, is totally inhibited by the selective antagonist of CB1 cannabinoid receptors, SR 141716A. However, blockade of dopaminergic (DA) D1 receptors by administration of SCH 23390, prior to THC, totally prevents ERK activation in the striatum, thus demonstrating a critical involvement of DA systems in THC‐induced ERK activation. DA‐D2 and glutamate receptors of NMDA subtypes also participate, albeit to a lesser extent, to THC‐induced ERK activation in the striatum, as shown after injection of selective antagonists (raclopride and MK801, respectively). Furthermore, THC‐induced phosphorylation of the transcription factor Elk‐1, and up‐regulation of zif268 mRNA expression are blocked by SL327, a specific inhibitor of MAPK/ERK kinase (MEK), the upstream kinase of ERK, as well as SCH 23390. Finally, using the place‐preference paradigm, we show that ERK inhibition blocks THC‐induced rewarding properties. Altogether, our data strongly support that ERK activation in the striatum is critically involved in long‐term neuronal adaptive responses underlying THC‐induced long‐term behaviours.
NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6‐OHDA rat model of Parkinson's disease
Authors: Crocker Stephen J. , Wigle Nichola , Liston Peter , Thompson Charlie S. , Lee Chris J. , Xu Daigen , Roy Sophie , Nicholson Donald W. , Park David S. , MacKenzie Alex , Korneluk Robert G. , Robertson George S. 
Published: March 2003

AbstractParkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6‐OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase‐3 activity in this adult 6‐OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase‐3. Although caspase‐3‐like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6‐OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase‐3 is not induced in the dopamine neurons of adult 6‐OHDA‐lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD.
Excess target‐derived neurotrophin‐3 alters the segmental innervation of the skin
Authors: Ritter Amy M. , Woodbury C. Jeffery , Davis Brian M. , Albers Kathryn , Koerber H. Richard 
Published: March 2003

AbstractIt is thought that dermatomes are established during development as a result of competition between afferents of neighbouring segments. Mice that overexpress neurotrophins in the skin provide an interesting model to test this hypothesis, as they possess increased numbers of sensory neurons, and display hyperinnervation of the skin. When dermatomal boundaries were mapped in adult mice, it was found that those in nerve growth factor and brain‐derived neurotrophic factor overexpressers were indistinguishable from wild‐type animals but that overlap between adjacent segments was greatly reduced in neurotrophin‐3 (NT‐3) overexpressers. However, dermatomes in heterozygous NT‐3 knockout mice displayed no more overlap than wild‐types. In order to quantify differences across strains, innervation territories of thoracic dorsal cutaneous nerves were mapped and measured in adult mice. Overlap between adjacent dorsal cutaneous nerves was normal in nerve growth factor overexpressing mice, but much reduced in NT‐3 overexpressers. However, this restriction was not reflected in the central projection of the dorsal cutaneous nerve, creating a mismatch between peripheral and central projections. Dorsal cutaneous nerve territories were also mapped in neonatal mice aged postnatal day 7–8. In neonates, nerve territories of NT‐3 overexpressers overlapped less than wild‐types, but in neonates of both strains the amount of overlap was much greater than in the adult. These results indicate that substantial separation of dermatomes occurs postnatally, and that excess NT‐3 enhances this process, resulting in more restricted dermatomes. It may exert its effects either by enhancing competition, or by direct effects on the stability and formation of sensory endings in the skin.
Hypocretin (orexin) in the rat pineal gland: a central transmitter with effects on noradrenaline‐induced release of melatonin
Authors: Mikkelsen Jens D. , Hauser Frank , DeLecea Luis , Sutcliffe J. Gregor , Kilduff Thomas S. , Calgari Chistiane , Pévet Paul , Simonneaux Valérie 
Published: March 2003

AbstractHypocretin‐1 (HCRT‐1) and hypocretin 2 (HCRT‐2), also known as orexin‐A and orexin‐B, are two neuropeptides derived from the same precursor. Hypocretinergic neurons have been found exclusively in the hypothalamic dorsolateral area. These neurons are implicated in sleep and feeding through activation of specific G‐protein‐coupled orexin‐1 and orexin‐2 receptor (OR‐R1 and OR‐R2). The purpose of this study was to determine the existence of the HCRT peptides in the central input of the rat pineal gland. Further, OR‐R1 and OR‐R2 expression was determined in the pineal gland and the effect of HCRT‐2 on melatonin synthesis and secretion was analysed in dissociated rat pinealocytes. A large contingent of HCRT‐positive nerve fibres and terminals were observed in the epithalamus, many of which entered into the pineal parenchyma. A significant number of nerve fibres endowed with positive boutons were identified in the pineal stalk, though the number of positive fibres decreased along the extension of the stalk. So far, no positive fibres have been found in the superficial pineal gland. RT‐PCR analysis revealed the expression of OR‐R2 mRNA, whereas OR‐R1‐receptor mRNA was not detected. When tested alone, HCRT‐2 had no effect on secretion of melatonin from cultured rat pinealocytes. However, HCRT‐2 partially inhibited (by a maximum of 30%) the β‐adrenergic‐induced melatonin secretion. The same effect was seen on activation of N‐acetyltransferase activity. The distribution and the large number of HCRT‐positive fibres together with the effect on noradrenaline‐mediated melatonin release through specific receptors suggests that these peptides may be significant central transmitters in pineal function, probably mediating homeostatic signals to the pineal gland.
A role for protein kinase intracellular messengers in substance P‐ and nociceptor afferent‐mediated excitation and expression of the transcription factor Fos in rat dorsal horn neurons in vitro
Authors: Badie‐Mahdavi H. , Worsley M. A. , Ackley M. A. , Asghar A. U. R. , Slack J. R. , King A. E. 
Published: March 2003

AbstractExpression of the inducible transcription factor Fos in the spinal dorsal horn in vivo is associated with nociceptive afferent activation, but the underlying stimulation‐transcription pathway is less clear. This in vitro spinal cord study concerns the role of protein kinase A and C second messengers in substance P receptor (NK1R)‐mediated or nociceptive afferent‐evoked neuronal excitation and Fos expression. Nociceptive afferent (dorsal root) stimulation of isolated spinal cords (10–14 day old rats) evoked a ‘prolonged’ excitatory polysynaptic potential (DR‐EPSP) that was attenuated (P < 0.05) by: the protein kinase A inhibitor, Rp‐cAMP; the protein kinase C inhibitor, bisindolymaleimide I; and the selective NK1R antagonist, GR82334. Neuronal excitations induced by the NK1R agonist [Sar9,Met(O2)11]‐SP were attenuated by Rp‐cAMP, bisindolymaleimide I and GR82334. Effects of the protein kinase A and C inhibitors on the DR‐EPSP or the [Sar9,Met(O2)11]‐SP‐induced depolarization were nonadditive, suggesting convergence of these intracellular signalling pathways onto a common final target. Nociceptor afferent‐induced Fos, detected by immunohistochemistry in superficial and deep dorsal horn laminae, was attenuated by Rp‐cAMP, bisindolymaleimide I and GR82334. In spinal cords pretreated with TTX to eliminate indirect neuronal activation, [Sar9,Met(O2)11]‐SP (1–20 µm) elicited a dose‐related expression of Fos that was reduced by Rp‐cAMP, bisindolymaleimide I and GR82334. The effects of these inhibitors were most pronounced in the deep laminae. These data support a causal relationship between protein kinase A‐ or C‐dependent signal transduction, nociceptive afferent‐ or NK1R‐induced neuronal excitation and Fos expression in dorsal horn. Implications for short‐ versus long‐term modulation of nociceptive circuitry are discussed.
BDNF increases the early expression of TRH mRNA in fetal TrkB+ hypothalamic neurons in primary culture
Authors: Guerra‐Crespo Magdalena , Ubieta Raimundo , Joseph‐Bravo Patricia , Charli Jean‐Louis , Pérez‐Martínez Leonor 
Published: March 2003

AbstractKnown effects of neurotrophins in the developing central nervous system include induction or regulation of peptide expression. Hypothalamic postmitotic thyrotropin‐releasing hormone (TRH)‐producing neurons may require neurotrophins for survival and/or differentiation. This issue was investigated using primary cell cultures derived from 17‐day‐old fetal rat hypothalamus seeded in serum‐free medium and analysed up to 4 days in vitro culture. Neurotrophin receptor (TrkB and TrkC) mRNA expression was detected by RT–PCR in fetal hypothalamus and throughout the culture period. Western blots confirmed the expression of the full‐length proteins in vitro. Semi‐quantitative RT–PCR showed that the addition of brain‐derived neurotrophic factor (BDNF) increases TRH mRNA levels while the addition of neurotrophin‐3 does not. TRH cell content was not modified. Studies on the effect of cell density or homologous conditioned medium demonstrated that endogenous factors probably contribute to determine TRH mRNA levels. One of these factors was BDNF because basal TRH mRNA levels were reduced by the addition of a Trk inhibitor or anti‐BDNF. TrkB mRNA was expressed in 27% of cells and TRH mRNA in 2% of cells. The number of TRH+ cells was not affected by BDNF treatment. Forty‐eight per cent of TRH neurons contained TrkB mRNA; these neurons had higher amounts of TRH mRNA than TrkB– neurons. Only TrkB+ cells responded to BDNF by increasing their TRH mRNA levels suggesting that BDNF may directly affect TRH biosynthesis. In conclusion, fetal hypothalamic TRH neurons are probably heterogeneous in regard to the neurotrophic factors enhancing peptide and mRNA levels. BDNF enhances TRH mRNA levels in a population of TrkB+ fetal hypothalamic TRHergic neurons in primary culture. However, additional influences may be necessary for the establishment of peptide phenotype in the TrkB+ neurons.
EGF‐responsive neural stem cells are a transient population in the developing mouse spinal cord
Authors: Represa Alfonso , Shimazaki Takuya , Simmonds Matthew , Weiss Samuel 
Published: March 2003

AbstractThe adult mouse forebrain, which exhibits substantial ongoing cell genesis, contains self‐renewing multipotent neural stem cells that respond to epidermal growth factor (EGF), but the adult spinal cord, which exhibits limited cell genesis, does not. Spinal cord development is a process characterized by defined periods of cell histogenesis. Thus, in the present study we asked whether EGF‐responsive neural stem cells are present within the spinal cord during development. At embryonic day (E) 11, subsequent to the onset of neurogenesis, only fibroblast growth factor (FGF) receptors and FGF‐2 (requiring heparan sulphate)‐responsive stem cells are present in the spinal cord. Between E12 and 14, at the peak of spinal cord neurogenesis and the onset of gliogenesis, EGF receptors appear along with clonally derived highly expandable EGF‐responsive neural stem cells. Following the cessation of cell histogenesis, the adult spinal cord is largely devoid of both EGF receptors and EGF‐responsive stem cells. On the other hand, the FGF receptor1c subtype and multipotent FGF‐2‐responsive neural stem cells are present in early development and in the adult. The order of appearance of spinal cord neural stem cells and in vitro lineage analysis suggests that a more primitive FGF‐2‐responsive stem cell produces the EGF‐responsive stem cell. These findings suggest that EGF‐responsive neural stem cells appear transiently in the spinal cord, during the peak period of cell histogenesis, but are no longer present in the relatively quiescent adult structure.
Astrocyte‐released cytokines induce ramification and outward K+ channel expression in microglia via distinct signalling pathways
Authors: Schilling Tom , Nitsch Robert , Heinemann Uwe , Haas Dorit , Eder Claudia 
Published: March 2003

AbstractDifferentiation of microglial cells is characterized by transformation from ameboid into ramified cell shape and up‐regulation of K+ channels. The processes of microglial differentiation are controlled by astrocytic factors. The mechanisms by which astrocytes cause developmental changes in morphological and electrophysiological properties of microglia have remained unclear. We show here that the cytokines transforming growth factor‐β (TGF‐β), macrophage colony‐stimulating factor (M‐CSF) and granulocyte/macrophage colony‐stimulating factor (GM‐CSF) are released by astrocytes at concentrations sufficient to induce ramification and up‐regulation of delayed rectifier (DR) K+ channels in microglia. Transformation from ameboid into ramified morphology induced in microglia by exposure to astrocyte‐conditioned medium (ACM) was inhibited by neutralizing antibodies against TGF‐β, M‐CSF or GM‐CSF, whilst ACM‐induced DR channel expression was exclusively inhibited by antibodies against TGF‐β. Although both ramification and DR channel up‐regulation occurred simultaneously, DR channel blockade by charybdotoxin failed to inhibit microglial ramification. The ACM‐induced ramification of microglia was inhibited by the tyrosine kinase inhibitor genistein, whereas DR channel up‐regulation did not occur in the presence of the serine/threonine kinase inhibitor H7. Our data suggest that astrocytes modulate processes of microglial differentiation in parallel but via distinct signalling pathways.
Cortical projections of the non‐entorhinal hippocampal formation in the cynomolgus monkey (Macaca fascicularis)
Authors: Insausti R. , Muñoz M. 
Published: March 2003

AbstractEpisodic memory consolidation requires the integrity of the anatomical pathways between the cerebral cortex and the hippocampal formation. Whilst the largest cortical output of the hippocampal formation originates in the entorhinal cortex, direct projections from CA1, subiculum and presubiculum to the cortex have been reported. The aim of this study is the assessment of the extent, topography and relative strength of those projections, as a parallel/alternate route of memory processing. A total of 45 injections in 28 Macaca fascicularis monkeys were used. Cortical deposits of fluorescent tracers (20 cases, 3% Fast Blue, 2% Diamidino Yellow) or 1% WGA‐HRP (eight cases) were made in different cortical areas of the frontal, temporal and parietal lobes, as well as cingulate cortex by direct exposure of the cortical surface. After appropriate survival, animals were perfused and the brains serially sectioned at 50 µm and the retrograde labelling charted with an X–Y digitizing system. Retrograde neuronal labelling was observed in CA1, subiculum, presubiculum and parasubiculum; it was absent in the dentate gyrus, CA3 and CA2. Compared to other portions of the hippocampal formation, the CA1–subiculum border had the highest number of labelled neurons (especially after deposits in the rostral perirhinal cortex), followed by medial frontal cortex, temporal pole, orbitofrontal, anterior and posterior cingulate cortices, parietal and inferotemporal cortices, and no labelling after posterior inferotemporal and lateral frontal cortices. Our results indicate that CA1, subiculum, presubiculum and parasubiculum send direct output to cortical areas. This nonentorhinal, hippocampal formation cortical output may be relevant in memory processing.
Effects of steroids on NMDA receptors and excitatory synaptic transmission in neonatal motoneurons in rat spinal cord slices
Authors: Abdrachmanova Galya , Chodounská Hana , Vyklický Ladislav 
Published: March 2003

AbstractThe effect of steroids on NMDA receptors and excitatory postsynaptic transmission was studied in fluorescence‐labelled motoneurons in thin spinal cord slices. In outside‐out patches, NMDA‐induced responses were potentiated by 79% in the presence of 20‐oxopregn‐5‐en‐3β‐yl sulfate (PS), while in the presence of 20‐oxo‐5α‐pregnan‐3α‐yl sulfate (3α5αS) and 20‐oxo‐5β‐pregnan‐3α‐yl sulfate (3α5βS) they were diminished by 57% and 66%, respectively. PS and 3α5βS had no effect on the amplitude of single NMDA receptor channel openings, however, both compounds altered relative distribution of the openings to individual conductance levels. In control cases, the most frequent openings of the NMDA receptor channels were at the 70 pS conductance level, while in the presence of PS or 3α5βS, the most frequent openings were at the 55 pS conductance level. Analysis of the mean current transferred by NMDA receptor channel openings at individual conductance levels indicated that in the presence of PS, the mean current induced by 55 pS conductance openings was significantly increased. In the presence of 3α5βS, the mean currents induced by 55 pS and 70 pS conductance openings were significantly decreased. The amplitude of NMDA receptor‐mediated EPSCs was potentiated by 54% in the presence of PS and the deactivation kinetics slowed. Neither the amplitude nor the kinetics of NMDA receptor‐mediated EPSCs was significantly changed in the presence of 3α5βS. The results of our experiments indicate that neurosteroids affect NMDA receptors in motoneurons. The effect appears to be influenced by the receptor subunit composition.
Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction
Authors: Katagiri Hiroyuki , Tanaka Kohichi , Manabe Toshiya 
Published: March 2003

AbstractAlthough glutamate transporters maintain low extracellular levels of the excitatory neurotransmitter glutamate in the nervous system, little is known about their roles in synaptic plasticity. Here, using knockout mice lacking GLT‐1, that is the most abundant glial subtype of glutamate transporters, we showed that long‐term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region. When tetanic stimulation was applied in the presence of low concentrations of an N‐methyl‐d‐aspartate (NMDA) receptor antagonist, the impairment was overcome. Consistent with these results, the increased glutamate in the synaptic cleft of mutant mice preferentially activated NMDA receptors. Furthermore, analyses of mutant mice revealed that the magnitude of NMDA receptor‐dependent transient synaptic potentiation during low‐frequency stimulation depended on the concentration of glutamate in the synaptic cleft. These findings suggest that GLT‐1 plays critical roles in LTP induction, as well as in short‐term potentiation, through regulation of extracellular levels of glutamate, which enables appropriate NMDA receptor activation.