bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological activity of RE‐1 silencing transcription factor (REST) towards distinct transcriptional activators
Authors: Lietz Michael , Bach Karl , Thiel Gerald 
Published: March 2003

AbstractThe zinc finger protein RE‐1 silencing transcription factor (REST) is a transcriptional repressor that represses neuronal genes in non‐neuronal tissues. We have analyzed the ability of REST and the REST mutants, RESTΔN and RESTΔC lacking either the N‐terminal or C‐terminal repression domains of REST, to inhibit transcription mediated by distinct transcriptional activator proteins. For this purpose we have designed an activator specific assay where transcription is activated as a result of only one distinct activation domain. In addition, binding sites for REST were inserted in the 5′‐untranslated region or at a distant position downstream of the polyadenylation signal. The results show that REST or the REST mutants containing only one repression domain were able to block transcriptional activation mediated by the transcriptional activation domains derived from p53, AP2, Egr‐1, and GAL4. Moreover, REST, as well as the REST mutants, blocked the activity of the phosphorylation‐dependent activation domain of Elk1. However, the activity of the activation domain derived from cAMP response element binding protein 2 (CREB2), was not inhibited by REST, RESTΔN or RESTΔC, suggesting that REST is able to distinguish between distinct transcriptional activation domains. Additionally, the activator specific assay, together with a positive‐dominant mutant of REST that activated instead of repressed transcription, was used in titration experiments to show that REST has transcriptional repression and no transcriptional activation properties when bound to the 5′‐untranslated region of a gene.
Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus
Authors: Banasr Mounira , Hery Micheline , Brezun Jean Michel , Daszuta Annie 
Published: March 2003

AbstractCharacterizing the mechanisms by which endogenous factors stimulate neurogenesis is of special interest in view of the possible implication of newly generated cells in hippocampal functions or disorders. The aim of this study was to determine whether serotonin (5‐HT) and oestradiol (E2) act through a common pathway to increase cell proliferation in the adult dentate gyrus (DG). We also investigated the effects of long‐lasting changes in oestrogen levels on cell proliferation. Combining ovariectomy with inhibition of 5‐HT synthesis using p‐chlorophenylalanine (PCPA) treatment produced approximately the same decreases in the number of bromodeoxyuridine (BrdU) and PSA‐NCAM immunolabelled cells in the subgranular layer as ovariectomy alone. Administration of 5‐hydroxytryptophan (5‐HTP) restored cell proliferation primarily decreased by ovariectomy, whereas oestradiol was unable to reverse this change in ovariectomized rats treated with PCPA. These findings demonstrate that 5‐HT mediates oestrogen stimulation of cell proliferation in adult dentate gyrus. However, increase in ovarian hormones during pregnancy has no effect on dentate cell proliferation. This finding suggests that concomitant changes in other factors, such as glucocorticoids, may counterbalance the positive regulation of cell proliferation by 5‐HT and oestradiol. Finally, oestrogen may regulate structural plasticity by stimulating PSA‐NCAM expression independently of neurogenesis, as shown for instance by the increases in the number of PSA‐NCAM labelled cells in pregnants. As 5‐HT and oestrogen are involved in mood disorders, our data suggest that the positive regulation of cell proliferation and neuroplasticity by these two factors may contribute to restore hippocampal connectivity in depressive patients.
GABAA‐receptor expression in glioma cells is triggered by contact with neuronal cells
Authors: Synowitz Michael , Ahmann Petra , Matyash Marina , Kuhn Susanne A. , Hofmann Birte , Zimmer Claus , Kirchhoff Frank , Kiwit Jürgen C. W. , Kettenmann Helmut 
Published: March 2003

AbstractThe expression of functional GABAA‐receptors in glioma cells correlates with low malignancy of tumours and cell lines from glioma lack these receptors. Here we show that contact with neurons induces the expression of functional GABAA‐receptors. C6 and F98 glioma cell lines were labelled by recombinant expression of enhanced green fluorescent protein injected into rat brain and studied in acute slices after two to three weeks of tumour growth. The cells responded to GABA or the specific agonist, muscimol with a current typical for GABAA‐receptors, as studied with the patch‐clamp technique. To get insight into the mechanism of GABAA receptor induction, the C6 or F98 cells were co‐cultured with neurons, astrocytes, oligodendrocytes and microglia. Glioma cells expressed functional GABAA receptors within 24 h only in cultures where physical contact to neurons occurred. Activation of GABAA‐receptors in the co‐cultures attenuated glioma cell metabolism while blockade of the receptors increased metabolism. We conclude that with this form of interaction, neurons can influence tumour behaviour in the brain.
Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6‐hydroxydopamine
Authors: Petersén Åsa , Hansson Oskar , Puschban Zoe , Sapp Ellen , Romero Norma , Castilho Roger F. , Sulzer David , Rice Margaret , DiFiglia Marian , Przedborski Serge , Brundin Patrik 
Published: March 2003

AbstractHuntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid‐induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA‐ and 6‐hydroxydopamine‐mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP‐32) in R6/2 mice does not provide the resistance, as DA‐induced striatal lesions are not reduced in size in DARPP‐32 knockout mice. Neither DA receptor antagonists nor a N‐methyl‐d‐aspartate (NMDA) receptor blocker reduce the size of DA‐induced striatal lesions, suggesting that DA toxicity is not dependent upon DA‐ or NMDA receptor‐mediated pathways. Moreover, superoxide dismutase‐1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin‐trap agent phenyl‐butyl‐tert‐nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6‐hydroxydopamine was also reduced in R6 mice, a yet‐to‐be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA‐induced toxicity with age.
Stress alleviates reduced expression of cell adhesion molecules (NCAM, L1), and deficits in learning and corticosterone regulation of apolipoprotein E knockout mice
Authors: Grootendorst J. , Oitzl M. S. , Dalm S. , Enthoven L. , Schachner M. , De Kloet E. R. , Sandi C. 
Published: March 2003

AbstractCell adhesion molecules (CAMs) involved in synaptic changes underlying learning and memory processes, are implicated in the effect of stress on behavioural performance. The present study was designed to test the hypothesis that (i) expression of CAMs is apolipoprotein E‐ (apoE) genotype dependent and (ii) repeated exposure to stress modulates the synthesis of CAMs in an apoE‐genotype dependent manner. Using ELISA we tested this hypothesis and measured expression of NCAM and L1 in different brain regions of naïve and stressed apolipoprotein E‐knockout (apoE0/0) and C57Bl6 (wild‐type) mice. Naïve apoE0/0 mice had elevated basal morning corticosterone and ACTH concentrations and decreased expression of NCAM and L1 compared to wild‐type mice. Repeated exposure of mice to rats, as the common stressor, alleviated the reduction in expression of CAMs in apoE0/0 mice; seven days after the last rat exposure, expression of NCAM was increased in frontal brain and hippocampus whereas expression of L1 was increased in hippocampus and cerebellum. Rat stress attenuated the elevation of basal morning corticosterone concentration in apoE0/0 mice towards concentrations detected in wild‐type mice. Moreover, rat stress improved learning and memory of apoE0/0 mice in the water maze. In conclusion, repeated exposure to stress eliminated apoE‐genotype‐related differences in expression of CAMs. Under these same conditions the differences in cognitive performance and corticosterone concentrations were abolished between wild type and apoE0/0 mice.
Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene
Authors: Hansson Oskar , Guatteo Ezia , Mercuri Nicola B. , Bernardi Giorgio , Li Xiao‐Jiang , Castilho Roger F. , Brundin Patrik 
Published: March 2003

AbstractTransgenic Huntington's disease (HD) mice, expressing exon 1 of the humanHDgene (lines R6/1 and R6/2), are totally resistant to striatal lesions caused by the NMDA receptor agonist quinolinic acid (QA). Here we show that this resistance develops gradually over time in both R6/1 and R6/2 mice, and that it occurred earlier in R6/2 (CAG‐155) than in R6/1 (CAG‐115) mice. The development of the resistance coincided with the appearance of nuclear inclusions and with the onset of motor deficits. In the HD mice, hippocampal neurons were also resistant to QA, especially in the CA1 region. Importantly, there was no change in susceptibility to QA in transgenic mice with a normal CAG repeat (CAG‐18). R6/1 mice were also resistant to NMDA‐, but not to AMPA‐induced striatal damage. Interestingly, QA‐induced current and calcium influx in striatal R6/2 neurons were not decreased. However, R6/2 neurons had a better capacity to handle cytoplasmic calcium ([Ca2+]c) overload following QA and could avoid [Ca2+]cderegulation and cell lysis. In addition, basal [Ca2+]clevels were increased five‐fold in striatal R6/2 neurons. This might cause an adaptation of R6 neurons to excitotoxic stress resulting in an up‐regulation of defense mechanisms, including an increased capacity to handle [Ca2+]coverload. However, the increased level of basal [Ca2+]cin the HD mice might also disturb intracellular signalling in striatal neurons and thereby cause neuronal dysfunction and behavioural deficits.
Role of adrenal medulla in development of sexual dimorphism in inflammation
Authors: Green Paul G. , Dahlqvist Solbritt Rantapää , Isenberg William M. , Miao Frederick J.‐P. , Levine Jon D. 
Published: March 2003

AbstractMany inflammatory diseases show a female predilection in adults, but not prepubertally. Because sex differences in the inflammatory response in the adult rat are mediated, in part, by sexual dimorphism in adrenal medullary function, we investigated the contribution of the adrenal medulla to the ontogeny of sexual dimorphism in inflammation. Whilst there was no sex difference in the magnitude of the plasma extravasation (PE) induced by the potent inflammatory mediator bradykinin (BK) in prepubertal rats, in adult rats BK‐induced PE was markedly greater in males. Also, adult male rats, gonadectomized prior to puberty, had a lower magnitude of BK‐induced PE than did adult male controls, whilst adult females gonadectomized prepubertally had higher BK‐induced PE than did controls. In rats gonadectomized after puberty, the magnitude of BK‐induced PE in adult males was not affected, whilst in females it resulted in significantly higher BK‐induced PE, similar to the effect of prepubertal gonadectomy. When tested prepubertally, adrenal denervation increased the magnitude of BK‐induced PE in females, but not in males. In contrast, in both males and females tested as adults, but castrated prepubertally, and in gonad‐intact adult females, adrenal denervation significantly increased the magnitude of BK‐induced PE. Adrenal denervation in prepubertal females given adult levels of 17β‐oestradiol produced a marked enhancement in the denervation‐induced increase in magnitude of BK‐induced PE compared to females not exposed prematurely to sex hormones. These studies suggest that an adrenal medulla‐dependent inhibition of BK‐induced PE is present in female but not male rats, and is enhanced by oestrogen but suppressed by testosterone.
mGlu1 receptors mediate a post‐tetanic depression at parallel fibre–Purkinje cell synapses in rat cerebellum
Authors: Neale Stuart A. , Garthwaite John , Batchelor Andrew M. 
Published: March 2003

AbstractMetabotropic glutamate (mGlu) receptors are located pre‐ and postsynaptically at central synapses. Activation of the receptors by exogenous agonists usually results in a reversible depression of fast glutamatergic neurotransmission. Evidence that synaptically released glutamate has such an action, however, is scarce. Sharp microelectrode recordings were used to investigate the modulatory role of mGlu receptors at a well‐studied glutamatergic synapse, the one between parallel fibres and Purkinje cells in rat cerebellar slices. Brief, tetanic stimulation of the parallel fibres caused a depression of subsequent fast EPSPs. This post‐tetanic depression (PTD) reached its maximum 4.5 s after the tetanus. Measured at this point, PTD was frequency‐dependent; 10 stimuli at 20 Hz produced no significant depression, whereas, at 100 Hz the same number of stimuli was maximally effective (∼50% depression). The nonselective mGlu antagonist, (S)‐α‐methyl‐4‐carboxyphenylglycine 1 mm or the GABAB antagonist, CGP35348 (1 mm), both decreased the magnitude of the PTD. In the presence of CGP35348 the mGlu1 antagonist, 7‐hydroxyiminocyclopropan[b]chromen‐1a‐carboxylic acid ethyl ester (300 µm), inhibited PTD further. A group II/III mGlu antagonist had no effect. These observations indicate that synaptically activated mGlu1 receptors not only generate a slow EPSP and induce Ca2+ mobilization in Purkinje cells, as reported previously, but also produce a transient depression of fast synaptic transmission. This short‐term plasticity may be important for shaping the output of cerebellar circuits and/or it could provide a substrate for long‐term depression when additional mechanisms are superimposed.
Regionally selective alterations in local cerebral glucose utilization evoked by charybdotoxin, a blocker of central voltage‐activated K+‐channels
Authors: Cochran S. M. , Harvey A. L. , Pratt J. A. 
Published: March 2003

AbstractThe quantitative [14C]‐2‐deoxyglucose autoradiographic technique was employed to investigate the effect of charybdotoxin, a blocker of certain voltage‐activated K+ channels, on functional activity, as reflected by changes in local rates of cerebral glucose utilization in rat brain. Intracerebroventricular administration of charybdotoxin, at doses below those producing seizure activity, produced a heterogeneous effect on glucose utilization throughout the brain. Out of the 75 brain regions investigated, 24 displayed alterations in glucose utilization. The majority of these changes were observed with the intermediate dose of charybdotoxin administered (12.5 pmol), with the lower (6.25 pmol) and higher (25 pmol) doses of charybdotoxin producing a much more restricted pattern of change in glucose utilization. In brain regions which displayed alterations in glucose at all doses of charybdotoxin administered, no dose dependency in terms of the magnitude of change was observed. The 21 brain regions which displayed altered functional activity after administration of 12.5 pmol charybdotoxin were predominantly limited to the hippocampus, limbic and motor structures. In particular, glucose utilization was altered within three pathways implicated within learning and memory processes, the septohippocampal pathway, Schaffer collaterals within the hippocampus and the Papez circuit. The nigrostriatal pathway also displayed altered local cerebral glucose utilization. These data indicate that charybdotoxin produces alterations in functional activity within selected pathways in the brain. Furthermore the results raise the possibility that manipulation of particular subtypes of Kv1 channels in the hippocampus and related structures may be a means of altering cognitive processes without causing global changes in neural activity throughout the brain.
In vivo labelling of the adenosine A2A receptor in mouse brain using the selective antagonist [3H]SCH 58261
Authors: El Yacoubi Malika , Ledent Catherine , Parmentier Marc , Ongini Ennio , Costentin Jean , Vaugeois Jean‐Marie 
Published: March 2003

AbstractThe selective A2A receptor antagonist [3H]SCH 58261 was injected intravenously in mice and the radioactivity accumulating in various brain regions was determined by tissue sampling. Radioactivity levels in regions of interest such as the striatum were highest 15 min after injection and quickly declined thereafter (30 min and 1 h postinjection) in a time‐dependent manner. The amount of labelling was ranked as follows: striatum (4.6 ± 0.3 fmol/mg protein) >> cortex > hippocampus > pons = hypothalamus > cerebellum (0.5 ± 0.05 fmol/mg protein). Specific labelling of the A2A receptor occurred in striatum and cortex because significantly less radioactivity accumulated in these areas from adenosine A2A receptor knockout mice as compared to wild‐type littermates. In control outbred CD1 mice, a striatum‐to‐cerebellum ratio of 7.6 ± 0.6 was found. At 30 min postinjection, the nonselective adenosine receptor antagonist caffeine reduced the radioactivity due to [3H]SCH 58261 in the striatum by 32% at 1 mg/kg i.p. and by 66% at the stimulant dose of 6.25 mg/kg i.p. Radioactivity in the striatum was lowered, respectively, by 66 and 86% 30 min after injection of 3 or 10 mg/kg i.p. doses of unlabelled SCH 58261. The present results indicate that [3H]SCH 58261 directly labels striatal A2A receptors in vivo. Thus [3H]SCH 58261 is an excellent tool for studying brain distribution and A2A receptor occupancy of various compounds ranging from xanthines, such as caffeine, to other A2A antagonists.
Impairment of eyeblink conditioning in GluRδ2‐mutant mice depends on the temporal overlap between conditioned and unconditioned stimuli
Authors: Kishimoto Yasushi , Kawahara Shigenori , Fujimichi Ryoko , Mori Hisashi , Mishina Masayoshi , Kirino Yutaka 
Published: March 2003

AbstractMice lacking the glutamate receptor subunit δ2 (GluRδ2) are deficient in cerebellar long‐term depression (LTD) at the parallel fibre–Purkinje cell synapses. We conducted delay and trace eyeblink conditioning with these mice, using various temporal intervals between the conditioned stimulus (CS) and unconditioned stimulus (US). During trace conditioning in which a stimulus‐free trace interval (TI) of 250, 100 or 50 ms intervened between the 352‐ms tone CS and 100‐ms US, GluRδ2‐mutant mice learned as successfully as wild‐type mice. Even in the paradigm with TI = 0 ms, in which the end of CS and onset of US are simultaneous, there was no difference between the GluRδ2‐mutant and wild‐type mice in their acquisition of a conditioned response. However, in the delay paradigm in which the 452‐ms CS overlapped temporally with the coterminating 100‐ms US, GluRδ2‐mutant mice exhibited severe learning impairment. The present study together with our previous work [Kishimoto, Y., Kawahara, S., Suzuki, M., Mori, H., Mishina, M. & Kirino, Y. (2001) Eur. J. Neurosci.,13, 1249–1254], indicates that cerebellar LTD‐independent learning is possible in paradigms without temporal overlap between the CS and US. On the other hand, GluRδ2 and cerebellar LTD are essential for learning when there is CS–US temporal overlap, suggesting that the cerebellar neural substrates underlying eyeblink conditioning may change, depending on the temporal overlap of the CS and US.
Ectopic expression of the neural cell adhesion molecule L1 in astrocytes leads to changes in the development of the corticospinal tract
Authors: Ourednik J. , Ourednik V. , Bastmeyer M. , Schachner M. 
Published: March 2003

AbstractThe cell recognition molecule L1, of the immunoglobulin superfamily, participates in the formation of the nervous system and has been shown to enhance cell migration and neurite outgrowth in vitro. To test whether ectopic expression of L1 would influence axonal outgrowth in vivo, we studied the development of the corticospinal tract in transgenic mice expressing L1 in astrocytes under the control of the GFAP‐promoter. Corticospinal axons innervate their targets by extending collateral branches interstitially along the axon shaft following a precise spatio‐temporal pattern. Using DiI as an anterograde tracer, we found that in the transgenic animals, corticospinal axons appear to be defasciculated, reach their targets sooner and form collateral branches innervating the basilar pons at earlier developmental stages and more diffusely than in wild type littermates. Collateral branches in the transgenic mice did not start out as distinct rostral and caudal sets, but they branched from the axon segments in a continuous rostrocaudal direction across the entire region of the corticospinal tract overlying the basilar pons. The ectopic branches are transient and no longer present at postnatal day 22. The earlier outgrowth and altered branching pattern of corticospinal axons in the transgenics is accompanied by an earlier differentiation of astrocytes. Taken together, our observations provide evidence that the ectopic expression of L1 on astrocytes causes an earlier differentiation of these cells, results in faster progression of corticospinal axons and influences the branching pattern of corticospinal axons innervating the basilar pons.
The regional cortical basis of achromatopsia: a study on macaque monkeys and an achromatopsic patient
Authors: Cowey Alan , Heywood Charles A. , Irving‐Bell Linda 
Published: March 2003

AbstractPrevious experiments have revealed total loss of colour vision following removal of all inferior temporal cortex, a condition akin to complete cerebral achromatopsia in humans. Whether less extensive ablation genuinely impairs colour perception without abolishing it or retards learning involving coloured stimuli is contested. We therefore tested macaque monkeys, with total removal of temporal areas TEO and TE but sparing rostral and perirhinal temporal cortex and the upper bank of the superior temporal sulcus. Compared with three monkeys with lateral parietal ablations, the monkeys with TEO/TE lesions were impaired at learning and retention of simultaneous two‐choice colour discriminations and with a nine‐choice oddity discrimination whether the coloured target was embedded among grey distracters of the same luminance or among isoluminant coloured distracters. However, their performance was superior to that of an achromatopsic human subject and to that previously measured in monkeys with much larger temporal lobe ablation. They were only mildly impaired at nine‐choice oddity discrimination for grey stimuli where the grey target was brighter than the grey distracters. The impairment could be exacerbated or alleviated by altering the colour of the background of the displays and by static and dynamic luminance masking of the entire display in a manner that indicates that the colour deficit reflects a change in perception rather than a disorder of learning and memory. It resembles central dyschromatopsia in human subjects but falls short of achromatopsia.