bluuebunny/crossref_metadata_2025 huggingface dataset:
Forelimb locomotor generators and quadrupedal locomotion in the neonatal rat
Authors: Ballion Bérangère , Morin Didier , Viala Denise
Published: March 2003

The spinal localization of the forelimb locomotor generators and their interactions with other spinal segments were investigated on in vitro brainstem–spinal cord preparations of new‐born rats. Superfusion of the cervicothoracic cord (C1–T4) with high K+/low Mg2+ artificial cerebrospinal fluid (aCSF) evoked rhythmic motor root activity that was limited to low cervical (C7, C8) and high thoracic (T1) spinal levels. This activity consisted of synchronous, homolateral bursts and a typical alternating bilateral pattern. Rhythmic activity with similar locomotor‐like characteristics could be induced with either serotonin (5‐HT, 5 µm), N‐methyl‐d‐aspartate (NMDA, 5 µm), kainate (10 µm) or a ‘cocktail’ of 5‐HT (5 µm) and NMDA (5 µm). During 5‐HT/NMDA perfusion of the cervicothoracic cord, induced bursting was no longer restricted to C7–T1 levels, but also occurred at cervical C3–C5 levels and with C5–C8 homolateral alternation. Spinal transections between C6 and C7 cervical segments did not abolish rhythmic activity in C7–T1, but suppressed locomotor‐like rhythmicity at C3–C5 levels. Reduced regions comprising the C7–C8 or C8–T1 segments maintained rhythmicity. Superfusion of the whole cord with 5‐HT/NMDA induced ventral root bursting with similar frequencies at all recorded segments (cervical, thoracic and lumbar). After isolation, the T3–T10 cord was unable to sustain any rhythmic activity while cervical and lumbar segmental levels continued to burst, albeit at different frequencies. We also found that the faster caudal and the slower rostral locomotor generators interact to produce coordinated locomotor‐like activity in all segments of the intact spinal cord. In conclusion, C7–T1 spinal levels display a strong motor rhythmogenic ability; with the lumbar generators, they contribute to coordinated rhythmic activity along the entire spinal cord of a quadrupedal locomoting mammal.
Reduction in CNS scar formation without concomitant increase in axon regeneration following treatment of adult rat brain with a combination of antibodies to TGFβ1 and β2
Authors: Moon L. D. F. , Fawcett J. W.
Published: March 2003

In this study we investigated whether CNS axons regenerate following attenuation of scar formation using a combination of antibodies against two isoforms of transforming growth factor beta (TGFβ). Anaesthetized adult rats were given unilateral mechanical lesions of the nigrostriatal tract. Implantation of transcranial cannulae allowed wounds to be treated with a combination of antibodies against TGFβ1 and TGFβ2 once daily for 10 days postaxotomy. Eleven days post‐transection brains from animals under terminal anaesthesia were recovered for histological evaluation. Gliosis, inflammation and the response of dopaminergic nigral axons were assessed by immunolabelling. Treatment with antibodies against TGFβ1 and TGFβ2 attenuated (but did not abolish) the response of glial fibrillary acidic protein (GFAP)‐immunoreactive astrocytes and of NG2‐immunoreactive glia but did not attenuate the response of CR3‐immunoreactive microglia and macrophages. However, this reduction in scar formation was not accompanied by growth of cut dopaminergic nigral axons. We conclude that treatment of injured adult rat brain with a combination of antibodies against TGFβ1 and TGFβ2 results in a reduction of scar formation but that this is not sufficient to enhance spontaneous long distance CNS axon regeneration.
The α1I T‐type calcium channel exhibits faster gating properties when overexpressed in neuroblastoma/glioma NG 108‐15 cells
Authors: Chemin Jean , Monteil Arnaud , Dubel Steve , Nargeot Joël , Lory Philippe
Published: March 2003

The recently cloned T‐type calcium channel α1I (Cav3.3) displays atypically slow kinetics when compared to native T‐channels. Possible explanations might involve alternative splicing of the α1I subunit, or the use of expression systems that do not provide a suitable environment (auxiliary subunit, phosphorylation, glycosylation…). In this study, two human α1I splice variants, the α1I‐a and α1I‐b isoforms that harbour distinct carboxy‐terminal regions were studied using various expression systems. As the localization of the α1I subunit is primarily restricted to neuronal tissues, its functional expression was conducted in the neuroblastoma/glioma cell line NG 108‐15, and the results compared to those obtained in HEK‐293 cells and Xenopus oocytes. In Xenopus oocytes, both isoforms exhibited very slow current kinetics compared to those obtained in HEK‐293 cells, but the α1I‐b isoform generated faster currents than the α1I‐a isoform. Both activation and inactivation kinetics of α1I currents were significantly faster in NG 108‐15 cells, while deactivating tail currents were two times slower, compared to those obtained in HEK‐293 cells. Moreover, the α1I‐b isoform showed significantly slower deactivation kinetics both in NG 1080‐15 and in HEK‐293 cells. Altogether, these data emphasize the advantage of combining several expression systems to reveal subtle differences in channel properties and further indicate that the major functional differences between both human α1I isoforms are related to current kinetics. More importantly, these data suggest that the expression of the α1I subunit in neuronal cells contributes to the ‘normalization’ of current kinetics to the more classical, fast‐gated T‐type Ca2+ current.
Motion processing in the auditory cortex of the rufous horseshoe bat: role of GABAergic inhibition
Authors: Firzlaff U. , Schuller G.
Published: March 2003

This study examined the influence of inhibition on motion‐direction‐sensitive responses of neurons in the dorsal fields of auditory cortex of the rufous horseshoe bat. Responses to auditory apparent motion stimuli were recorded extracellularly from neurons while microiontophoretically applying γ‐aminobutyric acid (GABA) and the GABAA receptor antagonist bicuculline methiodide (BMI). Neurons could respond with a directional preference exhibiting stronger responses to one direction of motion or a shift of receptive field (RF) borders depending on direction of motion. BMI influenced the motion direction sensitivity of 53% of neurons. In 21% of neurons the motion‐direction sensitivity was decreased by BMI by decreasing either directional preference or RF shift. In neurons with a directional preference, BMI increased the spike number for the preferred direction by a similar amount as for the nonpreferred direction. Thus, inhibition was not direction specific. BMI increased motion‐direction sensitivity by either increasing directional preference or magnitude of RF shifts in 22% of neurons. Ten percent of neurons changed their response from a RF shift to a directional preference under BMI. In these neurons, the observed effects could often be better explained by adaptation of excitation rather than inhibition. The results suggest, that adaptation of excitation, as well as cortex specific GABAergic inhibition, contribute to motion‐direction sensitivity in the auditory cortex of the rufous horseshoe bat.
Role of the corpus callosum in bimanual coordination: a comparison of patients with congenital and acquired callosal damage
Authors: Serrien Deborah J. , Nirkko Arto C. , Wiesendanger Mario
Published: March 2003

The objective of the study was to investigate temporal control in patients with congenital as compared to acquired pathology of the corpus callosum during two different bimanual paradigms: (i) a drawer‐opening task during which one hand opened a drawer while the other hand reached and grasped a small object, and (ii) rhythmical circling movements that were executed according to the in‐phase or antiphase mode. Synchronization values revealed that patients with acquired callosal dysfunction generally showed optimal behaviour during the goal‐directed and familiar drawer‐opening task but demonstrated strong tendencies towards desynchronization during circling movements, which became most apparent for antiphase coordination. Whereas one patient with callosal agenesis showed a similar performance, the other acallosal patients performed both activities successfully. These observations indicate that patients with congenital absence of the corpus callosum can make use of compensatory mechanisms for allowing temporal synchronization during bimanual movements whereas patients with acquired callosal dysfunction are severely hampered when the task places significant demands on the control processes. The data also underline that the ability of callosal patients to precisely time events in coordinated actions depend on the task constraints.
Glial‐derived arginine, the nitric oxide precursor, protects neurons from NMDA‐induced excitotoxicity
Authors: Grima Gilbert , Benz Beatrix , Do Kim Q.
Published: March 2003

Excitotoxic neuronal cell death is characterized by an overactivation of glutamate receptors, in particular of the NMDA subtype, and the stimulation of the neuronal nitric oxide synthase (nNOS), which catalyses the formation of nitric oxide (NO) from l‐arginine (L‐Arg). At low L‐Arg concentrations, nNOS generates NO and superoxide (O2•–), favouring the production of the toxin peroxynitrite (ONOO–). Here we report that NMDA application for five minutes in the absence of added L‐Arg induces neuronal cell death, and that the presence of L‐Arg during NMDA application prevents cell loss by blocking O2•– and ONOO– formation and by inhibiting mitochondrial depolarization. Because L‐Arg is transferred from glial cells to neurons upon activation of glial glutamate receptors, we hypothesized that glial cells play an important modulator role in excitotoxicity by releasing L‐Arg. Indeed, as we further show, glial‐derived L‐Arg inhibits NMDA‐induced toxic radical formation, mitochondrial dysfunction and cell death. Glial cells thus may protect neurons from excitotoxicity by supplying L‐Arg. This potential neuroprotective mechanism may lead to an alternative approach for the treatment of neurodegenerative diseases involving excitotoxic processes, such as ischemia.
Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat
Authors: Breit Sorin , Bouali‐Benazzouz Rabia , Benabid Alim‐Louis , Benazzouz Abdelhamid
Published: March 2003

The role of the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease is still unclear. Using microrecordings, we investigated the changes occurring in PPN neurons after lesions of the substantia nigra compacta (SNc) and the role of the subthalamic nucleus (STN) in these changes. In normal rats the firing rate of PPN neurons was 10.6 ± 1.4 spikes/s, the majority of neurons (91%) having a regular firing pattern, 6% irregular and 3% in bursts. In rats with 6‐hydroxydopamine lesions of the SNc, the firing rate increased significantly to 18.3 ± 3.0 spikes/s compared with normal rats. In addition, the firing pattern changed significantly: 70% of the neurons discharged regularly, 27% irregularly and 3% in bursts. In rats with ibotenic acid lesions of the STN, the firing rate decreased significantly to 7.2 ± 0.9 spikes/s and the firing pattern changed significantly: 50% of the neurons discharged regularly, 43% irregularly and 7% in bursts. The rats with combined SNc and STN lesions showed no change in the firing rate (8.5 ± 1.0 spikes/s) compared to normal rats. The firing pattern changed significantly: 69% of the cells discharged regularly, 26% irregularly and 5% in bursts. These findings demonstrate that PPN neurons are overactive and more irregular in the 6‐hydroxydopamine‐lesioned rats, suggesting the implication of this nucleus in the pathophysiology of parkinsonism. Moreover, the fact that STN lesions induced a reduction in the firing rate of the PPN in normal rats and a normalization of the firing rate in rats with 6‐hydroxydopamine lesions suggests that this nucleus is under major control of the STN.
Neural interactions between motor cortical hemispheres during bimanual and unimanual arm movements
Authors: Cardoso de Oliveira S. , Gribova A. , Donchin O. , Bergman H. , Vaadia E.
Published: March 2003

Cortico‐cortical connections through the corpus callosum are a major candidate for mediating bimanual coordination. However, aside from the deficits observed after lesioning this connection, little positive evidence indicates its function in bimanual tasks. In order to address this issue, we simultaneously recorded neuronal activity at multiple sites within the arm area of motor cortex in both hemispheres of awake primates performing different bimanual and unimanual movements. By employing an adapted form of the joint peri‐stimulus time histogram technique, we discovered rapid movement‐related correlation changes between the local field potentials (LFPs) of the two hemispheres that escaped detection by time‐averaged cross‐correlation methods. The frequency and amplitude of dynamic modifications in correlations between the hemispheres were similar to those within the same hemisphere. As in previous EEG studies, we found that, on average, correlation decreased during movements. However, a subset of recording site pairs did show transiently increased correlations around movement onset (57% of all pairs and conditions in monkey G, 39% in monkey P). In interhemispheric pairs, these increases were consistently related to the mode of coupling between the two arms. Both the correlations between the movements themselves and the interhemispheric LFP correlation increases were strongest during bimanual symmetric movements, and weaker during bimanual asymmetric and unimanual movements. Increased correlations occurred mainly around movement onset, whilst decreases in correlation dominated during movement execution. The task‐specific way in which interhemispheric correlations are modulated is compatible with the notion that interactions between the hemispheres contribute to behavioural coupling between the arms.
Neuroprotective effect of interleukin‐6 and IL6/IL6R chimera in the quinolinic acid rat model of Huntington's syndrome
Authors: Bensadoun Jean‐Charles , De Almeida Luis Pereira , Dréano Michel , Aebischer Patrick , Déglon Nicole
Published: March 2003

Ciliary neurotrophic factor prevents behavioural deficits and striatal degeneration in rat and primate models of Huntington's disease. Interleukin‐6, another member of the cytokine family, and the chimeric molecule (IL6/IL6R) in which interleukin‐6 and its soluble receptor are fused, have been shown to exert trophic action on various neuronal populations in the central nervous system. Therefore, we investigated the neuroprotective effect of these two molecules in the quinolinic acid model of Huntington's disease. LacZ‐, interleukin‐6‐ and IL6/IL6R‐expressing lentiviral vectors were stereotaxically injected into the striatum of Wistar rats. Three weeks later the animals were lesioned through the intrastriatal injection of 180 nmol of quinolinic acid. The extent of the striatal damage was significantly diminished in the rats that had been treated with interleukin‐6 or IL6/IL6R. The neuroprotective effect was, however, more pronounced with the IL6/IL6R chimera than with interleukin‐6 as indicated by the volume of the lesions (38.6 ± 10% in the IL6/IL6R group, 63.3 ± 3.6% in the IL‐6 group and 84.3 ± 2.9% in the control group). Quantitative analysis of striatal interneurons further demonstrated that the IL6/IL6R chimera is more neuroprotective than IL‐6 on ChAT‐ and NADPH‐d‐immunoreactive neurons. These results suggest that the IL6/IL6R chimera is a potential treatment for Huntington's disease.
Temporally controlled targeted somatic mutagenesis in the mouse brain
Authors: Weber Philipp , Metzger Daniel , Chambon Pierre
Published: March 2003

To develop spatio‐temporally controlled somatic mutagenesis in the adult mouse nervous system, we established transgenic mice expressing the tamoxifen‐inducible Cre‐ERT recombinase under the control of the mouse prion protein (PrP) promoter. Cre‐ERT was expressed in most regions of the brain and in the retina of one transgenic line, whereas its expression was mostly restricted to the hippocampus and the cerebellum in another line. As tamoxifen efficiently induced Cre‐mediated recombination in the various neuronal cell types expressing Cre‐ERT in the brain of adult mice, the PrP‐Cre‐ERT lines should be valuable tools to study the functions of genes involved in neurodegenerative diseases or regeneration, and in complex processes such as behaviour, learning and memory. Some limitations of presently available reporter lines for Cre‐mediated recombination in adult mouse CNS are discussed.
Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure
Authors: Hotsenpiller Gregory , Giorgetti Marco , Wolf Marina E.
Published: March 2003

To study the role of glutamate in cocaine‐conditioned responses, we developed a rat model in which conditioned locomotion is produced by repeated pairing of cocaine with discrete stimuli (flashing light and metronome). ‘Paired’ subjects received cocaine (15 mg/kg) prior to six exposures to stimuli for 30 min in the test environment. ‘Unpaired’ subjects received equivalent presentations of the stimuli yet received cocaine in home cages. Tests with the stimuli alone demonstrated that the conditioned locomotion displayed by Paired subjects was evident at 3 or 10 days post‐training and resistant to two sessions of testing. The degree of conditioned locomotion was not correlated with the subjects' response to novelty or cocaine. Administration of the noncompetitive AMPA receptor antagonist GYKI 52466 (2.5 mg/kg, a dose without effect on spontaneous activity) attenuated the expression of conditioned activity. In vivo microdialysis revealed that Paired subjects had significantly lower basal glutamate levels in the nucleus accumbens (NAc) than did Unpaired subjects when no stimuli were presented. Presentation of the conditioned stimuli resulted in significant increases in glutamate levels in the NAc in the Paired group whilst glutamate levels in the Unpaired group remained unchanged. The associative control of glutamate levels in the NAc by stimuli formerly paired with a drug of abuse is an unprecedented finding. It is likely to reflect the convergence of excitatory inputs that the NAc receives from limbic structures.
Changes in P2X receptor responses of sensory neurons from P2X3‐deficient mice
Authors: Zhong Yu , Dunn Philip M. , Bardini Michelle , Ford Anthony P. D. W. , Cockayne Debra A. , Burnstock Geoffrey
Published: March 2003

Dorsal root ganglion (DRG) neurons respond to ATP with transient, persistent or biphasic inward currents. In contrast, the ATP responses in nodose neurons are persistent. These sustained currents are also heterogeneous, with one component being accounted for by P2X2/3 receptors, and the residual response probably mediated by P2X2 receptors, although the direct evidence for this has been lacking. In the present study, we examined the P2X receptors on DRG and nodose neurons from P2X3‐deficient (P2X3−/−) mice, using whole cell voltage‐clamp recording and immunohistochemistry. We found that all P2X3−/− DRG neurons lacked rapidly desensitizing response to ATP, and both DRG and nodose neurons from P2X3‐null mutant mice no longer responded to α,β‐methylene ATP (αβmeATP). In contrast, ATP evoked persistent inward current in 12% of DRG neurons and 84% of nodose neurons from P2X3−/− mice. This retained persistent response to ATP on nodose neurons had an EC50 for ATP of 77 µm, was antagonized by Cibacron blue and pyridoxal‐5‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid, potentiated by Zn2+ and acidification, but not enhanced by ivermectin or diinosine pentaphosphate. 2′,3′‐O‐Trinitrophenyl‐ATP antagonized this response with an IC50 of 8 µm. All these properties are consistent with those of recombinant P2X2 homomeric receptors. Furthermore, specific P2X2 receptor immunoreactivity detected in wild‐type sensory neurons was unaltered in null mutant mice. Therefore, the αβmeATP‐insensitive persistent responses on nodose neurons are likely to be mediated by P2X2 homomers, which contribute to 60% of currents evoked by 100 µm ATP in the wild type.
The ubiquitin–proteasome cascade is required for mammalian long‐term memory formation
Authors: Lopez‐Salon Mariella , Alonso Mariana , Vianna Monica R. M. , Viola Haydee , E Souza Tadeu Mello , Izquierdo Ivan , Pasquini Juana M. , Medina Jorge H.
Published: March 2003

It has been recently demonstrated that ubiquitin–proteasome‐mediated proteolysis is required for long‐term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long‐term memory in the rat. Bilateral infusion of lactacystin, a specific proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one‐trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin–proteasome cascade, in hippocampus 4 h after training. Together, these findings indicate that the ubiquitin–proteasome cascade is crucial for the establishment of LTM in the behaving animal.
Cholinergic and noncholinergic septal neurons modulate strategy selection in spatial learning
Authors: Cahill Jonathan F. X. , Baxter Mark G.
Published: March 2003

Rats solving a simple spatial discrimination task in a plus maze initially employ a place‐learning strategy, then switch to a motor response strategy. The hippocampus is required for the use of a place‐learning strategy in this task. Rats with 192 IgG‐saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB), that selectively removed cholinergic neurons projecting to the hippocampus, were significantly facilitated in acquisition of the spatial discrimination, and switched from place to response strategies just as control rats did. Rats with ibotenic acid lesions of the MS/VDB, that produced cell loss in the MS/VDB but little damage to cholinergic neurons, were significantly impaired in acquiring the spatial discrimination and did not reliably employ either a place or response strategy at any point in training. This suggests that the MS/VDB modulates hippocampal involvement in place learning, but that cholinergic MS/VDB neurons are neither necessary nor sufficient for using a place strategy to solve a spatial discrimination.
HIV‐1 protein Tat reduces the glutamate‐induced intracellular Ca2+ increase in cultured cortical astrocytes
Authors: Köller Hubertus , Schaal Heiner , Freund Marcel , Garrido Sanuk Rafaela , Von Giesen Hans‐Jürgen , Ott Melanie , Rosenbaum Claudia , Arendt Gabriele
Published: March 2003

The trans‐activator protein Tat of the human immunodeficiency virus type 1 (HIV‐1) is regarded as an injurious molecule in the pathogenesis of HIV‐1 associated encephalopathy (HIVE). We investigated the effects of Tat on neuroligand‐induced intracellular Ca2+ increase in cultured astroglial cells. Rat cortical astrocytes, human glioblastoma cells and glial restricted precursor cells, from a human embryonic teratocarcinoma cell line, were incubated with recombinant Tat (100 ng/mL for 60 min) which induced a significant reduction of glutamate or ATP‐induced intracellular Ca2+ increase (‘glutamate response’, ‘ATP response’). The reduction of the glutamate response was also observed following cell incubation with cell extracts of HeLa‐T4+ cells transiently transfected with an expression plasmid coding for Tat. However, inactivation of the transcriptional trans‐activity of Tat, by using a mutant form of Tat, as well as inhibition of de novo protein synthesis by cycloheximide abolished the effect on the glutamate response. This suggests that Tat acts upon induction of a so far unknown cellular gene whoes gene product causes the reduction of glutamate responses. As the effect of Tat resembles the effect of TNFα on glutamate responses [Köller et al. (2001) Brain Res., 893, 237–243] which is locally released within the brains of HIVE patients, we also tested for synergistic effects of Tat and TNFα on the glutamate response. Low concentrations of Tat in combination with subthreshold concentrations of TNFα also elicited a marked reduction of astroglial glutamate responses. Our data suggest that Tat and TNFα, both by itself and synergistically, induce astroglial dysfunction.
Evidence that interleukin‐1β and reactive oxygen species production play a pivotal role in stress‐induced impairment of LTP in the rat dentate gyrus
Authors: Vereker Emily , O'Donnell Eamonn , Lynch Aileen , Kelly Áine , Nolan Yvonne , Lynch Marina A.
Published: March 2003

Long‐term potentiation (LTP) in both area CA1 and the dentate gyrus is attenuated by stress and the evidence is consistent with the view that this is a consequence of increased activation of glucocorticoid receptors, in the hippocampus, following the stress‐induced increase in circulating corticosterone. It has been shown that expression of the pro‐inflammatory cytokine, interleukin‐1β (IL‐1β), is increased in hippocampus in response to stress; this finding together with the observation that IL‐1β exerts an inhibitory effect on LTP, suggests that IL‐1β may play a key role in mediating this inhibitory effect of stress on LTP. In this study, we explore this possibility and report that stress is also associated with increased reactive oxygen species production. The evidence presented supports the view that this is secondary to the stress‐induced increase in IL‐1β concentration, as IL‐1β increased activity of superoxide dismutase and increased reactive oxygen species accumulation in hippocampus in vitro. We report that the inhibitory effect of stress on LTP is mimicked by H2O2, which increases reactive oxygen species accumulation, and by IL‐1β, the effect of which is overcome by the antioxidant, phenylarsine oxide. The hypothesis that the stress‐induced increase in reactive oxygen species production may underlie the suppression of LTP is further supported by the finding that the effect of stress is abrogated by dietary manipulation with antioxidant vitamins E and C.
Associative effects of Pavlovian differential inhibition of behaviour
Authors: Jones Dirk , Gonzalez‐Lima F.
Published: March 2003

The associative inhibitory control of behaviour is a major component of Pavlovian learning theory, but little is known about its functional neuroanatomy. The associative effects of differential inhibition of conditioned behaviour were investigated by mapping learning‐related changes in brain activity of the rat with fluorodeoxyglucose autoradiography. Of interest was how a tone is processed in auditory and extra‐auditory systems of the rat brain under similar behavioural, but different associative conditions. Conditioned emotional suppression to drink was used to assess training, and summation tests were used to verify that the tone became an inhibitor of conditioned behaviour. In the Inhibitor group, presentations of a tone stimulus alone were intermixed with presentations of a light stimulus followed by footshock. In the Pseudorandom group, the same numbers of tone, light and footshock presentations were used, but they were presented in a pseudorandom fashion. After training, fluorodeoxyglucose uptake was measured during tone presentations. Behavioural responding to the tone was similar during fluorodeoxyglucose uptake in the two groups, yet associative effects were found in brain activity. In the auditory system, the tone produced reduced fluorodeoxyglucose uptake in major relay nuclei (cochlear nucleus and inferior colliculus) in the Inhibitor group relative to the Pseudorandom group. The tone inhibitor produced similar decreases in the septohippocampal system and the retrosplenial cortex. In contrast, the tone inhibitor produced activity increases in somatosensory and reticulocerebellar systems. The findings provide the first detailed map of neural regions involved in the learned associations controlling differential inhibition of conditioned behaviour.
Acute modulation of synaptic transmission to motoneurons by BDNF in the neonatal rat spinal cord
Authors: Arvanian Victor L. , Mendell Lorne M.
Published: March 2003

We investigated the acute effects of bath applied BDNF on synaptic input to motoneurons in the hemisected spinal cord of the neonatal rat. Motoneurons were recorded intracellularly, and BDNF‐induced modulation of the synaptic response to stimulation of the homologous dorsal root (DR) and the ventrolateral funiculus (VLF) was examined. All motoneurons exhibited long‐lasting (up to several hours) depression of the DR‐activated monosynaptic AMPA/kainate‐receptor mediated EPSP in response to BDNF but in about half of the motoneurons this was preceded by facilitation. VLF‐evoked AMPA/kainate EPSPs in the same motoneurons were unaffected. BDNF effects were blocked by K252a and were not observed in neonates older than 1 week. Bath applied NMDA antagonists APV and MK‐801 abolished both facilitatory and inhibitory actions of BDNF on the AMPA/kainate responses indicating the requirement for functional NMDA receptors. The pharmacologically isolated, DR‐evoked, NMDA receptor‐mediated response exhibited the same pattern of changes after BDNF superfusion. When introduced into the motoneuron through the recording microelectrode, MK‐801 selectively blocked the facilitatory action of BDNF. Furthermore, BDNF enhanced NMDA‐induced depolarization of the motoneuron in the presence of tetrodotoxin (TTX), thus, confirming its facilitatory effect on motoneuron NMDA receptors. Bath application of either BDNF or NMDA depressed the monosynaptic EPSP after selective blockade of postsynaptic NMDA receptors indicating a role for presynaptic NMDA receptors in BDNF‐induced inhibitory action. Thus, BDNF‐induced facilitation of monosynaptic EPSPs in neonatal rats is mediated by direct effects on postsynaptic NMDA receptors, while its inhibitory action occurs presynaptically.
Increased cannabinoid CB1 receptor binding and activation of GTP‐binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP‐treated marmosets
Authors: Lastres‐Becker I. , Cebeira M. , de Ceballos M.L. , Zeng B. ‐Y. , Jenner P. , Ramos J. A. , Fernández‐Ruiz J. J.
Published: March 2003

Recent evidence obtained in rat models of Parkinson's disease showed that the density of cannabinoid CB1 receptors and their endogenous ligands increase in basal ganglia. However, no data exists from post‐mortem brain of humans affected by Parkinson's disease or from primate models of the disorder. In the present study, we examined CB1 receptor binding and the magnitude of the stimulation by WIN55,212‐2, a specific CB1 receptor agonist, of [35S]GTPγS binding to membrane fractions from the basal ganglia of patients affected by Parkinson's disease. In Parkinson's disease, WIN55,212‐2‐stimulated [35S]GTPγS binding in the caudate nucleus, putamen, lateral globus pallidus and substantia nigra was increased, thus indicating a more effective activation of GTP‐binding protein‐coupled signalling mechanisms via CB1 receptors. This was accompanied by an increase in CB1 receptor binding in the caudate nucleus and the putamen, although no changes were observed in the lateral globus pallidus and the substantia nigra. Because Parkinson's disease patients had been chronically treated with l‐DOPA, brains were studied from normal common marmosets and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated animals with and without chronic L‐DOPA treatment. MPTP‐lesioned marmosets had increased CB1 receptor binding in the caudate nucleus and the putamen compared to control marmosets, as well as increased stimulation of [35S]GTPγS binding by WIN55,212‐2. However, following l‐DOPA treatment these parameters returned towards control values. The results indicate that a nigro‐striatal lesion is associated with an increase in CB1 receptors in the basal ganglia in humans and nonhuman primates and that this increase could be reversed by chronic l‐DOPA therapy. The data suggest that CB1 receptor blockade might be useful as an adjuvant for the treatment of parkinsonian motor symptoms.
Neuronal coordination of arm and leg movements during human locomotion
Authors: Dietz V. , Fouad K. , Bastiaanse C. M.
Published: March 2003

We aimed to study the neuronal coordination of lower and upper limb muscles. We therefore evaluated the effect of small leg displacements during gait on leg and arm muscle electromyographic (EMG) activity in walking humans. During walking on a split‐belt treadmill (velocity 3.5 km/h), short accelerations or decelerations were randomly applied to the right belt during the mid or end stance phase. Alternatively, trains of electrical stimuli were delivered to the right distal tibial nerve. The EMG activity of the tibialis anterior (TA), gastrocnemius medialis (GM), deltoideus (Delt), triceps (Tric) and biceps brachii (Bic) of both sides was analysed. For comparison, impulses were also applied during standing and sitting. The displacements were followed by specific patterns of right leg and bilateral arm muscle EMG responses. Most arm muscle responses appeared with a short latency (65–80 ms) and were larger in Delt and Tric than in Bic. They were strongest when deceleration impulses were released during mid stance, associated with a right compensatory TA response. A similar response pattern in arm muscles was obtained following tibial nerve stimulation. The arm muscle responses were small or absent when stimuli were applied during standing or sitting. The arm muscle responses correlated more closely with the compensatory TA than with the compensatory GM responses. The amplitude of the responses in most arm muscles correlated closely with the background EMG activity of the respective arm muscle. The observations suggest the existence of a task‐dependent, flexible neuronal coupling between lower and upper limb muscles. The stronger impact of leg flexors in this interlimb coordination indicates that the neuronal control of leg flexor and extensor muscles is differentially interconnected during locomotion. The results are compatible with the assumption that the proximal arm muscle responses are associated with the swinging of the arms during gait, as a residual function of quadrupedal locomotion.
Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone‐marrow stromal cells
Authors: Dezawa Mari , Takahashi Izumi , Esaki Michiyo , Takano Masahiko , Sawada Hajime
Published: March 2003

Bone marrow stromal cells (MSCs) are multipotent stem cells that have the potential to differentiate into bone, cartilage, fat and muscle. We now demonstrate that MSCs can be induced to differentiate into cells with Schwann cell characteristics, capable of eliciting peripheral nervous system regeneration in adult rats. MSCs treated with beta‐mercaptoethanol followed by retinoic acid and cultured in the presence of forskolin, basic‐FGF, PDGF and heregulin, changed morphologically into cells resembling primary cultured Schwann cells and expressing p75, S‐100, GFAP and O4. The MSCs were genetically engineered by transduction with retrovirus encoding green fluorescent protein (GFP), and then differentiated by treatment with factors described above. They were transplanted into the cut ends of sciatic nerves, which then responded with vigorous nerve fibre regeneration within 3 weeks of the operation. Myelination of regenerated fibers by GFP‐expressing MSCs was recognized using confocal and immunoelectron microscopy. The results suggest that MSCs are able to differentiate into myelinating cells, capable of supporting nerve fibre re‐growth, and they can therefore be applied to induce nerve regeneration.
Protracted expression of serotonin transporter and altered thalamocortical projections in the barrelfield of hypothyroid rats
Authors: Ausó Eva , Cases Olivier , Fouquet Coralie , Camacho Miguel , García‐Velasco José‐Victor , Gaspar Patricia , Berbel Pere
Published: March 2003

In humans, thyroid hormone deficiency during development causes severe neurological diseases but the underlying mechanisms are unclear. We have examined the effects of thyroid hormones on the development of somatosensory thalamocortical projections, by inducing hypothyroidism in rats by methimazole treatment at embryonic day 13 and subsequent thyroidectomy at postnatal day 6 (P6). Initial development of the thalamocortical projections and their tangential and laminar patterning were similar in normal and hypothyroid rats from birth to P4. The tangential spread of the thalamocortical arbors is reduced in hypothyroid rats after P4, paralleling the overall cortical atrophy. Anterograde tracing and single axon reconstructions indicate that thalamic afferents reached layer IV but that they had fewer and shorter branches, with a 42% reduction in the number of boutons. The transient serotonin (5‐HT) immunostaining and 5‐HT transporter (5‐HTT) expression were both prolonged by 5 days in hypothyroid rats. This does not reflect a delayed maturation of the thalamus because other transiently expressed genes such as the vesicular monoamine transporter and the 5‐HT1B receptor are not modified. Protracted 5‐HTT expression also occurred in other areas with transient expression, but no changes were observed in the raphe nuclei where the 5‐HTT is expressed permanently. Thus, thyroid hormones appear to be important in regulating the extinction of the 5‐HTT in nonserotoninergic neurons. The transient stabilization of 5‐HT reuptake in hypothyroid rats could affect the growth of thalamic axons. Our data stress the importance of maternal and foetal thyroid hormones for the normal development of sensory systems.
Selective cardiorespiratory and catecholaminergic areas express the hypoxia‐inducible factor‐1α (HIF‐1α) under in vivo hypoxia in rat brainstem
Authors: Pascual Olivier , Denavit‐Saubié Monique , Dumas Sylvie , Kietzmann Thomas , Ghilini Ginette , Mallet Jacques , Pequignot Jean‐Marc
Published: March 2003

Under severe oxygen deprivation, all cells are able to express the transcription factor HIF‐1, which activates a wide range of genes. Under tolerable hypoxia, chemosensory inputs are integrated in brainstem areas, which control cardiorespiratory responses. However, the molecular mechanisms of this functional acclimatization are unknown. We investigated when and where the inducible HIF‐1α subunit is expressed in the rat brainstem in vivo, under physiological hypoxia. The regional localization of HIF‐1α mRNA and protein was determined by in situ hybridization and immunocytochemistry in adult male rats exposed to moderate hypoxia (10% O2) for 1–6 h. HIF‐1α protein was found in cell types identified by immunocytochemistry as catecholaminergic neurons. Hypoxia induced HIF‐1α mRNA and protein in only some parts of the brainstem located dorsomedially and ventrolaterally, which are those involved in the cardiorespiratory control. No labelling was detected under normoxia. The protein was detected in glia and neurons after 1 and 6 h of hypoxia, respectively. A subset of A2C2 and A1C1 catecholaminergic neurons colocalized tyrosine hydroxylase and HIF‐1α proteins under hypoxia, but no HIF‐1α was detected in more rostral catecholaminergic areas. In contrast to cardiorespiratory areas, HIF‐1α protein was already present under normoxia in glial cells of brainstem tracts but was not overexpressed under hypoxia, although HIF‐1α mRNA was up‐regulated. In conclusion, there appear to be two regulatory mechanisms for HIF‐1α expression in the brainstem: hypoxic induction of HIF‐1α protein in cardiorespiratory‐related areas and constitutive protein expression unaffected by hypoxia in brainstem tracts.
Steroid structure and pharmacological properties determine the anti‐amnesic effects of pregnenolone sulphate in the passive avoidance task in rats
Authors: Vallée M. , Shen W. , Heinrichs S. C. , Zorumski C. F. , Covey D. F. , Koob G. F. , Purdy R. H.
Published: March 2003

Pregnenolone sulphate (PREGS) has generated interest as one of the most potent memory‐enhancing neurosteroids to be examined in rodent learning studies, with particular importance in the ageing process. The mechanism by which this endogenous steroid enhances memory formation is hypothesized to involve actions on glutamatergic and GABAergic systems. This hypothesis stems from findings that PREGS is a potent positive modulator of N‐methyl‐d‐aspartate receptors (NMDARs) and a negative modulator of γ‐aminobutyric acidA receptors (GABAARs). Moreover, PREGS is able to reverse the amnesic‐like effects of NMDAR and GABAAR ligands. To investigate this hypothesis, the present study in rats examined the memory‐altering abilities of structural analogs of PREGS, which differ in their modulation of NMDAR and/or GABAAR function. The analogs tested were: 11‐ketopregnenolone sulphate (an agent that is inactive at GABAARs and NMDARs), epipregnanolone ([3β‐hydroxy‐5β‐pregnan‐20‐one] sulphate, an inhibitor of both GABAARs and NMDARs), and a newly synthesized (–) PREGS enantiomer (which is identical to PREGS in effects on GABAARs and NMDARs). The memory‐enhancing effects of PREGS and its analogs were tested in the passive avoidance task using the model of scopolamine‐induced amnesia. Both PREGS and its (–) enantiomer blocked the effects of scopolamine. The results show that, unlike PREGS, 11‐ketopregnenolone sulphate and epipregnanolone sulphate failed to block the effect of scopolamine, suggesting that altering the modulation of NMDA receptors diminishes the memory‐enhancing effects of PREGS. Moreover, enantioselectivity was demonstrated by the ability of natural PREGS to be an order of magnitude more effective than its synthetic enantiomer in reversing scopolamine‐induced amnesia. These results identify a novel neuropharmacological site for the modulation of memory processes by neuroactive steroids.
Seizure‐induced gene expression in area CA1 of the mouse hippocampus
Authors: French P. J. , O'Connor V. , Voss K. , Stean T. , Hunt S. P. , Bliss T. V. P.
Published: March 2003

Synaptic plasticity in the hippocampus requires activity‐dependent gene expression. We have therefore profiled gene expression in area CA1 following the induction of an electroshock‐evoked maximal seizure. Using cDNA microarrays, the differential expression of ≈ 9000 cDNAs was examined. In situ hybridization on 14 transcripts that showed strongest modulation in the microarray screen (1.8–2‐fold) confirmed the differential expression of a single gene that encodes for the nuclear hormone receptor NGFI‐B (Nur77, N10). Although this gene is only modestly up‐regulated (≈ 2‐fold) in area CA1, in situ hybridization revealed that maximal seizures induce a marked (≈ 12‐fold) up‐regulation of NGFI‐B in the dentate gyrus. These data support the notion [French et al. (2001) Eur. J. Neurosci., 13, 968–976] that CA1 pyramidal neurons are more refractory than granule cells of the dentate gyrus with respect to activity‐dependent gene transcription. Furthermore, our results argue against a large cohort of activity‐dependent genes in area CA1.
Cerebellar contribution to spatial event processing: involvement in procedural and working memory components
Authors: Mandolesi L. , Leggio M. G. , Graziano A. , Neri P. , Petrosini L.
Published: March 2003

Spatial function is one of the cognitive functions altered in the presence of cerebellar lesions. We investigated the cerebellar contribution to the acquisition of spatial procedural and working memory components by means of a radial maze. To establish whether a cerebellar lesion would cause a deficit in solving the radial maze, a first experiment was carried out by using a full‐baited maze procedure in different experimental groups, with or without cerebellar lesion and with or without pretraining. Non‐pretrained hemicerebellectomized (HCbed) animals exhibited impaired performances in all (motor, spatial and procedural) task aspects. Pre‐trained HCbed animals performed similarly to control animals in the task aspects linked to the processing of spatial and procedural factors. To distinguish procedural from working memory components, a forced‐choice paradigm of the radial maze was used in the second experiment. Non‐pretrained HCbed rats continued to make a lot of errors and show severe perseverative tendencies, already observed in the first experiment, supporting a specific cerebellar role in acquiring new behaviours and in modifying them in relation to the context. Interestingly, hindered from putting the acquired explorative patterns into action and compelled to use only working memory abilities, the pretrained HCbed group exhibited a dramatic worsening of performance. In conclusion, the present findings demonstrate that cerebellar damage induces a specific behaviour in radial maze tasks, characterized by an inflexible use of the procedures (if indeed any procedure was acquired before the lesion) and by a severe impairment in working memory processes.
Anti‐inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia
Authors: Wong Amanda , Dukic‐Stefanovic Sladjana , Gasic‐Milenkovic Jovana , Schinzel Reinhard , Wiesinger Heinrich , Riederer Peter , Münch Gerald
Published: March 2003

Advanced glycation endproducts (AGEs) accumulate on long‐lived protein deposits including β‐amyloid plaques in Alzheimer's disease (AD). AGE‐modified amyloid deposits contain oxidized and nitrated proteins as markers of a chronic neuroinflammatory condition and are surrounded by activated microglial and astroglial cells. We show in this study that AGEs increase nitric oxide production by induction of the inducible nitric oxide synthase (iNOS) on the mRNA and protein level in the murine microglial cell line N‐11. Membrane permeable antioxidants including oestrogen derivatives (e.g. 17β‐oestradiol) thiol antioxidants (e.g. (R+)‐α‐lipoic acid) and Gingko biloba extract EGb 761, but not phosphodiesterase inhibitors such as propentophylline, prevent the up‐regulation of AGE‐induced iNOS expression and NO production. These results indicate that oxygen free radicals serve as second messengers in AGE‐induced pro‐inflammatory signal transduction pathways. As this pharmacological mechanism is not only relevant for Alzheimer's disease, but also for many chronic inflammatory conditions, such membrane‐permeable antioxidants could be regarded not only as antioxidant, but also as potent therapeutic anti‐inflammatory drugs.