bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Transgenic 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

Many 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

Metabotropic 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

The 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

The 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

Mice 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

The 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

Previous 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.
A single exposure to morphine induces long‐lasting behavioural and neurochemical sensitization in rats
Authors: Vanderschuren Louk J. M. J. , De Vries Taco J. , Wardeh George , Hogenboom François A. C. M. , Schoffelmeer Anton N. M.
Published: March 2003

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long‐lasting sensitization. The present study was designed to evaluate whether long‐lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate–putamen, was assessed. In morphine‐pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate–putamen from morphine‐pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long‐lasting behavioural sensitization and associated neuroadaptations.
Modulation of the synchronization between cells in visual cortex by contextual targets
Authors: Bretzner Fréderic , Aïtoubah Jamila , Shumikhina Svetlana , Tan Yao‐Fang , Molotchnikoff Stéphane
Published: March 2003

It has been suggested that synchronization of action potentials encodes diverse features of a single image. However, properties of the synchronization, which occurs on a time scale of ≈ 1–5 ms, are still poorly understood. We have tested the modulation of synchronization by manipulating the contextual targets introduced in the surround of the receptive field. Experiments were carried out on anaesthetized cats prepared for multiunit and single‐cell recordings in area 17. Initially, a patch of sine‐wave drifting grating was positioned over the overlapping receptive fields of several neurons. If this coherent motion produced a significant synchronization in cross‐correlograms, contextual targets were added. The first contextual stimuli were two sine‐wave patches placed above and below the central compound receptive field. Only the contrast of contextual targets changed. Results show that the larger the differential contrast the higher the synchronization. The second contextual stimulus was a lateral shift of a sine‐wave patch. Data show that the wider the distance between the central and peripheral patches the better the synchronization. Furthermore, results suggest that the synchrony pattern computed by cross correlating multiunit recordings from two sites differs when the cross correlation is carried out between individual units belonging to each multiunit recording. Together with our previous results it appears that synchronization is stimulus dependent and its strength increases with larger disparities included in the whole stimulating image.
Orexins (hypocretins) directly excite tuberomammillary neurons
Authors: Bayer Laurence , Eggermann Emmanuel , Serafin Mauro , Saint‐Mleux Benoît , Machard D. , Jones Barbara , Mühlethaler Michel
Published: March 2003

Wakefulness has recently been shown to depend upon the newly identified orexin (or hypocretin) neuropeptides by the findings that alteration in their precursor protein, their receptors or the neurons that produce them leads to the sleep disorder narcolepsy in both animals and humans. The questions of how and where these brain peptides act to maintain wakefulness remain unresolved. The purpose of the present study was to determine whether the orexins could directly affect hypothalamic histaminergic neurons, which are known to contribute to the state of wakefulness by their diffuse projections through the brain. Using brain slices, we recorded in the ventral tuberomammillary nuclei from neurons identified as histaminergic on the basis of their previously described morphological and electrophysiological characteristics and found that they were depolarized and excited by the orexins through a direct postsynaptic action. We then compared the depolarizing effect of orexin A and B and found that they were equally effective upon these cells. This latter finding suggests that the effect of orexins is mediated by orexin type 2 receptors, which are those lacking in narcoleptic dogs. Our results therefore show that the histaminergic neurons of the tuberomammillary nuclei represent an important target for the orexin system in the maintenance of wakefulness.
Altered hippocampal gene expression prior to the onset of spontaneous seizures in the rat post‐status epilepticus model
Authors: Hendriksen H. , Datson Nicole A. , Ghijsen Wim E. J. M. , Van Vliet Erwin A. , Da Silva Fernando H. Lopes , Gorter Jan A. , Vreugdenhil Erno
Published: March 2003

Neuronal loss, gliosis and axonal sprouting in the hippocampal formation are characteristics of the syndrome of mesial temporal sclerosis (MTS). In the post‐status epilepticus (SE) rat model of spontaneous seizures these features of the MTS syndrome can be reproduced. To get a global view of the changes in gene expression in the hippocampus we applied serial analysis of gene expression (SAGE) during the early phase of epileptogenesis (latent period), prior to the onset of the first spontaneous seizure. A total of 10 000 SAGE tags were analyzed per experimental group, resulting in 5053 (SE) and 5918 (control group) unique tags (genes), each representing a specific mRNA transcript. Of these, 92 genes were differentially expressed in the hippocampus of post‐SE rats in comparison to controls. These genes appeared to be mainly associated with ribosomal proteins, protein processing, axonal growth and glial proliferation proteins. Verification of two of the differentially expressed genes by in situ hybridization confirmed the changes found by SAGE. Histological analysis of hippocampal sections obtained 8 days after SE showed extensive cell loss, mossy fibre sprouting and gliosis in hippocampal sub regions. This study identifies new high‐abundant genes that may play an important role in post‐SE epileptogenesis.
Cystatin C, a cysteine protease inhibitor, is persistently up‐regulated in neurons and glia in a rat model for mesial temporal lobe epilepsy
Authors: Aronica Eleonora , Van Vliet Erwin A. , Hendriksen Erik , Troost Dirk , Lopes da Silva Fernando H. , Gorter Jan A.
Published: March 2003

Cystatin C (CSTC), a cysteine protease inhibitor, has been implicated in the processes of neuronal degeneration and repair of the nervous system. Using serial analysis of gene expression (SAGE), we recently identified CSTC as one of the genes that are overexpressed after electrically induced status epilepticus (SE). In the present study, Western blot analysis extended the SAGE results, showing increased CSTC protein in the hippocampus and entorhinal cortex. Immunocytochemistry revealed an increase in CSTC expression in glial cells, which was first apparent 24 h after onset of SE, and persisted for at least 3 months. Double immunolabelling confirmed that both reactive astrocytes, and activated microglia were CSTC immunopositive. Within the hippocampus, up‐regulation was also observed in neuronal cells within one day after SE. Up‐regulation was still present in hippocampal pyramidal cells and surviving interneurons of chronic epileptic rats (3–8 months post‐SE). This study demonstrates that status epilepticus leads to a widespread and persistent up‐regulation of CSTC in the hippocampus and entorhinal cortex, which may represent an intrinsic neuroprotective mechanism in the course of epileptogenesis that may counteract progression of the disease.
Histamine H3 receptor‐mediated impairment of contextual fear conditioning and in‐vivo inhibition of cholinergic transmission in the rat basolateral amygdala
Authors: Passani M. Beatrice , Cangioli Iacopo , Baldi Elisabetta , Bucherelli Corrado , Mannaioni Pier Francesco , Blandina Patrizio
Published: March 2003

We investigated the effects of agents acting at histamine receptors on both, spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the effects of histamine on cognition might be explained by the modulation of cholinergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modulates the spontaneous release of ACh. The addition of 100 mm KCl to the perfusion medium strongly stimulated ACh release, whereas, 0.5 µm tetrodotoxin (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H3 antagonists (ciproxifan, clobenpropit and thioperamide), directly administered to the BLA, decreased ACh spontaneous release, an effect fully antagonized by the simultaneous perfusion of the BLA with cimetidine, an H2 antagonist. Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H1 antagonists failed to alter ACh spontaneous release. Rats receiving intra‐BLA, bilateral injections of the H3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear conditioning, showed memory consolidation impairment of contextual fear conditioning. Post‐training, bilateral injections of 50 µg scopolamine also had an adverse effect on memory retention. These observations provide the first evidence that histamine receptors are involved in the modulation of cholinergic tone in the amygdala and in the consolidation of fear conditioning.
Hypothalamic–pituitary–adrenal axis function and corticosterone receptor expression in behaviourally characterized young and aged Long–Evans rats
Authors: Bizon Jennifer L. , Helm Katherine A. , Han Jung‐Soo , Chun Hyun‐Ja , Pucilowska Jolanta , Lund Pauline Kay , Gallagher Michela
Published: March 2003

In the current investigation, hypothalamic–pituitary–adrenal (HPA) axis function was examined in young and aged male Long‐Evans rats that were initially assessed on a version of the Morris water maze sensitive to cognitive impairment during ageing. In behaviourally characterized rats, a 1‐h restraint stress paradigm revealed that plasma corticosterone concentrations in aged cognitively impaired rats took significantly longer to return to baseline following the stressor than did those in young or aged cognitively unimpaired rats. No differences in basal or peak plasma corticosterone concentrations, however, were observed between young or aged rats, irrespective of cognitive status. Using ribonuclease protection assays and in situ hybridization, we evaluated mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA abundance in young and aged rats characterized on the spatial task. Abundance of MR mRNA was decreased as a function of age in stratum granulosum but not hippocampus proper, and the decrease in MR mRNA was largely unrelated to cognitive status. However, GR mRNA was significantly reduced in several hippocampal subfields (i.e. stratum granulosum and temporal hippocampus proper) and other related cortical structures (medial prefrontal and olfactory regions) of aged cognitively impaired rats compared to either young or aged cognitively unimpaired cohorts, and was significantly correlated with spatial learning ability among the aged rats in each of these brain regions. In agreement with previous stereological data from this ageing model, no changes were detected in neuron density in the hippocampus of the rats used in the in situ hybridization analysis. These data are the first to describe a coordinated decrease in GR mRNA in a functional brain system including hippocampus and related cortical areas that occurs in tandem with impairments of the HPA response to stress and cognitive decline in ageing.
Discharge patterns of neurons in the medial pontobulbar reticular formation during fictive mastication in the rabbit
Authors: Westberg K.‐G. , Scott G. , Olsson K. Å. , Lund J. P.
Published: March 2003

In this study, we describe functional characteristics of neurons forming networks generating oral ingestive motor behaviours. Neurons in medial reticular nuclei on the right side of the brainstem between the trigeminal and hypoglossal motor nuclei were recorded in anaesthetized and paralysed rabbits during two types of masticatory‐like motor patterns induced by electrical stimulation of the left (contralateral) or right (ipsilateral) cortical masticatory areas. Sixty‐seven neurons in nucleus reticularis pontis caudalis (nPontc), nucleus reticularis parvocellularis (nParv), and nucleus reticularis gigantocellularis (Rgc) were studied. These were classified as phasic or tonic depending on their firing pattern during the fictive jaw movement cycle. Phasic neurons located in the dorsal part of nPontc were active during the jaw opening phase, whilst those in dorsal nParv tended to fire during the closing phase. In most neurons, burst duration and firing frequency changed between the two motor patterns, but there was little change in phase of firing. Tonic units were mainly recorded in the ventral half of nPontc, and at the junction between Rgc and caudal nParv. Cortical inputs with short latency from the contralateral masticatory area were more frequent in phasic (82%) than tonic (44%) neurons, whilst inputs from the ipsilateral cortex were equal in the two subgroups (57% and 56%). Phasic neurons had significantly shorter mean contralateral than ipsilateral cortical latencies, whilst there was no difference among tonic neurons. Intra‐ and perioral primary afferent inputs activated both types of neurons at oligo‐synaptic latencies. Our results show that subpopulations of neurons in medial reticular nuclei extending from the caudal part of the trigeminal motor nucleus to the rostral third of the hypoglossal motor nucleus are active during the fictive masticatory motor behaviour. Unlike masticatory neurons in the lateral tegmentum, the medial subpopulations are spatially organized according to discharge pattern.
Differential sensitivity of medium‐ and large‐sized striatal neurons to NMDA but not kainate receptor activation in the rat
Authors: Cepeda Carlos , Itri Jason N. , Flores‐Hernández Jorge , Hurst Raymond S. , Calvert Christopher R. , Levine Michael S.
Published: March 2003

Infrared videomicroscopy and differential interference contrast optics were used to identify medium‐ and large‐sized neurons in striatal slices from young rats. Whole‐cell patch‐clamp recordings were obtained to compare membrane currents evoked by application of N‐methyl‐d‐aspartate (NMDA) and kainate. Inward currents and current densities induced by NMDA were significantly smaller in large‐ than in medium‐sized striatal neurons. The negative slope conductance for NMDA currents was greater in medium‐ than in large‐sized neurons and more depolarization was required to remove the Mg2+ blockade. In contrast, currents induced by kainate were significantly greater in large‐sized neurons whilst current densities were approximately equal in both cell types. Spontaneous excitatory postsynaptic currents occurred frequently in medium‐sized neurons but were relatively infrequent in large‐sized neurons. Excitatory postsynaptic currents evoked by electrical stimulation were smaller in large‐ than in medium‐sized neurons. A final set of experiments assessed a functional consequence of the differential sensitivity of medium‐ and large‐sized neurons to NMDA. Cell swelling was used to examine changes in somatic area in both neuronal types after prolonged application of NMDA or kainate. NMDA produced a time‐dependent increase in somatic area in medium‐sized neurons whilst it produced only minimal changes in large interneurons. In contrast, application of kainate produced significant swelling in both medium‐ and large‐sized cells. We hypothesize that reduced sensitivity to NMDA may be due to variations in receptor subunit composition and/or the relative density of receptors in the two cell types. These findings help define the conditions that put neurons at risk for excitotoxic damage in neurological disorders.
Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus
Authors: Müller Marianne B. , Lucassen Paul J. , Yassouridis Alexander , Hoogendijk Witte J. G. , Holsboer Florian , Swaab Dick F.
Published: March 2003

In major depression, decreased hippocampal volume has been attributed to hypercortisolemia, a frequent sign of the disorder, because in animals an excess of corticosteroids has led to dendritic atrophy, astrogliosis and loss of neurons in this brain region. The present study is the first to investigate the structural integrity of the human hippocampus in major depression and following glucocorticoid treatment. Post‐mortem hippocampal tissue from 15 patients who had had major depression or bipolar affective disorder, 10 patients who had been treated with glucocorticoids and 16 controls was assessed using haematoxylin‐eosin, Nissl and Bodian staining. The patterns of reactive astrogliosis (glial fibrillary acidic protein, GFAP), synaptic density (synaptophysin), synaptic reorganization (growth‐associated protein B‐50) and early signs of Alzheimer's disease (Alz‐50) were examined immunocytochemically. Multivariate analysis, with the patients' age, tissue fixation time and postmortem delay as covariates, was performed. There was no evidence of neuronal cell loss or other major morphological alterations in any of the groups, nor was there a significant change in the distribution pattern of synaptophysin or Alz‐50. Changes in B‐50 and GFAP staining were observed in the steroid‐treated and depressed patients in areas CA1 and CA2 only. The human hippocampus in major depression and after glucocorticoid treatment does not reveal any major morphological changes or signs of neuronal cell death, but does show subtle alterations in B‐50 and GFAP expression in selected parts of the pyramidal cell layer.
Change blindness and time to consciousness
Authors: Niedeggen Michael , Wichmann Petra , Stoerig Petra
Published: March 2003

Detection of changes in a visual scene can be substantially delayed when the original and the modified image are separated by a brief screen flicker. We used this phenomenon of ‘change blindness’ to find when the brain detects the mismatch in relation to when the observer reports it, and whether changes in identity and position are processed similarly. Event‐related brain potentials (ERPs) recorded while the subjects searched for the change in alternating series of images showed that the epoch during which they indicated detection was characterized by a marked positivity from 300 to 700 ms. Analysis of data from image presentations preceding the subjects' response revealed a similar but smaller ERP positivity one (identity) or even two (position) epochs before detection. As each epoch lasted 1500 ms, the brain may register a change as early as 3000 ms before the observer.
Developmental expression of the calcium release channels during early neurogenesis of the mouse cerebral cortex
Authors: Faure Anne‐Valérie , Grunwald Didier , Moutin Marie‐Jo , Hilly Mauricette , Mauger Jean‐Pierre , Marty Isabelle , De Waard Michel , Villaz Michel , Albrieux Mireille
Published: March 2003

The developmental changes of intracellular calcium release channels of mouse neocortex were studied at the onset of neurogenesis, which occurs between embryonic days E11 and E17. The three main isoforms of the two families of intracellular calcium release channels, namely the inositol trisphosphate receptors (IP3R) and the ryanodine receptors (RyR), were detected by their transcripts in the cerebral hemispheres, as early as stage E11. The major isoforms of each family, IP3R‐1 and RyR‐2, were found at the protein level by Western blot analysis. Expression of these proteins increases progressively throughout brain development. Their localization in coronal sections of cortex has been observed by immunodetection from E12, and compared to the TuJ1 (anti‐class III β‐tubulin antibody) neuronal specific labelling. The expression of both channels is greatly enhanced after E12, and both were seen to be present in most of the proliferative and neuronal cells of the slice. Between E12 and E13, there is a striking transition in the pattern of calcium release elicited by specific agonists of these channels, thimerosal for IP3R and caffeine for RyR. The signals induced by thimerosal were not zone‐specific, while the observed calcium release signals induced by caffeine were predominantly restricted out of the ventricular zone. This zone‐specific caffeine sensitivity is consistent with the main RyR localization immunodetected at E13. Our results indicate that there is a time lag of several days between the molecular detection of calcium release channels and their functional expression, around the time of neuronal differentiation. Altogether, they provide a molecular basis for analyzing the developmental modulation of calcium signals useful for neurogenesis progression.
Nerve growth factor in combination with second messenger analogues causes neuronal differentiation of PC12 cells expressing a dominant inhibitory Ras protein without inducing activation of extracellular signal‐regulated kinases
Authors: Boglári Gábor , Szeberényi József
Published: March 2003

In the present work, nerve growth factor (NGF) was used in combination with the calcium ionophore, ionomycin or dibutyryl cyclic AMP (dbcAMP), to study the connection between neuronal differentiation and extracellular signal‐regulated kinase (ERK) activation of PC12 rat pheochromocytoma cells expressing a dominant negative, Ha‐Ras Asn17 protein. Due to the block of endogenous Ras activity, neurite outgrowth in response to NGF is completely inhibited in these cells. However, this blockade can be bypassed by combined treatment with NGF plus ionomycin or NGF plus dbcAMP. The mitogen‐activated protein kinase (MAPK)/ERK kinase inhibitor, PD98059, proved to be insufficient in inhibiting the neurite outgrowth under these conditions. Moreover, although both long‐term ERK activation and nuclear translocation of ERKs are believed to be key events in neuronal differentiation, neither detectable ERK phosphorylation, nor nuclear translocation of these enzymes, occurred upon combination treatments in our experimental system. However, the neuritogenesis induced by either the combination of NGF/ionomycin or NGF/dbcAMP was inhibited by the Trk inhibitor, K252a. Ras‐independent pathways, originating from the NGF receptor, can thus synergize with second messenger analogues bypassing the ERK cascade but leading to the same biological result – neurite formation.
Brain targeting and glomerulus formation of two olfactory neuron populations expressing related receptor types
Authors: Conzelmann Sidonie , Malun Dagmar , Breer Heinz , Strotmann Jörg
Published: March 2003

Olfactory sensory neurons expressing different members of the mOR37 odourant receptor subfamily send their axons to distinct glomeruli located in the immediate vicinity in the olfactory bulb [Strotmann, J., Conzelmann, S., Beck, A., Feinstein, P., Breer, H. & Mombaerts, P. (2000) J. Neurosci., 20, 6927–6938]. In this study, the potential of transgenic mouse lines was used to explore the onset of receptor expression, the outgrowth of axons as well as the glomerulus formation for two neuron populations expressing different mOR37 subtypes. The data indicate a synchronous time course of these features for both neuron populations. From E15 until the day of birth, the axons of the two mOR37 populations terminate in a common, small area of the presumptive olfactory bulb. During a short postnatal phase, the two axon populations segregate into distinct, protoglomerular structures; some aberrant fibers can still be observed during this period.
Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey
Authors: Takada M. , Tokuno H. , Hamada I. , Inase M. , Ito Y. , Imanishi M. , Hasegawa N. , Akazawa T. , Hatanaka N. , Nambu A.
Published: March 2003

The cingulate motor areas reside within regions lining the cingulate sulcus and are divided into rostral and caudal parts. Recent studies suggest that the rostral and caudal cingulate motor areas participate in distinct aspects of motor function: the former plays a role in higher‐order cognitive control of movements, whereas the latter is more directly involved in their execution. Here, we investigated the organization of cingulate motor areas inputs to the basal ganglia in the macaque monkey. Identified forelimb representations of the rostral and caudal cingulate motor areas were injected with different anterograde tracers and the distribution patterns of labelled terminals were analysed in the striatum and the subthalamic nucleus. Corticostriatal inputs from the rostral and caudal cingulate motor areas were located within the rostral striatum, with the highest density in the striatal cell bridges and the ventrolateral portions of the putamen, respectively. There was no substantial overlap between these input zones. Similarly, a certain segregation of input zones from the rostral and caudal cingulate motor areas occurred along the mediolateral axis of the subthalamic nucleus. It has also been revealed that corticostriatal and corticosubthalamic input zones from the rostral cingulate motor area considerably overlapped those from the presupplementary motor area, while the input zones from the caudal cingulate motor area displayed a large overlap with those from the primary motor cortex. The present results indicate that a parallel design underlies motor information processing in the cortico‐basal ganglia loop derived from the rostral and caudal cingulate motor areas.
Characterization of the single‐channel properties of NMDA receptors in laminae I and II of the dorsal horn of neonatal rat spinal cord
Authors: Green G. Mark , Gibb Alasdair J.
Published: March 2003

The single‐channel properties of native NMDA receptors in laminae I and II of the dorsal horn of the neonatal rat spinal cord were studied using outside‐out patch‐clamp techniques. These receptors were found to have several features that distinguish them from native NMDA receptors elsewhere in the CNS. Single‐channel currents activated by NMDA (100 nm) and glycine (10 µm) exhibited five distinct amplitude components with slope‐conductance values of 19.9 ± 0.8, 32.9 ± 0.6, 42.2 ± 1.1, 53.0 ± 1.0 and 68.7 ± 1.5 pS. Direct transitions were observed between all conductance levels but transitions between 69‐pS openings and 20‐, 33‐ and 42‐pS openings were rare. There was no significant difference in the frequency of direct transitions from 42‐ to 20‐pS compared to 20‐ to 42‐pS transitions. The Kb (0 mV) for Mg2+ was 89 µm. The Mg2+ unblocking rate constant was similar to other reported values. However, the Mg2+ blocking rate constant was larger than other reported values, suggesting an unusually high sensitivity to Mg2+. The NR2B subunit‐selective antagonist, ifenprodil, had no significant effect on overall channel activity but significantly decreased the mean open time of 53‐pS openings. These results suggest neonatal laminae I and II NMDA receptors are not simply composed of NR1 and NR2B subunits or NR1 and NR2D subunits. It is possible that these properties are due to an as yet uninvestigated combination of two NR2 subunits with the NR1 subunit or a combination of NR3A, NR2 and NR1 subunits.
C‐type natriuretic peptide (CNP) regulates cocaine‐induced dopamine increase and immediate early gene expression in rat brain
Authors: Thiriet Nathalie , Jouvert Peggy , Gobaille Serge , Solov'Eva Olga , Gough Bobby , Aunis Dominique , Ali Syed , Zwiller Jean
Published: March 2003

The neuropeptide C‐type natriuretic peptide (CNP) is the primary biologically active natriuretic peptide in brain. Using in situ hybridization, the present report demonstrates that CNP regulates egr‐1, c‐fos and junB immediate early gene expression in rat brain. In the frontal cortex, CNP induced immediate early gene expression whereas it inhibited dose‐dependently the cocaine‐induced early gene expression in the dopaminergic projection fields nucleus accumbens and caudate–putamen. CNP may produce its effect directly on dopaminergic neurons because we found that its receptor, guanylyl cyclase GC‐B, was expressed in the mesencephalon where dopaminergic neurons originate, as well as in their projection fields. The inhibition by CNP of the early gene expression elicited by cocaine in the caudate–putamen is correlated with a CNP‐evoked decrease in cocaine‐induced rise in extracellular dopamine, measured by in vivo microdialysis experiments. The significance of the inhibition of cocaine‐induced dopamine release and early gene induction by the endogenous peptide CNP is demonstrated by data indicating that CNP reduced the cocaine‐induced spontaneous locomotor activation. By inhibiting dopaminergic neuronal activity, CNP represents a potential negative regulator of related behavioural effects of cocaine.
Putative glycine receptors in Hydra: a biochemical and behavioural study
Authors: Pierobon Paola , Minei Rosario , Porcu Patrizia , Sogliano Cristiana , Tino Angela , Marino Giuseppe , Biggio Giovanni , Concas Alessandra
Published: March 2003

Glycine acts as an inhibitory transmitter in the lower brain stem and spinal cord of vertebrate species, while very few data are yet available to support a similar role in invertebrate nervous systems. Here we report the identification and characterization of glycine receptors in the freshwater polyp Hydra vulgaris (Cnidaria, Hydrozoa) by biochemical and behavioural studies. Saturation experiments revealed the occurrence of one population of binding sites of nanomolar affinity (KD = 33 nm) and low capacity (Bmax= 79 fmol/mg protein) for [3H]strychnine. The addition of glycine or taurine (0.1 µm–1 mm) produced a dose‐dependent inhibition of [3H]strychnine binding. β‐alanine (0.1–1 mm) did not significantly affect [3H]strychnine binding. The pharmacological properties of these receptors compare with those of vertebrate glycine receptors. Stimulation of Hydra polyps by reduced glutathione resulted in a significant increase in the duration of mouth opening in the presence of glycine, taurine or β‐alanine. The enhancement of the response was related both to amino acid (10–100 µm) and to glutathione concentration (1–10 µm). The effects of glycine or its agonists were suppressed by strychnine (1–10 µm). d‐serine, a glycine agonist at the vertebrate NMDA receptor, produced opposite effects to those of glycine. The effects of d‐serine were suppressed by 5,7‐dichlorokynurenic acid but not by strychnine. In vitro, [3H]strychnine binding was not displaced by d‐serine. These results indicate a dual action of glycine in Hydra tissues. The hypothesis that NMDA receptors may also be present in this elementary nervous system is proposed.
Immune surveillance of mouse brain perivascular spaces by blood‐borne macrophages
Authors: Bechmann Ingo , Priller Josef , Kovac Adam , Böntert Matthias , Wehner Tim , Klett Francisco Fernandez , Bohsung Joerg , Stuschke Martin , Dirnagl Ulrich , Nitsch Robert
Published: March 2003

Virchow–Robin's perivascular spaces lie between the basement membrane around pericytes and the basement membrane at the surface of the glia limitans of the brain vessels. They are directly connected to the subpial space and harbour a population of cells distinct from pericytes, perivascular microglia and other cells within perivascular spaces (e.g. T cells and mast cells) in their ability to quickly phagocytose particles from the cerebrospinal fluid (CSF). Morphology, function, and cell surface proteins of these perivascular cells suggest an origin from the monocyte/macrophage lineage. It is currently unclear to what extent these brain perivascular cells represent a resident population of histiocytes or undergo continuous supplementation from blood monocytes. Using transplants of green‐fluorescent‐protein (GFP)‐transfected bone marrow cells, we therefore investigated the replacement of perivascular cells by blood‐borne macrophages in adult mice. GFP‐positive cells in the perivascular spaces were found as early as 2 weeks post transplantation. The substitution of host perivascular cells by donor‐derived macrophages was then evaluated using immunocytochemistry and intraventricular injection of hydrophilic rhodamine‐fluorescent tracers. Such tracers diffuse along perivascular spaces and are subsequently phagocytosed by perivascular cells leading to stable phagocytosis‐dependent labelling. Thus, the population of newly immigrated macrophages could be related to the total number of perivascular macrophages. This approach revealed a continuous increase of donor‐derived perivascular cells. At 14 weeks post transplantation, all perivascular cells were donor‐derived. These data show that brain perivascular cells are a population of migratory macrophages and not resident histiocytes.