bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrophysiological analysis of suprachiasmatic nucleus projections to the ventrolateral preoptic area in the rat
Authors: Sun X. , Whitefield S. , Rusak B. , Semba K.
Published: March 2003

The circadian pacemaker housed in the suprachiasmatic nucleus (SCN) synchronizes daily sleep–wake cycles, presumably by modulating the sleep–wake regulatory system, including ventrolateral preoptic area (VLPO) neurons. We used whole‐cell patch‐clamp recording to study the projections from the SCN to the VLPO in horizontal slices of rat hypothalamus. Single‐pulse stimulation of the SCN region elicited postsynaptic currents (PSCs) in 20 of 66 neurons (30%) recorded within the VLPO region as verified by intracellular biocytin labelling. At a holding potential of −60 mV, the evoked PSCs had an amplitude of 17.6 ± 3.2 pA (SEM) and a latency of 6.3 ± 0.5 ms (n = 10). There was a trend for simple excitatory postsynaptic currents (EPSCs) to be evoked in the VLPO cluster, simple inhibitory postsynaptic currents (IPSCs) in the extended VLPO, and a combination of EPSCs and IPSCs in both regions. IPSCs were blocked reversibly by bicuculline (10 µm, n = 11). In both the presence and absence of bicuculline, EPSCs had fast and slow components that were blocked by 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX; 10 µm; n = 7), and (±)3‐(2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid (CPP; 10 µm, n = 6), respectively. Reversal potentials for the evoked IPSCs and EPSCs were consistent with mediation via GABAA and ionotropic glutamate receptors, respectively. These results suggest that the SCN region provides both inhibitory and excitatory inputs to single VLPO neurons, which are mediated, respectively, by GABAA receptors and by both non‐NMDA and NMDA glutamate receptors. These projections may play important roles in conveying circadian input to systems in the preoptic area that regulate sleep and waking.
Processing of facial emotional expression: spatio‐temporal data as assessed by scalp event‐related potentials
Authors: Krolak‐Salmon P. , Fischer C. , Vighetto A. , Mauguière F.
Published: March 2003

Event‐related potentials (ERPs) were recorded in 10 adult volunteers, who were asked to view pictures of faces with different emotional expressions, i.e. fear, happiness, disgust, surprise and neutral expression [Ekman, P. & Friesen, W.V. (1975). Pictures of Facial Affect. Consulting Psychologist Press, Palo Alto, CA]. ERPs were recorded during two different tasks with the same stimuli. Firstly, subjects were instructed to pay attention to the gender of the faces by counting males or females. Secondly, they had to focus on facial expressions by counting faces who looked surprised. The classical scalp ‘face‐related potentials’, i.e. a vertex‐positive potential and a bilateral temporal negativity, were recorded 150 ms after the stimulus onset. Significant differences were found, firstly between late‐latency ERPs to emotional faces and to neutral faces, between 250 and 550 ms of latency and, secondly, among the ERPs to the different facial expressions between 550 and 750 ms of latency. These differences appeared only during the expression discrimination task, not during the gender discrimination task. Topographic maps of these differences showed a specific right temporal activity related to each emotional expression, some particularities being observed for each expression. This study provides new data concerning the spatio‐temporal features of facial expression processing, particularly a late‐latency activity related to specific attention to facial expressions.
Intrinsic connectivity of human auditory areas: a tracing study with DiI
Authors: Tardif Eric , Clarke Stephanie
Published: March 2003

The human supratemporal plane contains the primary as well as several other auditory areas. We have investigated the intrinsic connectivity of these areas by means of antero‐ and retrograde labelling with the carbocyanin dye DiI (1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate). A total of 30 injections was placed in both hemispheres of four freshly fixed postmortem brains. Labelled neurons and axons were found in cortex around the injection. The retrograde labelling varied from faint to Golgi‐like; most of the retrograde labelled neurons were layers II–III pyramids and only a few were nonpyramidal neurons. Labelled axons were dense in all layers near the injection site, while they became relatively rare in layer IV further away. The tangential spread of labelling differed among auditory areas. On Heschl's gyrus (corresponding to the primary auditory cortex and cytoarchitectonic areas TD and part of TB) intrinsic connectivity involved a relatively narrow part of cortex. They spread over larger parts of cortex in plana polare and temporale (areas TG, TA and the remaining part of TB). A number of injections also produced anisotropic labelling patterns. These results reveal differences in intrinsic connectivity between auditory areas. They suggest that intrinsic connections within the primary auditory area, area TD and part of TB that is on Heschl's gyrus, involve mainly nearby units or modules, probably with similar coding properties, whereas in surrounding areas, connections spread over more distant units and may play an important role in the integration of different auditory features.
Tuning for the orientation of spatial attention in dorsal premotor cortex
Authors: Lebedev Mikhail A. , Wise Steven P.
Published: March 2003

We tested whether neuronal activity in the dorsal premotor cortex (PMd) reflected the orientation of selective spatial attention, as opposed to the target of a reaching movement, eye position and saccade direction. These four spatial variables were dissociated in two tasks, which both required that a monkey attend to a robot's location in order to know when to make a movement. However, the target of the reaching movement varied; it was the robot's location in one task, but a different location in the other task. Eye position was recorded, but not explicitly controlled. Of 199 PMd neurons sampled, 19% had activity related to eye position, and an overlapping 11% were related to saccade direction (totaling 24% of the PMd sample). Of the 152 PMd neurons that lacked oculomotor relationships, ≈ 20% reflected the orientation of selective spatial attention. Attentional tuning may account, at least in part, for gaze‐independent receptive fields and visuospatial, target or goal relationships in tasks involving stimulus–response incompatibility.
Fibroblast growth factor‐2 is selectively modulated in the rat brain by E‐5842, a preferential sigma‐1 receptor ligand and putative atypical antipsychotic
Authors: Ovalle Sergio , Zamanillo Daniel , Andreu Francesc , Farré Antoni J. , Guitart Xavier
Published: March 2003

Fibroblast growth factor‐2 (FGF‐2) is a member of a large family of trophic factors whose expression is regulated under several conditions in different areas of the brain. The goal of our experiments was to determine whether the administration of 4‐(4‐fluorophenyl)‐1,2,3,6‐tetrahydro‐1‐[4‐(1,2,4‐triazol‐1‐il)butyl] pyridine citrate (E‐5842), a sigma‐1 receptor ligand and putative atypical antipsychotic, could regulate the expression of FGF‐2. After chronic treatment with E‐5842 (21 days, and the animals killed 24 h after the last administration), an up‐regulation was observed of the expression of FGF‐2 mRNA in the prefrontal cortex and the striatum, and a down‐regulation of the expression of FGF‐2 mRNA in the hypothalamus of the rat brain. Acute treatment with E‐5842 (one single administration and animals killed 6 h later) up‐regulated FGF‐2 expression in the prefrontal cortex, the striatum, the hypothalamus and the hippocampus in a dose‐dependent manner. The acute up‐regulation was transient and disappeared 24 h after E‐5842 administration. The induction of FGF‐2 in the striatum after repeated administration has been described for clozapine, but our data concerning regulation in the prefrontal cortex suggest that this effect is unique to E‐5852 among other antipsychotics. Given the neuroprotective activity of FGF‐2, the data presented here might be relevant to the deficit in cognition and other symptoms that appear in schizophrenia.
Maternal defence as an emotional stressor in female rats: correlation of neuroendocrine and behavioural parameters and involvement of brain oxytocin
Authors: Neumann Inga D. , Toschi Nicola , Ohl Frauke , Torner Luz , Krömer Simone A.
Published: March 2003

In order to study neuroendocrine and behavioural stress responses in female rats post partum we aimed to establish a relevant emotional stressor – the maternal defence test based on maternal aggression of a lactating resident towards a virgin or lactating intruder approaching the cage. Exposure to maternal defence significantly elevated corticotropin (ACTH) and corticosterone responses of the residents and of virgin or lactating intruders, with an attenuated response in lactating residents and lactating intruders. Exposure to maternal defence increased plasma oxytocin in virgin intruders only. The aggressive behaviour displayed by the residents was directly correlated with the amount of defensive behaviour of the intruder and independent of the intruder's reproductive state. However, the amount of maternal and explorative behaviours displayed by the lactating residents was significantly higher when exposed to a lactating, compared to a virgin, intruder. ACTH responses in lactating residents exposed to virgin intruders were significantly correlated to the amount of offensive (direct correlation) and maternal (inverse correlation) behaviours they displayed. Plasma prolactin concentrations, elevated in lactating compared to virgin rats under basal conditions, were found to be reduced in the lactating residents and intruders in response to exposure to the maternal defence test, whereas it was unchanged in virgin intruders. To test for the involvement of brain oxytocin in neuroendocrine and behavioural responses of the lactating residents an oxytocin receptor antagonist (0.1 µg/5 µL) was infused icv 10 min prior to testing. This treatment increased basal, but not stress‐induced, ACTH, corticosterone and oxytocin secretion. Whereas parameters of aggressive behaviour were unchanged, the antagonist reduced signs of maternal behaviour during maternal defence. In summary, the maternal defence test has been characterized as a relevant emotional stressor for female rats which is useful for studying neuroendocrine and emotional responses in females, in particular in the context of reproductive adaptations.
Matrix metalloproteinase (MMP) system in brain: identification and characterization of brain‐specific MMP highly expressed in cerebellum
Authors: Sekine‐Aizawa Yoko , Hama Emi , Watanabe Kaori , Tsubuki Satoshi , Kanai‐Azuma Masami , Kanai Yoshiakira , Arai Hiroyuki , Aizawa Hiroyuki , Iwata Nobuhisa , Saido Takaomi C.
Published: March 2003

The matrix metalloproteinase (MMP) family, comprising more than 20 isoforms, modulates the extracellular milieu by degrading extracellular matrix (ECM) proteins. Because MMP is one of the few groups of proteinases capable of hydrolysing insoluble fibrillar proteins, they are likely to play crucial roles in regulating both normal and pathophysiological processes in the brain. However, little is yet known about their possible neuronal functions due presumably to their unusual redundancy and to the absence of a complete catalogue of isoforms. As an initial step in understanding the MMP system in the brain, we analysed an expression spectrum of MMP in rat brain using RT‐PCR and discovered a novel brain‐specific MMP, MT5‐MMP. MT5‐MMP was the predominant species among the nongelatinase‐type isoforms in brain. MT5‐MMP, present in all brain tissues examined, was most strongly expressed in cerebellum and was localized in the membranous structures of expressing neurons, as assessed biochemically and immunohistochemically. In cerebellum, its expression was regulated developmentally and was closely associated with dendritic tree formation of Purkinje cells, suggesting that MT5‐MMP may contribute to neuronal development. Furthermore, its stable postdevelopmental expression and colocalization with senile plaques in Alzheimer brain indicates possible roles in neuronal remodeling naturally occurring in adulthood and in regulating pathophysiological processes associated with advanced age.
Synthesis of progesterone in Schwann cells: regulation by sensory neurons
Authors: Robert F. , Guennoun R. , Désarnaud F. , Do‐Thi A. , Benmessahel Y. , Baulieu E. E. , Schumacher M.
Published: March 2003

In peripheral nerves, progesterone synthesized by Schwann cells has been implicated in myelination. In spite of such an important function, little is known of the regulation of progesterone biosynthesis in the nervous system. We show here that in rat Schwann cells, expression of the 3β‐hydroxysteroid dehydrogenase and formation of progesterone are dependent on neuronal signal. Levels of 3β‐hydroxysteroid dehydrogenase mRNA and synthesis of [3H]progesterone from [3H]pregnenolone were low in purified Schwann cells prepared from neonatal rat sciatic nerves. However, when Schwann cells were cultured in contact with sensory neurons, both expression and activity of the 3β‐hydroxysteroid dehydrogenase were induced. Regulation of 3β‐hydroxysteroid dehydrogenase expression by neurons was also demonstrated in vivo in the rat sciatic nerve. 3β‐hydroxysteroid dehydrogenase mRNA was present in the intact nerve, but could no longer be detected 3 or 6 days after cryolesion, when axons had degenerated. After 15 days, when Schwann cells made new contact with the regenerating axons, the enzyme was re‐expressed. After nerve transection, which does not allow axonal regeneration, 3β‐hydroxysteroid dehydrogenase mRNA remained undetectable. The regulation of 3β‐hydroxysteroid dehydrogenase mRNA after lesion was similar to the regulation of myelin protein zero (P0) and peripheral myelin protein 22 (PMP22) mRNAs, supporting an important role of locally formed progesterone in myelination.
Signal detection in amplitude‐modulated maskers. I. Behavioural auditory thresholds in a songbird
Authors: Langemann Ulrike , Klump Georg M.
Published: March 2003

Vertebrates have evolved mechanisms to exploit amplitude modulations in background noise for improving signal detection. However, the mechanisms underlying this masking release are not yet well understood. Here we present evidence for masking release observed in European starlings (Sturnus vulgaris, Aves) that were trained in a Go/NoGo paradigm to report the detection of a short tone (20 ms) in 100% sinusoidally amplitude‐modulated noise maskers (400 ms duration). Maskers centred at the tone frequency were composed of one, three, or five spectrally adjacent noise bands each of auditory filter bandwidth. Envelopes of the masking noise bands were either in‐phase (i.e. coherent) or successively phase shifted by 90° (i.e. incoherent). A release from masking of up to 28 dB was observed for detection of signals presented in dips of the envelope of coherent maskers compared with those presented in peaks of coherent maskers and in incoherent maskers. For maskers limited to one auditory filter (i.e. limited to the analysis channel tuned to the test signal) this masking release was about 10 dB less than that observed for maskers allowing a comparison across three or five auditory filters. This indicates that both within‐channel cues and across‐channel cues are important for signal detection. These behavioural data provide the reference for the study of responses of auditory forebrain neurons in the same species reported in a companion paper [Nieder & Klump (2001) Eur. J. Neurosci., 13, 1033–1044].
Signal detection in amplitude‐modulated maskers. II. Processing in the songbird's auditory forebrain
Authors: Nieder Andreas , Klump Georg M.
Published: March 2003

In the natural environment, acoustic signals have to be detected in ubiquitous background noise. Temporal fluctuations of background noise can be exploited by the auditory system to enhance signal detection, especially if spectral masking components are coherently amplitude modulated across several auditory channels (a phenomenon called ‘comodulation masking release’). In this study of neuronal mechanisms of masking release in the primary auditory forebrain (field L) of awake European starlings (Sturnus vulgaris), we determined and compared neural detection thresholds for 20‐ms probe tones presented in a background of sinusoidally amplitude modulated (10‐Hz) noise maskers. Responses of a total of 34 multiunit clusters were recorded via radiotelemetry with chronically implanted microelectrodes from unrestrained birds. For maskers consisting of a single noise band centred around the recording site's characteristic frequency, a substantial reduction in detection threshold (21 dB on average) was found when probe tones were presented during envelope dips rather than during envelope peaks. Such effects could also explain results obtained for masking protocols where the on‐frequency noise band was presented together with excitatory or inhibitory flanking bands that were either coherently modulated (in‐phase) or incoherently modulated (phase‐shifted). Generally, masking release for probe tones in maskers with flanking bands extending beyond the frequency range of a cell cluster's excitatory tuning curve was not substantially improved. Only some of the neurophysiological results are in agreement with behavioural data from the same species if only the average population response is considered. A subsample of individual neurons, however, could account for behavioural thresholds.
Overexpression of the myristoylated alanine‐rich C kinase substrate decreases uptake and K+‐evoked release of noradrenaline in the human neuroblastoma SH‐SY5Y
Authors: Hartness Matthew E. , Wade Jennifer A. , Walker John H. , Vaughan Peter F. T.
Published: March 2003

The aim of this study was to investigate a possible role of the myristoylated alanine‐rich C kinase substrate (MARCKS) in the mechanism of noradrenaline uptake and release in the human neuroblastoma cell line SH‐SY5Y. A stable cell line showing a twofold overexpression of MARCKS was prepared by transfecting SH‐SY5Y with pCEP4 containing MARCKS cDNA in the sense orientation. This cell line showed no changes in the expression of neurofilaments or markers of noradrenergic large dense‐cored vesicles compared with both untransfected SH‐SY5Y and SH‐SY5Y transfected with pCEP4 only (mock transfected). Similarly, no differences in the rate of cell growth could be detected between these three cell lines. In contrast, specific uptake and depolarization‐evoked (100 mm K+) release of noradrenaline from the cell line overexpressing MARCKS was inhibited by approximately 50% compared with mock‐transfected SH‐SY5Y. K+‐evoked noradrenaline release enhanced by pretreatment with 12‐O‐tetradecanoylphorbol 13‐acetate (100 nm) was also inhibited by 50%. In contrast, carbachol‐evoked noradrenaline release was unaffected. Thus, in SH‐SY5Y cells, overexpression of MARCKS leads to a decrease in the K+‐evoked noradrenaline release possibly by increased actin cross‐linking preventing the movement of noradrenaline containing large dense‐cored vesicles to the plasma membrane in response to depolarization.
Subfield‐specific immediate early gene expression associated with hippocampal long‐term potentiation in vivo
Authors: French P. J. , O'Connor V. , Jones M. W. , Davis S. , Errington M. L. , Voss K. , Truchet B. , Wotjak C. , Stean T. , Doyère V. , Maroun M. , Laroche S. , Bliss T. V. P.
Published: March 2003

It is not known whether NMDA receptor‐dependent long‐term potentiation (LTP) is mediated by similar molecular mechanisms in different hippocampal areas. To address this question we have investigated changes in immediate early gene and protein expression in two hippocampal subfields following the induction of LTP in vivo and in vitro. In granule cells of the dentate gyrus, LTP induced in vivo by tetanic stimulation of the perforant path was followed by strong induction of the immediate early genes (IEGs) Zif268, Arc and Homer. The increase in Zif268 mRNA was accompanied by an increase in protein expression. In contrast, we were unable to detect modulation of the IEGs Zif268, Arc, Homer and HB‐GAM following induction of LTP by high‐frequency stimulation of the commissural projection to CA1 pyramidal cells in vivo. In this pathway, we also failed to detect modulation of Zif268 protein levels. Zif268, Arc and Homer can be modulated in CA1 pyramidal cells approximately twofold after electroshock‐induced maximal seizure, which demonstrates potential responsiveness to electrical stimuli. When LTP was induced in vitro neither CA1 pyramidal cells nor granule cells showed an increase in Zif268, Arc or Homer mRNA. However, in the slice preparation, granule cells have a different transcriptional state as basal IEG levels are elevated. These results establish the existence of subfield‐specific transcriptional responses to LTP‐inducing stimulation in the hippocampus of the intact animal, and demonstrate that in area CA1‐enhanced transcription of Zif268, Arc and Homer is not required for the induction of late LTP.
Nonactivated microglia promote oligodendrocyte precursor survival and maturation through the transcription factor NF‐κB
Authors: Nicholas Richard ST. J. , Wing Mark G. , Compston Alastair
Published: March 2003

We demonstrate a role for nonactivated rat microglia in the survival and maturation of oligodendrocyte precursor cells (OPCs). Media conditioned by nonactivated microglia increase the number of surviving galactocerebroside+ (GalC+) oligodendrocytes in vitro at 48 h by inhibiting the apoptosis of OPCs and stimulating their maturation to GalC+ oligodendrocytes. These effects are not observed with medium conditioned by microglia activated with interferon‐γ (IFN‐γ). Conditioned medium from nonactivated microglia is associated with upregulation in OPCs of nuclear factor of kappa binding (NF‐κB) p65 subunit. The use of antisense to the inhibitor of kappa binding (IκB) induces p65 subunit activation in OPCs and, in common with medium conditioned by nonactivated microglia, also inhibits OPC apoptosis and promotes cell maturation. Anti‐platelet‐derived growth factor (PDGF) antibody abolishes this effect even though PDGF‐A chain is expressed at similar levels within both nonactivated and IFN‐γ‐activated microglia and both conditioned media have similar levels of PDGF‐A chain bioactivity. However, only conditioned medium from nonactivated microglia recruit phosphatidyl‐3‐inositol (PI‐3) kinase to the PDGF‐α receptor and synergise with endogenous PDGF‐A chain to increase NF‐κB activation. These results suggest that, dependent on their state of activation, microglia produce soluble factors that promote oligodendrocyte development through an effect on the PDGF‐α receptor‐signalling pathway.
Dopamine and noradrenaline efflux in the rat prefrontal cortex after classical aversive conditioning to an auditory cue
Authors: Feenstra M. G. P. , Vogel M. , Botterblom M. H. A. , Joosten R. N. J. M. A. , De Bruin J. P. C.
Published: March 2003

We used bilateral microdialysis in the medial prefrontal cortex (PFC) of awake, freely moving rats to study aversive conditioning to an auditory cue in the controlled environment of the Skinner box. The presentation of the explicit conditioned stimuli (CS), previously associated with foot shocks, caused increased dopamine (DA) and noradrenaline (NA) efflux. This conditioned response was dependent on the immediate pairing of the two stimuli; in the pseudoconditioned group that received an equal number of both stimuli, but in an unpaired fashion, no conditioned increases in efflux were observed.
Activation of frontoparietal cortices during memorized triple‐step sequences of saccadic eye movements: an fMRI study
Authors: Heide W. , Binkofski F. , Seitz R. J. , Posse S. , Nitschke M. F. , Freund H.‐J. , Kömpf D.
Published: March 2003

To determine the cortical areas controlling memory‐guided sequences of saccadic eye movements, we performed functional magnetic resonance imaging (fMRI) in six healthy adults. Subjects had to perform a memorized sequence of three saccades in darkness, after a triple‐step stimulus of successively flashed laser targets. To assess the differential contribution of saccadic subfunctions, we applied several control conditions, such as central fixation with or without triple‐step visual stimulation, self‐paced saccades in darkness, visually guided saccades and single memory‐guided saccades. Triple‐step saccades strongly activated the regions of the frontal eye fields, the adjacent ventral premotor cortex, the supplementary eye fields, the anterior cingulate cortex and several posterior parietal foci in the superior parietal lobule, the precuneus, and the middle and posterior portion of the intraparietal sulcus, the probable location of the human parietal eye field. Comparison with the control conditions showed that the right intraparietal sulcus and parts of the frontal and supplementary eye fields are more involved in the execution of triple‐step saccades than in the other saccade tasks. In accordance with evidence from clinical lesion studies, we propose that the supplementary eye field essentially controls the triggering of memorized saccadic sequences, whereas activation near the middle portion of the right intraparietal sulcus appears to reflect the necessary spatial computations, including the use of extraretinal information (efference copy) about a saccadic eye displacement for updating the spatial representation of the second or third target of the triple‐step sequence.
Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease
Authors: Costantini Lauren C. , Cole Douglas ,   Pravin Chaturvedi, Isacson Ole
Published: March 2003

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug‐induced side‐effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) mouse model, we compared an immunophilin ligand (V‐10,367) documented to bind the immunophilin FKBP12 with V‐13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose‐dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6‐hydroxydopamine‐infusion rat model was utilized. Oral treatment with the FKBP12‐binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD.
Bacterial endotoxin sensitizes the immature brain to hypoxic–ischaemic injury
Authors: Eklind Saskia , Mallard Carina , Leverin Anna‐Lena , Gilland Erik , Blomgren Klas , Mattsby‐Baltzer Inger , Hagberg Henrik
Published: March 2003

Epidemiological studies show a markedly increased risk of cerebral palsy following the combined exposure of infection and birth asphyxia. However, the underlying mechanisms of this increased vulnerability remain unclear. We have examined the effects of a low dose of bacterial endotoxin on hypoxic–ischaemic injury in the immature brain of rats. Bacterial endotoxin (lipopolysaccharide 0.3 mg/kg) was administered to 7‐day‐old rats 4 h prior to unilateral hypoxia–ischaemia and the neurological outcome was determined 3 days later. Rectal temperature and cerebral blood flow was measured during the study and the expression of CD14 and toll‐like receptor‐4 mRNA in the brain was examined. We found that a low dose of endotoxin dramatically sensitizes the immature brain to injury and induces cerebral infarction in response to short periods of hypoxia–ischaemia that by themselves caused no or little injury. This effect could not be explained by a reduction in cerebral blood flow or hyperthermia. In association with the sensitization of injury we found an altered expression of CD14 mRNA and toll‐like receptor‐4 mRNA in the brain. These results suggest that the innate immune system may be involved in the vulnerability of the immature brain following the combination of infection and hypoxia–ischaemia.
Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy
Authors: Knuesel Irene , Zuellig Richard A. , Schaub Marcus C. , Fritschy Jean‐Marc
Published: March 2003

Dystrophin and its autosomal homologue utrophin are coexpressed in muscle cells, and utrophin is functionally able to replace dystrophin in models of Duchenne muscular dystrophy. In brain, the two proteins are expressed differentially, suggesting distinct functional roles. Dystrophin is associated with postsynaptic GABAA receptors in hippocampus, cortex and cerebellum, whereas utrophin is present extrasynaptically, notably in large brainstem neurons. Here, the regulation of dystrophin and utrophin was investigated in a model of temporal lobe epilepsy. Adult mice were injected unilaterally with kainic acid into the dorsal hippocampus to induce loss of pyramidal cells and hypertrophy of dentate gyrus (DG) granule cells, as described (Suzuki, F., Junier, M.P., Guilhem, D., Sorensen, J.C. & Onteniente, B. (1995)Neuroscience, 64, 665–674.). These morphological changes were associated with an increase in postsynaptic GABAA‐receptors in the ipsilateral DG, as demonstrated by a parallel increase in punctate immunoreactivity to GABAA‐receptor α2 subunit, gephyrin and dystrophin in the molecular layer. Thus, both dystrophin and gephyrin were involved in postsynaptic clustering of GABAA receptors. A transient induction of utrophin was seen at the onset of degeneration in CA1 and CA3 pyramidal cells and in the hilus. Most strikingly, however, utrophin immunoreactivity appeared in the granule cell layer of the DG and became very strong in hypertrophic granule cells 1–2 months post‐kainate treatment. These results suggest that utrophin provides structural support of neuronal membranes, whereas dystrophin is a component of GABAergic synapses.
VP‐RBP, a protein enriched in brain tissue, specifically interacts with the dendritic localizer sequence of rat vasopressin mRNA
Authors: Mohr Evita , Fuhrmann Carola , Richter Dietmar
Published: March 2003

The concept of mRNA localization suggests that this process is mediated by sequences residing in the transcript to which proteins specifically bind and ultimately deliver the mRNA along cytoskeletal elements to specific intracellular destinations. The mRNA encoding the vasopressin (VP) precursor protein is localized to the nerve cell processes both in hypothalamic magnocellular neurons and in primary cultured neurons derived from embryonic rat superior cervical ganglia microinjected with a corresponding eukaryotic expression vector. The last 395 nucleotides of the VP mRNA encompassing part of the coding region, as well as the complete 3′‐untranslated region, are sufficient to confer dendritic targeting to a normally nonlocalized reporter transcript. Here we report that, by employing in vitro crosslinking analyses with rat brain proteins and radiolabelled VP transcripts, an RNA‐binding protein specifically interacts with the dendritic localizer sequence of the VP mRNA. This protein is enriched in nerve cell tissues. Peripheral tissues and various cell lines contain only low amounts of the binding activity. It therefore represents a candidate protein that may be involved in any aspect related to subcellular VP mRNA sorting in nerve cells, including transport and anchoring of the mRNA and possibly its translational control.
Noradrenergic modulation of calcium currents and synaptic transmission in the olfactory bulb of Xenopus laevis tadpoles
Authors: Czesnik Dirk , Nezlin Leonid , Rabba Jörg , Müller Birgitt , Schild Detlev
Published: March 2003

Norepinephrine (NE) has various modulatory roles in both the peripheral and the central nervous systems. Here we investigate the function of the locus coeruleus efferent fibres in the olfactory bulb of Xenopus laevis tadpoles. In order to distinguish unambiguously between mitral cells and granule cells of the main olfactory bulb and the accessory olfactory bulb, we used a slice preparation. The two neuron types were distinguished on the basis of their location in the slice, their typical branching pattern and by electrophysiological criteria. At NE concentrations lower than 5 µm there was only one effect of NE upon voltage‐gated conductances; NE blocked a high‐voltage‐activated Ca2+‐current in mitral cells of both the main and the accessory olfactory bulbs. No such effect was observed in granule cells. The effect of NE upon mitral cell Ca2+‐currents was mimicked by the α2‐receptor agonists clonidine and α‐methyl‐NE. As a second effect, NE or clonidine blocked spontaneous synaptic activity in granule cells of both the main and the accessory olfactory bulbs. NE or clonidine also blocked the spontaneous synaptic activity in mitral cells of either olfactory bulb. The amplitude of glutamate‐induced currents in granule cells was modulated neither by clonidine nor by α‐methyl‐NE. Taken together, the main effect of the noradrenergic, presynaptic, α2‐receptor‐mediated block of Ca2+‐currents in mitral cells appeared to be a wide‐spread disinhibition of mitral cells in the accessory olfactory bulb as well as in the main olfactory bulb.
GABAA and GABAB receptors on neocortical neurons are differentially distributed
Authors: Eder M. , Rammes G. , Zieglgänsberger W. , Dodt H.‐U.
Published: March 2003

The distribution of functional neurotransmitter receptors on the surface of neurons is highly relevant for synaptic transmission and signal processing. To map functional GABAA and GABAB receptors on the somadendritic membrane of rat neocortical layer V pyramidal neurons we used patch‐clamp recording in combination with infrared‐guided laser stimulation to release γ‐aminobutyric acid (GABA) photolytically. The data strongly suggest that relatively more GABAA receptors are located at the apical dendrite and relatively more GABAB receptors near the soma. Such a specific distribution of GABAA and GABAB receptors may serve to compensate for differences in electrotonic voltage attenuation between GABAA and GABAB receptor‐mediated inhibitory postsynaptic potentials (IPSPs).
Place‐cell firing does not depend on the direction of turn in a Y‐maze alternation task
Authors: Lenck‐Santini Pierre‐Pascal , Save Etienne , Poucet Bruno
Published: March 2003

Hippocampal place cells were recorded while rats solved a continuous spatial alternation task requiring short‐term spatial memory. All cells that had a firing field on the stem of the Y‐shaped maze were found to have a very similar pattern of discharge whether the rat was about to make a right or a left turn, and whether the preceding turn was a right or a left turn. Thus, the view that place cells encode a variety of events (including the direction of turns) useful for solving memory tasks is not well supported by the present data. We suggest several possible explanations to account for the discrepancy with other recent studies showing turn‐related modulation of place‐cell activity.
Restricted‐feeding‐induced anticipatory activity rhythm is associated with a phase‐shift of the expression of mPer1 and mPer2 mRNA in the cerebral cortex and hippocampus but not in the suprachiasmatic nucleus of mice
Authors: Wakamatsu Hisanori , Yoshinobu Yuko , Aida Reiko , Moriya Takahiro , Akiyama Masashi , Shibata Shigenobu
Published: March 2003

Daily restricted feeding (RF) can produce food‐entrainable oscillations in both intact and suprachiasmatic nucleus (SCN)‐lesioned animals. Thus, there are two circadian rhythms, one of which is SCN‐dependent and the other SCN‐independent. Recently, it has been established that several mouse clock genes, such as mPer1, mPer2 and mPer3 are expressed in the SCN and other brain tissues. Although the role of mPer genes expressed in the SCN has recently been evaluated in the SCN‐dependent rhythm, their function in the SCN‐independent rhythm is still poorly understood. In order to understand the role of these genes in SCN‐independent rhythm, we examined the expression pattern of mPer1 and mPer2 mRNA in each brain area of mice under RF. Mice were allowed access to food for 4 h during either the daytime under a light‐dark cycle or the subjective daytime under constant dark. After 6 days of scheduled RF, the night‐time or subjective night‐time peak of mPer mRNA changed to a daytime peak in the cerebral cortex and hippocampus, with moderate expression in the striatum, pyriform cortex and paraventricular nucleus, and no expression in the SCN. The daytime peak in the cerebral cortex returned to a night‐time peak after the release of RF to a free‐feeding schedule. Although the basal rhythm of mPer expression disappeared in SCN‐lesioned mice, RF produced mPer mRNA rhythm in the cerebral cortex of these mice. The present results provide evidence of an association between food‐entrainable oscillations and the expression of mPer1 and mPer2 in the cerebral cortex and hippocampus.
Differential regulation by exercise of BDNF and NT‐3 in rat spinal cord and skeletal muscle
Authors: Gómez‐Pinilla F. , Ying Z. , Opazo P. , Roy R. R. , Edgerton V. R.
Published: March 2003

We have investigated the impact of neuromuscular activity on the expression of neurotrophins in the lumbar spinal cord region and innervating skeletal muscle of adult rats. Rats were exercised on a treadmill for 1 day or 5 consecutive days and euthanized at 0, 2 or 6 h after the last bout of exercise. By Day 1, there was no clear evidence of an increase in brain‐derived neurotrophic factor (BDNF) mRNA in the spinal cord or the soleus muscle. By Day 5, there was a significant increase in BDNF mRNA in the spinal cord at 2 h post‐training, and the soleus muscle showed a robust increase between 0 and 6 h post‐training. Immunoassays showed significant increases in BDNF protein in the soleus muscle by training Day 5. Immunohistochemical analyses showed elevated BDNF levels in motoneuron cell bodies and axons in the ventral horn. Neurotrophin‐3 (NT‐3) mRNA was measured to determine whether selected neurotrophins respond with a selective pattern of induction to neuromuscular activity. In the spinal cord, there was a progressive post‐training decrease in NT‐3 mRNA following a single bout of training, while there was a significant increase in NT‐3 mRNA at 2 h post‐training by Day 5. The soleus muscle showed a progressive increase in NT‐3 mRNA by Days 1 and 5 following training. These results show that neuromuscular activity has specific effects on the BDNF and NT‐3 systems, and that repetitive exercise affects the magnitude and stability of these responses.
Dopaminergic control of synaptic plasticity in the dorsal striatum
Authors: Centonze Diego , Picconi Barbara , Gubellini Paolo , Bernardi Giorgio , Calabresi Paolo
Published: March 2003

Cortical glutamatergic and nigral dopaminergic afferents impinge on projection spiny neurons of the striatum, providing the most significant inputs to this structure. Isolated activation of glutamate or dopamine (DA) receptors produces short‐term effects on striatal neurons, whereas the combined stimulation of both glutamate and DA receptors is able to induce long‐lasting modifications of synaptic excitability. Repetitive stimulation of corticostriatal fibres causes a massive release of both glutamate and DA in the striatum and, depending on the glutamate receptor subtype preferentially activated, produces either long‐term depression (LTD) or long‐term potentiation (LTP) of excitatory synaptic transmission. D1‐like and D2‐like DA receptors interact synergistically to allow LTD formation, while they operate in opposition during the induction phase of LTP. Corticostriatal synaptic plasticity is severely impaired after chronic DA denervation and requires the stimulation of DARPP‐32, a small protein expressed in dopaminoceptive spiny neurons which acts as a potent inhibitor of protein phosphatase‐1. In addition, the formation of LTD and LTP requires the activation of PKG and PKA, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1‐like receptors in distinct neuronal populations.
Long‐trace interval eyeblink conditioning is impaired in mutant mice lacking the NMDA receptor subunit ε1
Authors: Kishimoto Yasushi , Kawahara Shigenori , Mori Hisashi , Mishina Masayoshi , Kirino Yutaka
Published: March 2003

To elucidate the role of the N‐methyl‐d‐aspartate (NMDA) ‐type glutamate receptor subunit ε1 (GluRε1) in classical eyeblink conditioning, delay and trace eyeblink conditioning were investigated in GluRε1‐null mutant mice. In delay conditioning and short‐trace interval conditioning with a trace interval of 250 ms, GluRε1 mutant mice attained a normal level of the conditioned response (CR), although acquisition was a little slower than in wild‐type mice. In contrast, GluRε1 mutant mice exhibited severe impairment of the attained level of the CR and disturbed temporal pattern of CR expression in trace conditioning with a longer trace interval of 500 ms. These findings indicate that GluRε1 is essential for long‐trace interval eyeblink conditioning. The impairments of the associative learning with a long temporal separation between the conditioned and unconditioned stimuli observed in the GluRε1 mutant mice could be attributed to an impairment of hippocampal long‐term potentiation in this line of mutant mice.
Place fields of rat hippocampal pyramidal cells and spatial learning in the watermaze
Authors: Hollup Stig A. , Molden Sturla , Donnett James G. , Moser May‐Britt , Moser Edvard I.
Published: March 2003

To provide a background for studying place‐related activity in hippocampal neurons during spatial learning, we compared the activity of hippocampal place cells in an annular watermaze and an analogous land‐based task. Complex‐spike cells had robust place correlates in both conditions, and a significant proportion of the cells had place fields at the same locations. However, the in‐field firing rates were slightly higher in the wet condition. Elevated firing was observed also in an open water task. There was no enhancement when the platform location was varied randomly or when there was no platform at all. Second, the place fields were under stronger directional modulation during swimming. In the annular task, directional sensitivity appeared regardless of whether the animals were trained to find a platform or not. There were directionally modulated units also in the open watermaze, but the number was smaller than in the corridor. Altogether, these observations suggest that place fields in the watermaze are largely controlled by the same factors as on dry land, in spite of the differences in kinaesthetic and vestibular input. Differences in firing rate and directional control may depend on the geometric and cognitive structure of the task rather than the medium on which the rats are moving.
Classical eyeblink conditioning in glutamate receptor subunit δ2 mutant mice is impaired in the delay paradigm but not in the trace paradigm
Authors: Kishimoto Yasushi , Kawahara Shigenori , Suzuki Michiyuki , Mori Hisashi , Mishina Masayoshi , Kirino Yutaka
Published: March 2003

In mice lacking glutamate receptor subunit δ2 (GluRδ2–/– mice), cerebellar long‐term depression (LTD) at the parallel fibre–Purkinje cell synapses is disrupted. Unlike the cerebellar LTD‐deficient mice previously used for eyeblink conditioning, however, the abnormalities of the GluRδ2–/– mice are restricted to the cerebellar cortex. In delay eyeblink conditionings (interstimulus interval of 252 and 852 ms), in which the conditioned stimulus (CS) overlaps temporally with a coterminating unconditioned stimulus (US), GluRδ2–/– mice are severely impaired in learning, strongly supporting the hypothesis that cerebellar cortical LTD is essential for delay conditioning. In the trace paradigm, in which a stimulus‐free trace interval of 500 ms intervened between the CS and US, GluRδ2–/– mice learned as successfully as wild‐type mice, indicating that cerebellar LTD is not necessary for trace conditioning. Thus, the present study has revealed a cerebellar LTD‐independent learning in eyeblink conditioning.
Correlation between electrophysiological and morphological characteristics during maturation of rat supraoptic neurons
Authors: Chevaleyre Vivien , Moos Françoise C. , Desarménien Michel G.
Published: March 2003

The neurohypophysial peptides oxytocin (OT) and vasopressin (AVP) are well known for their role in reproductive functions and fluid balance regulation, respectively. During development, these peptides are thought to act as trophic factors on both peripheral and central structures. However, despite this early developmental function, the maturation of their secreting neurons remains poorly investigated. In this study, we have characterized the electrical and morphological characteristics displayed by OT and AVP supraoptic (SO) neurons between embryonic day 21 and postnatal day 20. Transient changes in passive membrane properties, correlated with a transient increase in the dendritic arborization, were observed at the beginning of the second postnatal week (PW2). The action potential matured mostly during PW1 and its threshold progressively hyperpolarized in parallel with the resting membrane potential. During PW1, SO neurons displayed unique characteristics with a low‐threshold Ca2+‐dependent depolarizing potential and a prominent hyperpolarization‐activated current (Ih). This latter is involved in a depolarizing sag during hyperpolarization and an after hyperpolarizing potential following a depolarization. During this period, maintaining ECl unchanged by the use of gramicidin‐perforated patch recordings revealed excitatory GABAergic potentials, that became inhibitory during PW2, whilst glutamatergic potential appeared. The electrical activity was very erratic in young neurons and progressively differentiated in the typical firing observed in mature neurons (tonic and phasic for OT and AVP neurons, respectively) during PW2–3. These results show that the development of electrical properties of SO neurons is correlated with the maturation of their dendritic arborization.