bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomical evidence for a mechanism of lateral inhibition in the rat thalamus
Authors: Pinault Didier , Deschênes Martin
Published: March 2003

The aim of this study was to determine whether or not thalamic reticular nucleus (Rt) neurons form synaptic connections with the thalamocortical (TC) neurons from which they receive synaptic contacts. Therefore, we examined, in adult rats, the relationships between single TC and Rt neurons, which had been marked simultaneously with an anterograde/retrograde tracer (biocytin or Neurobiotin), using the extracellular or juxtacellular technique. (i) From 30 successful extracellular microapplications of marker into the Rt, 22 gave retrogradely marked TC somatodendritic arbors at the fringe of or clear outside the anterogradely darkly stained Rt axon terminal fields. Following biocytin application into the thalamus, few cells were retrogradely stained in the Rt at the periphery of the anterogradely labelled axon terminal field. (ii) The juxtacellular filling of a single Rt cell was accompanied by the back‐filling of a single TC neuron (n = 4 pairs), which presumably formed synaptic contacts with the former cell. The somatodendritic complex of the back‐filled TC neuron was located outside the Rt cell's axonal arbor.

 These anatomical data provide clear evidence that Rt and thalamic neurons predominantly form between themselves open rather than closed loop connections. Because TC neurons make glutamatergic synapses onto Rt cells, which are GABAergic, and are the first elements synaptically activated by prethalamic afferents into the TC‐Rt network, the present results strongly support the hypothesis that Rt neurons principally generate a mechanism of lateral inhibition in the thalamus.
Identification of the reptilian basolateral amygdala: an anatomical investigation of the afferents to the posterior dorsal ventricular ridge of the lizard Podarcis hispanica
Authors: Lanuza Enrique , Belekhova Margarita , Martínez‐Marcos Alino , Font Cristian , Martínez‐García Fernando
Published: March 2003

The presence of multimodal association in the telencephalon of reptiles has been investigated by tracing the afferent connections to the posterior dorsal ventricular ridge (PDVR) of the lizard Podarcis hispanica. The PDVR receives telencephalic afferents from the lateral (olfactory) and dorsal cortices, and from the three unimodal areas of the anterior dorsal ventricular ridge, in a convergent manner. From the diencephalon, it receives afferents from the dorsomedial anterior and medial posterior thalamic nuclei, and from several hypothalamic nuclei. Brainstem afferents to the PDVR originate in the dorsal interpeduncular nucleus, the nucleus of the lateral lemniscus and parabrachial nucleus.

 The afferents to the thalamic nuclei that project to the PDVR have also been studied. The dorsomedial anterior thalamic nucleus receives projections mainly from limbic structures, whereas the medial posterior thalamic nucleus is the target of projections from structures with a clear sensory significance (optic tectum, torus semicircularis, nuclei of the lateral and spinal lemniscus, superior olive and trigeminal complex).

 As a result, the PDVR appears as an associative centre that receives visual, auditory, somatosensory and olfactory information from several telencephalic and non‐telencephalic centres, and a multimodal projection from the medial posterior thalamic nucleus. This pattern of afferents of the PDVR is similar to that of the caudal neostriatum in birds and the basolateral division of the mammalian amygdala. These results indicate that a multimodal amygdala is already present in reptiles, and has probably played a key role in the evolution of the vertebrate brain.
Structure and dynamics of receptive fields in the visual cortex of the cat (area 18) and the influence of GABAergic inhibition
Authors: Pernberg Joachim , Jirmann Kay‐Uwe , Eysel Ulf T.
Published: March 2003

Receptive fields (RFs) in the visual cortex are characterized by spatiotemporal profiles that have been described in detail for area 17 simple cells. In this study, we analyse spatial and temporal RF properties of simple and complex cells in layer II/III of area 18 of the anaesthetized adult cat, using the reverse correlation method with brief 50 ms presentations of flashing bright and dark bars. Stimuli were presented with preferred orientation as previously determined by moving bars. Simple cell RFs were characterized by spatially and temporally separable ON and OFF subfields, while in complex cells ON and OFF subfields were superimposed. To discriminate possible contributions of GABAergic inhibition to RF structure and response dynamics in area 18, we have used three‐barrelled micropipettes for single cell recordings and microiontophoresis, and have documented ON and OFF responses before, during and after application of bicuculline methiodide for blockade of GABAA receptors. During blockade of GABAergic inhibition, the stimulus‐induced and resting discharge frequency increased, and in about 50% of the cells both ON and OFF subfields changed significantly in space and/or time in a reversible manner. In space, blockade of inhibition widened RF subfields, whereas in time, it shortened the duration of the excitatory cell response in simple and complex cells. ON and OFF subfields separated in space and time (simple cells), or time (complex cells) became less isolated or even superimposed. The results indicate substantial local inhibitory processing contributing to spatiotemporal RF properties in layers II/III of area 18 of the cat.
BDNF overexpression induces differential increases among subsets of sympathetic innervation in murine back skin
Authors: Botchkarev Vladimir A. , Botchkareva Natalia V. , Lommatzsch Marek , Peters Eva M. J. , Lewin Gary R. , Subramaniam Arun , Braun Armin , Renz Harald , Paus Ralf
Published: March 2003

Besides their recognized dependence on nerve growth factor (NGF) during development, the dependence of mature sympathetic ganglion neurons on other neurotrophins is still unclear. Here, we have investigated the sympathetic innervation of back skin in mice overexpressing brain‐derived neurotrophic factor (BDNF) under the alpha‐myosin heavy‐chain promoter, as well as in BDNF knockout (–/–) mice. Compared with wild‐type controls, the dorsal skin of BDNF overexpressing mice displayed a significantly enhanced number of adrenergic, tyrosine hydroxylase‐immunoreactive (IR) nerve fibres, while cholinergic or peptidergic sensory nerve fibres appeared unaltered. The adrenergic hyperinnervation in dorsal skin of BDNF overexpressing mice was most pronounced in the arrector pili muscle of hair follicles, while no increase of tyrosine hydroxylase‐or neuropeptide Y‐IR fibres associated with subcutaneous blood vessels was found. Instead, back skin of BDNF knockout (–/–) mice contained significantly fewer tyrosine hydroxylase‐IR dermal nerve fibres than wild‐type animals. This suggests that BDNF plays an important role in the control of different subsets of adrenergic innervation in murine back skin, and indicates that paravertebral sympathetic ganglia display a previously unrecognized differential BDNF‐dependence in vivo.
Up‐ and down‐expression of the dopamine transporter by plasmid DNA transfer in the rat brain
Authors: Martres Marie‐Pascale , Demeneix Barbara , Hanoun Naïma , Hamon Michel , Giros Bruno
Published: March 2003

The functional role of the dopamine transporter (DAT) in central dopaminergic neurotransmission was assessed further by investigating the consequences on dopamine (DA) turn‐over of up‐ and down‐regulation of this protein induced by a non‐viral gene transfer approach. For this purpose, expression plasmids containing the sense or antisense coding sequence of DAT complexed with the cationic polymer, polyethylenimine (PEI), were injected into the rat substantia nigra, the brain region containing the majority of DA cell bodies.

 Before in vivo injection, the efficacies of the different DNA constructs were assessed by transfection studies into LLC‐PK1 cells. Stereotaxic administration of the sense plasmid complexed to PEI induced, 3 days later, a significant increase in the immunoautoradiographic labelling by anti‐DAT antibodies of the substantia nigra and various DA projection areas. These effects were associated with a significantly enhanced capacity of striatal synaptosomes to take up [3H]‐DA and lasted up to 14 days postinjection. In contrast, 7 days after intranigral administration of the antisense plasmid complexed to PEI, we observed a significant decrease of DAT immunolabelling in the substantia nigra and [3H]‐DA uptake by striatal synaptosomes.

 Whereas DA turnover in the striatum was unaltered 3 days after intranigral administration of the sense plasmid, it was increased 7 days after intranigral administration of the antisense construct.

 These data indicate that non‐viral transfer of the sense or antisense coding sequence of DAT can be used as a novel approach to induce long‐term changes in central DA neurotransmission.
Properties of bipolar VIPergic interneurons and their excitation by pyramidal neurons in the rat neocortex
Authors: Porter James T. , Cauli Bruno , Staiger Jochen F. , Lambolez Bertrand , Rossier Jean , Audinat Etienne
Published: March 2003

In the rat neocortex, a subset of GABAergic interneurons express the neuropeptide vasoactive intestinal peptide (VIP). Previously, we demonstrated that a population of VIPergic interneurons could be accurately identified by their irregular spiking (IS) pattern and their bipolar morphology. IS interneurons were studied in neocortical slices from 16–22‐day‐old rats using whole‐cell recordings, intracellular labelling and single‐cell RT‐PCR. In response to a depolarizing pulse, IS interneurons typically discharged a burst of action potentials followed by spikes emitted at an irregular frequency. Several seconds of depolarization, micromolar concentrations of 4‐aminopyridine, and nanomolar concentrations of either dendrotoxin I or K converted this irregular pattern to a sustained discharge, suggesting the involvement of an ID‐like K+ current. The main glutamate receptor subunits detected in IS cells were GluR1 flop and GluR2 flop, GluR5 and GluR6, and NR2B and NR2D for the α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), kainate and N‐methyl‐d‐aspartic acid (NMDA) subtypes, respectively. Paired whole‐cell patch‐clamp recordings indicated that pyramidal neurons provide intracortical glutamatergic inputs onto IS interneurons. Most connections had high probabilities of response and exhibited frequency‐dependent paired pulse depression. Comparison of the amplitude distribution of paired responses suggested that most of these connections consisted of multiple functional release sites. Finally, two discrete subpopulations of IS cells could be identified based on the duration of the initial burst of action potentials and the differential expression of calretinin and choline acetyltransferase.
Drug‐induced reinstatement of heroin‐ and cocaine‐seeking behaviour following long‐term extinction is associated with expression of behavioural sensitization
Authors: De Vries Taco J. , Schoffelmeer Anton N. M. , Binnekade Rob , Mulder Arie H. , Vanderschuren Louk J. M. J.
Published: March 2003

The present study was designed to evaluate the relationship between reinstatement of drug‐seeking behaviour following long‐term extinction of intravenous (i.v.) drug self‐administration (an animal model for craving) and long‐term behavioural sensitization. Rats were allowed to self‐administer heroin (50 μg/kg per inj., 14 daily sessions), cocaine (500 μg/kg per inj., 10 daily sessions) or saline. Following a 3‐week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on non‐reinforced drug‐seeking behaviour. In addition, the occurrence of long‐term behavioural sensitization in rats with a history of heroin or cocaine self‐administration was determined. Heroin‐seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self‐administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine‐seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self‐administration. In other words, the induction of drug‐seeking behaviour following a prolonged drug‐free period was found to be associated with the expression of long‐term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug‐seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug‐induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.
Cultured oligodendrocyte progenitors derived from cerebral cortex express a glycine receptor which is pharmacologically distinct from the neuronal isoform
Authors: Belachew Shibeshih , Rogister Bernard , Rigo Jean‐Michel , Malgrange Brigitte , Mazy‐Servais Cécile , Xhauflaire Gaël , Coucke Paul , Moonen Gustave
Published: March 2003

Using the whole‐cell patch‐clamp technique, we demonstrate glycine‐induced currents in oligosphere‐derived oligodendrocyte progenitors cultured from newborn rats. Similar inward currents are also triggered by β‐alanine and taurine, two established glycine receptor agonists. In our recording conditions, glycine‐gated currents in oligodendrocyte progenitors reverse about 0 mV and are reversibly inhibited by the glycine competitive antagonist strychnine, the Cl–channel blocker picrotoxinin and the non‐competitive antagonist cyanotriphenylborate. The oligodendrocyte progenitors glycine receptor (GlyR) differs from the corresponding neuronal receptor: [3H]strychnine binding data and the strychnine inhibition curve of glycine‐induced currents in oligodendrocyte progenitor cultures suggest the existence of two strychnine binding sites on the oligodendroglial GlyR. Using total RNA isolated from oligodendrocyte progenitors cultures, reverse transcription–polymerase chain reaction analysis of glycine receptor subunit expression shows the presence of α2and β subunits and immunocytochemical stainings confirm that this GlyR contains an α subunit which is not α1. The molecular structure of the oligodendroglial GlyR could be either homopentameric α2or heteromeric α2β but in both cases, the sequence of the α2or β subunits have to be different from the known neuronal sequences in order to explain, respectively, the cyanotriphenylborate (α2) and picrotoxinin (β) sensitivities. This work thus demonstrates that GlyR are expressed by oligodendrocytes obtained not only from spinal cord but also from supraspinal structures. The pharmacological properties and presumably the molecular structure of oligodendroglial GlyR are original. The physiological meaning of the presence of such receptors on developing and mature oligodendrocytes remains unknown.
Nociceptive integration in the rat spinal cord: role of non‐linear membrane properties of deep dorsal horn neurons
Authors: Morisset Valérie , Nagy Frédéric
Published: March 2003

Deep dorsal horn neurons (DHNs) involved in nociception can relay long‐lasting inputs and generate prolonged afterdischarges believed to enhance the transfer of nociceptive responses to the brain. We addressed the role of neuronal membrane properties in shaping these responses, by recording lamina V DHNs in a slice preparation of the rat cervical spinal cord. of 256 neurons, 102 produced accelerating discharges in response to depolarizing current pulses, whereas the other neurons showed spike frequency adaptation. Two mechanisms mediated the firing acceleration: a slow inactivation of a K+ current expressed upon activation of the neuron from hyperpolarized holding potentials, and the expression of a regenerative plateau potential activating around resting membrane potential. The increase in firing frequency was much stronger when sustained by the plateau potential (71 DHNs, 28%). A few neurons produced adaptation and both types of acceleration, in different membrane potential domains, showing that the firing pattern of a deep DHN is not a rigid characteristic. Plateau potentials could be elicited by stimulation of nociceptive primary afferent fibres. The bistability associated with plateau potentials permitted afterdischarges. Because plateau potentials had slow activation kinetics and were voltage‐dependent, the neurons had non‐linear input–output relationships in both the amplitude and time domains. Nociceptive primary afferent stimulation elicited intense and prolonged responses in plateau‐generating DHNs, while brief bursts of spikes were evoked otherwise. These results indicate that in a population of deep DHNs, intense firing and prolonged afterdischarges in response to nociceptive stimulation depend on non‐linear intrinsic membrane properties.
Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8
Authors: Corti Corrado , Restituito Sophie , Rimland Joseph M. , Brabet Isabelle , Corsi Mauro , Pin Jean Philippe , Ferraguti Francesco
Published: March 2003

Novel mRNA isoforms for two members of the group III metabotropic glutamate receptors (mGluRs), called mGluR7band mGluR8b, were identified from rat brain cerebral cortex and hippocampus. In both cases, the alternative splicing is generated by a similar out‐of‐frame insertion in the carboxyl‐terminus that results in the replacement of the last 16 amino acids of mGluR7 and mGluR8 by 23 and 16 different amino acids, respectively. Distribution analysis for mGluR7 and mGluR8 isoforms revealed that the two splice variants are generally coexpressed in the same brain areas. The few exceptions were the olfactory bulb, in which only the mGluR7aform could be detected by reverse transcription–polymerase chain reaction, and the lateral reticular and ambiguus nuclei, which showed only mGluR8alabelling. Despite expression in the same regions, different mRNA abundance for the two variants of each receptor were observed. When transiently coexpressed in HEK 293 cells with the phospholipase C‐activating chimeric Gαqi9‐G‐protein, thea and bforms for both receptor subtypes showed a similar pharmacological profile. The rank order of potencies for both was:dl‐amino‐4‐phosphonobutyrate > l‐serine‐O‐phosphate > glutamate. However, the agonist potencies were significantly higher for mGluR8a,bcompared with mGluR7a,b. InXenopusoocytes, glutamate evoked currents only with mGluR8 when coexpressed with Kir 3.1 and 3.4. Glutamate‐induced currents were antagonized by the group II/III antagonist (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine. In conclusion, the two isoforms of each receptor have identical pharmacological profiles when expressed in heterologous systems, despite structural differences in the carboxyl‐terminal domains.
Modification of haloperidol‐induced pattern of c‐fos expression by serotonin agonists
Authors: Tremblay Pierre‐Olivier , Gervais Julie , Rouillard Claude
Published: March 2003

Acute challenge with clozapine and haloperidol produce different anatomical patterns of c‐fos expression in the forebrain. The pharmacological profile of atypical antipsychotics suggests that serotonin might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, we examined the abilities of 5‐HT1A and 5‐HT2A/2C agonists to modify the pattern of c‐fos expression induced by haloperidol and clozapine. Various groups of rats were pretreated with either saline, DOI, 8‐OH‐DPAT, and 8‐OH‐DPAT + DOI 30 min prior to haloperidol or clozapine administration. Rats were killed 90 min after antipsychotic administration. In saline‐pretreated rats, haloperidol produced intense Fos‐LI in all four striatal quadrants while the effect of clozapine was restricted to the medial part of the striatum. Prior administration of 8‐OH‐DPAT significantly reduced haloperidol‐induced Fos‐LI in all four striatal quadrants while DOI and 8‐OHDPAT + DOI significantly reduced Fos‐LI only in dorso‐ and ventrolateral quadrants. In the nucleus accumbens, haloperidol induced intense Fos‐LI in the core and the shell regions whereas clozapine induced c‐fos expression only in the shell. Pretreatment with 8‐OHDPAT in haloperidol treated rats reduced Fos‐LI in the core region yielding to a c‐fos pattern similar to that induced by clozapine. In the prefrontal cortex of saline‐pretreated rats, haloperidol produced a moderate c‐fos expression compared with the intense expression produced by clozapine. Pretreatment with serotonin agonists before haloperidol brought the number of FOS‐positive neurons to the same level as in clozapine treated rats. These results show the ability of 5‐HT agonists to transform the typical pattern of c‐fos expression induced by haloperidol into a pattern resembling that of clozapine.
Morphological and functional study of dwarf neurons in the rat striatum
Authors: Sancesario Giuseppe , Pisani Antonio , D'Angelo Vincenza , Calabresi Paolo , Bernardi Giorgio
Published: March 2003

Combination of morphological and electrophysiological techniques provided data, suggesting existence in the young rat striatum of a peculiar class of neurons, the neurogliaform or dwarf neurons. Striatal neurons (n = 92), intracellularly recorded from rat brain slices, were filled (one in each slice) with the intracellular marker biocytin, to compare physiological and morphological properties in the same cell. Moreover, some neurons (n = 7) were filled with biocytin plus the fluorescent calcium indicator fura‐2, identifying cells during electrophysiological recording.

Electrophysiological recordings showed that striatal neurons had different firing patterns, suggestive in most cases (n = 80) of spiny neuron class and in others (n = 12) of interneuron class. Fura‐2 injection clearly identified the body of six medium‐sized cells and of one distinctive tiny cell. This small cell, however, showed a resting membrane potential and spontaneous and evoked firing pattern characteristic of striatal interneurons. Moreover, the fura‐2 injected in such small neuron also completely filled the cell body of a near large neuron; the fura‐2 fluorescence changed synchronously in the two paired neurons after electrical stimulation of the impaled small one. Accordingly, the biocytin staining identified the morphology of the small recorded neuron as a neurogliaform‐like cell apposed to a dendrite of an aspiny neuron, suggesting that the dye injected in one neuron had diffused to the other of a different type. Furthermore, such heterologous dye coupling unexpectedly involved seven pairs of cells detected with biocytin staining (7.6% of the recorded neurons), invariably represented by a medium or large neuron on one side, and on the other side by a small (5.44 ± 0.15 × 9.14 ± 0.7 μm, mean ± SD;n = 7) neurogliaform cell, roundish in shape with few slender and short processes, usually apposed to a dendrite of the companion neurons (six out of seven). In the other cases, the biocytin staining revealed in each slice either the morphology of single spiny or aspiny neurons (80.4% of recorded neurons), or of two–three medium‐sized spiny neurons detected near to each other, suggesting that dye coupling had occurred typically between similar neurons (11.9% of the recorded neurons).

These data suggest that some neurogliaform cells in the striatum of young rat can be identified as dwarf interneurons, that may be dye‐coupled with neurons of different classes.
Stimulation of benzodiazepine receptors in the dorsal hippocampus and median raphé reveals differential GABAergic control in two animal tests of anxiety
Authors: Gonzalez Luis E. , Ouagazzal Abdel‐Mouttalib , File Sandra E.
Published: March 2003

The effects of pharmacological challenges to the benzodiazepine receptors in the dorsal hippocampus and median raphé nucleus were investigated in the social interaction and the elevated plus‐maze tests of anxiety in rats. In the social interaction test, bilateral administration of midazolam (1 and 2 μg), into the dorsal hippocampus had anxiolytic effects; flumazenil (500 ng) was silent, but was able to antagonize the anxiolytic effects of midazolam (2 μg). In the social interaction test, midazolam was also anxiolytic when infused into the median raphé nucleus; flumazenil (100 and 500 ng) increased locomotor activity, but did not change anxiety measures. As an anatomical control, midazolam (1 and 2 μg) was infused into the adjacent pontine reticular nucleus, and was without effect. In contrast to the social interaction test, local infusion of midazolam (1 and 2 μg) and flumazenil (100 and 500 ng) into either the dorsal hippocampus or the median raphé nucleus failed to change anxiety measures in the elevated plus‐maze (trials 1 and 2). These results show that stimulation of the benzodiazepine receptors in the hippocampus or the median raphé nucleus leads to anxiolytic effects in the social interaction test, but not in the elevated plus‐maze. It would therefore appear that the two tests detect different types of anxiety that are differentially modulated by GABAA‐benzodiazepine receptors in the dorsal hippocampus and the median raphé nucleus.
Regions in the human brain activated by simultaneous orientation discrimination: a study with positron emission tomography
Authors: Dupont Patrick , Vogels Rufin , Vandenberghe Rik , Rosier Annemie , Cornette Luc , Bormans Guy , Mortelmans Luc , Orban Guy A.
Published: March 2003

In order to compare regional cerebral activity involved in simultaneous as opposed to successive orientation discrimination, we used positron emission tomography to measure regional cerebral blood flow, in two threefold sets of conditions, in a large number of subjects. The first such triad involved simultaneous orientation discrimination, orientation identification and detection, with all tasks using the same pair of gratings. The second triad consisted of successive orientation discrimination with its corresponding identification and detection tasks. Comparisons between tasks within each triad isolate attention to orientation and, respectively, spatial or temporal comparison. The subtraction of detection from simultaneous discrimination revealed activation of right fusiform, right lingual, left precentral, left cingulate and left temporal cortex, in addition to right insula, cerebellum and left thalamus. Only the fusiform, insular and precentral activations remained when the corresponding identification was subtracted from simultaneous discrimination. In contrast, most of the non‐visual activation sites remained when simultaneous discrimination was compared with successive discrimination, which also revealed a left lingual activation. These experiments provide further evidence for task‐dependent processing in the human visual system and suggest that the right fusiform cortex is involved in spatial as much as temporal comparisons.
Behavioural characterization of interleukin‐6 overexpressing or deficient mice during agonistic encounters
Authors: Alleva Enrico , Cirulli Francesca , Bianchi Mauro , Bondiolotti Gian Pietro , Chiarotti Flavia , De Acetis Luigi , Panerai Alberto E.
Published: March 2003

Interleukin‐6 (IL‐6) is a cytokine released by activated immune cells which has been shown to affect brain function. In this experiment aggressive and affiliative behaviour exhibited during agonistic encounters by transgenic male mice either not expressing (IL‐6 –/–) or overexpressing (NSE‐hIL‐6) IL‐6 in the central nervous system was investigated. All subjects were isolated for 24 days before the aggressive encounter and were 52 days old at the time of testing. Subjects were placed for 5 consecutive days in a neutral cage for 15 min with an opponent of the Balb/c strain that had been previously isolated for the same amount of time. The first and the last test sessions were videotaped to evaluate the first approach and the establishment of the social role, respectively. A number of behavioural categories were later scored. When compared with wild‐type controls,

IL‐6 –/– mice showed a higher degree of aggressive behaviour as indicated by a higher frequency of Offensive Upright Posture, an effect more pronounced on the fifth encounter. On the contrary, NSE‐hIL‐6 subjects showed a tendency to be more involved in affiliative‐type social interactions, displaying a higher frequency and duration of behaviours such as Anogenital, Nose or Body Sniff. IL‐6 –/– mice showed a clear tendency to exhibit less affiliative interactions compared with their controls while dopamine levels were found to be modified in a number of brain regions in these mice.

Overall, these data suggest that IL‐6 affects both aggressive and affiliative‐type interactions, although the behaviour of the NSE‐hIL‐6 subjects was less affected than that of the IL‐6 –/– group. The effects of the genetic background of the animal in screening the outcome of gene manipulations on behaviour are also discussed.
Growth/differentiation factor 5 and glial cell line‐derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease
Authors: Sullivan Aideen M. , Pohl Jens , Blunt Stavia B.
Published: March 2003

Growth/differentiation factor 5 is a member of the transforming growth factor β superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line‐derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line‐derived neurotrophic factor prior to transplantation into the left striatum of rats with 6‐hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft‐induced compensation of amphetamine‐stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft‐induced recovery of striatal binding of [11C]RTI‐121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line‐derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.
Activated microglial cells migrate towards sites of excitotoxic neuronal injury inside organotypic hippocampal slice cultures
Authors: Heppner Frank L. , Skutella Thomas , Hailer Nils P. , Haas Dorit , Nitsch Robert
Published: March 2003

The aim of this study was to analyse microglial reactions to excitotoxic N‐methyl‐d‐aspartic acid (NMDA)‐induced degeneration of rat dentate and hippocampal neurons in vitro. We used a migration model combining the techniques of microglial single cell culture and organotypic hippocampal slice culture (OHSC). Site‐specific oxidative damage in OHSCs was induced by pretreatment with 50 μm NMDA. Neuronal injury determined by propidium iodide (PI) uptake included the hippocampal cell layers of the dentate gyrus (DG) and the cornu ammonis (CA). Fluorescence‐prelabelled microglial cells with ameboid morphology were transferred onto the OHSC and migrated predominantly to the prelesioned cell layers of DG and CA when compared with unlesioned areas of the OHSC. In NMDA pretreated slices, microglial cells clustered around degenerating granule cells in the DG and pyramidal cells in the CA. This effect was significantly inhibited in unlesioned slice cultures and in NMDA‐exposed cultures that were pretreated with the NMDA‐antagonist MK‐801. Our observations suggest that microglia – attracted by the presence of stimuli provided by NMDA‐induced neuronal death – migrate specifically towards these lesioned neurons.
Subcellular and subsynaptic distribution of the NR1 subunit of the NMDA receptor in the neostriatum and globus pallidus of the rat: co‐localization at synapses with the GluR2/3 subunit of the AMPA receptor
Authors: Bernard Véronique , Bolam J. Paul
Published: March 2003

Glutamatergic neurotransmission in the neostriatum and the globus pallidus is mediated through NMDA‐type as well as other glutamate receptors and is critical in the expression of basal ganglia function. In order to characterize the cellular, subcellular and subsynaptic localization of NMDA receptors in the neostriatum and globus pallidus, multiple immunocytochemical techniques were applied using antibodies that recognize the NR1 subunit of the NMDA receptor. In order to determine the spatial relationship between NMDA receptors and AMPA receptors, double labelling was performed with the NR1 antibodies and an antibody that recognizes the GluR2 and 3 subunits of the AMPA receptor.

In the neostriatum all neurons with characteristics of spiny projection neurons, some interneurons and many dendrites and spines were immunoreactive for NR1. In the globus pallidus most perikarya and many dendritic processes were immunopositive. Immunogold methods revealed that most NR1 labelling is associated with asymmetrical synapses and, like the labelling for GluR2/3, is evenly spread across the synapse. Double immunolabelling revealed that in neostriatum, over 80% of NR1‐positive axospinous synapses are also positive for GluR2/3. In the globus pallidus most NR1‐positive synapses are positive for GluR2/3. In both regions many synapses labelled only for GluR2/3 were also detected.

These results, together with previous data, suggest that NMDA and AMPA receptor subunits are expressed by the same neurons in the neostriatum and globus pallidus and that NMDA and AMPA receptors are, at least in part, colocalized at individual asymmetrical synapses. The synaptic responses to glutamate in these regions are thus likely be mediated by both AMPA and NMDA receptors at the level of individual synapses.
Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats
Authors: Oitzl Melly S. , Fluttert Marc , Sutanto Win , De Kloet E. Ron
Published: March 2003

Previously, a corticosterone surge associated with a learning task was shown to facilitate cognitive processes through brain glucocorticoid receptors (GR) while chronic overexposure to this stress hormone impaired cognition. In the present study we tested the hypothesis that opposing effects on learning and memory might also occur after either phasic or continuous blockade of brain GR by intracerebroventricular (i.c.v.) administration of the GR antagonist RU38486 (aGR). We used a Morris water maze procedure to assess spatial learning and memory abilities in male Wistar rats. The effect of phasic brain GR blockade was studied following daily pretraining administration of 10 and 100 ng/μL aGR i.c.v. on 3 consecutive days. This repetitive aGR treatment impaired spatial learning and memory dose‐dependently in comparison with vehicle controls. For continuous brain GR blockade, animals received an i.c.v. infusion of aGR (10 and 100 ng/0.5 μL per h or vehicle) over 10 days. Infusion of 100 ng aGR per hour resulted in a long‐lasting facilitation of spatial performance. The 10 ng aGR infusion also caused initially a facilitating effect, which was, however, transient and performance became impaired during retest. Possible anxiolytic properties of the drugs were excluded in view of the animals' behaviour in the elevated plus maze. Both doses of aGR infusion reduced the number of mineralocorticoid receptors in the hippocampus, but only the high dose of aGR resulted in a significant reduction of available GR sites. In conclusion, continuous administration of GR antagonist improves cognitive function, while phasic blockade of brain GR function causes a cognitive deficit.
Neurotrophic ACTH4–9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis
Authors: Duckers H. J. , Van Dokkum R. P. , Verhaagen J. , Van Luijtelaar E. L. , Coenen A. M. , Da Silva F. H. Lopes , Gispen W. H.
Published: March 2003

Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event‐related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE‐affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a neurotrophic peptide treatment [H‐Met(O2)‐Glu‐His‐Phe‐d‐Lys‐Phe‐OH, an ACTH4–9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17‐week follow‐up of CEAE. CEAE animals treated with the neurotrophic peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by peptide treatment. The peak‐to‐peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age‐matched control group. This increase in beta power mainly consisted of a prevailing 20–21 Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4–9 analogue‐treated animals. The present findings underscore the potential importance of a neurotrophic peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.
Direction discrimination of moving gratings and plaids and coherence in dot displays without primary visual cortex (V1)
Authors: Benson Philip J. , Guo Kun , Blakemore Colin
Published: March 2003

We present new experimental observations of G.Y., a well‐tested patient with unilateral loss of primary visual cortex. We stimulated G.Y.'s blind hemifield using first‐ and second‐order motion stimuli at velocities around psychophysical threshold. Using a dual response paradigm (awareness level of visual motion, motion direction discrimination) psychophysical performance improved with increasing velocity and dot coherence. We were also able to influence directly G.Y.'s performance for the better and at will, by placing the emphasis solely on direction discrimination. In the absence of V1, graduated detection and discrimination of stimuli known to activate both V1 and extrastriate motion areas MT/V5 and MST is still possible. These results are in line with residual visual processing but did not show evidence of unconscious processing of motion stimuli characteristic of ‘blindsight’.
Direct glutamate‐mediated presynaptic inhibition of sensory afferents by the postsynaptic motor neurons
Authors: Cattaert Daniel , Ray Didier Le
Published: March 2003

An in vitro preparation of the crayfish central nervous system was used to study a negative feedback control exerted by the glutamatergic motor neurons (MNs) on to their presynaptic cholinergic sensory afferents. This negative control consists in small amplitude, slowly developing depolarizations of the primary afferents (sdPADs) strictly timed with MN bursts. They were not blocked by picrotoxin, but were sensitive to glutamate non‐N‐methyl‐d‐aspartate (NMDA) antagonists. Intracellular recordings were performed within thin branches of sensory terminals while electrical antidromic stimulation were applied to the motor nerves, or while glutamate (the MN neurotransmitter) was pressure‐applied close to the recording site. Electrical motor nerve stimulations and glutamate pressure application had similar effects on to sensory terminals issued from the coxo‐basipodite chordotonal organ (CBTs): like sdPADs, both stimulation‐induced depolarizations were picrotoxin‐resistant and were dramatically reduced by non‐NMDA antagonist bath application. These results indicate that sdPADs are likely directly produced by MNs during locomotor activity. A functional scheme is proposed.
The serotonin inhibition of high‐voltage‐activated calcium currents is relieved by action potential‐like depolarizations in dissociated cholinergic nucleus basalis neurons of the guinea‐pig
Authors: Williams Sylvain , Serafin Mauro , Mühlethaler Michel , Bernheim Laurent
Published: March 2003

The aim of the present study was to investigate whether the voltage‐dependent inhibition of calcium currents by serotonin 5‐HT1A agonists can be alleviated (facilitated) by action potential‐like depolarizations. In dissociated cholinergic basal forebrain neurons using whole‐cell recordings, it is shown that a selective serotonin 5‐HT1A agonist (8‐OH‐DPAT) predominantly blocks N‐type HVA calcium current, although a minor reduction of P‐type current was also observed. The inhibition may principally occur through Gi‐Go subtypes of G‐proteins because it was prevented by N‐ethylmaleimide, a substance known to block specifically pertussis‐sensitive G‐proteins. The inhibitory effect of 8‐OH‐DPAT on calcium currents is voltage‐dependent because it was alleviated by long‐lasting depolarizing prepulses. Interestingly, the inhibition could also be reversed by prepulses made‐up of action potential‐like depolarizations that were given at a frequency of 200 Hz. This observation may have important implications during periods of high‐frequency rhythmic bursts, a firing pattern that is prevalent in cholinergic basal forebrain neurons.
Immunocytochemical localization of somatostatin receptor sst2A in the rat spinal cord and dorsal root ganglia
Authors: Schulz Stefan , Schreff Matthias , Schmidt Harald , Händel Manuela , Przewlocki Ryszard , Höllt Volker
Published: March 2003

Intrathecal administration of octreotide, a stable somatostatin analogue, provides pain relief in patients, and locally applied somatostatin inhibits firing of nociceptive dorsal horn neurons. In the present study, we have raised polyclonal antibodies that specifically detect the somatostatin receptor sst2A and used these antisera for immunocytochemical localization of the receptor protein in the rat spinal cord and dorsal root ganglia. In the superficial layers of the dorsal horn, sst2A‐like immunoreactivity (Li) formed a dense network consisting of neuronal perikarya and dendrites which were often closely apposed by, but not co‐contained within, somatostatin‐14‐immunoreactive nerve fibres and terminals. sst2A‐Li was resistant to dorsal rhizotomy and did not colocalize with either substance P or calcitonin gene‐related peptide suggesting that sst2A‐Li was not located to primary afferents, but rather confined to second‐order spinal neurons. The position of sst2A‐Li perikarya and dendrites in the dorsal horn appeared to be similar to those containing μ‐opioid receptor‐Li; however, double labelling experiments revealed no instances of coexistence of these two receptors. sst2A‐Li was also observed in the dorsal root ganglia predominantly targeted to the somatic plasmalemma of medium size neurons distinct from those expressing somatostatin‐14 or δ‐opioid receptors. Thus, the present results not only provide a morphological substrate for spinal octreotide analgesia but also show that somatostatin and opioids are poised to modulate nociceptive transmission by distinct anatomical systems.
Differential time‐ and dose‐related effects of haemorrhage on tyrosine hydroxylase and neuropeptide Y mRNA expression in medullary catecholamine neurons
Authors: Chan Raymond K. W. , Sawchenko Paul E.
Published: March 2003

Hypotensive haemorrhage induces nuclear Fos expression and upregulates tyrosine hydroxylase (TH) mRNA in catecholamine‐containing cell groups of the rat medulla oblongata. To shed light on the significance of the coexistence of neuropeptide Y (NPY) in aminergic neurons, the impact of graded levels of haemorrhage on temporal changes in the expression of TH and NPY mRNAs was compared; concurrent staining for Fos permitted comparisons between cells that ostensibly were and were not targeted by the stimulus. A 15% haemorrhage provoked increased NPY expression in all medullary catecholamine cell groups except the A2; these changes were detected predominantly in Fos‐immunoreactive neurons (Fos‐ir) at later (2–4 h) time points. Upregulation of TH and NPY mRNAs in Fos‐ir neurons followed distinct time courses, with NPY responses peaking more rapidly, particularly in the C1 and C2 cell groups. Adrenergic cell groups displayed greater maximal increases in NPY expression than the A1 noradrenergic cell group while the converse was true of TH mRNA response. Increasing the severity of haemorrhage resulted in more pronounced increases in both mRNA responses in each aminergic region. These findings indicate that haemorrhage differentially affects TH and NPY expression in medullary catecholamine cell groups that participate in the maintenance of cardiovascular homeostasis. The differential nature of these responses suggests them not to be a simple consequence of metabolic alterations pursuant to increased synaptic activity. The prompt and robust NPY mRNA responses in adrenergic neurons suggests a mechanism by which peptide content of these cell groups' terminal projections is defended.
Retrograde amnesia for spatial information: a dissociation between intra and extramaze cues following hippocampus lesions in rats
Authors: Ramos Juan M. J.
Published: March 2003

Several recent studies have shown a flat retrograde amnesia for spatial information following lesions to the hippocampus in rats and mice. However, the results of the present investigation demonstrate that in rats that presurgically learned a spatial reference memory task based on extramaze cues, a temporally graded retrograde amnesia is evident following lesions to the hippocampus (1, 16, 32 or 64 days after learning) if two conditions are met. First, that a wide range of retention intervals is used, and second, that independent groups of rats are tested, not a single group that learns different spatial discrimination tasks at different times (expt 1). The results of expt 2 show that the hippocampus does not serve as a consolidating mechanism when the spatial task learned presurgically is based on intramaze cues. Taken together, these results indicate that the hippocampus is critical for the storage and/or retrieval of spatial reference information that was learned up to 1 month before hippocampus damage; however, in the absence of the hippocampus, efficient retention can still occur provided that the spatial knowledge was learned in a simple associative manner.
Rapid increase in PKA activity during long‐term potentiation in the hippocampal afferent fibre system to the prefrontal cortex in vivo
Authors: Jay Thérèse M. , Gurden Hirac , Yamaguchi Tomoko
Published: March 2003

The purpose of the present study was to examine whether cAMP‐dependent protein kinase (PKA) was implicated in the process of long‐term potentiation (LTP) in the hippocampal afferent fibre system to the prefrontal cortex in vivo. Using a biochemical approach, we measured PKA activity at different times after induction of LTP. We show that there is an NMDA receptor‐dependent increase in PKA activity in the prefrontal cortex, only at five minutes after LTP induction. These data demonstrate a role of PKA in the induction and not the expression of cortical LTP and suggest that if PKA is involved in the late phase of LTP, it does not appear to be a persistent activation.