bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐related behavioural deficits in transgenic mice expressing the HIV‐1 coat protein gp120
Authors: D'Hooge R. , Franck F. , Mucke L. , De Deyn P. P.
Published: March 2003

Transgenic mice expressing HIV‐1 coat glycoprotein gp120 in brain glial cells were previously shown to display AIDS dementia‐like neuropathological changes and reduced hippocampal long‐term potentiation. In this report, neuromotor and cognitive performance in 3‐ and 12‐month‐old gp120‐expressing mice was compared with wildtype controls. Rotarod and cage activity measures showed no significant differences between transgenic animals and controls of either age. Open field activity was slightly altered in 12‐month‐old gp120 animals (reduced corner crossings and dwell in centre), but not in the 3‐month‐olds. Cognitive assessment using the Morris water maze showed unimpaired performance in 3‐month‐old mice during acquisition and (no‐platform) probe trials. In 12‐month‐old gp120 animals, escape latency and swimming velocity during the acquisition trials were significantly reduced, but performance improved at roughly the same rate as in control animals. However, the probe trials revealed a highly significant reduction in spatial retention in transgenic mice of this age. This demonstration of age‐dependent impairments in open field activity and spatial reference memory may relate to cognitive and neuromotor deficits seen in a proportion of HIV‐1‐infected individuals.
Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5‐HT2A sites for PCP‐induced locomotion in the rat
Authors: Millan M. J. , Brocco M. , Gobert A. , Joly F. , Bervoets K. , Rivet J. ‐M. , Newman‐Tancredi A. , Audinot V. , Maurel S.
Published: March 2003

In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP‐induced locomotion (PLOC) was potently blocked by the selective serotonin (5‐HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine‐induced locomotion (ALOC). In contrast, the selective D2 vs. 5‐HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5‐HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5‐HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5‐HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra‐accumbens PCP, but not intra‐accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5‐HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra‐accumbens 6‐hydroxydopamine (6‐OHDA), which depleted DA but not 5‐HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens‐localized 5‐HT2A receptors by 5‐HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5‐HT2A receptors.
Genetic and epigenetic regulation of NMDA receptor expression in the rat visual cortex
Authors: Nase Gabriele , Weishaupt Jochen , Stern Peter , Singer Wolf , Monyer Hannah
Published: March 2003

The susceptibility of cortical networks to use‐dependent modifications declines with age (critical period) and this decline of neuronal plasticity during development is paralleled by the shortening of NMDA receptor EPSCs. We showed previously in the somatosensory cortex that the shortening of NMDA receptor kinetics correlates with a developmentally‐regulated increase in the NR2A subunit expression. Here we examine whether this developmental regulation of NR2A expression is related to the duration of critical periods and whether it is influenced by experience. Functional NMDA receptors and their molecular characteristics are studied in identified layer IV neurons of rat visual cortex. In this structure the time course of the critical period differs from that in the somatosensory cortex and can be changed by sensory deprivation, thus permitting examination of correlations between the time course of receptor expression and the duration of the critical period. We find that the developmental expression of the NR2A subunit is delayed compared with the somatosensory cortex, in agreement with the prolonged critical period in the visual cortex. Moreover, sensory deprivation further delays the developmental change in the NMDA receptor subunit composition, demonstrating the activity dependence of this process and strengthening the correlation between changes in subunit composition and the time course of the critical period.
Hippocampal Cajal–Retzius cells project to the entorhinal cortex: retrograde tracing and intracellular labelling studies
Authors: Ceranik Katja , Deng Jinbo , Heimrich Bernd , Lübke Joachim , Zhao Shanting , Förster Eckart , Frotscher Michael
Published: March 2003

Cajal–Retzius (CR) cells are characteristic horizontally orientated, early‐generated transient neurons in the marginal zones of the neocortex and hippocampus that synthesize the extracellular matrix protein reelin. They have been implicated in the pathfinding of entorhino‐hippocampal axons, but their role in this process remained unclear. Here we have studied the axonal projection of hippocampal CR cells. Following injection of the carbocyanine dye DiI into the entorhinal cortex of aldehyde‐fixed rat embryos and young postnatal rats, neurons in the outer molecular layer of the dentate gyrus and stratum lacunosum‐moleculare of the hippocampus proper with morphological characteristics of CR cells were retrogradely labelled. In a time course analysis, the first retrogradely labelled CR cells were observed on embryonic day 17. This projection of hippocampal CR cells to the entorhinal cortex was confirmed by retrograde tracing with Fast Blue in new‐born rats and by intracellular biocytin filling of CR cells in acute slices from young postnatal rat hippocampus/entorhinal cortex and in entorhino‐hippocampal slice cocultures using infrared videomicroscopy in combination with the patch‐clamp technique. In double‐labelling experiments CR cells were identified by their immunocytochemical staining for reelin or calretinin, and their interaction with entorhino‐hippocampal axons labelled by anterograde tracers was analysed. Future studies need to investigate whether this early transient projection of hippocampal CR cells to the entorhinal cortex is used as a template by the entorhinal axons growing to their target layers in the hippocampus.
Sensorimotor transformation in cat nociceptive withdrawal reflex system
Authors: Levinsson Anders , Garwicz Martin , Schouenborg Jens
Published: March 2003

The withdrawal reflex system of higher vertebrates has been extensively used as a model for spinal sensorimotor integration, nociceptive processing and plasticity. In the rat, the nociceptive withdrawal reflex system appears to have a modular organization. Each reflex module controls a single muscle or a few synergistic muscles, and its cutaneous receptive field corresponds to the skin area withdrawn upon contraction of the effector muscle(s) when the limb is in the standing position. This organization principle is at odds with the ‘flexion reflex’ concept postulated from cat studies. To assess the generality of the modular organization principle we have therefore re‐examined the cutaneous input to the withdrawal reflex system of the cat. The cutaneous receptive fields of hindlimb and forelimb muscles were mapped using calibrated noxious pinch stimulation and electromyographic recording technique in barbiturate anaesthetized animals. The investigated muscles had specific cutaneous receptive fields that appeared to correspond to the area of the skin withdrawn upon contraction of the muscle when the limb is in the standing position. The spatial organization of receptive fields in the cat was similar to that in the rat. However, differences in gain properties of reflexes to some anatomically equivalent muscles in the two species were observed, possibly reflecting adaptations to the biomechanics characteristic of the digitigrade and plantigrade stance in cats and rats, respectively. Implications of the findings for the generality of the modular organization of the withdrawal reflex system and for its adaptive properties are discussed.
Short‐lasting conditioned stimulus applied to the middle cerebellar peduncle elicits delayed conditioned eye blink responses in the decerebrate ferret
Authors: Svensson P. , Ivarsson M.
Published: March 2003

In delay eye blink conditioning, the conditioned stimulus (CS) ends at the time of the unconditioned stimulus (US). If the CS duration is decreased, there will be a ‘trace’ period with no ongoing CS before the onset of the US. During this period some neural activity has to continue after the CS offset to: (i) permit association between the CS and the US; and (ii) elicit a conditioned response appearing after the CS offset. In this study we test the role of the cerebellum in maintaining CS activity required for eliciting a conditioned response after the CS offset. Decerebrate ferrets were trained in a delay conditioning paradigm with an electrical stimulation of the forelimb as CS and of the periorbital area as US. The conditioned responses in the upper eyelid were monitored with electromyographical techniques. In well‐trained animals, test CSs of short duration down to 0.2 ms were applied to the forelimb or the middle cerebellar peduncle, while the interstimulus interval between CS onset and US onset was kept constant at 300 ms. Test CSs of short duration applied to the forelimb elicited conditioned responses. More importantly, also a short‐lasting CS to the middle cerebellar peduncle could elicit conditioned responses. The results indicate that precerebellar CS pathways are not required for maintaining the neural activity that elicits conditioned responses after the CS offset. It is suggested that neurons maintaining such activity are located in the cerebellum, either the cortex alone or the cortex and the deep nuclei.
Orientation topography of layer 4 lateral networks revealed by optical imaging in cat visual cortex (area 18)
Authors: Yousef Tagrid , Bonhoeffer Tobias , Kim Dae‐Shik , Eysel Ulf T. , Tóth Éva , Kisvárday Zoltán F.
Published: March 2003

The functional specificity of corticocortical connections with respect to the topography of orientation selectivity was studied by optical imaging of intrinsic signals and bulk injections of fluorescent latex beads (green and red) and biocytin into layer 4. The distributions of retrogradely labelled cells and anterogradely labelled axon terminals were histologically reconstructed from all cortical laminae, and the resulting anatomical maps compared with the optically imaged functional maps. Layer 4 injections produced extensive horizontal labelling up to 2–3 mm from the injection centres albeit without the clear patchy pattern described after layer 2/3 injections (Gilbert & Wiesel 1989, J. Neurosci., 9, 2432–2442; Kisvárday et al. 1997, Cerebral Cortex, 7, 605–618). The functional (orientation) distribution of the labelled projections was analysed according to laminar location and lateral spread. With regard to the former, no major difference in the orientation topography between supragranular‐ (upper tier), granular‐ (middle tier) and infragranular (lower tier) layers was seen. Laterally, proximal and distal projections were distinguished and further dissected into three orientation categories, iso‐ (± 30°), oblique‐ (± 30–60°) and cross‐orientations (± 60–90°) with respect to the orientation preference at the injection sites. The majority of distal connections (retrograde and anterograde) was equally distributed across orientations (35.4% iso‐, 33.7% oblique‐, and 30.9% cross‐orientations) that are equivalent with a preponderance to dissimilar orientations (oblique‐ and cross‐orientations, 64.6%). In one case, distal excitatory and inhibitory connections could be morphologically distinguished. For both categories, a marked bias to dissimilar orientations was found (excitatory, 63.7%; inhibitory, 86.6%). Taken together, these results suggest that the long‐range layer 4 circuitry has a different functional role from that of the iso‐orientation biased (52.9%, Kisvárday et al. 1997, Cerebral Cortex, 7, 605–618) layer 2/3 circuitry, and is perhaps involved in feature difference‐based mechanisms, e.g. figure ground segregation.
Ulip/CRMP proteins are recognized by autoantibodies in paraneoplastic neurological syndromes
Authors: Honnorat Jérôme , Byk Tamara , Kusters Inca , Aguera Michèle , Ricard Damien , Rogemond Véronique , Quach Tam , Aunis Dominique , Sobel André , Mattei Marie‐Geneviève , Kolattukudy Pappachan , Belin Marie‐Françoise , Antoine Jean Christophe
Published: March 2003

Anti‐CV2 autoantibodies have recently been discovered in patients with paraneoplastic neurological diseases (PND). These disorders are associated with neuronal degeneration, mediated by autoimmune processes, in patients with systemic cancer. Anti‐CV2 autoantibodies recognize a brain protein of 66 kDa developmentally regulated and specifically expressed by a subpopulation of oligodendrocytes in the adult brain. Here, we demonstrate that anti‐CV2 sera recognize several post‐translationally modified forms of Ulip4/CRMP3, a member of a protein family related to the axonal guidance and homologous to the Unc‐33 gene product in Caenorhabditis elegans. The sequence of the human Ulip4/CRMP3 was determined and the gene localized to chromosome 10q25.2–q26, a region mutated in glioblastomas and containing tumour suppressor genes. The identification of the Ulip/CRMP proteins as recognized by anti‐CV2 sera should provide new insights into the role of Ulip/CRMPs in oligodendrocytes and into pathophysiology of PND.
Activity‐dependent neurotransmitter release kinetics: correlation with changes in morphological distributions of small and large vesicles in central nerve terminals
Authors: Leenders A. G. Miriam , Scholten Greet , Wiegant Victor M. , Da Silva Fernando H. Lopes , Ghijsen Wim E. J. M.
Published: March 2003

In central nerve terminals transmitter release is tightly regulated and thought to occur in a number of steps. These steps include vesicle mobilization and docking prior to neurotransmitter release. Intrasynaptic changes in vesicle distribution were determined by electron microscopical analysis and neurotransmitter release was monitored by biochemical measurements. We correlated K + ‐induced changes in distribution of small and large vesicles with the release of their transmitters. For small synaptic vesicles, amino acid release as well as recruitment to and docking at the active zone were activated within 1 s of depolarization. In contrast, the disappearance of large dense‐cored vesicles and the release of the neuropeptide cholecystokinin were much slower, and no docking was observed. Studies with diverse Ca2 +  channel blockers indicated that mobilization and neurotransmitter release from both vesicle types were regulated by multiple Ca2 +  channels, although in different ways. Neurotransmitter release from small synaptic vesicles was predominantly regulated by P‐type Ca2 +  channels, whereas primarily Q‐type Ca2 +  channels regulated neurotransmitter release from large dense‐cored vesicles. The different Ca2 +  channnel types directly regulated mobilization of and neurotransmitter release from small synaptic vesicles whereas, by their cooperativity in raising the intracellular Ca2 +  concentration above release threshold, they more indirectly regulated large dense‐cored vesicle exocytosis.
Cortically driven Fos induction in the striatum is amplified by local dopamine D2‐class receptor blockade
Authors: Berretta Sabina , Sachs Zohar , Graybiel Ann M.
Published: March 2003

Dopamine D2‐class receptors have been shown to control the excitability of striatal neurons in response to cortical activation. It has been unclear, however, whether such receptors could regulate the number of striatal neurons activated by cortical stimulation, and thus affect the population response of the striatum to its cortical inputs. We used Fos induction as a readout to measure the ensemble response of striatal neurons to localized stimulation of the frontal cortex and tested for the effects of D2‐class dopamine receptor blockade on this response. In freely moving rats, we stimulated the frontal cortex by local epidural application of a dose of a GABAA receptor antagonist (picrotoxin) just threshold for inducing Fos in the striatum. We combined this treatment with D2‐class dopamine receptor antagonist treatments at dose levels also just threshold for inducing Fos, using either (i) systemic haloperidol or (ii) intrastriatal (–)sulpiride. Both systemic and intrastriatal blockade of D2‐class receptors sharply increased the numbers of striatal neurons exhibiting cortically evoked Fos induction. These findings suggest that local activation of intrastriatal D2‐class dopamine receptors can regulate the number of striatal neurons responsive to cortical inputs, thus dynamically shaping the flow of information through the striatum.
Dopamine cells in nigral grafts differentiate prior to implantation
Authors: Sinclair Simon R. , Fawcett James W. , Dunnett Stephen B.
Published: March 2003

The yield of surviving dopamine cells in nigral grafts is typically low. It is unclear whether the dopamine neurons that do survive are postmitotic at the time of implantation, or are precursor cells that differentiate into dopamine neurons following transplantation in the host brain. We have therefore compared the survival of dopamine neurons in grafts that have been labelled with BrdU at different times prior to or following implantation in order to identify those cells that undergo final cell division at each stage of the procedure. Seven groups of rats were prepared with unilateral nigrostriatal lesions. Three groups received nigral grafts derived from E14 embryos labelled with BrdU in utero on either E12, E13 or E14 days of embryonic age (the E14 injection made 2 h prior to preparation of the graft cell suspension). Three further groups received nigral grafts from untreated E14 embryos, and then dividing cells within the grafts were labelled by injection of BrdU into the host lateral ventricle, 2 h, 1 day or 2 days after implantation (equivalent to E14, E15 and E16 days of embryonic age). The control group received standard (unlabelled) E14 grafts. Five weeks after the transplantation surgery, the host brains were processed using double immunohistochemical techniques to detect tyrosine hydroxylase (TH)‐positive neurons which had incorporated BrdU. In the grafts labelled with BrdU prior to implantation, there was an increasing proportion of double‐labelled cells (out of the total TH‐positive cells surviving in the grafts) with birth dates on E12, E13 and E14 (1%, 12% and 10% per day, respectively). By contrast, grafts labelled following implantation, although containing many dividing neurons, had very few of these BrdU‐labelled cells expressing a dopaminergic phenotype; <  1% surviving TH‐positive cells were double‐labelled from the 2 h post‐transplant injection, and <  0.1% from each subsequent injection. This suggests not only that the great majority of TH‐positive neurons in nigral grafts were already differentiated at the time of implantation, but also that transplantation of E14 ventral mesencephalic tissue either kills dopaminergic precursors or (more likely in our opinion) prevents their differentiation into a dopaminergic phenotype. Precursor cells that would differentiate into dopaminergic neurons beyond E14 if left in situ in the intact ventral mesencephalon do not readily differentiate into mature dopamine neurons following transplantation. If we are to enhance yields of functional dopamine‐rich transplants, then we must identify strategies both to protect predifferentiated dopamine neurons in the grafts and to promote differentiation of a dopaminergic phenotype in precursor cells that continue to divide within the grafts following transplantation into an adult host environment.
Selective sensitivity of early postmitotic retinal cells to apoptosis induced by inhibition of protein synthesis
Authors: Rehen S. K. , Neves D. D. C. , Fragel‐Madeira L. , Britto L. R. G. , Linden R.
Published: March 2003

In previous work we showed that apoptosis in retinal tissue from developing rats can be induced by inhibition of protein synthesis (Rehen et al. 1996, Development, 122, 1439–1448). Here we show that recent postmitotic cells are the cells sensitive to apoptosis triggered by blockade of protein synthesis. To label all proliferating cells in the retina, a series of injections of the nucleotide analogue, bromo‐deoxy‐uridine (BrdU, 60 mg/kg b.w.), was given in rat pups. Then, explants of the retina were incubated in vitro with the inhibitor of protein synthesis anisomycin (1.0–3.2 μg/mL) for 1 day to induce apoptosis. Detection of apoptotic bodies under differential interference contrast microscopy was combined with immunocytochemistry for BrdU, proliferating cell nuclear antigen (PCNA) or for various markers of retinal cell differentiation. Despite the large number of BrdU‐ and PCNA‐labelled cells in the tissue, the vast majority of the cells that underwent apoptosis were postmitotic cells which have left the mitotic cycle 3–4 days before. However, these cells were not labelled with antibodies to calretinin, calbindin, rhodopsin or to a Muller glial cell marker, suggesting that these are early postmitotic neurons. We suggest that during migration and initial differentiation, the apoptotic machinery is blocked by suppressor proteins, thus allowing recent postmitotic cells to find their final positions and differentiate while protected from apoptosis.
Adenosine suppresses protein kinase A‐ and C‐induced enhancement of glutamate release in the hippocampus
Authors: Bouron Alexandre
Published: March 2003

Cultured hippocampal neurons from neonatal rats were used to investigate the effect of adenosine on the release of glutamate. Spontaneous tetrodotoxin‐resistant miniature excitatory postsynaptic currents (mEPSCs) through AMPA receptor channels were recorded by means of the whole‐cell patch‐clamp technique. Adenosine (50 μm) reversibly reduced the frequency of mEPSCs by ∼ 50–60%, but did not change their amplitudes. The protein kinase A inhibitor Rp‐cyclic adenosine monophosphate (100–150 μm) did not block the adenosine‐dependent reduction of the mEPSC frequency, showing that adenosine is not depressing synaptic transmission via a protein kinase A (PKA)‐dependent mechanism. The D1 dopamine agonist SKF‐38393 (250 μm), forskolin (5 μm) and 8Br‐cAMP (2 mm), known to activate the cAMP/PKA‐dependent signalling pathway, all enhanced the mEPSC frequency. A subsequent application of adenosine (50 μm) strongly reduced the potentiation produced by any one of these three drugs. It also reversed protein kinase C (PKC)‐dependent stimulation of glutamate release induced by phorbol myristate acetate (100 nm). Taken together, adenosine not only inhibits the spontaneous release of glutamate independently of protein kinases A and C but also reverses the enhancement of exocytosis produced by protein kinases A and C activators.
Induction of stable long‐term depression in vivo in the hippocampal–prefrontal cortex pathway
Authors: Takita Masatoshi , Izaki Yoshinori , Jay Thérèse M. , Kaneko Hidekazu , Suzuki Shinya S.
Published: March 2003

We studied excitatory field potentials in the medial prefrontal cortex (mPFC, prelimbic area) to electrostimulation of the ventral hippocampus (CA1/subicular region) in the anaesthetized rat. Nine hundred stimulus trains (5 pulses at 250 Hz) applied at 1 Hz to the ventral hippocampus significantly and persistently depressed the amplitude and maximal slope (∼ 55% for each index) of the prelimbic field potentials, but did not change the latency of the maximal slope or peak negativity. Twelve stimulus trains (50 pulses at 250 Hz) applied subsequently at 0.1 Hz restored the depression back to control level, and this reversible depression was maintained for at least 13 h. Cumulative depressive effects on the prelimbic field potential amplitude and maximal slope were observed upon addition of stimulus trains in the hippocampus. An important implication of the results is that the direct pathway from the hippocampus to the mPFC in the rat retains long‐term depression (LTD) as a neuroplastic form in vivo. This form could cooperate with long‐term potentiation (LTP) and such a bi‐directional synaptic plasticity in the prefrontal cortex contributes to how cortical neural networks store information.
Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination
Authors: Nait‐Oumesmar Brahim , Decker Laurence , Lachapelle François , Avellana‐Adalid Virginia , Bachelin Corinne , Van Evercooren Anne Baron‐.
Published: March 2003

Identifying a source of cells with the capacity to generate oligodendrocytes in the adult CNS would help in the development of strategies to promote remyelination. In the present study, we examined the ability of the precursor cells of the adult mouse subventricular zone (SVZ) to differentiate into remyelinating oligodendrocytes. After lysolecithin‐induced demyelination of the corpus callosum, progenitors of the rostral SVZ (SVZa) and the rostral migratory pathway (RMS), expressing the embryonic polysialylated form of the neural cell adhesion molecule (PSA‐NCAM), increased progressively with a maximal expansion occurring after 2 weeks. This observation correlated with an increase in the proliferation activity of the neural progenitors located in the SVZa and RMS. Moreover, polysialic acid (PSA)‐NCAM‐immunoreactive cells arizing from the SVZa were detected in the lesioned corpus callosum and within the lesion. Tracing of the constitutively cycling cells of the adult SVZ and RMS with 3H‐thymidine labelling showed their migration toward the lesion and their differentiation into oligodendrocytes and astrocytes but not neurons. These data indicate that, in addition to the resident population of quiescent oligodendrocyte progenitors of the adult CNS, neural precursors from the adult SVZ constitute a source of oligodendrocytes for myelin repair.
Nitric oxide stimulates cGMP formation in rat optic nerve axons, providing a specific marker of axon viability
Authors: Garthwaite Giti , Goodwin David A. , Garthwaite John
Published: March 2003

A major transduction pathway for nitric oxide (NO) is stimulation of soluble guanylyl cyclase and the generation of cyclic GMP (cGMP). In the central nervous system, the NO–cGMP pathway has previously been associated primarily with synapses, particularly glutamatergic synapses. We report here that NO caused a large increase in the levels of cGMP in a central white matter tract devoid of synapses, namely in the rat isolated optic nerve. Cyclic GMP immunohistochemistry indicated that this response was confined to the axons. Accordingly, nerves previously subjected to 1 h of oxygen/glucose deprivation, which leads to irreversible axonal damage, displayed an 80% reduction in their subsequent capacity to generate cGMP in response to NO and a corresponding reduction in the numbers of cGMP‐immunostained axons. Protection of the axon cGMP response against this insult was achieved by omission of Ca2 +  or Na +  from the incubation medium, and by the pharmacological agents tetrodotoxin, lamotrigine, BW619C89 and BW1003C87, all of which protect axonal structure from oxygen/glucose deprivation‐induced damage. The results suggest that the NO–cGMP pathway has a hitherto unsuspected function in the optic nerve. Additionally, the expression of NO‐stimulated guanylyl cyclase in optic nerve axons provides a simple, sensitive and specific marker of their functional integrity that is likely to be valuable in investigating the mechanisms responsible for axon degeneration in ischaemia and other conditions.
Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice)
Authors: Knuesel Irene , Mastrocola Mario , Zuellig Richard A. , Bornhauser Beat , Schaub Marcus C. , Fritschy Jean‐Marc
Published: March 2003

Dystrophin is selectively localized in the postsynaptic density of neurons in cerebral cortex, hippocampus and cerebellum. Here, we show by double‐immunofluorescence staining that dystrophin is extensively colocalized with GABAA receptor subunit clusters in these brain regions. To determine the relevance of this observation, we investigated in mdx mice, which provide a model of Duchenne muscular dystrophy, whether the absence of dystrophin affects the synaptic clustering of GABAA receptors. A marked reduction in the number of clusters immunoreactive for the α1 and α2 subunits was observed in, respectively, cerebellum and hippocampus of mdx mice, but not in striatum, which is normally devoid of dystrophin. Furthermore, these alterations were not accompanied by a change in gephyrin staining, although gephyrin is colocalized with the majority of GABAA receptor clusters in these regions. These results indicate that dystrophin may play an important role in the clustering or stabilization of GABAA receptors in a subset of central inhibitory synapses. These deficits may underlie the cognitive impairment seen in Duchenne patients.
Mapping of somatosensory cortices with functional magnetic resonance imaging in anaesthetized macaque monkeys
Authors: Hayashi Toshihiro , Konishi Seiki , Hasegawa Isao , Miyashita Yasushi
Published: March 2003

Functional magnetic resonance imaging (fMRI) in macaque monkeys is emerging as a potent candidate to bridge the gap between data from human fMRI studies and data from anatomy, electrophysiology and lesion studies in monkeys. The primary (SI) and secondary (SII) somatosensory cortices are the principal regions for somatosensory information processing and contain systematic representations of the body surface map (somatotopy). To examine the functional organization of the somatosensory cortices in anaesthetized macaque monkeys with fMRI, we asked whether focal and differential activation could be observed in SI and SII in response to tactile stimulation with two parameters: body sides (right and left) and body regions (hand and face). We found that changes in stimulus parameters elicited differential focal activation in both SI and SII in two ways. First, the hand and face stimulation activated SI and SII in the contralateral, but not in the ipsilateral, hemisphere. Second, the hand and face stimulation differentially activated two adjacent regions in both SI and SII. These fMRI results appear to correlate with previous mapping studies by other methods in the macaque somatosensory cortices. This study shows the feasibility of fMRI studies in mapping multiple sensory areas in monkeys by which we can distinguish between adjacent functionally distinct regions.
Molecular Characterization and In Situ Localization Of A Full‐Length Cyclic Nucleotide‐Gated Channel In Rat Brain
Authors: Strijbos Paul J. L. M. , Pratt Gerard D. , Khan Shahid , Charles Ian G. , Garthwaite John
Published: March 2003

Ion channels gated directly by cyclic nucleotides are required for the transduction of sensory signals in photoreceptor cells and olfactory cells. Cyclic nucleotide‐gated (CNG) channels may also be expressed in the central nervous system because partial transcripts that share homology with CNG channels have been found therein. We have now isolated and cloned a full‐length CNG channel cDNA from adult rat brain. The sequence is identical to that of the α‐subunit originally found in the olfactory epithelium (CNCα3). In situ hybridization, using probes specific for the CNCα3 mRNA, suggest that this channel is expressed widely in the rat brain, albeit mostly at relatively low levels. Certain neuronal populations, however, such as deep cerebellar nuclei, olfactory bulb mitral cells and cerebellar Purkinje neurons, appeared specially enriched. The study demonstrates for the first time that a full‐length CNG channel mRNA is expressed in the brain, supporting the possibility that CNG channels are involved in central neural communication and plasticity. The sequence reported in this paper has been deposited in the GenBank data base (accession no. AF126808).
Expression of nonclassical MHC class I (RT1‐U) in certain neuronal populations of the central nervous system
Authors: Lidman Olle , Olsson Tomas , Piehl Fredrik
Published: March 2003

Major histocompatibility complex (MHC) class I genes consist of classical (Ia) and nonclassical (Ib) types. Recently, a set of structurally similar MHC class Ib genes in the rat, denoted RT1‐U, was described. We here demonstrate expression of RT1‐U mRNA using highly stringent oligonucleotide in situ hybridization in several different neuronal populations, including different motor nuclei and the substantia nigra in the rat MHC (c) and (n) haplotypes under normal conditions. The expression pattern for β2‐microglobulin mRNA was almost identical. In contrast, neuronal expression of classical MHC class I (RT1‐A) was low. Interestingly, after mechanical nerve injury, glial cells predominantely upregulated expression of RT1‐A, whereas neuronal expression of RT1‐U remained unchanged. Neuronal expression of nonclassical MHC class I may thus be important for immune surveillance in the nervous system.
α‐Gustducin expression in the vomeronasal organ of the mouse
Authors: Zancanaro Carlo , Caretta Carla Mucignat , Merigo Flavia , Cavaggioni Andrea , Osculati Francesco
Published: March 2003

The expression of α‐gustducin, a G protein α subunit involved in bitter and sweet taste transduction, was investigated in chemosensory tissues of adult mice. By immunohistochemistry, α gustducin was absent in the olfactory neuroepithelium. Instead, α gustducin was expressed in a subset of bipolar cells in the proliferative zone of the vomeronasal neuroepithelium as well as in taste buds. Northern blot analysis confirmed the presence of α gustducin in isolated vomeronasal organs. Moreover, immunohisto‐ chemistry revealed the expression of α gustducin in scattered cells of the nasal respiratory epithelium. These results show for the first time that α gustducin is expressed in chemosensory tissue outside the alimentary tract, suggesting that common transduction mechanisms could be shared by apparently unrelated chemosensory tissues.
Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region
Authors: Good Mark , Day Mark , Muir Janice L.
Published: March 2003

The present study investigated the effects of naturally fluctuating endogenous levels of oestrogen on the induction and maintenance of long‐term potentiation (LTP) and long‐term depression (LTD) in the CA1 region of the hippocampus. Using an anaesthetized in vivo preparation, the results showed that the induction of LTP was augmented during the pro‐oestrous stage of the oestrous cycle. In contrast to LTP, however, the induction of paired‐pulse LTD was severely attenuated during pro‐oestrous, but was clearly manifested by rats during met/dioestrous and oestrous stages of the cycle. These findings are discussed with reference to: (i) the modulatory effects of oestrogen on N‐methyl‐d‐aspartate (NMDA) receptor function and γ‐aminobutyric acid (GABA) neurotransmission in the hippocampus; and (ii) the functional implications that such cyclical changes in synaptic plasticity have for learning and memory processes supported by the hippocampus.
Visual response augmentation in cat (and macaque) LGN: potentiation by corticofugally mediated gain control in the temporal domain
Authors: Cudeiro Javier , Rivadulla Casto , Grieve Kenneth L.
Published: March 2003

Visual responses of neurons are dependent on the context of a stimulus, not only in spatial terms but also temporally, although evidence for temporally separate visual influences is meagre, based mainly on studies in the higher cortex. Here we demonstrate temporally induced elevation of visual responsiveness in cells in the lateral geniculate nucleus (LGN) of cat and monkey following a period of high intensity (elevated contrast) stimulation. This augmentation is seen in 40–70% (monkey–cat) of cells tested and of all subtypes. Peaking at ∼ 3 min following the period of intense stimulation, it can last for 10–12 min and can be repeated and summed in time. Furthermore, it is dependent on corticofugal input, is seen even when high contrast stimuli of orthogonal orientation are used and therefore results from a/any prior increase in activity in the retino‐geniculo‐striate pathway. We suggest that this reflects a general mechanism for control of visual responsiveness; both a flexible and dynamic means of changing effectiveness of thalamic activity as visual input changes, but also a mechanism which is an emergent property of the thalamo‐cortico‐thalamic loop.
Evidence for functional compartmentalization of trigeminal muscle spindle afferents during fictive mastication in the rabbit
Authors: Westberg K. ‐G. , Kolta A. , Clavelou P. , Sandström G. , Lund J. P.
Published: March 2003

Primary afferent neurons innervating muscle spindles in jaw‐closing muscles have cell bodies in the trigeminal mesencephalic nucleus (NVmes) that are electrically coupled and receive synapses. Each stem axon gives rise to a peripheral branch and a descending central branch. It was previously shown that some spikes generated by constant muscle stretch fail to enter the soma during fictive mastication. The present study examines whether the central axon is similarly controlled. These axons were functionally identified in anaesthetized and paralysed rabbits, and tonic afferent firing was elicited by muscle stretch. For the purpose of comparison, responses were recorded extracellularly both from the somatic region and from the central axon in the lateral brainstem. Two types of fictive masticatory movement patterns were induced by repetitive stimulation of the masticatory cortex and monitored from the trigeminal motor nucleus. Field potentials generated by spike‐triggered averaging of action potentials from the spindle afferents were employed to determine their postsynaptic effects on jaw‐closing motoneurons. Tonic firing of 32% NVmes units was inhibited during the jaw‐opening phase, but spike frequency during closing was almost equal to the control rate during both types of fictive mastication. A similar inhibition occurred during opening in 83% of the units recorded along the central branch. However, firing frequency in these was significantly increased during closing in 94%, probably because of the addition of antidromic action potentials generated by presynaptic depolarization of terminals of the central branch. These additional spikes do not reach the soma, but do appear to excite motoneurons. The data also show that the duration and/or frequency of firing during the bursts varied from one pattern of fictive mastication to another. We conclude that the central axons of trigeminal muscle spindle afferents are functionally decoupled from their stem axons during the jaw‐closing phase of mastication. During this phase, it appears that antidromic impulses in the central axons provide one of the inputs from the masticatory central pattern generator (CPG) to trigeminal motoneurons.
Localization of the A kinase anchoring protein AKAP79 in the human hippocampus
Authors: Sík Attila , Gulácsi Alexandra , Lai Yvonne , Doyle Werner K. , Pacia Stephan , Mody Istvan , Freund Tamás F.
Published: March 2003

The phosphorylation state of the proteins, regulated by phosphatases and kinases, plays an important role in signal transduction and long‐term changes in neuronal excitability. In neurons, cAMP‐dependent protein kinase (PKA), protein kinase C (PKC) and calcineurin (CN) are attached to a scaffold protein, A kinase anchoring protein (AKAP), thought to anchor these three enzymes to specific sites of action. However, the localization of AKAP, and the predicted sites of linked phosphatase and kinase activities, are still unknown at the fine structural level. In the present study, we investigated the distribution of AKAP79 in the hippocampus from postmortem human brains and lobectomy samples from patients with intractable epilepsy, using preembedding immunoperoxidase and immunogold histochemical methods. AKAP79 was found in the CA1, presubicular and subicular regions, mostly in pyramidal cell dendrites, whereas pyramidal cells in the CA3, CA2 regions and dentate granule cells were negative both in postmortem and in surgical samples. In some epileptic cases, the dentate molecular layer and hilar interneurons also became immunoreactive. At the subcellular level, AKAP79 immunoreactivity was present in postsynaptic profiles near, but not attached to, the postsynaptic density of asymmetrical (presumed excitatory) synapses. We conclude that the spatial selectivity for the action of certain kinases and phosphatases regulating various ligand‐ and voltage‐gated channels may be ensured by the selective presence of their anchoring protein, AKAP79, at the majority of glutamatergic synapses in the CA1, but not in the CA2/CA3 regions, suggesting profound differences in signal transduction and long‐term synaptic plasticity between these regions of the human hippocampus.
Expression of neuronal nitric oxide synthase/NADPH‐diaphorase during olfactory deafferentation and regeneration
Authors: Weruaga E. , Briñón J. G. , Porteros A. , Arévalo R. , Aijón J. , Alonso J. R.
Published: March 2003

Neuronal nitric oxide synthase (nNOS) expression can be regulated under natural or experimental conditions. This work aims at elucidating whether the expression of nNOS or its related NADPH‐diaphorase (ND) activity are modified by manipulation of the normal inputs to neurons. We used the olfactory bulbs from two mouse strains, BALB and CD1, because they show divergences in their synapse patterns, and these differences affect periglomerular cells, interneurons expressing tyrosine hydroxylase or nNOS/ND. The olfactory inputs to these neurons can be disrupted by inhalation of methyl bromide. The effect of this gas on olfactory axons, as well as the synaptic features in both mouse strains, were studied using electron microscopy. The changes in expression were analysed qualitatively and quantitatively at different times after lesion to nine topographical regions of the olfactory bulb. Methyl bromide inhalation induced a degeneration of olfactory axons in both strains, but had different effects on the expression of nNOS/ND and tyrosine hydroxylase. In BALB mice, where periglomerular cells do not receive direct inputs from olfactory axons, no changes were detected in tyrosine hydroxylase or in ND expression. In CD1 periglomerular cells, where olfactory axons establish direct synapses, a significant down‐regulation of both markers was observed. These changes were observed differentially across the olfactory bulb, being more pronounced in rostral regions and more acute for ND than for tyrosine hydroxylase. Our results indicate that the synaptic inputs influence the expression of ND activity related to nNOS and that the activation of the enzyme is more severely affected than its protein expression.
MDMA (‘ecstasy’) enhances basal acetylcholine release in brain slices of the rat striatum
Authors: Fischer H. S. , Zernig G. , Schatz D. S. , Humpel C. , Saria A.
Published: March 2003

The pharmacological basis of acute (±)‐MDMA (3,4‐methylenedioxymethamphetamine) intoxication still awaits full characterization. According to present knowledge, MDMA enhances the release of serotonin and dopamine in striatal slices and interacts with different types of receptors such as 5‐HT2 (5‐hydroxytryptamine or serotonin), M1 and M2 muscarinic acetylcholine (ACh), and histamine H1 receptors. Currently, no information is available about the influence of (±)‐MDMA on striatal cholinergic neurotransmission. In the present study, we used the in vitro perfusion technique to investigate the effect of (±)‐MDMA on ACh release in rat striatal slices. Perfusions with (±)‐MDMA (10–300 μm) resulted in a dose‐dependent increase of spontaneous ACh release (EC50≈ 30 μm). The effect was reversible and Ca++‐ and tetrodotoxin‐sensitive. To determine the neurochemical pathways underlying this response, we perfused with (±)‐MDMA in the presence of various inhibitors of neurotransmitter receptors. Blockade of glutamate or muscarinic ACh receptors as well as 5‐HT1, 5‐HT2, 5‐HT3C or dopamine D2 receptors did not modulate (±)‐MDMA–induced ACh release. However, the presence of histamine H1 receptor antagonists in the perfusion medium abolished (±)‐MDMA‐induced ACh release. The present data clearly demonstrate that (±)‐MDMA enhances the activity of striatal cholinergic neurons and suggest an involvement of histamine H1 receptors. The effect is not mediated by glutamate and does not involve the activation of receptors of dopamine D2, 5‐HT1, 5‐HT2, 5‐HT3C or muscarinic ACh. Considering the relatively high affinity of (±)‐MDMA for the H1 histamine receptor (Ki 6 μm), a direct activation of this type of receptor might represent a plausible mechanism for (±)‐MDMA‐induced ACh release.
Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT)
Authors: Schwaiger Franz‐Werner , Schmitt Gerhard Hager andreas B. , Horvat Andrea , Hager Gundel , Streif Robert , Spitzer Christoph , Gamal Singer , Breuer Sebastian , Brook Gary A. , Nacimiento Wilhelm , Kreutzberg Georg W.
Published: March 2003

Nerve injury leads to the release of a number of cytokines which have been shown to play an important role in cellular activation after peripheral nerve injury. The members of the signal transducer and activator of transcription (STAT) gene family are the main mediators in the signal transduction pathway of cytokines. After phosphorylation, STAT proteins are transported into the nucleus and exhibit transcriptional activity. Following axotomy in rat regenerating facial and hypoglossal neurons, a transient increase of mRNA for JAK2, JAK3, STAT1, STAT3 and STAT5 was detected using in situ hybridization and semi‐quantitative polymerase chain reaction (PCR). Of the investigated STAT molecules, only STAT3 protein was significantly increased. In addition, activation of STAT3 by phosphorylation on position Tyr705 and enhanced nuclear translocation was found within 3 h in neurons and after 1 day in astrocytes. Unexpectedly, STAT3 tyrosine phosphorylation was obvious for more than 3 months. In contrast, none of these changes was found in response to axotomy of non‐regenerating Clarke's nucleus neurons, although all the investigated models express c‐Jun and growth‐associated protein‐43 (GAP‐43) in response to axonal injury. Increased expression of Janus kinase (JAK) and STAT molecules after peripheral nerve transection suggests changes in the responsiveness of the neurons to signalling molecules. STAT3 as a transcription factor, which is expressed early and is activated persistently until the time of reinnervation, might be involved in the switch from the physiological gene expression to an ‘alternative program’ activated only after peripheral nerve injury.