bluuebunny/crossref_metadata_2025 huggingface dataset:
Cloning and Characterization of a Neural Cell Recognition Molecule on Axons of the Retinotectal System and Spinal Cord
Authors: Brümmendorf Thomas , Spaltmann Frank , Treubert Ullrich
Published: April 2006

Immunoglobulin superfamily molecules in the brain are involved in distinct aspects of nervous system histogenesis, for example neuronal migration and axonal growth. To identify novel members of this superfamily in the chick nervous system, we developed a polymerase chain reaction‐based approach making use of sequence motifs of immunoglobulin‐like domains. In the present study, we report the molecular cloning of three isoforms, the biochemical analysis and the immunohistochemical characterization of one of the proteins identified in this screen. This molecule has 91% sequence identity with the limbic system‐associated membrane protein (LAMP) characterized in the rat and is therefore referred to as the chicken homologue of the latter (chLAMP). The molecule is a glycosylphosphatidyl‐inositol‐anchored 60 kDa protein with three immunoglobulin‐like domains and contains 40% N‐linked carbohydrate. We identify three different mRNA forms of chLAMP and show that two forms with distinct 5′‐termini are differentially transcribed in neural development. In addition, we demonstrate using a fusion protein expressed in eukaryotic cells that chLAMP has homophilic binding activity. The protein was found on a subset of axons in the central and peripheral nervous system and is likely to be involved in specific cell‐cell interactions in neurohistogenesis.
Increased Intermale Aggression and Neuroendocrine Response in Mice Deficient for the Neural Cell Adhesion Molecule (NCAM)
Authors: Stork O. , Welzl H. , Cremer H. , Schachner M.
Published: April 2006

Mice deficient for the neural cell adhesion molecule (NCAM) show morphological and behavioural abnormalities in the adult form, including a reduced size of the olfactory bulb, reduced exploratory behaviour, and deficits in spatial learning. Here we report increased aggressive behaviour of both homozygous (NCAM ‐/–) and heterozygous (NCAM +/–) male mutant mice towards an unfamiliar male intruding into their home cage. While plasma testosterone concentrations did not differ between genotypes before or after behavioural testing, corticosterone levels were higher in mutant residents than in wild‐type (NCAM +/+) residents 30 min after encountering the intruder. Levels of c‐fos mRNA, analysed to monitor neuronal activation, were similar in primary output structures of the olfactory bulb in NCAM‐deficient and NCAM +/+ mice, but were increased in brain areas of the limbic system in both NCAM –/– and NCAM +/– mutant mice after the behavioural test. These results indicate that abnormalities in social behaviour correlate with enhanced neuronal activity in limbic brain areas and result in increased social stress in NCAM‐deficient mice.
Effects of GDNF on Axotomized Sensory and Motor Neurons in Adult Rats
Authors: Munson John B. , McMahon Stephen B.
Published: April 2006

Glial cell‐line‐derived neurotrophic factor (GDNF) is a potent neurotrophic factor shown to rescue developing and adult motoneurons in vitro and in vivo from programmed and injury‐induced cell death. To test whether GDNF would rescue adult mammalian sensory and motor neurons from physiological consequences of injury, the tibial nerve of rats was axotomized and, after a 10 day delay to permit injury processes to proceed, vehicle or GDNF was supplied directly to the nerve for 2 or 4 weeks or GDNF intrathecally for 2 weeks. Conduction velocity (CV) of both sensory and motor axons declined during the initial 10 days, and even more so if then treated with vehicle. Treatment with GDNF resulted in marginal improvement of sensory axon CV. CV of motor axons recovered significantly in a dose‐ and time‐dependent manner. The results suggest that GDNF may have therapeutic potential in the treatment of peripheral neuropathies.
GABAergic Transcallosal Neurons in Developing Rat Neocortex
Authors: Kimura Fumitaka , Baughman Robert W.
Published: April 2006

In the mature cerebral cortex the interhemispheric connections across the corpus callosum appear to be essentially completely excitatory on the basis of both immunocytochemical and electrophysiological studies. During late embryonic development, however, immunocytochemical staining reveals numerous GABA‐positive fibres in the callosum, which later largely disappear. The origin of these fibres and whether they represent functional GABAergic neurons has not been established. In the present study we used a combination of retrograde labelling in vivo with electrophysiology and immnunocytochemistry in cell culture to show that transiently at birth in rat pups a substantial number of transcallosal cortical cells are functional GABAergic neurons. Possible roles and fates for these neurons are discussed.
Inhibition of [Ca2+]i Transients in Rat Adrenal Chromaffin Cells by Neuropeptide Y Role for a cGMP‐dependent Protein Kinase‐activated K+ Conductance
Authors: Lemos Virginia Soares , Bucher Bernard , Côrtes Steyner F. , Takeda Kenneth
Published: April 2006

The effects of neuropeptide Y on the intracellular level of Ca2+ ([Ca2+]i) were studied in cultured rat adrenal chromaffin cells loaded with fura‐2. A proportion (16%) of cells exhibited spontaneous rhythmic [Ca2+]i oscillations. In silent cells, oscillations could be induced by forskolin and 1,9–dideoxyforskolin. This action of forskolin was not modified by H‐89, an inhibitor of protein kinase A. Spontaneous [Ca2+i fluctuations and [Ca2+]i fluctuations induced by forskolin‐ and 1,9‐dideoxyforskolin were inhibited by neuropeptide Y. Increases in [Ca2+]i induced by 10 and 20 mM KCI but not by 50 mM KCI were diminished by neuropeptide Y. However, neuropeptide Y had no effect on [Ca2+]i increases evoked by (‐)BAY K8644 and the inhibitory effect of neuropeptide Y on responses induced by 20 mM KCI was not modified by o‐conotoxin GVIA, consistent with neither L‐ nor N‐type voltage‐sensitive Ca2+ channels being affected by neuropeptide Y. Rises in [Ca2+]i provoked by 10 mM tetraethylammonium were not decreased by neuropeptide Y, suggesting that K+ channel blockade reduces the effect of neuropeptide Y. However, [Ca2+]i transients induced by 1 mM tetraethylammonium and charybdotoxin were still inhibited by neuropeptide Y, as were those to 20 mM KCI in the presence of apamin. The actions of neuropeptide Y on [Ca2+]i transients provoked by 20 and 50 mM KCI, 1 mM tetraethylammonium, (‐)BAY K8644 and charybdotoxin were mimicked by 8–bromo‐cGMP. In contrast, 8–bromo‐CAMP did not modify responses to 20 mM KCI or 1 mM tetraethylammonium. The inhibitory effects of neuropeptide Y and 8–bromo‐cGMP on increases in [Ca2+]i induced by 1 mM tetraethylammonium were abolished by the Rp‐8–pCPT‐cGMPS, an inhibitor of protein kinase G, but not by H‐89. A rapid, transient increase in cGMP level was found in rat adrenal medullary tissues stimulated with 1 μM neuropeptide Y. Rises in [Ca2+]i produced by DMPP, a nicotinic agonist, but not by muscarine, were decreased by neuropeptide Y. Our data suggest that neuropeptide Y activates a K+ conductance via a protein kinase G‐dependent pathway, thereby opposing the depolarizing action of K+ channel blocking agents and the associated rise in [Ca2+]i.
PrP and β‐Amyloid Fragments Activate Different Neurotoxic Mechanisms in Cultured Mouse Cells
Authors: Brown David R. , Herms Jochen W. , Schmidt Bernhard , Kretzschmar Hans A.
Published: April 2006

Alzheimer's disease and prion diseases such as Creutzfeldt‐Jakob disease are caused by as yet undefined metabolic disturbances of normal cellular proteins, the amyloid precursor protein and the prion protein (PrP). Synthetic fragments of both proteins, β‐amyloid 25–35 (βA25–35) and PrP106–126, have been shown to be toxic to neurons in culture. Cell death in both cases occurs by apoptosis. Here we show that there are considerable differences in the mechanisms involved. Thus, PrP106–126 is not toxic to cortical cell cultures of PrP knockout mouse neurons whereas PA25–35 is. The toxicity of both peptides involves Ca2+ uptake through voltage‐sensitive Ca2+ channels but only PrP106–126 toxicity involves the activity of NMDA receptors. The toxicity of PA25–35, but not PrP106–126, is attenuated by the action of forskolin. These results indicate that PrP106–126 and βA25–35 induce neuronal apoptosis through different mechanisms.
Heparin Inhibits Acetylcholine Receptor Aggregation at Two Distinct Steps in the Agrin‐induced Pathway
Authors: Hopf Carsten , Hoch Werner
Published: April 2006

Muscle cells depend on motoneurons for the initiation of postsynaptic differentiation during early development of the neuromuscular junction. Motoneurons secrete specific isoforms of the extracellular matrix protein agrin which trigger the aggregation of acetylcholine receptors (AChRs) on the muscle surface. Both motoneuron‐ and agrin‐induced AChR aggregation are inhibited by heparin. Here we show that this inhibition is due to two separate and distinguishable mechanisms. At high concentrations, heparin directly binds to agrin isoforms which contain the peptide KSRK, resulting in a virtually complete inhibition of AChR clustering. Heparin and other polyanions do not bind to agrin splicing variants without KSRK insert. Isoforms containing or lacking the KSRK insert have a high potency to induce AChR aggregation in the presence of an activating eight‐amino‐acid insert. This activity is inhibited by low concentrations of heparin even in the absence of any binding of heparin to agrin. Therefore, this second type of inhibition is due to the interaction of heparin with a downstream component of the agrin‐induced clustering pathway. Binding of heparin to this yet unidentified component substantially decreases, but does not completely abolish AChR aggregation. The inhibition is particularly strong on myotubes which have not completely matured in culture.
Induction of Adhesion/Differentiation of Human Neuroblastoma Cells by Tumour Necrosis Factor‐α Requires the Expression of an Inducible Nitric Oxide Synthase
Authors: Obregón Eva , Punzón M. Carmen , González‐Nicolás Josefa , Fernández‐Cruz Eduardo , Fresno Manuel , Muñoz‐Fernández M. Angeles
Published: April 2006

Neuroblastoma cell lines (SK‐N‐SH and SK‐N‐MC) were induced to differentiate, as detected by the expression of neurofilament proteins of 68 and 200 kDa, and to express adhesion molecules (intercellular adhesion molecule‐1 and vascular cell adhesion molecule) after stimulation with tumour necrosis factor‐α (TNF‐α). This induction was accompanied by the arrest of cell growth. The induction of neuroblastoma adhesion by TNF‐α could be inhibited by the nitric oxide synthase inhibitors, L‐N‐monomethyl arginine (L‐NMMA) andL‐N6‐(1–imidoethyl)‐lysine (highly specific for the inducible enzyme), but not by the inactive enantiomer D‐NMMA. These results indicate that TNF‐α induces the adhesion of neuroblastoma cells via nitric oxide. This was confirmed by the finding that the adhesion/differentiation of SK‐N‐SH and SK‐N‐MC cells can be directly induced by the addition of nitric oxide donors, sodium nitroprusside and S‐nitroso‐N‐acetyl‐penicillamine, into the culture medium. The isoform of the nitric oxide synthase induced in human neuroblastoma cells by TNF‐α treatment was identified enzymatically as isoform II by Western blotting and by the polymerase chain reaction. Thus TNF‐α induces the in vitro adhesion/differentiation of human neuroblastoma cells through nitric oxide synthesized by a calcium‐independent inducible form of nitric oxide synthase, clearly indicating that isoform II of nitric oxide synthase can be expressed in human neuronal cell types.
Localization of Neuropeptide Y Y1 mRNA in the Human Brain: Abundant Expression in Cerebral Cortex and Striatum
Authors: Caberlotto Laura , Fuxe Kjell , Sedvall Göran , Hurd Yasmin L.
Published: April 2006

Many neurobiological functions have been ascribed to the NPY Y1 receptor subtype, but autoradiographic analysis has failed to detect Y1 binding sites in most human brain areas, in contrast to the rat. We examined the regional distribution of Y1 mRNA‐containing cells in the post‐mortem human brain to clarify if there is a major species difference in terms of the existence of Y1 receptors in the human telencephalon, in particular the striatum and cortex. In situ hybridization experiments revealed widespread distribution of Y1 mRNA signals in all layers of most limbic and neocortical regions, predominantly in layer IV (most cortical regions) and layer VI. The striatum showed moderate Y1 receptor mRNA expression levels with intensely expressing cells localized to the nucleus accumbens. The highest Y1 receptor mRNA expression was apparent within the dentate gyrus, and the lowest in the subiculum, parahippocampal gyrus, cerebellum, and thalamus. In vitro autoradiography using [125I]Leu31Pro34‐PYY and [125I]PYY with NPY (13–36) or Leu31 Pro34 NPY; confirmed the presence of low Y1–like binding in the human brain despite abundant Y1 mRNA expression. However, using a rat model of the human autopsy process, it was apparent that the inability to reveal high Y1– versus Y2–like receptors in the human brain was related in part to marked reductions of Y1–like, but not Y2–like, receptors within a 4 h post‐mortem delay. Altogether, the results indicate that the Y1 receptor gene is abundant in the human brain and this receptor may have important roles in cognitive, limbic and motor function.
Neuronal and Glial Glutamate Transporters Possess an SH‐based Redox Regulatory Mechanism
Authors: Trotti Davide , Rizzini Barbara Lodi , Rossi Daniela , Haugeto Oyvind , Racagni Giorgio , Danbolt Niels C. , Volterra Andrea
Published: April 2006

Glutamate uptake into nerve cells and astrocytes via high‐affinity transporters controls the extracellular glutamate concentration in the brain, with major implications for physiological excitatory neurotransmission and the prevention of excitotoxicity. We report here that three recently cloned rat glutamate transporter subtypes, viz. EAAC1 (neuronal), GLT1 and GLAST (glial), possess a redox‐sensing property, undergoing opposite functional changes in response to oxidation or reduction of reactive sulphydryls present in their structure. In particular, thiol oxidation with 5,5′‐dithio‐bis(2–nitrobenzoic) acid (DTNB) and disulphide reduction with dithiothreitol (DTT) result, respectively, in reduced and increased uptake capacity by a preparation of partially purified brain transporters as well as by the three recombinant proteins reconstituted into liposomes. In this model system, EAAC1, GLT1 and GLAST react similarly to DTT/DTNB exposures despite their different contents of cysteines, suggesting that only the conserved residues might be involved in redox modulation. Redox sensitivity is a property of the glutamate transporters also when present in their native cell environment. Thus, by using cultured cortical astrocytes and the whole‐cell patch‐clamp technique we were able to observe dynamic increase and decrease of the glutamate uptake current in response to application of DTT and DTNB in sequence. Moreover, in the same paradigm, DDT‐reversible current inhibition was observed with hydrogen peroxide instead of DTNB, indicating that the SH‐based redox modulatory site is targeted by endogenous oxidants and might constitute an important physiological or pathophysiological regulatory mechanism of glutamate uptake in vivo
Leukaemia Inhibitory Factor is Retrogradely Transported by a Distinct Population of Adult Rat Sensory Neurons: C‐o‐localization with trkA and other Neurochemical Markers
Authors: Thompson Stephen W. N. , Vernallis Ann B. , Heath John K , Priestley John V.
Published: April 2006

Sciatic sensory afferents that retrogradely transport and accumulate leukaemia inhibitory factor (LIF) within their soma were characterized in the adult rat in vivo. Twenty‐four percent of neurons within the L4 and L5 dorsal root ganglia accumulated biotinylated LIF following intraneural injection of the cytokine into the sciatic nerve. Labelled cell bodies were predominantly of small diameter (20.1 ± 2 0.5 μm). Retrograde transport was eliminated by excess unlabelled LIF but not by the related cytokines, ciliary‐derived neurotrophic factor (CNTF) and interleukin‐6 (IL‐6). Double labelling revealed that the majority (81%) of LIF‐accumulating neurons were immunopositive for CGRP and 34% were immunopositive for the cell surface glycoconjugate IB4. Sixty‐two percent of LIF‐accumulating neurons were immunopositive for trkA. Our results demonstrate a group of small‐diameter sensory neurons that retrogradely transport LIF, comprising cells that constitutively express neuropeptides and those likely to be peptide‐deficient. LIF‐accumulating neurons expressing trkA are also potentially responsive to nerve growth factor. It is likely that the LIF‐accumulating neurons described in this study are nociceptive in function.
Role of the Dorso—Caudal Neostriatum in Filial Imprinting of the Domestic Chick: a Pharmacological and Autoradiographical Approach Focused on the Involvement of NMDA‐Receptors
Authors: Bock Jörg , Schnabel Reinhild , Braun Katharina
Published: April 2006

Newly hatched domestic chicks were either acoustically imprinted on 400 Hz tone pulses or visually imprinted on a rotating red light. Compared to naive control animals, both groups of imprinted chicks expressed significantly enhanced stimulus evoked 2‐fluoro‐2‐deoxyglucose (2‐FDG) uptake in circumscribed areas of the dorso‐caudal neostriatum (Ndc). This enhanced excitability after imprinting seems not to be related to changes of NMDA‐receptor densities as measured by quantitative receptor autoradiography. However, pharmacological blockade of NMDA‐receptors in the dorso‐caudal neostriatum leads to a marked suppression of stimulus‐evoked 2‐FDG uptake in the dorso‐caudal neostriatum and also in the interconnected imprinting relevant forebrain area, medio‐rostral neostriatum/hyperstriatum ventrale (MNH). Furthermore, chicks which received bilateral Ndc injections of the competitive NMDA antagonist DL‐2‐amino‐5‐phosphono valeric acid (APV) during the imprinting experiments showed a dose‐dependent decrease of imprinting success compared to vehicle‐injected controls. These results indicate that the dorso‐caudal neostriatum may represent a polysensory associative brain region in which visual and acoustic features of imprinting objects may be integrated. The activation in this area evoked by the imprinting stimulus during and after imprinting is critically dependent on NMDA‐receptor activation, which appears to be required for this learning process.
Na+—Ca2+ Exchange Currents in Cortical Neurons: Concomitant Forward and Reverse Operation and Effect of Glutamate
Authors: Yu Shan Ping , Choi Dennis W.
Published: April 2006

Na+‐Ca2+ exchanger‐associated membrane currents were studied in cultured murine neocortical neurons, using whole‐cell recording combined with intracellular perfusion. A net inward current specifically associated with forward (Na+o‐Ca2+i) exchange was evoked at ‐40 mV by switching external 140 mM Li+ to 140 mM Na+. The voltage dependence of this current was consistent with that predicted for 3Na+:1Ca2+ exchange. As expected, the current depended on internal Ca2+, and could be blocked by intracellular application of the exchanger inhibitory peptide, XIP. Raising internal Na+ from 3 to 20 mM or switching the external solution from 140 mM Li+ to 30 mM Na+ activated outward currents, consistent with reverse (Na+,‐Ca2+o) exchange. An external Ca2+‐sensitive current was also identified as associated with reverse Na+‐Ca2+ exchange based on its internal Na+ dependence and sensitivity to XIP. Combined application of external Na+ and Ca2+ in the absence of internal Na+ triggered a 3.3–fold larger inward current than the current activated in the presence of 3 mM internal Na+, raising the intriguing possibility that Na+‐Ca2+ exchangers might concurrently operate in both the forward and the reverse direction, perhaps in different subcellular locations. With this idea in mind, we examined the effect of excitotoxic glutamate receptor activation on exchanger operation. After 3–5 min of exposure to 100–200 μM glutamate, the forward exchanger current was significantly increased even when external Na+ was reduced to 100 mM, and the external Ca2+‐activated reverse exchanger current was eliminated.
FGF‐2 Induces Nerve Growth Factor Expression in Cultured Rat Hippocampal Neurons
Authors: Ferhat Lotfi , Represa Alfonso , Zouaoui‐Aggoun Djamila , Ferhat Walid , Ben‐Ari Yezekiel , Khrestchatisky Michel
Published: April 2006

Basic fibroblast growth factor (FGF‐2) is expressed in the hippocampus and has been demonstrated to promote neurotrophic effects on hippocampal neurons in vifro. We show that these neurons, even at the embryonic stage, express the mRNAs encoding the FGF receptors, bek and flg. We have characterized the effects of FGF‐2 on the expression of nerve growth factor (NGF) using the reverse transcription‐coupled polymerase chain reaction, in situ hybridization and immunocytochemistry. In hippocampal neurons grown in the absence of serum, FGFB exposure induces an important elevation of NGF mRNA expression followed by a marked increase in NGF immunoreactivity. Combining in situ hybridization with an NGF probe and microtubule‐associated protein‐2 (MAP2) immunocytochemistry we show that the induction of NGF mRNA by FGF‐2 is localized in MAP2–immunoreactive neurons. These results suggest roles for FGF‐2 in the development of hippocampal neurons and in the maintenance of connections in the central nervous system, particularly the septo‐hippocampal pathway, via the regulation of an important neurotrophins
192 IgG—Saporin‐induced Loss of Cholinergic Neurons in the Septum Abolishes Cholinergic Sprouting After Unilateral Entorhinal Lesion in the Rat
Authors: Naumann Thomas , Deller Thomas , Bender Roland , Frotscher Michael
Published: April 2006

After unilateral lesion of the entorhinal cortex, cholinergic septohippocampal fibres are believed to sprout in the denervated outer molecular layer of the rat dentate gyrus. This cholinergic sprouting has been demonstrated by acetylcholinesterase (AChE) histochemistry, a method said selectively to label cholinergic septohippocampal fibres in the hippocampus. However, a recent report has questioned this concept, suggesting that AChE may not be an adequate marker to monitor cholinergic sprouting and that other, non‐cholinergic axons sprouting after entorhinal cortex lesion cause the dense AChE‐positive band in the denervated outer molecular layer. In order to determine the contribution of cholinergic septohippocampal fibres to the dense AChE band appearing after entorhinal cortex lesion, the neurotoxin 192 IgG‐saporin, known to destroy cholinergic neurons in the basal forebrain selectively, was used. Rats received bilateral injections of 192 IgG‐saporin into the lateral ventricles 3 weeks before entorhinal cortex lesion, simultaneously with entorhinal cortex lesion, or 8 weeks after entorhinal cortex lesion. lmmunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrated the loss of cholinergic neurons in the medial septum and diagonal band after 192 IgG‐saporin treatment. The cholinergic sprouting response in the molecular layer, as visualized with AChE histochemistry, was abolished in all animals treated with immunotoxin. These data indicate that the dense AChE band forming after entorhinal cortex lesion represents the sprouting of cholinergic septohippocampal fibres.
A Metabolic Mapping Study of Orientation Discrimination and Detection Tasks in the Cat
Authors: Vanduffel Wim , Vandenbussche Erik , Singer Wolf , Orban Guy A.
Published: April 2006

Increasing evidence suggests that a large number of distinct cortical areas and associated subcortical structures participate in the processing of visual information and that different aspects of visual scenes are evaluated in different areas. This necessitates identification of cortical and subcortical regions cooperating in particular visual tasks. Using the 2‐deoxyglucose technique, we monitored the differential activation of areas in the cat visual cortex participating in an orientation discrimination and a detection task. Concordant with previous lesion studies, we found increased activity levels in area 17 in the discrimination condition relative to the detection condition. In addition, the 2‐deoxyglucose technique revealed discrimination‐related increased activations in the claustrum, the putamen and in parts of the anteromedial, anterolateral and posterolateral lateral suprasylvian visual areas. Regions activated differentially with the detection task comprised subdivisions of areas 17, 18, 19 and 21, posterior area 7 (7p), several areas of the posterior part of the middle and posterior suprasylvian sulcus, the pulvinar complex and the superior colliculus. These results show that the 2‐deoxyglucose technique is useful to investigate cognitive brain functions, and that different sets of cortical and subcortical regions are activated during two visual tasks with similar visual stimulation.
The Functional Organization of Working Memory Processes Within Human Lateral Frontal Cortex: The Contribution of Functional Neuroimaging
Authors: Owen Adrian M.
Published: April 2006

Recent functional neuroimaging studies have provided a wealth of new information about the likely organization of working memory processes within the human lateral frontal cprtex. This article seeks to evaluate the results of these studies in the context of two contrasting theoretical models of lateral frontal‐lobe function, developed through lesion and electrophysiological recording work in non‐human primates (Goldman‐Rakic, 1994, 1995; Petrides, 1994, 1995). Both models focus on a broadly similar distinction between anatomically and cytoarchitectonically distinct dorsolateral and ventrolateral frontal cortical areas, but differ in the precise functions ascribed to those regions. Following a review of the relevant anatomical data, the origins of these two theoretical positions are considered in some detail and the main predictions arising from each are identified. Recent functional neuroimaging studies of working memory processes are then critically reviewed in order to assess the extent to which they support either, or both, sets of predictions. The results of this meta‐analysis suggest that lateral regions of the frontal lobe are not functionally organized according to stimulus modality, as has been widely assumed, but that specific regions within the dorsolateral or ventrolateral frontal cortex make identical functional contributions to both spatial and non‐spatial working memory.
Type 2 Metabotropic Glutamate (mGlu) Receptors Tonically Inhibit Transmitter Release in Rat Caudate Nucleus: In Vivo Studies with (2S,1′S,2′S,3′R)‐2‐(2′‐carboxy‐3′‐phenylcyclopropyl)glycine, a New Potent and Selective Antagonist
Authors: Cozzi Andrea , Attucci Sabina , Peruginelli Fiamma , Marinozzi Maura , Luneia Roberto , Pellicciari Roberto , Moroni Flavio
Published: April 2006

Anatomical, biochemical and electrophysiological studies have previously shown that cortico‐striatal terminals contain abundant presynaptic group 2 metabotropic glutamate (mGlu) receptors. Using brain slices we have previously shown that these receptors inhibit depolarization‐induced transmitter release. Using microdialysis in freely moving rats, we now report the effects of group 2 mGlu receptor agonists and antagonists on glutamate concentration in the caudate extracellular fluid. A mild decrease (20–30%) in glutamate concentration in caudate dialysates was observed when 1S,3R‐1‐aminocyclopentane‐1,3‐dicarboxylic acid or (2S,3S,4S)‐α‐carboxycyclopropyl‐glycine (L‐CCG‐1), mGlu receptor agonists, was locally administered. On the contrary, α‐methyl‐4‐carboxyphenylglycine, an antagonist of type 1 and type 2 mGlu receptors, increased the glutamate concentration in dialysates by up to 3.5‐fold, and its effects were prevented by the simultaneous administration of L‐CCG‐1, a preferential type 2 mGlu receptor agonist. A significant increase of glutamate output in striatal dialysate was also found after local administration of (2S,1′S,2′S,3′R)‐2‐(2′‐carboxy‐3′‐phenylcyclopropyl)glycine, another structurally unrelated, relatively selective and potent type 2 mGlu receptor antagonist. The results suggest that type 2 mGlu receptors tonically inhibit transmitter release from corticostriatal terminals. Since the cortico‐striatal pathway profoundly affects the function of a large percentage of caudate neurons, it is reasonable to predict that the use of selective type 2 mGlu receptor agents will be helpful for scientific and therapeutic studies on the physiopathology of basal ganglion disorders.
Noradrenaline Modulates GIutamate‐mediated Neurotransmission in the Rat Basolateral Amygdala In Vitro
Authors: Ferry Barbara , Magistretti Pierre J. , Pralong Etienne
Published: April 2006

The entorhinal cortex and the amygdala are interconnected structures of the limbic system in which paroxysmal activity occurs during temporal lobe epilepsy. Conflicting evidence shows that noradrenaline (i) inhibits the spreading to other parts of the limbic system of paroxysmal activity generated in the amygdala or the entorhinal cortex, but also (ii) increases glutamatergic transmission in the basolateral amygdala. Given our previous work on the inhibitory effect of noradrenaline on entorhinal cortex neurons, we developed an in vitro slice preparation to study the synaptic transmission in the basolateral amygdala and its modulation by noradrenaline. Noradrenaline reduced the fast excitatory postsynaptic potential (EPSP) by ∼40% at 100 μM and the slow EPSP by ∼50% at 50 μM. A similar effect was obtained with the α2‐agonist UK 14304 at 100 and 50 μM respectively. In contrast, the β‐agonist isoproterenol increased the fast EPSP by ∼40% at 100 μM and the slow EPSP by ∼20% at 50 μM. Accordingly, the effect of noradrenaline on the EPSPs was blocked by the α2‐antagonist yohimbine (10 μM) but not by the α1‐antagonist prazosine (10 μM) and the β‐antagonist propranolol (10 μM). Noradrenaline (50–100 μM) was ineffective on most (14/16) of the isolated inhibitory postsynaptic potentials (IPSPs). These experiments provide evidence that noradrenaline inhibits the excitatory synaptic response of basolateral amygdala neurons. A pharmacological analysis revealed that the noradrenergic modulation of the excitatory transmission in the basolateral amygdaia can be dissected into a predominant α2‐adrenoreceptor‐mediated inhibition and a β‐adrenoreceptor‐mediated excitation.
How Reliably Does a Neuron in the Visual Motion Pathway of fhe Fly Encode Behaviourally Relevant Information?
Authors: Warzecha Anne‐Kathrin , Egelhaaf Martin
Published: April 2006

How reliably neurons convey information depends on the extent to which their activity is affected by stochastic processes which are omnipresent in the nervous system. The functional consequences of neuronal noise can only be assessed if the latter is related to the response components that are induced in a normal behavioural situation. In the present study the reliability of neural coding was investigated for an identified neuron in the pathway processing visual motion information of the fly (Lucilia cuprina). The stimuli used to investigate the neuronal performance were not exclusively defined by the experimenter. Instead, they were generated by the fly itself, i.e. by its own actions and reactions in a behavioural closed‐loop experiment, and subsequently replayed to the animal while the activity of an identified motion‐sensitive neuron was recorded. Although the time course of the neuronal responses is time‐locked to the stimulus, individual response traces differ slightly from each other due to stochastic fluctuations in the timing and number of action potentials. Individual responses thus consist of a stimulus‐induced and a stochastic response component. The stimulus‐induced response component can be recovered most reliably from noisy neuronal signals if these are smoothed by intermediate‐sized time windows (40–100 ms). At this time scale the best compromise is achieved between smoothing out the noise and maintaining the temporal resolution of the stimulus‐induced response component. Consequently, in the visual motion pathway of the fly, behaviourally relevant motion stimuli can be resolved best at a time scale where the timing of individual spikes does not matter.
GABA‐ and Glutamate‐evoked Responses in the Rat Ventral Pallidum are Modulated by Dopamine
Authors: Johnson Patricia I. , Napier T. Celeste
Published: April 2006

Microiontophoresis was used to investigate the influence of dopamine on GABA‐ and glutamate‐induced responses from ventral pallidal neurons recorded extracellularly in chloral hydrate‐anaesthetized rats. Modulation was determined by comparing dopamine‐induced alterations in amino acid‐induced activity (‘signal’) with dopamine‐induced effects on spontaneous firing (‘noise’). A dopamine ejection current‐response curve was generated to determine the current levels that did not alter spontaneous firing (‘subthreshold’) and those that produced ∼50% of the maximal dopamine‐induced response (ECur50). Co‐iontophoresis of dopamine with GABA generally diminished the inhibitory influence of GABA on pallidal neuron firing; 70% of neurons tested with ECur50 dopamine demonstrated a decrease in the signal‐to‐noise ratio whereas 10% displayed an increase. At subthreshold dopamine ejection currents, 59% of neurons responded with a decrease and 18% responded with an increase in the GABA signal‐to‐noise ratio. When ECur50 dopamine was co‐iontophoresed with glutamate, 84% of the neurons displayed a decrease in the signal‐to‐noise ratio for glutamate‐evoked excitations whereas 11% demonstrated an increase. Subthreshold dopamine ejection currents decreased the signal‐to‐noise ratio in 62% of the ventral pallidal neurons excited by glutamate and increased the ratio in 23%. These data illustrate that dopamine substantially alters GABA‐ and glutamate‐evoked responses even at ejection currents that are below those necessary to change spontaneous firing. Thus, it appears that neuromodulation is an important means by which dopamine influences ventral pallidal neuronal activity.
Subthalamic Ablation Reverses Changes in Basal Ganglia Oxidative Metabolism and Motor Response to Apomorphine Induced by Nigrostriatal Lesion in Rats
Authors: Blandini Fabio , Garcia‐Osuna Monica , Greenamyre J. Timothy
Published: April 2006

In Parkinson's disease, the functional architecture of the basal ganglia nuclei undergoes profound alterations, one of the most important of which is overactivity of the basal ganglia output nuclei. This phenomenon seems to be intimately related to pathological overactivity of the subthalamic nucleus, which directly modulates the basal ganglia output through its glutamatergic projections. In this study, we investigated the effects of unilateral subthalamic nucleus lesions on the activities of succinate dehydrogenase and cytochrome oxidase, two markers of neuronal activity, in rats with prior unilateral lesions of the nigrostriatal tract. We also explored the effect of subthalamic nucleus lesions on the rotational response to systemic apomorphine. Rats with unilateral lesions of the nigrostriatal tract showed ipsilateral increases in enzyme activity in the basal ganglia output nuclei, entopeduncular nucleus and substantia nigra pars reticulata. Selective subthalamic nucleus destruction completely reversed this phenomenon. In addition, subthalamic nucleus lesions abolished the rotational response to apomorphine. These results confirm that overactivity of the subthalamic nucleus plays a pivotal role in the functional alterations of basal ganglia associated with Parkinson's disease. They also shed further light on the neural mechanisms through which manipulations of subthalamic activity can ameliorate Parkinson's disease symptoms
Diffusion in Axon Guidance
Authors: Goodhill Geoffrey J.
Published: April 2006

Axon guidance by target‐derived diffusible factors plays an important role in the development of the nervous system. This paper considers the constraints imposed on this process by the mathematics of diffusion. A point source continuously producing a factor into an infinite three‐dimensional volume is considered as a model for both the in vivo and in vitro situation. Basic constraints for effective guidance are assumed to be that the concentration falls between certain maximum and minimum limits, and that the percentage change in concentration across the width of the growth cone exceeds a certain minimum value. The evolution of the shape of the gradient over time is analysed. Using biologically reasonable parameter values, it is shown that the maximum range over which growth cone guidance by a diffusible factor is possible for large times (several days) after the start of the production of the factor is 500–1000 μm. This maximum distance is independent of the diffusion constant of the diffusing molecule, applies to both chemoattractants and chemorepellents, and agrees with experimental data. At earlier times, however, the constraints may be satisfied for distances up to several millimetres. The time it takes for this maximum guidance distance to fall to the asymptotic value depends on the diffusion constant. This time is a few hours for a small molecule but as much as a few days for a large molecule. The model therefore predicts that guidance over distances larger than 1000 μm is possible if the start of production of the factor is carefully matched to the time when guidance is required.
Expression of Pro‐Inflammatory Cytokine and Chemokine mRNA Upon Experimental Spinal Cord Injury in Mouse: an In Situ Hybridization Study
Authors: Bartholdi Deborah , Schwab Martin E.
Published: April 2006

Injury to the spinal cord induces a complex cascade of cellular reactions at the local lesion area: secondary cell death and inflammatory reactions as well as scar and cavity formation take place. In order to investigate the molecular features underlying this local wounding response and to determine their pathophysiological implications, we studied the expression pattern of pro‐inflammatory and chemoattractant cytokines in an experimental spinal cord injury model in mouse. We show by in situ hybridization that transcripts for the pro‐inflammatory cytokines TNFα and IL‐1 as well as the chemokines MIP‐1 α and MIP‐1β are upregulated within the first hour following injury. In this early phase, the expression of the pro‐inflammatory cytokines is restricted to cells in the surroundings of the lesion area probably resident CNS cells. While TNFα is expressed in a very narrow time window, IL‐1 can be detected in a second phase in a subset of polymorphonuclear granulocytes which immigrate into the spinal cord around 6 h. Message for the chemokines MIP‐1α and β is expressed in a generalized way in the grey matter of the entire spinal cord around 24 h and gets again restricted to the cellular infiltrate at the lesion site at 4 days following injury. Interestingly, our data suggest that resident CNS cells, most probably microglial cells, and not peripheral inflammatory cells, are the main source for cytokine and chemokine mRNAs. The defined cytokine pattern observed indicates that the inflammatory events upon lesioning the CNS are tightly controlled. The very early expression of pro‐inflammatory cytokine and chemokine messages may represent an important element of the recruitment of inflammatory cells. Additional pathophysiological consequences of the specific cytokine pattern observed remain to be determined.
NMDA Receptor Properties in Rat Supraoptic Magnocellular Neurons: Characterization and Postnatal Development
Authors: Hussy Nicolas , Boissin‐Agasse Line , Richard Philippe , Desarménien Michel G.
Published: April 2006

Hypothalamo‐neurohypophysial magnocellular neurons display specific electrical activities in relation to the mode of release of their hormonal content (vasopressin or oxytocin). These activities are under strong glutamatergic excitatory control. The implication of NMDA receptors in the control of vasopressinergic and oxytocinergic neurons is still a matter of debate. We here report the first detailed characterization of functional properties of NMDA receptors in voltage‐clamped magnocellular neurons acutely dissociated from the supraoptic nucleus. All cells responded to NMDA with currents that reversed polarity around 0 mV and were inhibited by D‐2‐amino‐5‐phosphonovalerate (d‐APV) and by 100 μM extracellular Mg2+ (at ‐80 mV). Sensitivity to the co‐agonist glycine (EC50, 2 μM) was low compared with most other neuronal preparations. The receptors displayed low sensitivity to ifenprodil, were insensitive to glycine‐independent potentiation by spermine, and had a unitary conductance of 50 pS. No evidence was found for two distinct cell populations, suggesting that oxytocinergic and vasopressinergic neurons express similar NMDA receptors. Characterization of NMDA receptors at different postnatal ages revealed a transient increase in density of NMDA currents during the second postnatal week. This was accompanied by a specific decrease in sensitivity to d‐APV, with no change in NMDA sensitivity or any other properties studied. Supraoptic NMDA receptors thus present characteristics that strikingly resemble those of reconstituted receptors composed of NR1 and NR2A subunits. Understanding the functional significance of the development of NMDA receptors in the supraoptic nucleus will require further knowledge about the maturation of neuronal excitability, synaptic connections and neurohormone release mechanisms.
Influence of Interleukin‐6 on Neural Activity and Transcription of the Gene Encoding Corticotrophin‐releasing Factor in the Rat Brain: An Effect Depending Upon the Route of Administration
Authors: Vallières Luc , Lacroix Steve , Rivest Serge
Published: April 2006

Interleukin‐6 (IL‐6) is a pleiotropic cytokine produced by various lymphoid and neural cells. In addition to its classic role during immune and inflammatory responses, IL‐6 acts on the central nervous system to elicit changes, such as activation of the hypothalamic‐pituitary‐adrenal (HPA) axis. This study investigated the effects of systemic and central injection of IL‐6 on neural activity and transcription of the corticotrophin‐releasing factor (CRF) gene in the brain of conscious rats. The animals were killed 1 and 3 h after a single infusion of IL‐6 into the right jugular vein (0.83 or 3.0 μg) or the right lateral ventricle (0.2 μg) and their brains cut from the olfactory bulb to the end of the medulla in 30‐μm coronal sections. Messenger RNA encoding the protein Fos, a marker of neural activity, and the neuropeptide CRF were localized by in situ hybridization histochemistry using 35S‐labelled exonic and intronic riboprobes. The results show that systemic injection of IL‐6 induced specific transcription of c‐fos gene in most of the sensorial circumventricular organs, including the organum vasculosum lamina terminalis, subfornical organ, median eminence, and area postrema, as well as in the central nucleus of the amygdala and bed nucleus of the stria terminalis. On the other hand, central injection of IL‐6 increased cellular level of c‐fos mRNA in the ependymal layer and the walls of the ventricles, meninges, nucleus of the solitary tract, and circumventricular organs. These effects were rapid and transient, since the signals for c‐fos mRNA were detected 1 h after both treatments and vanished 3 h afterwards. Moreover, the CRF gene was not activated by either systemic or central administration of IL‐6 in the paraventricular nucleus of the hypothalamus. Taken together, these results suggest that circumventricular organs hold a privileged position in mediating the central effects of systemic IL‐6 and that centrally injected IL‐6 can strongly activate cells of the ventricular system and surrounding structures. Although this differential circuitry may explain distinct origin‐dependent functions of IL‐6, this cytokine seems insufficient, in itself, to induce transcription of the gene encoding neuroendocrine CRF, the neuropeptide responsible for control of the HPA axis.
Voltage Oscillations in Xenopus Spinal Cord Neurons: Developmental Onset and Dependence on Co‐activation of NMDA and 5HT Receptors
Authors: Scrymgeour‐Wedderburn John F. , Reith Carolyn A. , Sillar Keith T.
Published: April 2006

The development of intrinsic, N‐methyl‐D‐aspartate (NMDA) receptor‐mediated voltage oscillations and their dependence on co‐activation of 5‐hydroxytryptamine (5HT) receptors was explored in motor neurons of late embryonic and early larval Xenopus laevis. Under tetrodotoxin, 100 μM NMDA elicited a membrane depolarization of around 20 mV, but did not lead to voltage oscillations. However, following the addition of 2–5 μM 5HT, oscillations were observed in 12% of embryonic and 70% of larval motor neurons. The voltage oscillations depended upon co‐activation of NMDA and 5HT receptors since they were curtailed by selectively blocking NMDA receptors with D‐2‐amino‐5‐phosphonovaleric acid (APV) or by excluding Mg2+ from the experimental saline. 5HT applied in the absence of NMDA also failed to elicit oscillations. Oscillations could be induced by the non‐selective 5HT1a receptor agonist, 5‐carboxamidotryptamine (5CT) and both 5HT‐ and 5CT‐induced oscillations were abolished by pindobind‐5HT1, a selective 5HT1a receptor antagonist. To test whether 5HT enables voltage oscillations by modulating the voltage‐dependent block of NMDA channels by Mg2+, membrane conductance was monitored under tetrodotoxin. Although 5HT caused membrane hyperpolarization of 4–8 mV, there was little detectable change in conductance. NMDA application caused an approximate 20 mV depolarization and an ‘apparent’ decrease in conductance, presumably due to the conductance pulse bringing the membrane into a voltage region where Mg2+ blocks the NMDA ionophore. 5HT further decreased conductance, which we propose is due to its enhancement of the voltage‐dependent Mg2+ block. When the membrane potential was depolarized by ∼20 mV via depolarizing current injection (to mimic the NMDA‐induced depolarization), 5HT increased rather than decreased membrane conductance. Furthermore, 5HT did not affect the increase in membrane conductance following NMDA applications in zero Mg2+ saline. The results suggest that intrinsic, NMDA receptor‐mediated voltage oscillations develop in a brief period after hatching, and that they depend upon the co‐activation of 5HT and NMDA receptors. The enabling function of 5HT may involve the facilitation of the voltage‐dependent block of the NMDA ionophore by Mg2+ through activation of receptors with 5HT1a‐like pharmacology.