bluuebunny/crossref_metadata_2025 huggingface dataset:
Partial denervation of the whiskerpad in adult mice: pattern and origin of reinnervation
Authors: Corthésy Marc‐Etienne , Bronchti Gilles , Welker Egbert
Published: March 2003

We studied sensory organ reinnervation after nerve transection in the mouse whisker‐to‐barrel pathway. In one set of adult mice, we determined at light microscopy level the number of fibres reaching the caudal whisker follicles 5, 15, 20, 60, 100 days and 1 year after transection of the sensory nerve of row C. Regenerated fibres were first detected 15 days post lesionem (p.l.) and myelin first observed at 20 days. Between 60 and 100 days, the number of fibres stayed at ≈ 80% of the values obtained in control animals. At that time, myelinated fibres reached only 58% of their number in controls. At the electron microscopy level, these fibres differ from control ones by a smaller fibre diameter. The innervation of follicles of adjacent rows was not modified, indicating that follicular reinnervation is row specific. We checked this feature by injecting in another set of mice the denervated follicles and the adjacent ones with distinct retrograde tracers 45 days and 1 year after nerve transection. The percentage of double‐labelled neurons in the Gasserian ganglion did not increase in experimental animals. This confirms the absence of colonization of intact follicles by regenerating fibres and indicates that reinnervation of the whisker follicles takes place by regeneration of the degenerated axons without collateral reinnervation. The companion paper describes the pattern of activation of the barrel cortex relative to the present findings.
Dietary preferences of Brattleboro rats correlated with an overexpression of galanin in the hypothalamus
Authors: Odorizzi Myriam , Max Jean‐Pierre , Tankosic Pierre , Burlet Claude , Burlet Arlette
Published: March 2003

Galanin (GAL) is a neuropeptide cosynthesized with vasopressin (AVP) in neurons of the hypothalamo‐neurohypophysial system. It increases food intake when injected into the brain and elicits an overconsumption of fat. The Brattleboro rat (DI) is genetically unable to produce AVP; the AVP‐deficient‐producing neurons of the hypothalamo‐neurohypophysial system of DI rats are chronically stimulated and DI rats suffer from diabetes insipidus. We studied the central expression of GAL and the dietary preferences in the DI rat. GAL was overexpressed in the hypothalamus of the DI rat. GAL mRNA was higher by 1.8‐fold in the supraoptic (P < 0.05) and by four‐fold in the paraventricular nuclei (P < 0.001) of male and female DI rats compared with those of control Long Evans (LE) rats. However, GAL mRNA was lower in the arcuate nuclei of DI rats and equal to that of LE rats in the dorsomedian nuclei. We also measured a high preference for a lipid diet (45% of the daily consumption) when DI rats ate from a choice of the three macronutrients. Chronic infusion with deamino‐8D‐AVP (agonist of AVP V2 receptors) prevented the diabetes insipidus and the chronic stimulation of the hypothalamo‐neurohypophysial system of the DI rats. However, the treatment did not suppress the overexpression of GAL, nor did it affect the rats’ preference for a lipid diet. We conclude that the DI rat provides a novel animal model in which a spontaneous dietary preference correlates with the overexpression of one of the hypothalamic peptides, GAL.
Network analysis in episodic encoding and retrieval of word‐pair associates: a PET study
Authors: Krause B. J. , Horwitz B. , Taylor J. G. , Schmidt D. , Mottaghy F. M. , Herzog H. , Halsband U. , Müller‐Gärtner H. ‐W.
Published: March 2003

The involvement of distributed brain regions in declarative memory has been hypothesized based on studies with verbal memory tasks. To characterize episodic declarative memory function further, 14 right‐handed volunteers performed a visual verbal learning task using paired word associates. The volunteers underwent positron emission tomography. 15O‐butanol was used as a tracer of regional cerebral blood flow (rCBF). Inter‐regional functional interactions were assessed based on within‐task, across‐subject inter‐regional rCBF correlations. Anatomical connections between brain areas were based on known anatomy. Structural equation modelling was used to calculate the path coefficients representing the magnitudes of the functional influences of each area on the ones to which it is connected by anatomical pathways. The encoding and the retrieval network elicit similarities in a general manner but also differences. Strong functional linkages involving visual integration areas, parahippocampal regions, left precuneus and cingulate gyrus were found in both encoding and retrieval; the functional linkages between posterior regions and prefrontal regions were more closely linked during encoding, whereas functional linkages between the left parahippocampal region and posterior cingulate as well as extrastriate areas and posterior cingulate gyrus were stronger during retrieval. In conclusion, these findings support the idea of a global bihemispheric, asymmetric encoding/retrieval network subserving episodic declarative memory. Our results further underline the role of the precuneus in episodic memory, not only during retrieval but also during encoding.
Requirement for DARPP‐32 in mediating effect of dopamine D2 receptor activation
Authors: Nishi Akinori , Snyder Gretchen L. , Fienberg Allen A. , Fisone Gilberto , Aperia Anita , Nairn Angus C. , Greengard Paul
Published: March 2003

It is well documented that dopamine and dopamine D1 agonists convert the protein phosphatase‐1 inhibitor, DARPP‐32, from its dephosphorylated, inactive form into its Thr34‐phosphorylated, active form, and that these effects on DARPP‐32 constitute essential components of the mechanism by which dopamine and D1 agonists achieve their biological effects. In contrast to dopamine and D1 agonists, dopamine D2 agonists dephosphorylate and inactivate DARPP‐32. Here we have examined the possibility that the biological effects of dopamine D2 receptor agonists might also involve DARPP‐32. For this purpose, we have examined regulation of the activity of the electrogenic ion pump Na+,K+‐ATPase, an established target for dopamine signalling. We have found that dopamine D1 agonists and dopamine D2 agonists inhibit Na+,K+‐ATPase activity in dissociated cells from the mouse neostriatum and that, in each case, the effect is abolished in cells from mice deficient in DARPP‐32. We conclude that DARPP‐32 may play an obligatory role in dopaminergic signalling mediated both by D1 receptors and by D2 receptors.
Caffeine‐mediated induction of c‐fos, zif‐268 and arc expression through A1 receptors in the striatum: different interactions with the dopaminergic system
Authors: Dassesse Donald , Vanderwinden Jean‐Marie , Goldberg Ilan , Vanderhaeghen Jean‐Jacques , Schiffmann Serge N.
Published: March 2003

Adenosine and the adenosine receptor antagonist, caffeine, modulate locomotor activity and striatal neuropeptide expression through interactions with the dopaminergic system by mechanisms which remain partially undetermined. We adressed this question by using quantitative immunocytochemistry and in situ hybridization, combined with retrograde tracing of striatal neurons, to characterize the mechanism(s) leading to the striatal increase in the immediate early genes (IEG), c‐fos, zif‐268 and arc, following a single injection of caffeine or the A1 antagonist, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX). Caffeine and DPCPX induced c‐fos, zif‐268 and arc expression, both at mRNA and protein levels, in large proportions of striatonigral and striatopallidal neurons. The involvement of dopamine systems was evaluated by manipulations of the dopaminergic transmission. Quinpirole, a D2 agonist, almost completely blocked the caffeine‐induced IEG increase in both striatopallidal and striatonigral neurons. Conversely, the lesion of the nigrostriatal pathway and the D1 antagonist SCH23390 abolished the caffeine effects in striatonigral neurons but had no or slight effect, respectively, on its action in striatopallidal neurons. These observations demonstrate that caffeine‐ and DPCPX‐mediated IEG inductions involved different mechanisms in striatonigral and striatopallidal neurons through blockade of A1 receptors. Immediate early gene inductions result from a stimulation of dopamine release in striatonigral neurons and from activation of glutamate release and probably also acetylcholine release in striatopallidal neurons. These results also support the idea that, besides A2A receptors, adenosine acting at the A1 receptor plays pivotal functions in the basal ganglia physiology and that blockade of these receptors by specific or nonspecific antagonists, DPCPX and caffeine, may influence a broad range of neuronal functions in the striatum.
LSD and DOB: interaction with 5‐HT2A receptors to inhibit NMDA receptor‐mediated transmission in the rat prefrontal cortex
Authors: Arvanov Viktor L. , Liang Xiaofu , Russo Angelo , Wang Rex Y.
Published: March 2003

Both the phenethylamine hallucinogen (–)‐1‐2,5‐dimethoxy‐4‐bromophenyl‐2‐aminopropane (DOB), a selective serotonin 5‐HT2A,2C receptor agonist, and the indoleamine hallucinogen d‐lysergic acid diethylamide (LSD, which binds to 5‐HT1A, 1B, 1D, 1E, 1F, 2A, 2C, 5, 6, 7, dopamine D1 and D2, and α1 and α2 adrenergic receptors), but not their non‐hallucinogenic congeners, inhibited N‐methyl‐d‐aspartate (NMDA)‐induced inward current and NMDA receptor‐mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices. The inhibitory effect of hallucinogens was mimicked by 5‐HT in the presence of selective 5‐HT1A and 5‐HT3 receptor antagonists. The inhibitory action of DOB, LSD and 5‐HT on the NMDA transmission was blocked by the 5‐HT2A receptor antagonists r‐(+)‐α‐(2,3‐dimethoxyphenil)‐1‐[4‐fluorophenylethyl]‐4‐piperidinemethanol (M100907) and ketanserin. However, at low concentrations, when both LSD and DOB by themselves only partially depressed the NMDA response, they blocked the inhibitory effect of 5‐HT, suggesting a partial agonist action. Whereas N‐(4‐aminobutyl)‐5‐chloro‐2‐naphthalenesulphonamide (W‐7, a calmodulin antagonist) and N‐[2‐[[[3‐(4′‐chlorophenyl)‐ 2‐propenyl]methylamino]methyl]phenyl]‐N‐(2‐hydroxyethyl)‐4′‐methoxy‐benzenesulphonamide phosphate (KN‐93, a Ca2+/CaM‐KII inhibitor), but not the negative control 2‐[N‐4′methoxybenzenesulphonyl]amino‐N‐(4′‐chlorophenyl)‐2‐propenyl‐N‐methylbenzylamine phosphate (KN‐92), blocked the inhibitory action of LSD and DOB, the selective protein kinase C inhibitor chelerythrine was without any effect. We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5‐HT2A receptors via a Ca2+/CaM‐KII‐dependent signal transduction pathway as partial agonists and modulating the NMDA receptors‐mediated sensory, perceptual, affective and cognitive processes.
Differential effects of Bcl‐2 overexpression on fibre outgrowth and survival of embryonic dopaminergic neurons in intracerebral transplants
Authors: Schierle Gabriele S. , Leist Marcel , Martinou Jean‐Claude , Widner Håkan , Nicotera Pierluigi , Brundin Patrik
Published: March 2003

The causes of death of transplanted neurons are not known in detail, but apoptotic mechanisms involving caspase activation are likely to play a role. We examined whether overexpression of the anti‐apoptotic protein Bcl‐2 may enhance the survival of dopaminergic [tyrosine hydroxylase (TH)‐immunoreactive] grafted neurons. For this purpose, we prepared cells from embryonic day 13 ventral mesencephalon (VM) of mice overexpressing human Bcl‐2, or from their wild‐type littermates. The bcl‐2 transgene was strongly expressed in these cells, and resulted in protection of neuronal cultures from death triggered by serum deprivation or exposure to staurosporine. To model pretransplantation stress more closely in vitro, we stored dissociated embryonic mesencephalic cells for 8 h in the same type of medium used for intracerebral transplantation. This resulted in massive cell death as quantified by lactate dehydrogenase (LDH) release, and increased DNA fragmentation. Although this cell loss was strongly reduced by a caspase inhibitor, Bcl‐2 had no significant protective effect. Finally, mesencephalic cell suspensions were xenografted into the striatum of immunosuppressed hemiparkinsonian rats. Neither the survival of TH‐immunopositive transplanted neurons nor the functional recovery of the rats was improved by Bcl‐2, although the Bcl‐2 protein was strongly expressed in transgenic grafts 5 weeks after implantation, and dopaminergic fibre outgrowth from the grafts was significantly improved. These data suggest that cell death in neuronal transplants involves apoptotic mechanisms that can bypass negative regulation by Bcl‐2.
Action of serotonin on the hyperpolarization‐activated cation current (Ih) in rat CA1 hippocampal neurons
Authors: Gasparini Sonia , DiFrancesco Dario
Published: March 2003

We studied the effects of serotonin (5‐HT) on hippocampal CA1 pyramidal neurons. In current‐clamp mode, 5‐HT induced a hyperpolarization and reduction of excitability due to the opening of inward rectifier K+ channels, followed by a late depolarization and partial restoration of excitability. These two components could be dissociated, as in the presence of BaCl2 to block K+ channels, 5‐HT induced a depolarization accompanied by a reduction of membrane resistance, whereas in the presence of ZD 7288 [4‐(N‐ethyl‐N‐phenylamino)‐1,2‐dimethyl‐6‐(methylamino) pyrimidinium chloride], a selective blocker of the hyperpolarization‐activated cation current (Ih), 5‐HT only hyperpolarized neurons. We then studied the action of 5‐HT on Ih in voltage‐clamp conditions. 5‐HT increased Ih at −90 mV by 29.1 ± 2.9% and decreased the time constant of activation by 20.1 ± 1.7% (n = 16), suggesting a shift in the voltage dependence of the current towards more positive potentials; however, the fully activated current measured at −140 mV also increased (by 14.1 ± 1.7%, n = 14); this increase was blocked by ZD 7288, implying an effect of 5‐HT on the maximal conductance of Ih. Both the shift of activation curve and the increase in maximal conductance were confirmed by data obtained with ramp protocols. Perfusion with the membrane‐permeable analogue of cAMP, 8‐bromoadenosine 3′5′‐cyclic monophosphate (8‐Br‐cAMP), increased Ih both at −90 and −140 mV, although the changes induced were smaller than those due to 5‐HT. Our data indicate that 5‐HT modulates Ih by shifting its activation curve to more positive voltages and by increasing its maximal conductance, and that this action is likely to contribute to the 5‐HT modulation of excitability of CA1 cells.
Myelination and behaviour of tenascin‐C null transgenic mice
Authors: Kiernan B. W. , Garcion E. , Ferguson J. , Frost E. E. , Torres E. M. , Dunnett S. B. , Saga Y. , Aizawa S. , Faissner A. , Kaur R. , Franklin R. J. M. , Ffrench‐Constant C.
Published: March 2003

The extracellular matrix glycoprotein tenascin‐C is widely expressed during development and repair, making it surprising that few abnormalities have been found in transgenic mice lacking this molecule. We have therefore re‐examined the transgenic mice described by Saga et al. [Saga, Y., Yagi, T., Ikawa, Y., Sakakura, T. & Aizawa, S. (1992) Genes Dev., 6 1821–1831] in which tenascin‐C was knocked‐out by homologous recombination, focusing on two aspects of the nervous system likely to reveal any abnormalities that might follow the loss of tenascin‐C. First, we have determined the pattern of myelin and distribution of oligodendrocyte precursor cells in those areas, such as the optic nerve and retina where local concentrations of tenascin‐C have been proposed to act as barriers to oligodendrocyte precursor migration and so prevent inappropriate myelination. Secondly, we have examined the behaviour of the mice in a number of well‐characterized tests, e.g. beam‐walking, passive avoidance and the Morris water maze. We find no abnormalities of myelination or oligodendrocyte precursor distribution in adult mice, showing that local concentrations of tenascin‐C are not the sole mechanism responsible for the pattern of myelination in these regions of CNS. However, we do find a number of behavioural abnormalities in these mice and show that hyperlocomotion and deficits in coordination during beam walking can be ascribed to tenascin‐C deficiency. The effects on coordination are, however, not seen on a 129 genetic background. Taken together, these results significantly extend the phenotype associated with tenascin‐C deficiency but argue against a role in myelination.
Long‐term neuroprotective effects of glycosaminoglycans–IGF‐I cotreatment in the motor neuron degeneration (mnd ) mutant mouse
Authors: Gorio A. , Germani E. , Lesma E. , Rossoni G. , Muller E. E. , Di Giulio A. M.
Published: March 2003

This study shows that cotreatment with insulin‐like growth factor‐I (IGF‐I) and glycosaminoglycans (GAGs) prevents the onset of neuromuscular deficit in the m/m mutant mouse. These mice show a mid‐to‐late‐life onset of progressive paralysis of the hind limb, that is correlated with altered innervation and reduced nerve‐evoked isometric twitch tension in the extensor digitorum longus (EDL) muscle. Almost 50% of EDL nerve endings are negative for antisynaptophysin staining, while retrograde labelling with β‐cholera‐toxin coupled to type IV horseradish and quantitative histological analysis show a small loss of EDL and lumbar cord motor neurons. At 10 months of age also forelimb function evaluated as grip strength is significantly reduced. Animals treated either with glycosaminoglycans alone or with IGF‐I alone at low and high doses showed only a partial improvement of their condition. However, cotreatment of m/m mice with IGF‐I and GAGs fully prevented the neuromuscular abnormalities, the twitch tension loss, the motor neuron decrease and the reduction of forelimb grip strength.
Peptide‐mediated glial responses to Leydig neuron activity in the leech central nervous system
Authors: Schmidt Joachim , Deitmer Joachim W.
Published: March 2003

Neuronal activity may lead to a variety of responses in neighbouring glial cells; in general, an ensemble of neurons needs to be active to evoke a K+‐ and/or neurotransmitter‐induced glial membrane potential change. We have now detected a signal transfer from a single neuromodulatory Leydig neuron to the giant neuropil glial cells in the central nervous system of the leech Hirudo medicinalis. Activation of a Leydig neuron, two of which are located in each segmental ganglion, elicits a hyperpolarization in the giant neuropil glial cells. This hyperpolarization could be mimicked by bath application of the peptide myomodulin A (1 nm–1.0 μm). Myomodulin‐like immunoreactivity has recently been found to be present in a set of leech neurons, including Leydig neurons (Keating & Sahley 1996, J. Neurobiol., 30, 374–384). The glial responses to Leydig neuron stimulation persisted in a high‐divalent cation saline, when polysynaptic pathways are suppressed, indicating that the effects on the glial cell were direct. The glial responses to myomodulin A application persisted in high‐Mg2+/low‐Ca2+ saline, when chemical synaptic transmission is suppressed, indicating a direct effect of myomodulin A on the glial membrane. The glial hyperpolarization evoked by myomodulin A was dose dependent (EC50 = 50 nm) and accompanied by a membrane conductance increase of ≈ 25%. Ion substitution experiments indicated that myomodulin A triggered a Ca2+‐independent K+ conductance. Thus, our results suggest, for the first time, direct signal transmission from an identified modulatory neuron to an identified glial cell using a myomodulin‐like peptide.
A new conotoxin isolated from Conus consors venom acting selectively on axons and motor nerve terminals through a Na+‐dependent mechanism
Authors: Le Gall Frédéric , Favreau Philippe , Benoit Evelyne , Mattei César , Bouet Françoise , Menou Jean‐Louis , Ménez André , Letourneux Yves , Molgó Jordi
Published: March 2003

A novel conotoxin was isolated and characterized from the venom of the fish‐hunting marine snail Conus consors. The peptide was identified by screening chromatography fractions of the crude venom that produced a marked contraction and extension of the caudal and dorsal fins in fish, and noticeable spontaneous contractions of isolated frog neuromuscular preparations. The peptide, named CcTX, had 30 amino acids and the following scaffold: X11CCX7CX2CXCX3C. At the frog neuromuscular junction, CcTx at nanomolar concentrations selectively increased nerve terminal excitability so that a single nerve stimulation triggered trains of repetitive or spontaneous synaptic potentials and action potentials. In contrast, CcTx had no noticeable effect on muscle excitability even at concentrations 100 × higher than those that affected motor nerve terminals, as revealed by direct muscle stimulation. In addition, CcTx increased miniature endplate potential (MEPP) frequency in a Ca2+‐free medium supplemented with ethylene glycol‐bis‐(β‐aminoethyl ether)‐N,N,N′,N′‐tetraacetic acid (EGTA). Blockade of voltage‐dependent sodium channels with tetrodotoxin (TTX) either prevented or suppressed the increase of MEPP frequency induced by the toxin. CcTx also produced a TTX‐sensitive depolarization of the nodal membrane in single myelinated axons giving rise, in some cases, to repetitive and/or spontaneous action potential discharges. In addition, CcTx increased the nodal volume of myelinated axons, as determined using confocal laser scanning microscopy. This increase was reversed by external hyperosmolar solutions and was prevented by pretreatment of axons with TTX. It is suggested that CcTx, by specifically activating neuronal voltage‐gated sodium channels at the resting membrane potential, produced Na+ entry into nerve terminals and axons without directly affecting skeletal muscle fibres. CcTx belongs to a novel family of conotoxins that targets neuronal voltage‐gated sodium channels.
Postural responses to combined vestibular and hip proprioceptive stimulation in man
Authors: Popov K. E. , Kozhina G. V. , Smetanin B. N. , Shlikov V. Y.
Published: March 2003

Vestibular–proprioceptive interaction in human postural control in the frontal plane was studied by analysing the lateral body sway evoked in a standing subject by a weak, near‐threshold galvanic vestibular stimulation combined with a balanced, bilateral vibration of the medial gluteus muscles. The intensities of the stimuli were adjusted so that none of them produced a consistent postural response when delivered alone. The pattern of the lateral body sway evoked by the combined stimulation was compared with postural responses to suprathreshold vestibular stimulation and asymmetric (unilateral) vibration of the hip abductors. During the vestibular stimulation alone the head movement started earlier and was larger than movement of the hip. During unilateral vibration the head movement was delayed with respect to the hip movement and the amplitude of head deviation was less than that of the hip. The pattern of postural response to combined vestibular stimulation and balanced vibration resembled that observed under unbalanced, unilateral vibration in terms of both the latencies and amplitudes of deviation of the body segments from their respective baseline positions. It is suggested that the asymmetric vestibular signal provided by galvanic stimulation of the labyrinth introduces a bias into the reference frame for central interpretation of proprioceptive signals so that a symmetric proprioceptive input gives rise to a lateral body sway when referenced to an asymmetric vestibular input.
Rises in [Ca2+]i mediate capsaicin‐ and proton‐induced heat sensitization of rat primary nociceptive neurons
Authors: Guenther S. , Reeh P. W. , Kress M.
Published: March 2003

Capsaicin (CAPS) as well as acidic pH induces Ca2+ influx in a subset of rat dorsal root ganglion neurons. Here we show that CAPS as well as three different approaches to induce experimental tissue acidification (phosphate buffered solution pH 5.4, CO2‐gassed solution pH 6.1 and NPE‐caged protons) yielded a transient heat sensitization of peripheral nociceptive terminals in rat skin in vitro. The heat sensitization induced by CAPS (1 μm) could be prevented by preloading the neurons with the neuroprotective calcium chelator BAPTA‐AM (1 mm). However, this pretreatment had no effect on the sensitization following exposure to acidic solutions (pH 5.4 and pH 6.1). Therefore, the membrane‐permeant proton buffer SNARF‐AM (200 μm) was used together with BAPTA‐AM in order to prevent changes in intracellular pH. Under these conditions heat sensitization by low pH did not occur. To investigate the underlying membrane mechanisms, current recordings together with simultaneous calcium measurements using FURA‐2 were performed in neurons isolated from rat dorsal root ganglia. In a subset of these neurons, an increase in [Ca2+]i and concomitant facilitation of heat‐activated ionic currents was observed after application of CAPS as well as pH 5.6. Rises in [Ca2+]i thus appear to play an essential role in plastic changes not only of central neurons but also of peripheral nociceptive terminals which may account for heat hyperalgesia.
Spontaneous regeneration of severed optic axons restores mapped visual responses to the adult rat superior colliculus
Authors: Foerster Anne P. , Holmes Michael J.
Published: March 2003

To test whether a spontaneous and functional regeneration of severed axons could occur within the adult mammalian central nervous system, a long‐term recovery of microelectrode‐mapped visual response was sought in the superior colliculus (SC) after its total or near‐total abolition by a precise guillotine cut of the retinocollicular pathway. Recoveries were found 3 weeks or later in 15 of the 36 animals studied; in 10 of these recoveries, half or more of the width of the SC was involved. The recovered responses were often activated from within a normally small area of the visual field. Appropriate retinotopic maps were restored. Intraocular horseradish peroxidase tracing revealed a variety of novel optic trajectories, passing around lesions even of totally cut pathways, which eventually terminated in normally retinorecipient layers of those recovered SCs. Such detours could not be explained by a mechanical reorientation of brain structures. When exactly comparable lesions were examined within a few days, there were no detours: severed optic axons faced the cuts. In long‐term animals where responsiveness remained absent, optic axonal reorientations were observed near lesions but the SC was not innervated. Extensive long‐term recoveries were in marked contrast to the occasional rapid ones, found within a few days postlesion, which involved only an outermost silenced border of SC. These were attributed to a rapid reversal of conduction failure in spared, bordering, axons of this topographically organized pathway. The findings support the conclusion that, after they are cut, numbers of optic axons can regenerate to the SC and restore appropriate circuitry therein.
Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex
Authors: Lu Wenxiao , Monteggia Lisa M. , Wolf Marina E.
Published: March 2003

Glutamate plays a critical role in neuroadaptations induced by drugs of abuse. This study determined whether expression of the NMDAR1 subunit of the NMDA receptor is altered by repeated amphetamine administration. We quantified NMDAR1 mRNA (using in situ hybridization with 35S‐labelled oligonucleotide probes) and immunolabelling (using immunocytochemistry with 35S‐labelled secondary antibodies) in rat ventral midbrain, nucleus accumbens and prefrontal cortex after 3 or 14 days of withdrawal from five daily injections of saline or amphetamine sulphate (5 mg/kg/day). No changes in NMDAR1 expression were observed after 3 days of withdrawal, whereas significant decreases were observed in all regions after 14 days. NMDAR1 mRNA levels in midbrain were too low for reliable quantification, but immunolabelling was decreased significantly in intermediate and caudal portions of the substantia nigra. This may indicate a reduction in excitatory drive to substantia nigra dopaminergic neurons. In the nucleus accumbens, there were significant decreases in NMDAR1 mRNA levels (74.8 ± 7.7% of control, P < 0.05) and immunolabelling (76.7 ± 4.4%, P < 0.05). This may account for previously‐reported decreases in the electrophysiological responsiveness of nucleus accumbens neurons to NMDA after chronic amphetamine treatment, and contribute to dysregulation of goal‐directed behaviour. In prefrontal cortex, there was a significant decrease in NMDAR1 mRNA levels (76.1 ± 7.1%, P < 0.05) and a trend towards decreased immunolabelling (89.5 ± 7.0%). This may indicate decreased neuronal excitability within prefrontal cortex. A resultant decrease in activity of excitatory prefrontal cortical projections to nucleus accumbens or midbrain could synergize with local decreases in NMDAR1 to further reduce neuronal excitability in these latter regions.
Effects of nerve growth factor on visual cortical plasticity require afferent electrical activity
Authors: Caleo Matteo , Lodovichi Claudia , Maffei Lamberto
Published: March 2003

It is known that administration of nerve growth factor (NGF) prevents the ocular dominance shift induced by monocular deprivation in the rat. To determine whether electrical activity in the visual afferent pathway is required for NGF effects on ocular dominance, we infused NGF into the cortex of animals subjected to complete monocular blockade of retinal discharges. Rats at the peak of the critical period received intravitreal tetrodotoxin (TTX) injections to silence activity in one eye for a period of 6–7 days; NGF was concurrently delivered into the visual cortex by means of osmotic minipumps. At the end of the treatment period, the ocular dominance distribution of cortical neurons was assessed by single‐cell recordings. The results demonstrate that while infusion of NGF is effective in preventing the ocular dominance shift in lid‐sutured rats, virtually no rescue can be observed in TTX‐injected animals. Identical results were obtained when a specific agonist of the NGF receptor TrkA, the bivalent anti‐rat TrkA IgG (RTA), was infused into the cortex in place of NGF. We conclude that NGF signalling via the TrkA receptor must be coupled to afferent electrical activity to produce its effects on the eye preference of cortical neurons. This suggests a generalized mechanism in which high‐affinity neurotrophin receptor activation and afferent discharge interact to modulate neuronal plasticity in the developing visual cortex.
Re‐examination of the human taste region: a positron emission tomography study
Authors: Frey S. , Petrides M.
Published: March 2003

There is considerable uncertainty regarding the cortical areas in the human brain that are involved in gustatory processing. Evidence from nonhuman primates indicates that parts of the peri‐central opercular region (secondary somatosensory cortex) and insular cortex may be important for gustatory processing. The aim of the study was to examine changes in cerebral blood flow during gustatory stimulation (with sucrose or water) in the insulo‐opercular region of the human brain with positron emission tomography using only movement of the tongue and mouth as control conditions. This is important because subtractions of responses to one gustatory stimulus from those to another may mask gustatory activity that is common to both stimuli, even when the control stimulus is an apparently tasteless one (e.g. water). Bilateral increases in activity were observed in the insulo‐opercular region and, consistent with animal work, they indicate that there are a number of separate foci within this general area where primary gustatory inputs may be processed.
NGFI‐A gene expression induced in the rat suprachiasmatic nucleus by photic stimulation: spread into hypothalamic periventricular somatostatin neurons and GABA receptor involvement
Authors: Tanaka Masaki , Iijima Norio , Amaya Fumimasa , Tamada Yoshitaka , Ibata Yasuhiko
Published: March 2003

We studied NGFI‐A gene expression in response to photic stimulation in the rat suprachiasmatic nucleus (SCN) using in situ hybridization histochemistry. This gene expression spread within the SCN and extended dorsally into the anterior hypothalamus after 30 min–1 h of light exposure at circadian time (CT) CT18. It appeared first in the ventrolateral SCN where the retinohypothalamic tract (RHT) innervates, then it expanded dorsomedially in the SCN and beyond the SCN to the anterior hypothalamus. However, stimulation for 2 h light exposure decreased its expression in the SCN. NGFI‐A expression in the somatostatin neurons in the periventricular nucleus increased from 8.7% to 41% with increasing exposure time from 5 to 30 min. NGFI‐A mRNA expression in the SCN was suppressed by pretreatment with baclofen, the GABAB receptor agonist. The spread of photic information from the retina to the SCN was visualized at immediate early gene level not only in the SCN but also in the area beyond the SCN. Somatostatin neurons in the periventricular nucleus which project to the external layer of the median eminence and are involved in regulation of growth hormone release showed NGFI‐A gene expression corresponding to the duration of photic stimulation. Photic‐induced NGFI‐A gene expression in the SCN was also shown to be regulated by GABAergic transmission via GABAB receptors. These NGFI‐A gene‐expressing cells in the SCN may be involved in the circadian entrainment by light and some of those outside the SCN may participate in the regulation of neuroendocrine function.
Knowing which and knowing what: a potential mouse model for age‐related human declarative memory decline
Authors: Marighetto Aline , Etchamendy Nicole , Touzani Khalid , Torrea Cedric Cortes , Yee Benjamin K. , Rawlins John Nicholas P. , Jaffard Robert
Published: March 2003

The present study was built on the original report of Eichenbaum et al. [Eichenbaum, H., Fagan, A., Mathews, P. & Cohen, N.J. (1988), Behav. Neurosci., 102, 3531–3542] on the contrasting effects of fornix lesion in different versions of an odour‐guided discrimination task in rats, and attempted to extend this into a mouse model for the preferential loss of declarative memory seen in human senescence. Each of the two experiments reported here consisted of a two‐stage paradigm, with an initial learning phase followed by a test phase. The information acquired in the first stage was identical in both experiments, i.e. the valence or reward contingency associated with six (three positive and three negative) arms of a radial maze. The only parameter which was varied between Experiment A and B, and also between the two successive stages within each experiment, was the way of presenting the arms to the mice, i.e. either in pairs (simultaneous discriminations) or one at a time (successive go : no‐go discrimination). Performance in the first stage demonstrated that our aged mice were impaired in learning concurrent simultaneous discriminations but not successive go/no‐go discrimination, thereby resembling that reported in rats with hippocampal damage. Most importantly, our present set of data supports the conclusion that two forms of memory expression for the same piece of acquired experience can be assessed in the same subjects by manipulating the way of presenting two arms that were previously experienced separately. These two forms of memory expressions are differentially affected in aged mice, thereby demonstrating the highly selective and specific deleterious effect of ageing.
Novelty causes time‐dependent retrograde amnesia for one‐trial avoidance in rats through NMDA receptor‐ and CaMKII‐dependent mechanisms in the hippocampus
Authors: Izquierdo I. , Schröder N. , Netto C. A. , Medina J. H.
Published: March 2003

Exposure to a novel environment (an open field) for 2 min, 1 h after one‐trial inhibitory avoidance training, hindered memory of the avoidance task measured 24 h later. The effect was seen regardless of the intensity of the avoidance training footshock. The effect was not seen if the exposure to novelty was carried out 5 min before, or 6 h after, the avoidance training, or if the animals did not perceive the open field as new and react accordingly. The amnesic effect of the novelty presented 1 h after avoidance training was blocked by the intrahippocampal infusion of d‐2‐amino‐5‐phosphono‐pentanoic acid (AP5, 25 nmoles per side) or 1‐(N,O‐bis‐[5‐isoquinolinylsulphonyl]‐N‐methyl‐l‐tyrosyl)‐4‐phenylpiperazine (KN62, 100 μmoles per side) but not by that of C32H25N3O6 (KT5720, 90 μmoles per side) given 5 min before the novelty. In the open field there was habituation, measured by the decrease in exploration between the first and second minute. AP5 and KN62 impaired this habituation, but not KT5720. Exploration of the open field was similar in the groups exposed to the avoidance task 5 min later, or 1 h or 6 h before. Therefore, there was no reciprocity between the effect of the two tasks: novelty was amnesic for the one‐trial avoidance task, but the opposite was not true. The amnesic effect of novelty appears to rely on N‐methyl‐d‐aspartate (NMDA) receptor‐ and calcium/calmodulin‐dependent protein kinase II (CaMKII)‐dependent, but not on PKA‐dependent, aspects of its habituation learning.
Cyclosporin A and its nonimmunosuppressive analogue N‐Me‐Val‐4‐cyclosporin A mitigate glucose/oxygen deprivation‐induced damage to rat cultured hippocampal neurons
Authors: Khaspekov Leonid , Friberg Hans , Halestrap Andrew , Viktorov Ilja , Wieloch Tadeusz
Published: March 2003

When mouse hippocampal neuronal cultures, 2–3 weeks in vitro, were transiently exposed to combined glucose and oxygen deprivation (100% argon, 5% CO2, in glucose‐free medium) for 90 min, extensive neuronal degeneration had occurred after 24 h of reoxygenation. When these cultures were preincubated with cyclosporin A, a calcineurin inhibitor and a blocker of the mitochondrial permeability transition, neuronal death diminished by 30–50%. Similarly, the cyclosporin A analogue, N‐Me‐Val‐4‐cyclosporin A, a potent blocker of the mitochondrial permeability transition with no significant calcineurin blocking activity, decreased cell death by 70–80%. Both cyclosporin A and N‐Me‐Val‐4‐cyclosporin A markedly attenuated calcium‐induced swelling of isolated mouse brain mitochondria by blocking the mitochondrial permeability transition. The potassium thiocyanate‐stabilized binding of cyclophilin D to mouse brain mitochondrial membranes was completely prevented by cyclosporin A and N‐Me‐Val‐4‐cyclosporin A. Our results strongly suggest that the mitochondrial permeability transition is involved in oxygen/glucose deprivation‐induced cell death in vitro. Cyclophilin D and other components of the mitochondrial permeability transition may be important targets for neuroprotective and anti‐ischaemic drugs.
Multiple trophic actions of heparin‐binding epidermal growth factor (HB‐EGF) in the central nervous system
Authors: Kornblum Harley I. , Zurcher Shelley D. , Werb Zena , Derynck Rik , Seroogy Kim B.
Published: March 2003

The epidermal growth factor (EGF) family of ligands interacts with the epidermal growth factor receptor (EGF‐R) to produce numerous direct and indirect actions on central nervous system cells. They induce the proliferation of astrocytes and multipotent progenitors (‘stem’ cells) and promote the survival and differentiation of postmitotic neurons. Heparin‐binding epidermal growth factor (HB‐EGF) interacts with both EGF‐R and a related receptor, ErbB4, whereas transforming growth factor alpha (TGFα) interacts only with EGF‐R. Because of the unique characteristics of HB‐EGF and the potential utility of EGF family members in brain repair, we examine the effects of HB‐EGF on rat and mouse CNS cells in vitro and compare them to those of TGFα. We find that, like TGFα, HB‐EGF stimulates the proliferation of CNS astrocytes and multipotent progenitors. These proliferative effects require the expression of EGF‐R, as no such effects are observed in cells derived from EGF‐R–/– mice. Both HB‐EGF and TGFα enhanced the survival of neurons derived from the neocortex and the striatum. Within these neuron‐enriched cultures, nestin‐positive cells but not neurons express EGF‐R mRNA, indicating that the neurotrophic actions of EGF‐R ligands are a result of indirect stimulation mediated by non‐neuronal cells. The neurotrophic actions of HB‐EGF and TGFα are accompanied by an elevation in immunoreactive dual phosphorylated mitogen‐activated protein kinase (MAP kinase) in neurons, providing evidence that the MAP kinase cascade mediates these actions. In situ hybridization studies demonstrate that HB‐EGF mRNA is present within the brainstem as early as E14 and subsequently is found in the developing cortical plate, hippocampus, cerebellar Purkinje cells and ventrobasal thalamus, among other brain areas. These findings indicate that HB‐EGF may be an important trophic factor in the developing CNS and is a useful candidate molecule for brain repair strategies.
Pyruvate and lactate protect striatal neurons against N‐methyl‐d‐aspartate‐induced neurotoxicity
Authors: Maus Marion , Marin Philippe , Israël Maurice , Glowinski Jacques , Prémont Joël
Published: March 2003

A sustained release of glutamate contributes to neuronal loss during cerebral ischaemia. Using cultured mouse striatal neurons, we observed that glucose deprivation, which occurs in this pathological process, enhanced the N‐Methyl‐d‐aspartate (NMDA)‐ or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA)‐induced neurotoxicity. The end products of glycolysis, lactate and pyruvate, strongly protected neurons from these neurotoxic effects. The neuroprotective effect of pyruvate (which is more prominent in the absence of glucose) was not related to its ability to react with H2O2 by a decarboxylation process. Pyruvate and l‐lactate strongly counteracted the deep decrease in the neuronal ATP content induced by NMDA, indicating that they might protect striatal neurons by rescuing cellular energy charge. Addition of MK‐801 after the NMDA withdrawal completely protected neurons, suggesting that NMDA neurotoxicity resulted from a delayed NMDA receptor activation probably linked to a delayed release of an endogenous agonist in the extracellular medium. The strong accumulation of extracellular glutamate which was found in both sham and NMDA‐treated cultures was markedly decreased by pyruvate. Thus, pyruvate might also exert its protecting activity by decreasing the delayed accumulation of glutamate which seemed to be neurotoxic only after a preexposure of neurons to NMDA.
Seasonal regulation of food intake and body weight in the male Siberian hamster: studies of hypothalamic orexin (hypocretin), neuropeptide Y (NPY) andpro‐opiomelanocortin (POMC)
Authors: Reddy Akhilesh B. , Cronin Anna S. , Ford Hazel , Ebling Francis J. P.
Published: March 2003

The aim of these experiments was to investigate the relationship between hypothalamic expression of orexin (also called hypocretin), neuropeptide Y (NPY) and pro‐opiomelanocortin (POMC) mRNA and seasonal cycles of body weight and food intake in the Siberian hamster. Adult males were transferred from long days of 16 h light and 8 h dark to short days of 8 h light and 16 h dark, a procedure known to induce major reductions in food intake and body weight in this species. After 8 weeks of exposure to short days, while body weight was declining, hypothalamic NPY mRNA levels as assessed by in situ hybridization were slightly lower (P < 0.05) than in age‐matched controls exposed to long days. After 12 weeks with short days, when body weight would be expected to have reached its seasonal nadir, POMC mRNA levels were lower (P < 0.05) than in hamsters under long days. At no stage did orexin mRNA levels in hamsters under short days differ significantly from levels in those under long days. To investigate further the role of these peptide systems in seasonal changes in body weight and food intake, two provocative tests were carried out. Firstly, a 48‐h fast induced a significant increase (P < 0.025) in hypothalamic NPY mRNA levels in both long‐ and short‐day conditions, but did not change hypothalamic POMC or orexin mRNA levels. Secondly, systemic (intraperitoneal) treatment with recombinant murine leptin (5 mg/kg body weight) significantly decreased (P < 0.01) food intake over a 6‐h post‐treatment period in both long‐ and short‐day conditions. However, this acute leptin treatment did not induce significant changes in hypothalamic orexin, NPY or POMC mRNA abundance. The increase in NPY expression in both long‐ and short‐day conditions following food restriction and the suppression of food intake by leptin in both conditions suggests that acute homeostatic mechanisms operate in both long‐day (obese) and short‐day (nonobese) conditions. The lack of major changes in orexin, NPY and POMC in such different metabolic states suggest that other central systems must play a greater role in generating these states. Such findings are consistent with the ‘sliding set‐point’ hypothesis, that is, seasonal cycles in food intake and fat metabolism are brought about by as yet unknown central mechanisms that chronically alter the level (‘set point’) around which homeostasis occurs, rather than resulting from changes in the potency of the acute feedback mechanisms themselves.
Repetitive transcranial magnetic stimulation in rats: evidence for a neuroprotective effect in vitro and in vivo
Authors: Post Anke , Müller Marianne B. , Engelmann Mario , Keck Martin E.
Published: March 2003

In recent years, repetitive transcranial magnetic stimulation (rTMS) of the human brain has been used as a therapeutic tool in a variety of psychiatric and neurological disorders. However, to understand the mechanisms underlying any potential therapeutic effects, and possible adverse effects, studies are necessary on how magnetic stimuli induced by rTMS interact with central nervous system (CNS) regulation. In the current study, we failed to find cognitive impairments or structural alterations in rat brains after 11 weeks of long‐term treatment with rTMS, which if present would indicate neuronal damage. In contrast, our in vitro studies showed that magnetic stimulation analogous to rTMS increased the overall viability of mouse monoclonal hippocampal HT22 cells and had a neuroprotective effect against oxidative stressors, e.g. amyloid beta (Aβ) and glutamate. The treatment increased the release of secreted amyloid precursor protein (sAPP) into the supernatant of HT22 cells and into cerebrospinal fluid from rats. HT22 cells preincubated with cerebrospinal fluid from rTMS‐treated rats were found to be protected against Aβ. These findings suggest that neurochemical effects induced by rTMS do not lead to reduced neuronal viability, and may even reduce the detrimental effects of oxidative stress in neurons.