bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebellar Contribution to Spatial Event Processing: Right/Left Discrimination Abilities in Rats
Authors: Molinari Marco , Grammaldo Liliana G. , Petrosini Laura
Published: April 2006

Recently, we demonstrated the involvement of cerebellar circuits in the procedural components of spatial information processing by testing hemicerebellectomized (HCbed) rats in classical spatial paradigms, such as the Morris Water Maze and the water T‐maze. Since procedural components are strongly present in these tests, an impairment also in processing more abstract spatial information, linked to ‘where an object is’ rather than to ‘how to find it’, could be hidden by the severe procedural deficits. On this basis, we investigated the influence of cerebellar lesions on spatial abilities strictly reducing procedural variables by employing an active avoidance task, first without and then with a request for righvleft discrimination. In the two‐way active avoidance task without spatial requests, controls and cerebellar operated rats developed active avoidance responses which were not statistically different, demonstrating that this kind of associative learning is not significantly affected by hemicerebellectomy (HCb). A second experimental group of cerebellar lesioned rats was tested in a modified version of this basic paradigm in which a rightheft discrimination request was added. This group displayed severe deficits, which even in the last testing sessions prevented them from performing comparably to the control animals. Reversal of the rewarded choice, even if it affected the performances of both controls and operated rats in the first inversion trials, elicited the lowest number of correct responses in HCbed rats throughout the entire spatial reversal learning, suggesting a severe deficit in the ability to change an initially learned behaviour. These results demonstrate that, beside having a marked impairment in facing procedural components of spatial processing, cerebellar lesioned rats are severely defective also in rightlleft discrimination tasks, suggesting a role of cerebellar networks also in the discriminative spatial information processing.
Expression and Coupling to Polyphosphoinositide Hydrolysis of Group I Metabotropic Glutamate Receptors in Early Postnatal and Adult Rat Brain
Authors: Casabona G. , Knopfel T. , Kuhn R. , Gasparini F. , Baumann P. , Sortino M. A. , Copani A. , Nicolettii F.
Published: April 2006

We investigated the expression and coupling to the phospholipase C signal transduction pathway of metabotropic glutamate receptor (mGluR) subtypes by Western blot analysis and agonist‐stimulated inositol monophosphate formation in several brain regions of postnatal day 9 (P9) and adult rats. In the cerebral cortex, hippocampus, corpus striatum, olfactory bulb, cerebellum and hypothalamus, the expression level of mGluR5 was greater at P9 than in adulthood. The mGluR5 signal was very low or absent in the adult cerebellum and hypothalamus. The expression of mGluR1a was slightly greater at P9 in the hypothalamus, hippocampus and olfactory bulb, whereas it substantially increased with age in the cerebellum, and did not change in the cerebral cortex and corpus striatum. mGluR1b and ‐1c were nearly undetectable by Western blot analysis. The expression level of mGluR5, but not that of mGluR1a, was significantly correlated with the extent of phosphoinositide hydrolysis stimulated by mGluR agonists in slices prepared from these brain regions. The mGluR antagonist cyclopropan[b]chromen‐1a‐carboxylic acid ethylester (CPCCOEt), potently antagonized responses mediated by mGluR1, but much less potently those mediated by mGluR5a in recombinant cells. CPCCOEt, at a concentration which efficently blocks mGluR1 responses, did not substantially affect the polyphosphoinositide response in hippocampal or cerebellar slices from newborn animals, and antagonized only a minor component of the polyphosphoinositide response in adult hippocampal slices. CPCCOEt, however, prevented the small stimulation of polyphosphoinositide hydrolysis by mGluR agonists in adult cerebellar slices. We conclude that (i) the efficient mGluR‐mediated polyphosphoinositide hydrolysis in 9‐day‐old rats is mediated by mGluR5; (ii) the increased expression of mGluR1 in the adult cerebellum does not substitute for the decline of mGluR5 expression in the ability to mediate polyphosphoinositide hydrolysis; and therefore (iii) mGluRla might couple less efficiently than mGluR5 to polyphosphoinositide hydrolysis.
Prevention of Kainic Acid‐induced Limbic Seizures and Fos Expression by the GABA‐A Receptor Agonist Muscimol
Authors: Zhang Xia , Le Gal La Salle Gildas , Ridoux Valerie , Yu Peter H. , Ju Gong
Published: April 2006

Fos oncoprotein expression has been shown to be a sensitive marker for sequential neuronal activation in response to a specific stimulus. The present study investigated the effect of the γ‐aminobutyric acid (GABA)‐A receptor agonist muscimol on kainic acid (KA)‐induced limbic seizures and Fos expression in the rat forebrain. One hour after KA injection, a substantial Fos expression was observed in the hippocampal dentate gyrus, whereas only a low level of Fos induction was seen in CA1–3 fields. Six hours post‐injection a prominent increase of Fos expression occurred in most forebrain structures, including the whole hippocampus. Following 0.5 mg/kg muscimol treatment a remarkable decrease of Fos expression occurred but only in the caudate putamen and core of the accumbens nucleus. Treatment with 1 mg/kg muscimol led to further significant decreases of Fos expression in CA1–3 pyramidal neurons and the disappearance of Fos induction in the cerebral cortex above the rhinal fissure, reticular thalamic nucleus, claustrum, fundus striati, ventral pallidum, septal nucleus, lateral habenular nucleus, and lateral amygdaloid nucleus. When 2 mg/kg muscimol was injected, animals exhibited ‘absence seizures’ instead of limbic seizures, and Fos expression in the hippocampus was effectively blocked. These results suggest that a reduction of GABAergic inhibition plays a crucial role not only in limbic seizure genesis in the dentate gyrus, but also in the seizure spread mechanism in many brain structures, among which the hippocampal CA1–3 fields are most markedly involved, less marked in the cerebral cortex and some other structures, and least marked in the caudate putamen and core of the accumbens nucleus.
Novelty‐elicited, Noradrenaline‐dependent Enhancement of Excitability in the Dentate Gyrus
Authors: Kitchigina Valentina , Vankov Andrey , Harley Carolyn , Sara Susan J.
Published: April 2006

In order to relate noradrenaline‐dependent potentiation in the dentate gyrus to behavioural events, rats were made to explore an environment in which their encounters with novel stimuli could be strictly controlled and monitored. Previous experiments have shown that an encounter with novel objects in a holeboard elicits a burst response in a large population of noradrenergic neurons of the locus coeruleus. Such a burst response has been demonstrated to produce a large and transient potentiation of the population spike in the dentate gyrus. In the present series of experiments, rats were chronically implanted with stimulating electrodes in the perforant pathway and recording electrodes in the dentate gyrus. Evoked potentials were monitored in the awake rat, first while it was resting quietly in a familiar environment and then while it was exploring the holeboard containing a novel object in a specific hole. There was a tonic increase in population spike amplitude when the rat was placed in the novel holeboard environment, but this effect gradually dissipated. This increase was partly blocked by the β‐noradenergic antagonist propranolol. In addition there was a robust phasic increase in spike amplitude when the rat encountered a novel stimulus. This phasic response lasted ˜T50–75 s and was absent in animals treated with propranolol. These results show that a behavioural encounter with a novel stimulus can transiently enhance information transmission through the hippocampus, and suggest that activation of the noradrenergic system by the novel stimulus mediates this behaviour‐dependent gating.
A Slow Excitatory Postsynaptic Current Mediated by G‐protein‐coupled Metabotropic Glutamate Receptors in Rat Ventral Tegmental Dopamine Neurons
Authors: Shen Ke‐Zhong , Johnson Steven W.
Published: April 2006

Dopamine neurons in the substantia nigra and ventral tegmental area express metabotropic glutamate receptors, but activation of these receptors by synaptic release of neurotransmitter has not been demonstrated thus far. Patch pipettes were used to record membrane currents under voltage clamp from presumed dopamine‐containing neurons in the whole‐cell configuration in the rat brain slice. A short train of electrical stimuli delivered to bipolar electrodes placed in the slice evoked a slow excitatory postsynaptic current (EPSC; 50–300 pA at ‐70 mV) which peaked 560 ms after onset and lasted several seconds, with a decay time‐constant of 630 ms. This slow EPSC was voltage‐dependent, and was abolished by tetrodotoxin (0.5 μM) or by perfusate containing low calcium (0.5 mM) and high magnesium (10 mM). The metabotropic glutamate receptor antagonist (±)‐α‐methyl‐4‐carboxyphenylglycine (MCPG; 300 μM) blocked the slow EPSC, but L(+)‐2‐amino‐3‐ phosphonopropionic acid (AP3; 300 μM) had no effect. The slow EPSC was largely occluded by inward current produced by the metabotropic receptor agonist trans‐(±)‐1‐amino‐1, 3‐cyclopentanedicarboxylic acid (t‐ACPD; 300 μM), and the EPSC was reduced >90% during acute desensitization produced by prolonged perfusion with f‐ACPD. (±)‐2‐Amino‐4‐phosphonobutyric acid (AP4; 300 μM), another metabotropic receptor agonist, reduced the slow EPSC but had no effect on currents evoked by t‐ACPD applied by pressure‐ejection from micropipettes. The slow EPSC was progressively reduced in amplitude when pipettes contained the G‐protein inhibitor GDP‐β‐S (0.5 mM). When pipettes contained GTP‐γ‐S (0.5 mM), a non‐hydrolysable analogue of GTP, onset of the slow EPSC was more rapid and its decay was significantly prolonged. These results demonstrate that a slow EPSC mediated by G‐protein‐coupled metabotropic glutamate receptors can be evoked in dopamine neurons.
Relationship Between GAP‐43 Expression in the Dentate Gyrus and Synaptic Reorganization of Hippocampal Mossy Fibres in Rats Treated with Kainic Acid
Authors: Bendotti C. , Baldessari S. , Pende M. , Southgate T. , Guglielmetti F. , Samanin R.
Published: April 2006

Kainic acid‐induced seizures in adult rats produce neurodegeneration in the hippocampus followed by sprouting of the mossy fibres in the inner molecular layer of the dentate gyrus and changes in GAP‐43 expression in the granule cells. In the present study we observed that 4 days after kainic acid injection a dense plexus of silver impregnated degenerating terminals detected by Gallyas's method and a decrease of GAP‐43 immunostaining was observed in the inner molecular layer of the dentate gyrus indicating deafferentiation of this region. This was associated with the formation of an intense GAP‐43 immunostained band in the supragranular layer. MK‐801, a non‐competitive inhibitor of the NMDA receptor, which partially inhibited the behavioural seizures induced by KA, also protected from the inner molecular layer deafferentation and markedly reduced the expression of GAP‐43 mRNA in the granule cells and the intense GAP‐43 immunostained band in the supragranular layer, suggesting a relationship among these events. Two months after kainic acid injection the intense supragranular GAP‐43 positive band was no longer evident but the whole inner molecular layer appeared more labelled in association with the formation of the collateral sprouting of the mossy fibres in the inner molecular layer as detected by Timm's staining. These effects were also markedly reduced by the pretreatment with MK‐801. Taken together, these experiments indicate for the first time a direct relationship between the increase of GAP‐43 immunostaining in the inner molecular layer of the dentate gyrus and the collateral sprouting of mossy fibres in this district in response to kainic acid induced seizures. This further supports the hypothesis that the early induction of GAP‐43 in granule cells may be one of the molecular mechanisms required for the synaptic reorganization of the mossy fibres.
Transplant of Schwann Cells Allows Normal Development of the Visual Cortex of Dark‐reared Rats
Authors: Fagiolini Michela , Pizzorusso Tommaso , Porciatti Vittorio , Cenni MariaCristina , Maffei Lamberto
Published: April 2006

Visual experience is necessary for the correct development of the visual cortex. Dark‐rearing from birth affects normal maturation of the functional properties of mammalian visual cortex: cortical cells show rapid habituation to repeated stimulation, decreased orientation selectivity, and enlarged receptive fields. Spatial resolution and response latency are also impaired. Recent experiments have demonstrated that visual deprivation reduces the expression of neurotrophins in the visual cortex. We formulated the hypothesis that visual experience drives the maturation of functional properties of the visual cortex by regulating cortical levels of neurotrophins. If this hypothesis is correct, exogenous supply of neurotrophins during dark‐rearing from birth should prevent, or at least ameliorate, the effects of a lack of visual experience. Since Schwann cells are efficient biological minipumps of neurotrophic factors, we transplanted 1.0 or 1.5 × 106 Schwann cells or infused vehicle solution as a control into the lateral ventricles of 13 day old rats reared in total darkness from birth until the end of the critical period (postnatal day 45). Single‐cell responses and visual‐evoked potentials were recorded from the binocular zone of the primary visual cortex of each group. We found that in Schwann cell‐transplanted animals all parameters tested were significantly improved upon those of dark‐reared control rats and were in the range of normal adult values. Thus, Schwann cell transplant contributed to the normal development of visual response properties in the visual cortex, compensating for a complete absence of visual experience.
Vulnerability of Midbrain Dopaminergic Neurons in Calbindin‐D28k‐deficient Mice: Lack of Evidence for a Neuroprotective Role of Endogenous Calbindin in MPTPtreated and Weaver Mice
Authors: Airaksinen Matti S. , Thoenen Hans , Meyer Michael
Published: April 2006

Calbindin‐D28k (calbindin) is an intracellular calcium binding protein of unknown in vivo function. It is abundantly expressed in many populations of neurons, and it can, presumably by buffering calcium overload, protect cells against excitotoxic damage. In the midbrain, calbindin is preferentially expressed in those dopamine neurons which are spared from degeneration in Parkinson's disease and its animal models. Whether calbindin itself determines neuronal vulnerability is questioned in other lesion models where calbindin expression is not positively correlated with neuronal resistance. To study the possible neuroprotective role of calbindin in vivo, we generated calbindin‐deficient mice by gene targeting and assessed the viability of midbrain dopamine neurons in both a chemical and a genetic lesion paradigm. Tyrosine hydroxylase‐immunoreactive neurons were counted in calbindin null‐mutant mice treated with the neurotoxin 1 ‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) and in a calbindin‐deficient weaver strain (homozygous for weaver and the calbindin null mutation). The extent and pattern of neuron loss observed in MPTP‐treated wild‐type and homozygous weaver mice were as previously described. Surprisingly, no significant differences were observed between MPTP‐treated calbindin null mutants and their wild‐type littermates, or between calbindin‐weaver double mutant mice and weaver mice. Thus, in all four groups the same subpopulation of tyrosine hydroxylase‐positive midbrain neurons (i.e. those normally containing calbindin) were preferentially spared. Calretinin, a closely related calcium‐binding protein, which is also expressed in some midbrain dopamine neurons, was not up‐regulated in these surviving neurons. These findings indicate that the resistance of calbindin‐containing neurons in the MPTP and weaver models is not causally related to the expression of calbindin, and that endogenous calbindin is not required for protection of these neurons.
Locatization of Voltaae‐sensitive Ca2+ Fluxes and Neuropeptide Y Immunoreactivity to Varicosities in SH‐SY5Y Human Neuroblastoma Cells Differentiated by Treatment with the Protein Kinase Inhibitor Staurosporine
Authors: Kukkonen Jyrki P. , Shariatmadari Ramin , Courtney Michael J. , Akerman Karl E. O.
Published: April 2006

The distribution of voltage‐sensitive elevations of the level of Ca2+ in untreated SH‐SY5Y cells and cells that had been induced to differentiate with staurosporine was investigated by monitoring fura‐2 fluorescence in cell suspensions, and by using microfluorometry and quantitative fluorescence imaging on cell bodies and on cellular processes. Cell bodies of both types of cells displayed small Ca2+ elevations, which were composed of transient and sustained components. Elevations were partially sensitive to the L‐ and N‐channel blockers nifedipine (1 μM) and ω‐conotoxin GVIA (100 nM) respectively. Up to ten times higher Ca2+ elevations were observed in varicosities of treated cells than in cell bodies of treated and untreated cells. These elevations were insensitive to compounds known to release Ca2+ from intracellular stores. Elevations of Ca2+ were sustained, and they were insensitive to 5 pM nifedipine, 100 nM ω‐agatoxin IVA and 100 nM ω‐conotoxin GVIA, and partially sensitive to 2 pM ω‐conotoxin GVIA, indicating predominance of non‐L‐type, non‐N‐type, non‐P‐type channel activity. The intracellular localization of neuropeptide Y, a marker of differentiation in these cells, was also investigated by fluorescence immunocytochemistry. Varicosities of treated cells displayed marked fluorescence when viewed in a confocal microscope. These findings show that the varicosities of staurosporine‐treated cells exhibit some of the functional properties of nerve terminals. The varicosities resemble boutons en passant nerve endings and they seem to express Ca2+ channels different from those in the cell body.
AL‐1‐induced Growth Cone Collapse of Rat Cortical Neurons is Correlated with REK7 Expression and Rearrangement of the Actin Cytoskeleton
Authors: Meima Leonie , Kljavin Ivar J. , Moran Paul , Shih Ai , Winslow John W. , Caras Ingrid W.
Published: April 2006

Previous experiments identified AL‐1 as a glycosylphosphatidylinositol (GPI)‐linked ligand for the Eph‐related receptor, REK7, and showed that a REK7‐IgG fusion protein blocks axon bundling in co‐cultures of cortical neurons on astrocytes, suggesting a role for REK7 and AL‐1 in axon fasciculation. Subsequent identification of RAGS, the chick homologue of AL‐1, as a repellent axon guidance molecule in the developing chick visual system led to speculation that AL‐1, expressed on astrocytes, provides a repellent stimulus for cortical axons, inducing them to bundle as an avoidance mechanism. Using a growth cone collapse assay to test this hypothesis, we show that a soluble AL‐1‐IgG fusion protein is a potent collapsing factor for embryonic rat cortical neurons. The response is strongly correlated with REK7 expression, implicating REK7 as a receptor mediating AL‐1‐induced collapse. Morphological collapse is preceded by an AL‐1‐IgG‐induced reorganization of the actin cytoskeleton that resembles the effects of cytochalasin D. This suggests a pathway whereby REK7 activation by AL‐1 leads to perturbation of the actin cytoskeleton, possibly by an effect on actin polymerization, followed by growth cone collapse. We further show that AL‐1‐IgG causes collapse of rat hippocampal neurons and rat retinal ganglion cells. These data suggest a role for REK7 and AL‐1 in the patterning of axonal connections in the developing cortex, hippocampus and visual system.
Cytochemical Evidence for Nitric Oxide/Cyclic GMP Signal Transmission in the Visual System of the Locust
Authors: Bicker Gerd , Schmachtenberg Oliver
Published: April 2006

Nitric oxide is a membrane‐permeant messenger molecule which activates soluble guanylyl cyclase. Using NADPH diaphorase staining as a marker for the enzyme nitric oxide synthase and an antiserum against cyclic GMP (cGMP), we investigated the possible sites of nitric oxide and cGMP synthesis in the retina and lamina of Schisfocerca gregaria. The photoreceptor cells did not express NADPH diaphorase staining but monopolar cells of the lamina were strongly stained. After inhibition of phosphodiesterase activity and incubation of tissue in a nitric oxide donor, the photoreceptor cells showed cGMP immunoreactivity. In contrast to the photoreceptors, the monopolar cells of the lamina were not stained. Since the presynaptic photoreceptors were cGMP‐immunoreactive and the postsynaptic targets of the monopolar cells did not express immunoreactivity, it is conceivable that nitric oxide released by monopolar cells may play a role as a retrograde messenger in visual information processing.
Nociceptin/Orphanin FQ Microinjected into Hippocampus Impairs Spatial Learning in Rats
Authors: Sandin Johan , Georgieva Jeanette , Schött Pär A. , Ögren Sven O. , Terenius Lars
Published: April 2006

The newly discovered peptide nociceptin/orphanin FQ has been found to increase reactivity to pain and to influence locomotor activity after intracerebroventricular administration. This study investigated the possible role of hippocampal nociceptin/orphanin FQ in spatial learning and in spontaneous locomotion. Male rats were trained in the Morris water task after microinjection of 10 nmol nociceptin/orphanin FQ or artificial cerebrospinal fluid (as control) into the CA3 region of the dorsal hippocampus. Nociceptin/orphanin FQ was found to severely impair spatial learning without interfering with swimming performance. Itrahippocampal injection of nociceptin/orphanin FQ markedly decreased exploratory locomotor activity including vertical movements (rearing). The data suggest that nociceptin/orphanin FQ is a potent modulator of synaptic plasticity within the hippocampus.
Regulation of NMDA Receptor Subunit mRNA Expression in the Guinea Pig Vestibular Nuclei Following Unilateral Labyrinthectomy
Authors: Sans Nathalie , Sans Alain , Raymond Jacqueline
Published: April 2006

The localization of neurons expressing mRNAs for the NRI and NR2A‐D subunits of the glutamatergic NMDA receptor was examined by non‐radioactive in situ hybridization throughout the guinea pig vestibular nuclei. After deafferentation of the vestibular nuclei by unilateral labyrinthectomy, modifications of the mRNA distributions were followed for 30 days. A quantitative analysis was performed in the medial vestibular nucleus by comparison of the labelled neurons in the ipsi‐ and contra‐lateral nuclei. In vestibular nuclei, the NR1 subunit mRNA was found in various populations of neurons. The NR2A and NR2C subunit mRNAs were less widely distributed, whereas little NR2D mRNA was detected and only rare cells contained NR2B mRNA. NRI and NR2A‐D mRNAs were colocalized in some but not other neuronal types. Twenty hours after the lesion, there was a transient ipsilateral increase of NR1 mRNA level in the medial vestibular nucleus, followed by a decrease 48 h after the lesion and, at 3 days, by recovery to the control level. An ipsilateral increase in the mRNA level of NR2C subunit was detected 20 h after lesion and maintained at 48 h. No significant changes were apparent in NR2A, NR2B and NR2D mRNA levels. The distributions and the differential signal intensities of NR2A‐D mRNAs suggest various subunit organizations of the NMDA receptors in different neurons of the vestibular nuclei. Neuronal plasticity reorganizations in the vestibular nuclei following unilateral labyrinthectomy appear to include only changes in NR1 and NR2C mRNA levels modifying the functional diversity of the NMDA receptor in the ipsilateral medial vestibular nucleus neurons. The transient changes in NRI and the NR2C subunit mRNA expressions in response to sensory deprivation are consistent with an active role for NMDA receptors in the appearance and development of the vestibular compensatory process.
Quantitative Autoradiographic Analysis of lonotropic Glutamate Receptor Subtypes in Human Temporal Lobe Epilepsy: Up‐regulation in Reorganized Epileptogenic Hippocampus
Authors: Brines Michael L. , Sundaresan Sanjoy , Spencer Dennis D. , de Lanerolle Nihal C.
Published: April 2006

Medically intractable temporal lobe epilepsy is a common disease typically associated with hippocampal damage (sclerosis) and synaptic remodelling. These changes could include increased glutamate receptor expression, enhancing excitability and the potential for neuronal injury. We directly assessed this hypothesis using quantitativein vitroreceptor autoradiography to determine the densities of glutamate‐, NMDA‐, quisqualateh‐amino‐3‐hydroxy‐5‐methyl‐isoxazoleproprionic acid (AMPA)‐ and kainic acid‐preferring binding sites in surgically removed hippocampi from patients with mesial temporal lobe epilepsy (sclerosis; MTLE) and patients with mass‐associated temporal lobe epilepsy (no sclerosis: MaTLE), compared with autopsy material. Neuronal cell counts andin situtotal protein densities were also obtained. In general, MaTLE and autopsy binding densities were indistinguishable. In contrast, some regions of MTLE hippocampi exhibited decreased receptor densities, with a corresponding loss of protein. In the hilus and CA1, however, ligand binding densities did not differ from the comparison groups in spite of markedly reduced protein content, consistent with increased glutamate receptor density. Kainate‐preferring sites were distributed differently from the other glutamate subtypes and were uniformly decreased throughout the MTLE hippocampus, except for a unique expression within the outer dentate molecular layer. Along with increased NMDA and AMPA receptor densities in the hilus and CA1, this distinctive population of kainate receptors establishes that increased glutamate receptor expression is a feature of the remodelled MTLE hippocampus. These observations suggest that enhanced sensitivity to glutamate may be an important element in the pathophysiology of temporal lobe epilepsy.
Severe Sensory Deficits but Normal CNS Development in Newborn Mice Lacking TrkB and TrkC Tyrosine Protein Kinase Receptors
Authors: Silos‐Santiago Inmaculada , Fagan Anne M. , Garber Melinda , Fritzsch Bernd , Barbacid Mariano
Published: April 2006

Analysis of mice carrying targeted mutations in genes encoding neurotrophins and their signalling Trk receptors has provided critical information regarding the role that these molecules play in the mammalian nervous system. In this study we generated mice defective in both TrkB and TrkC tyrosine kinase receptors to determine the biological effects of these receptors in the absence of compensatory mechanisms. trkB(–/–);trkC(–/–) double‐mutant mice were born at the expected frequency, indicating that TrkB and TrkC signalling are not required for embryonic survival. However, these double‐mutant mice had a significantly shorter lifespan and displayed more severe sensory defects than their single‐mutant trkB(–/–) and trkC(–/–) littermates. The most dramatic sensory deficit observed in trkB(–/–); trKC(–/–) mutant mice was the absence of vestibular and cochlear ganglia. Interestingly, these mice developed inner ear sensory epithelia in spite of the complete absence of sensory innervation. Analysis of the CNS in trkB(–/–); trkC(–/–) mutant mice revealed a well formed hippocampus, cortex and thalamus. Moreover, the pattern of expression of several neuronal markers appeared normal in these animals. These observations suggest that neurotrophin signalling through TrkB and TrkC receptors is essential for the development of sensory ganglia: however, it does not play a major role in the differentiation and survival of CNS neurons during embryonic development.
Contribution of Blockade of the Noradrenaline Carrier to the Increase of Extracellular Dopamine in the Rat Prefrontal Cortex by Amphetamine and Cocaine
Authors: Tanda Gianluigi , Pontieri Francesco E. , Frau Roberto , Di Chiara Gaetano
Published: April 2006

This study was performed to investigate the relative role of noradrenaline (NA) and dopamine (DA) carrier blockade in the effects of psychostimulants on DA transmission in the rat prefrontal cortex (PFCX). To this end, changes of extracellular DA and NA in the PFCX and of extracellular DA in the nucleus accumbens (NAc) were measured following the administration of amphetamine and cocaine, which are known to bind to both DA and NA carriers, or GBR 12909, a selective DA carrier blocker. After non‐intravenous injection, amphetamine (0.25 and 0.5 mg/kg, s.c.) and cocaine (5 and 10 mg/kg, i.p.) increased extracellular DA in the PFCX to a larger extent than in the NAc, while the reverse applied to GBR 12909 (2.5 and 5 mg/kg, i.p.). These differences were obtained in spite of the fact that the three drugs elicited at each dose level a similar peak increase of extracellular DA in the NAc. Amphetamine and cocaine also increased extracellular NA in the PFCX and this effect was quantitatively similar to that on extracellular DA in the same area. Intravenous doses of cocaine and GBR 12909, corresponding to those which maintain self‐administration in the rat, while equieffective in raising extracellular DA in the NAG, had different effects on extracellular DA in the PFCX. In fact, in contrast to cocaine, GBR 12909 increased extracellular DA in the PFCX to a lesser extent than in the NAc or did not modify it at all. The peak increase of extracellular DA in the PFCX was highly correlated to that of NA in the same area but was poorly correlated to the increase of extracellular DA in the NAc. These results suggest that amphetamine and cocaine increase extracellular DA in the PFCX largely through the blockade of the NA carrier. Direct evidence for this hypothesis was provided by the observation that, when the NA carrier was blocked by reverse dialysis of the PFCX with desipramine (1 μM), cocaine and GBR 12909 lost their differences in the ability to increase extracellular DA in the PFCX.
In Vivo Regulation of Amyloid Precursor Protein Secretion in Rat Neocortex by Cholinergic Activity
Authors: Rossner Steffen , Ueberham Uwe , Yu Juan , Kirazov Ludmil , Schliebs Reinhard , Perez‐Polo J. Regino , Bigl Volker
Published: April 2006

The proteolytic cleavage of the amyloid precursor protein (APP) has been shown to be modulated through specific muscarinic receptor activation in vitro in both transfected cell lines and native brain slices, whereas a demonstration of receptor‐mediated control of APP processing under in vivo conditions is still lacking. To simulate alterations in muscarinic receptor stimulation in vivo, we have (i) specifically reduced the cortical cholinergic innervation in rats using partial immunolesions with 192lgG–saporin, and (ii) restored cholinergic function in lesioned rats by transplantation of nerve growth factor producing fibroblasts. While total APP levels in cortical homogenates were unaffected by cholinergic deafferentation, we observed a significant reduction in the abundance of secreted APP and a concomitant increase in membrane‐bound APP. These changes were reversed in immunolesioned rats with nerve growth factor‐producing fibroblasts. There was a strong positive correlation between the ratio of secreted APP to membrane‐bound APP and the activity of choline acetyltransferase and M1 muscarinic acetylcholine receptor density (measured by [3H]pirenzepine binding) in experimental groups. Additionally, we observed a transient decrease in the ratio of cortical APP transcripts containing the Kunitz protease inhibitor domain (APP 770 and APP 751) versus APP 695 in rats with cholinergic hypoactivity. The data presented suggest that cortical APP processing is under basal forebrain cholinergic control, presumably mediated through M1 muscarinic acetylcholine receptors on cholinoceptive cortical target cells.
Neuropeptide Y and the Calcitonin Gene‐related Peptide Attenuate Learning Impairments Induced by MK‐801 via a Sigma Receptor‐related mechanism
Authors: Bouchard Pascale , Maurice Tangui , St‐Pierre Serge , Privat Alain , Quirion Rémi
Published: April 2006

It has been shown recently that low doses of sigma (σ) receptor ligands like 1,3‐di‐(2‐tolyl)guanidine (DTG), (+)N‐allylnormetazocine [(+)SKF 10 047] and (+)pentazocine can antagonize learning impairments induced by dizocilpine (MK‐801), a non‐competitive antagonist at the NMDA receptor channel. This antagonism has been proposed to involve σ receptor sites since it is blocked by the administration of purported o antagonists such as NE‐100 and BMY‐14802. It has also been demonstrated that peptides of the neuropeptide Y (NPY) and calcitonin gene‐related peptide (CGRP) families modulate, in vivo, é labelling and electrophysiological effects in the hippocampal formation. Accordingly, we investigated if NPY‐ and CGRP‐related peptides modulate cognitive processes by interacting with σ sites in mice. In order to test this hypothesis, a step‐down passive avoidance task was used. Interestingly, similarly to various σ agonists, NPY, peptide YY (PYY) and the Y1 agonist [Leu31Pro34]NPY (but not NPY13–36, a purported Y2 agonist), as well as hCGRPα and the purported CGRP2 agonist [CyS(ACM)2–7]hCGRPα (but not CGRP8–37, a CGRP1 receptor antagonist), significantly attenuated learning impairments induced by MK‐801. Furthermore, the effects of NPY, [Leu31 Pro34]NPY, hCGRPα and [CYS(ACM)2–7]hCGRPα were blocked by the administration of the σ antagonist, BMY‐14802. The present data suggest that NPY‐ and CGRP‐related peptides can indirectly interact in vivo with σ receptors to modulate cognitive processes associated with NMDA receptor function.
TrkA Expression Levels of Sympathetic Neurons Correlate with NGF‐dependent Survival During Development and After Treatment with Retinoic Acid
Authors: Holst Alexander V. , Lefcort Frances , Rohrer Hermann
Published: April 2006

Sympathetic neurons depend on the classical neurotrophin nerve growth factor (NGF) for survival by the time they innervate their targets, but not before. The acquisition of NGF responsiveness is thought to be controlled by environmental cues in sympathetic neurons. We have investigated the expression of the signal transducing NGF receptor trkA on mRNA and protein level during development of chick sympathetic neurons obtained from lumbosacral, paravertebral chain ganglia between embryonic days (E) 6.5 and 10. We demonstrate that trkA mRNA levels increase between E6.5 and E10, whereas the levels of trkC and p75 do not change. We also observed a similar increase in trkA protein during this time period. This increase correlates with the increase in NGF‐dependent survival of sympathetic neurons from the corresponding stages in vitro. To define the correlation between trkA expression and NGF‐mediated survival in more detail, trkA expression was adjusted to different levels by treatment with increasing concentrations of retinoic acid. We observed that small changes of trkA mRNA expression levels, below one order of magnitude, are decisive for the ability of immature sympathetic neurons to survive in the presence of NGF. A small and transient increase in trkA mRNA expression was also elicited in vivo by application of retinoids. These data provide evidence that sympathetic neurons upregulate the NGF receptor trkA and in this way acquire NGF‐dependency.
ω‐Agatoxin IVA, a P‐Type Calcium Channel Antagonist, Reduces Nociceptive Processing in Spinal Cord Neurons with Input From the Inflamed But Not From the Normal Knee Joint — An Electrophysiological Study in the Rat In Vivo
Authors: Nebe J. , Vanegas H. , Neugebauer V. , Schaible H.‐G.
Published: April 2006

High threshold voltage‐dependent P‐ and Q‐type calcium channels are involved in neurotransmitter release. In order to investigate the role of P‐ and Q‐type calcium channels in the mechanosensory (nociceptive) processing in the spinal cord, their participation in the responses of spinal wide‐dynamic‐range neurons to innocuous and noxious mechanical stimulation of the knee and ankle joints was studied in 30 anaesthetized rats. The knee was either normal or acutely inflamed by kaolin/carrageenan. During the topical application of ω‐agatoxin IVA (P‐type channel antagonist, 0.1 μM) onto the dorsal surface of the spinal cord, the responses to innocuous and noxious pressure applied to the normal knee were increased to respectively 124 ± 42% and 114 ± 23% of predrug values (mean ± SD, P < 0.05, 14 neurons). By contrast, in rats with an inflamed knee, the responses to innocuous and noxious pressure applied to the knee were reduced to respectively 72 ± 19 and 73 ± 22% of baseline (mean ± SD, P < 0.01, 13 neurons). In the same neurons, ω‐agatoxin IVA slightly increased the responses to pressure on the non‐inflamed ankle whether the knee was normal or inflamed. Thus P‐type calcium channels seem to acquire a predominant importance in the excitation of spinal cord neurons by mechanosensory input from inflamed tissue and hence in the generation of inflammatory pain. By contrast, the Q‐type channel antagonist, ω‐conotoxin MVllC (1 or 100 μM), had no significant effect upon responses to innocuous or noxious pressure applied to either normal or inflamed knees (25 neurons).
AMPA Receptors in Cultured Vestibular Ganglion Neurons: Detection and Activation
Authors: Rabejac Denis , Devau Gina , Raymond Jacqueline
Published: April 2006

The presence and the activity of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) glutamate receptors were investigated in mouse cultured vestibular ganglion neurons using immunocytochemistry and measurement of intracellular calcium concentration ([Ca2+],) by spectrofluorimetry. Cultures of dissociated vestibular ganglia from 18 gestation day mouse embryos were grown in vitro for 3–4 days. lmmunocytochemical labelling of AMPA receptor subunits GluR2/R3 and GluR4 was detected in neuron cell bodies and proximal neurites and more lightly in glial cells. There was no clear selective subcellular localization of the different subunits. For the GluR1 subunit a signal was observed only in some neurons and neurites and was weak. Vestibular ganglion neurons responded to fast application of 1 mM glutamate and 10 mM aspartate through unknown receptors by a transient increase in [Ca2+]i. The mean amplitude of this rapid increase was about nine times the resting level and recovery was complete within 30–45 s after the application. If separated by an interval of at least 10 min, consecutive applications produced similar calcium responses. AMPA (1 mM) application induced the same type of responses. Five minutes prior to the AMPA exposure, the application of a specific AMPA antagonist, 6, 7‐dinitroquinoxaline‐2, 3‐dione (DNQX, 1.5 mM), in the external medium inhibited the response to AMPA. Chelation of external calcium by EGTA (1.5 mM) abolished the responses to drug applications, indicating that an influx of external calcium is involved in the [Ca2+]i increase. These observations suggest that heteromeric AMPA receptors are expressed in vestibular ganglion neurons in culture and play a functional role in their glutamate‐induced depolarization. Experiments are in progress using specific AMPA and NMDA antagonists to characterize the participation of the two types of ionotropic glutamate receptors in the glutarnate/aspartate‐induced intracellular calcium response.
Effects of Inferior Temporal Lesions on Two Types of Orientation Discrimination in the Macaque Monkey
Authors: Vogels Rufin , Saunders Richard C. , Orban Guy A.
Published: April 2006

Rhesus monkeys with transection of the forebrain commissures were trained in two different tasks in which grating orientation was the discriminandum. In the temporal same—different task, the monkeys had to judge whether or not two successively presented gratings differed in orientation. In the identification task, we measured how well the monkey could judge the orientation of the grating. The performance in any task was affected neither by a unilateral anterior temporal cortical area lesion nor by a subsequent posterior temporal cortical area lesion in the same hemisphere resulting in a two‐stage inferior temporal (IT) lesion. However, a single stage IT (combined anterior and posterior temporal cortical areas) lesion of the other hemisphere severely disrupted the performance in the temporal same‐different task, but only barely increased just noticeable differences in orientation in the identification task. This indicates that the impairment in a temporal comparison task after an IT lesion is not due to a perceptual coding deficit, but is related to the temporal comparison per se. Thus, IT is involved in the temporal comparison of successively presented stimuli. On the other hand, the two IT lesions, each having a different history (single versus two stage) had dramatically different behavioural effects, suggesting an important role for adult brain plasticity in determining the behavioural outcome of a brain lesion.
Human Brain Activity Related to Orientation Discrimination Tasks
Authors: Orban Guy A. , Dupont Patrick , Vogels Rufin , Bormans Guy , Mortelmans Luc
Published: April 2006

In order to relate regional activity in the human brain to the different components of discrimination tasks, we compared regional cerebral blood flow, measured with positron emission tomography, under four conditions: successive orientation discrimination, orientation identification, detection and passive viewing. By adding successive discrimination and passive viewing at a second, lower rate we were able to investigate the main effects and interaction between task and presentation rate. Four occipital regions—the posterior calcarine region bilaterally, the right lingual gyrus and the right inferior occipital cortex‐displayed a main effect of presentation rate. Two regions—a right posterolateral occipital region and a right posterior fusiform region—displayed a significant main effect of task. The involvement of this posterior fusiform region in successive discrimination was also revealed by the subtraction of detection from successive discrimination, as was that of the right middle fusiform gyrus. Finally, a more anterior right middle fusiform region was differentially active in successive discrimination compared to identification, suggesting that activity in this region is related to the temporal comparison of orientation.
Positive Correlations Between Cerebral Protein Synthesis Rates and Deep Sleep in Macaca mulatta
Authors: Nakanishi Hajime , Sun Yun , Nakamura Richard K. , Mori Kentaro , Ito Masanori , Suda Sumio , Namba Hiroki , Storch Fredric I. , Dang Thao P. , Mendelson Wallace , Mishkin Mortimer , Kennedy Charles , Gillin J. Christian , Smith Carolyn Beebe , Sokoloff Louis
Published: April 2006

Local rates of cerebral protein synthesis (ICPSleu), were determined with the autoradiographic L‐[1‐14C]leucine method in seven awake and seven asleep, adult rhesus monkeys conditioned to sleep in a restraining chair in a darkened, ventilated chamber while EEG, EOG, and EMG were monitored. Prior to the period of measurement all animals slept for 1–4 h. Controls were awakened after at least one period of rapid‐eye‐movement (REM) sleep. Experimental animals were allowed to remain asleep, and they exhibited non‐REM sleep for 71–99% of the experimental period. Statistically significant differences in ICPSleu between control and experimental animals were found in four of the 57 regions of brain examined, but these effects may have occurred by chance. In the sleeping animals, however, correlations between ICPSleu, and percent time in deep sleep were positive in all regions and were statistically significant (P≤ 0.05) in 35 of the regions. When time in deep sleep was weighted for the integrated specific activity of leucine in grey matter, positive correlations were statistically significant (P≤ 0.05) in 18 regions in the experimental animals. These results suggest that rates of protein synthesis are increased in many regions of the brain during deep sleep compared with light sleep.
Activation of the GABAA Receptor Inhibits the Proliferative Effects of bFGF in Cortical Progenitor Cells
Authors: Antonopoulos J. , Pappas I. S. , Parnavelas J. G.
Published: April 2006

Recent studies have localized γ‐aminobutyric acid (GABA)‐containing neurons and identified cells that express subunits of the GABAA receptor in the proliferative zone of the developing cerebral cortex and have demonstrated a role for GABA in cortical neurogenesis. We examined here the interactions between a number of neurotrophic factors, known to be involved in cortical cell proliferation and differentiation, and the GABAergic system (GABA and GABAA receptors) in the regulation of cell production in dissociated cortical cell cultures. We found that basic fibroblast growth factor (bFGF) increased the number of cells labelled for the α1 subunit of the GABAA receptor but not for the α2, α3 or α5 subunits. The α1 subunit was expressed by the majority of proliferating neuroepithelial cells as well as by differentiated neurons. We also found that activation of the GABAA receptor by GABA or muscimol inhibited the proliferative effects of bFGF on cortical progenitors, leading to an increased number of differentiated neurons. These results suggest that bFGF stimulates cell proliferation and GABAA receptor expression in cultured progenitor cells of the developing neocortex, and that GABA regulates cell production by providing a feedback signal that terminates cell division.
The Effects of Light Reversals on Photoreceptor Synaptogenesis in the Fly Musca domestica
Authors: Rybak J. , Meinertzhagen I. A.
Published: April 2006

The short‐term influence of visual experience was studied in the first‐order tetrad synapses of the first optic neuropil, or lamina, underlying the compound eye in the housefly (Musca domestica). We report the effects of single light reversals, in which flies reared in constant darkness were exposed to light or those in constant light were exposed to darkness, on this defined population of synapses. The synaptic population was characterized by quantitative electron microscopic methods using three parameters: (i) the number of synaptic contacts per photoreceptor terminal; (ii) the size of these synapses, given by the mean platform width of their presynaptic ribbons; and (iii) the proportion (up to ˜20%) of small synapses—those having a ribbon platform less than 0.17 μm wide. The effects of light exposures in'flies reared in constant darkness include decreased mean synaptic size and increased numbers of synapses. These effects are seen in flies of all ages (to 10 days). Long light exposures (2–6 h) are much less effective than short exposures (down to 20 s), with maximum effects obtained at 15 min (up to 45% more synapses). Small synapses are reasoned to be new junctions formed only recently; the decreased mean synaptic size and the increased number of synapses seen after short light exposures are both interpreted to result from a recent burst of synaptogenesis in the adult lamina. The effects of dark exposure in flies reared in constant light are the reciprocal of those seen in dark‐reared flies exposed to light, but they are less pronounced. Although the function of such changes is not yet known, they may form part of the light adaptation mechanism of the photoreceptor, and occur along with a redistribution of other organelles involving membrane invaginations into its terminal. These changes occur against a background trend for control flies reared under constant conditions to have fewer, larger synapses with increasing age up to 10 days, an effect that is most pronounced in constant darkness, when synaptic number decreases by 21% and size increases by 13%.