bluuebunny/crossref_metadata_2025 huggingface dataset:
The mouse Ptprr gene encodes two protein tyrosine phosphatases, PTP‐SL and PTPBR7, that display distinct patterns of expression during neural development
Authors: Van Den Maagdenberg A. M. J. M. , Bächner D. , Schepens J. T. G. , Peters W. , Fransen J. A. M. , Wieringa B. , Hendriks W. J. A. J.
Published: March 2003

The protein tyrosine phosphatases PTP‐SL and PTPBR7 differ only in the length of their N‐terminal domain. We show here that PTP‐SL and PTPBR7 are isoforms derived from a single gene (Ptprr) through developmentally regulated use of alternative promoters. Isoform‐specific reverse transcriptase‐polymer chain reaction (RT‐PCR) and RNA in situ hybridization experiments reveal that PTPBR7 is expressed during early embryogenesis in spinal ganglia cells as well as in developing Purkinje cells. Post‐natally, PTPBR7 is expressed in various regions of the adult mouse brain, but expression in Purkinje cells has ceased and is replaced by the PTP‐SL‐specific transcript. In transient transfection experiments it is confirmed that PTPBR7 is a type I transmembrane protein tyrosine phosphatase (PTPase). PTP‐SL, however, appears to be a cytosolic membrane‐associated PTPase that is located at perinuclear vesicular structures that partly belong to the endosomal compartment. Thus, during maturation of Purkinje cells, a gene‐promoter switch results in the replacement of a receptor‐type PTPase by a cytosolic vesicle‐associated isoform.
Astroglia inhibit the proliferation of neocortical cells and prevent the generation of small GABAergic neurons in vitro
Authors: De Lima Ana D. , Voigt Thomas
Published: March 2003

We quantitatively studied the dynamics of rat neocortical precursor proliferation in vitro, and additionally examined the effects of neuron–glia interactions on the proliferation and differentiation of neurons, and particularly of γ‐aminobutyric acid (GABA)‐containing cells. In cultures grown on glia‐free substrate, cellular proliferation was detected at least until the end of the second week in vitro, but most neurons which expressed detectable amounts of microtubule‐associated protein at 12 days in vitro were generated early during the first week. Further double‐labelling experiments, combining 5′‐bromo‐2′‐deoxyuridine with GABA or β‐tubulin III immunohistochemistry, provided direct evidence that neuronal proliferation continued through the second week in vitro, and that a population of small GABAergic neurons was generated between 3 and 12 days in vitro. Culturing cells on a glial substrate significantly reduced the generation of small GABAergic cells and strongly inhibited the total cell proliferation. Inhibition also occurred if astrocytes were added to the culture after 6 days in vitro, but was significantly decreased if cells were grown on a fixed glial substrate, suggesting that the effect might be at least partially mediated by active interactions between neurons and glia. In conclusion, our results show that the sustained proliferation of precursor cells in neocortical cultures is necessary for the differentiation of small GABAergic neurons, and that mature astroglia effectively inhibit the proliferation of neocortical precursors thereby affecting the appearance of a population of GABAergic cells.
Neuronal correlates of real and illusory contour perception: functional anatomy with PET
Authors: Larsson Jonas , Amunts Katrin , Gulyás Balázs , Malikovic Aleksandar , Zilles Karl , Roland Per E.
Published: March 2003

Illusory contours provide a striking example of the visual system's ability to extract a meaningful representation of the surroundings from fragmented visual stimuli. Psychophysical and neurophysiological data suggest that illusory contours are processed in early visual cortical areas, and neuroimaging studies in humans have shown that Kanizsa‐type illusory contours activate early retinotopic visual areas that are also activated by real contours. It is not known whether other types of illusory contours are processed by the same mechanisms, nor is it clear to what extent attentional effects may have influenced these results, as no attempt was made to match the salience of real and illusory stimuli in previous imaging studies. It therefore remains an open question whether there are any brain regions specifically involved in the perception of illusory contours. To address these questions, we have used 15O‐butanol positron emission tomography (PET) and a novel kind of illusory contour stimulus that is induced only by aligned line ends. By employing a form discrimination task that was matched for attention and stimulus salience across conditions we were able to directly contrast perception of real and illusory contours. We found that the regions activated by illusory contour perception were the same as those activated by real contours. Only one region, located in the right fusiform gyrus, was significantly more strongly activated by perception of illusory contours than by real contours. In addition, a principal component analysis suggested that illusory contour perception is associated with a change in the correlation between V1 and V2. We conclude that different kinds of illusory contours are processed by the same cortical regions and that these regions overlap extensively with those involved in processing of real contours. At the regional level, perception of illusory contours thus appears to differ from perception of real contours by the degree of involvement of higher visual areas as well as by the nature of interaction between early visual areas.
3‐Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum
Authors: Guidetti Paolo , Schwarcz Robert
Published: March 2003

l‐3‐Hydroxykynurenine (L‐3‐HK) and quinolinate (QUIN) are two metabolites of the kynurenine pathway, the major route of tryptophan degradation in mammals. L‐3‐HK is a known generator of highly reactive free radicals, whereas QUIN is an endogenous excitotoxin acting specifically at N‐methyl‐d‐aspartate (NMDA) receptors. This study was designed to examine possible synergistic interactions between L‐3‐HK and QUIN in the rat brain in vivo. Intrastriatal coinjection of 5 nmol L‐3‐HK and 15 nmol QUIN, i.e. doses which caused no or minimal neurodegeneration on their own, resulted in substantial neuronal loss, determined both behaviourally (apomorphine‐induced rotations) and histologically (quantitative assessment of lesion size). The excitotoxic nature of the lesion was verified by tyrosine hydroxylase immunohistochemistry, showing the survival of dopaminergic striatal afferents. There was also a relative sparing of large striatal neurons, and neurodegeneration was prevented both by NMDA receptor blockade (using CGP 40116) and free radical scavenging [using N‐tert‐butyl‐α‐(2‐sulphophenyl)‐nitrone, S‐PBN]. The pro‐excitotoxic features of L‐3‐HK were especially pronounced at low QUIN doses and were not observed when QUIN was substituted by NMDA. Notably, the effect of L‐3‐HK was not due to its intracerebral conversion to QUIN and was duplicated by equimolar D,L‐3‐HK. These data indicate that an elevation of L‐3‐HK levels constitutes a significant hazard in situations of excitotoxic injury. Pharmacological interventions aimed at decreasing L‐3‐HK formation may therefore be particularly useful for the treatment of neurological diseases which are associated with an abnormally enhanced flux through the kynurenine pathway.
Time‐dependent induction of depotentiation in the dentate gyrus of freely moving rats: involvement of group 2 metabotropic glutamate receptors
Authors: Kulla Alexander , Reymann Klaus G. , Manahan‐Vaughan Denise
Published: March 2003

Depotentiation comprises a reversal of tetanization‐induced long‐term potentiation (LTP) which occurs following low‐frequency stimulation (LFS) in the hippocampus in vivo. Although depotentiation has been consistently demonstrated in the CA1 region, no positive reports of the existence of depotentiation in the dentate gyrus in vivo have occurred. This study therefore investigated whether depotentiation is possible in the dentate gyrus in vivo. We found that depotentiation can be induced, but it is very tightly dependent on the interval between tetanization and LFS. Thus, LFS given 2 or 5 min following tetanization produced significant depotentiation, whereas LFS given 10–30 min following tetanization had no significant effect on the expression of LTP. Depotentiation occurred in two phases: a transient depression of evoked responses to below pre‐tetanization values, which occurred in the first 60 min following LFS, and a recovery of this response to a stable level of synaptic transmission which comprised a significant reduction in the magnitude of LTP. Group 2 metabotropic glutamate receptors (mGluRs) play an important role in the expression of long‐term depression in vivo. We therefore investigated whether group 2 mGluRs contribute to depotentiation. The group 2 antagonist (2S)‐α‐ethylglutamic acid (EGLU) inhibited the early transient depression at a concentration which inhibits LTD in vivo, but did not block the expression of depotentiation. EGLU also inhibited the transient depression induced by 5 Hz given alone. Increasing the concentration of EGLU prevented depotentiation, however. The group 2 agonist (S)‐4‐carboxy‐3‐hydroxyphenyl‐ glycine (4C3HPG) inhibited LTP and enhanced depotentiation. These data suggest a role for group 2 mGluRs in depotentiation.
Proliferation of microglia and astrocytes in the dentate gyrus following entorhinal cortex lesion: a quantitative bromodeoxyuridine‐labelling study
Authors: Hailer Nils P. , Grampp Anne , Nitsch Robert
Published: March 2003

Entorhinal cortex lesion of adult rats induces glial activation and proliferation in the deafferented dentate molecular layer. Double‐labelling immunocytochemistry for the astrocyte‐specific antigen glial fibrillary acidic protein or the microglial cell marker Griffonia simplicifolia isolectin B4 with bromodeoxyuridine detection revealed that microglia counts and the proliferation rate in the ipsilateral dentate gyrus reached a maximum in the molecular layer at 3 days post‐lesion (dpl) and returned to control levels by 30 dpl. Astrocyte counts in the ipsilateral dentate gyrus peaked at 30 dpl, with maximum proliferation at 7 dpl. At 100 dpl the astrocyte count had reverted to control levels. Glial proliferation was not restricted to the ipsilateral molecular layer but also occurred to some degree in the granule cell layer and the contralateral dentate gyrus. Thus entorhinal cortex lesion induces a rapid microglia reaction and long‐lasting astrocyte activation in the deafferented termination zone of the perforant path. We conclude that glial proliferation after entorhinal cortex lesion follows a complex temporal and spatial pattern that coincides with processes of neuronal and axonal reorganization.
NT‐3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord
Authors: Bradbury Elizabeth J. , Khemani Sameer , Von R . , King . , Priestley John V. , McMahon Stephen B.
Published: March 2003

The regeneration capacity of spinal cord axons is severely limited. Recently, much attention has focused on promoting regeneration of descending spinal cord pathways, but little is known about the regenerative capacity of ascending axons. Here we have assessed the ability of neurotrophic factors to promote regeneration of sensory neurons whose central axons ascend in the dorsal columns. The dorsal columns of adult rats were crushed and either brain‐derived neurotrophic factor (BDNF), glial cell line‐derived neurotrophic factor (GDNF), neurotrophin‐3 (NT‐3) or a vehicle solution was delivered continuously to the lesion site for 4 weeks. Transganglionic labelling with cholera toxin β subunit (CTB) was used to selectively label large myelinated Aβ fibres. In lesioned rats treated with vehicle, CTB‐labelled fibres were observed ascending in the gracile fasciculus, but these stopped abruptly at the lesion site, with no evidence of sprouting or growth into lesioned tissue. No CTB‐labelled terminals were observed in the gracile nucleus, indicating that the lesion successfully severed all ascending dorsal column axons. Treatment with BDNF did not promote axonal regeneration. In GDNF‐treated rats fibres grew around cavities in caudal degenerated tissue but did not approach the lesion epicentre. NT‐3, in contrast, had a striking effect on promoting growth of lesioned dorsal column axons with an abundance of fibre sprouting apparent at the lesion site, and many fibres extending into and beyond the lesion epicentre. Quantification of fibre growth confirmed that only in NT‐3‐treated rats did fibres grow into the crush site and beyond. No evidence of terminal staining in the gracile nucleus was apparent following any treatment. Thus, although NT‐3 promotes extensive growth of lesioned axons, other factors may be required for complete regeneration of these long ascending projections back to the dorsal column nuclei. The intrathecal delivery of NT‐3 or other neurotrophic molecules has obvious advantages in clinical applications, as we show for the first time that dorsal column axonal regeneration can be achieved without the use of graft implantation or nerve lesions.
Stimulation of adenosine A1 receptors attenuates dopamine D1 receptor‐mediated increase of NGFI‐A, c‐fos and jun‐B mRNA levels in the dopamine‐denervated striatum and dopamine D1 receptor‐mediated turning behaviour
Authors: Ferré Sergi , Rimondini Roberto , Popoli Patrizia , Reggio Rosaria , Pèzzola Antonella , Hansson Anita C. , Andersson Annica , Fuxe Kjell
Published: March 2003

Adenosine A1 receptors antagonistically and specifically modulate the binding and functional characteristics of dopamine D1 receptors. In the striatum this interaction seems to take place in the GABAergic strionigro‐strioentopeduncular neurons, where both receptors are colocalized. D1 receptors in the strionigro‐strioentopeduncular neurons are involved in the increased striatal expression of immediate‐early genes induced by the systemic administration of psychostimulants and D1 receptor agonists. Previous results suggest that a basal expression of the immediate‐early gene c‐fos tonically facilitates the functioning of strionigro‐strioentopeduncular neurons and facilitates D1 receptor‐mediated motor activation. The role of A1 receptors in the modulation of the expression of striatal D1 receptor‐regulated immediate‐early genes and the D1 receptor‐mediated motor activation was investigated in rats with a unilateral lesion of the ascending dopaminergic pathways. The systemic administration of the A1 agonist N6‐cyclopentyladenosine (CPA, 0.1 mg/kg) significantly decreased the number of contralateral turns induced by the D1 agonist SKF 38393 (3 mg/kg). Higher doses of CPA (0.5 mg/kg) were necessary to inhibit the turning behaviour induced by the D2 agonist quinpirole (0.1 mg/kg). By using in situ hybridization it was found that CPA (0.1 mg/kg) significantly inhibited the SKF 38393‐induced increase in the expression of NGFI‐A and c‐fos mRNA levels in the dopamine‐denervated striatum. The increase in jun‐B mRNA expression could only be inhibited with the high dose of CPA (0.5 mg/kg). A stronger effect of the A1 agonist was found in the ventral striatum (nucleus accumbens) compared with the dorsal striatum (dorsolateral caudate‐putamen). The results indicate the existence of antagonistic A1–D1 receptor–receptor interactions in the dopamine‐denervated striatum controlling D1 receptor transduction at supersensitive D1 receptors.
Long‐term enhancement of REM sleep by the pituitary adenylyl cyclase‐activating polypeptide (PACAP) in the pontine reticular formation of the rat
Authors: Ahnaou A. , Basille M. , Gonzalez B. , Vaudry H. , Hamon M. , Adrien J. , Bourgin P.
Published: March 2003

In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM‐promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase‐activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP‐27 and PACAP‐38 (0.3 and 3 pmol) induced a marked enhancement (60–85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP‐(6–27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP‐27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP‐27 and PACAP‐38 (IC50 = 2.4 and 3.2 nm, respectively), but very low affinity for VIP (IC50 > 1 μm). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long‐term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long‐term action of PACAP on REM sleep.
Granule cell dispersion is restricted across transverse boundaries in mouse chimeras
Authors: Hawkes Richard , Beierbach Elaine , Tan Seong‐Seng
Published: March 2003

The granular layer of the developing and adult cerebellum is marked by the presence of several transverse boundaries, revealed in gene expression patterns or as a consequence of genetic mutations. It is unclear whether these boundaries represent fundamental differences between granule cell populations or if they are a secondary response to regional differences in the underlying Purkinje cells. One possibility is that boundaries mark different spatial domains of granule cells in a lineage‐dependent fashion. To test this hypothesis, we have analysed a series of murine embryonic stem cell chimeras marked by the constitutive expression of β‐galactosidase in donor granule cells. The chimeras show a consistent spatial restriction boundary, located in the granular layer of lobule VI in the vermis and extending laterally into crus I of the hemispheres. A second boundary was found separating lobules IX and X in the vermis. No correlation was found between the genotypes of molecular layer interneurons and the underlying granule cells, suggesting that they arise independently. No transverse boundaries were observed for the molecular layer interneurons, consistent with the hypothesis that they are not generated from precursors in the external granular layer. These results indicate that the granular layer of the cerebellum comprises cellular domains with different histories separated by consistent spatial restriction boundaries.
Brain activity underlying stereotyped and non‐stereotyped retrieval of learned stimulus–response associations
Authors: Vandenberghe R. , Dupont P. , Bormans G. , Mortelmans L. , Orban G. A.
Published: March 2003

When humans retrieve learned stimulus–response associations in a stereotyped manner the necessary brain structures may differ from those required when the same associations must be retrieved and adapted to new circumstances. We tested this hypothesis by means of tasks that resembled those employed in monkeys, using positron emission tomography (PET). Stimuli consisted of abstract two‐dimensional shapes. Stereotyped retrieval of learned stimulus–response associations was studied by the use of a concurrent discrimination task with fixed pairing. This was contrasted with conditions requiring retrieval and adaptation of learned associations: forced‐choice recognition, response reversal and concurrent discrimination with random pairing. Visuomotor control, passive viewing and fixation conditions were also included. During concurrent discrimination with fixed pairing, the left lower precentral gyrus and rostral anterior cingulate demonstrated higher blood flow levels in comparison with recognition, concurrent discrimination with random pairing, and to a lesser degree, response reversal. In the left lower precentral gyrus these blood flow levels were also higher in comparison with control conditions. Conversely, during recognition, concurrent discrimination with random pairing and reversal, a single region within the right inferior frontal gyrus demonstrated higher blood flow levels in comparison with concurrent discrimination with fixed pairing and control conditions. This right inferior frontal gyrus activation did not depend on the need for active familiarity judgements or response inhibition. To conclude, the left lower precentral gyrus is more active during stereotyped retrieval of learned stimulus–response associations and the right inferior prefrontal cortex is more active when a learned stimulus–response association must be retrieved and adapted to new circumstances.
Nerve growth factor (NGF) induces motoneuron apoptosis in rat embryonic spinal cord in vitro
Authors: Sedel Frédéric , Béchade Catherine , Triller Antoine
Published: March 2003

Recent studies have demonstrated that nerve growth factor (NGF) induces apoptosis of several cell types in the central nervous system through its low‐affinity p75 neurotrophin receptor (p75NTR). To test the effect of NGF on embryonic motoneuron survival, we developed an organotypic culture system which allowed the in vitro development of intact embryonic rat spinal cords. In our system, neural tubes were taken and cultured at E13, just before the onset of physiological motoneuron death. After 2 days in vitro (DIV), motoneurons underwent apoptosis over a time‐course similar to that in vivo. In this system, the addition of NGF (200 ng/mL) for 2 days enhanced the number of apoptotic motoneurons by 37%. This pro‐apoptotic effect was completely reversed by the blocking anti‐p75NTR (REX) antibody which inhibits NGF binding to p75NTR. Other neurotrophins, e.g. brain‐derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5) did not have any effect, while glial cell‐derived neurotrophic factor (GDNF) promoted motoneuron survival. Anti‐BDNF blocking antibodies enhanced motoneuron death indicating that endogenous BDNF promotes motoneuron survival in explants. Our results demonstrate, for the first time, that NGF can induce embryonic motoneuron apoptosis through its receptor p75NTR.
Vasopressin in the lateral septum promotes elemental conditioning to the detriment of contextual fear conditioning in mice
Authors: Desmedt Aline , Garcia René , Jaffard Robert
Published: March 2003

Previous experiments using a classical fear conditioning paradigm have provided evidence that the processing of contextual conditional stimuli (CSs) by the hippocampus would be controlled by the amygdala through a modulation of hippocampal‐lateral septal (H‐LS) excitability. More specifically, our suggestion was that vasopressin release into the LS would occur in an elemental conditioning case [pairing CS–US (unconditional stimulus) procedure] and would result in less hippocampal‐dependent contextual stimuli processing (i.e. overshadowing of CSs by the simple CS). Conversely, when an unpairing CS–US procedure is used, this would result in more contextual stimuli processing through a decrease in vasopressin release into the LS. The aim of the present experiment was to test this hypothesis using intraseptal injection of vasopressin or its V1/V2 antagonist. In agreement with this hypothesis, results suggest that vasopressin release into the LS would constitute a device by which priority is given to the more salient simple stimulus to the detriment of contextual information.
The neurosteroid pregnenolone sulphate increases dopamine release and the dopaminergic response to morphine in the rat nucleus accumbens
Authors: Barrot Michel , Vallée Monique , Gingras Mireille A. , Le Moal Michel , Mayo Willy , Piazza Pier Vincenzo
Published: March 2003

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Clinical studies in humans have associated some of these hormones with a generic sensation of ‘well‐being’ and with pathologies such as depression. In rodents, the neurosteroid pregnenolone sulphate (Preg‐S) has been shown to present antidepressant‐like effects. These observations suggest that neurosteroids could interact with reward‐related processes, mood and motivation. However, the possible neural substrates of such an effect remain unclear. In this report, we studied the action of Preg‐S on the activity of the mesencephalic dopaminergic projection to the nucleus accumbens which is considered one of the biological substrates of motivation and reward. Both the direct effect of Preg‐S and the influence of this hormone on the dopaminergic response to the pharmacological reward provided by the opiate morphine, were studied by means of microdialysis. Pregnenolone sulphate dose‐dependently increased dopamine release in the nucleus accumbens. Furthermore, this hormone doubled the dopaminergic response to morphine. These effects were observed for Preg‐S doses of 100, 200, and 400 pmol injected intracerebroventricularly. The stimulant effect of Preg‐S on dopamine could mediate some of the behavioural effects of neurosteroids and in particular the interaction of these hormones with mood and motivation.
The cortical visual area V6: brain location and visual topography
Authors: Galletti Claudio , Fattori Patrizia , Gamberini Michela , Kutz Dieter F.
Published: March 2003

The brain location and topographical organization of the cortical visual area V6 was studied in five hemispheres of four awake macaque monkeys. Area V6 is located in the caudal aspect of the superior parietal lobule (SPL). It occupies a ‘C’‐shaped belt of cortex whose upper branch is in the depth of the parieto‐occipital sulcus (POS) and lower one is in the depth of the medial parieto‐occipital sulcus (POM), with the medial surface of the brain as a zone of junction between the two branches. Area V6 contains a topographically organized representation of the contralateral visual field up to an eccentricity of at least 80 °. The lower visual field representation is located dorsally, in the ventral part of POS, and the upper field ventrally, in the dorsal wall of POM. The representation of the horizontal meridian forms the posterior border of V6. It is adjacent to area V3 in POS as well as in the caudal part of POM, on the ventral convexity of the brain. The lower vertical meridian forms the anterior border of V6, adjacent to area V6A. The upper vertical meridian is in the depth of POM. The representation of the central visual field is not magnified relative to that of the periphery. The central visual field (below 20–30 ° of eccentricity) is represented in the medial‐most aspect of the annectant gyrus, in the lateral part of the posterior bank of POS. The visuotopic organization of area V6 suggests a role in the analysis of the flow field resulting from self‐motion, in selecting targets during visual searching as well as in the control of arm‐reaching movements towards non‐foveated targets.
The paleocortical ventricle is the origin of reelin‐expressing neurons in the marginal zone of the foetal human neocortex
Authors: Meyer Gundela , Wahle Petra
Published: March 2003

The subpial granular layer (SGL) is a transient cell layer in the cortical marginal zone during the period of neuronal migration into the cortical plate. The origin of the SGL has been studied by immunocytochemistry for calretinin (CR) and reelin in human foetuses from 11 to 40 gestational weeks (GW). At 11 GW, the paleocortical ventricle, a rostral dilatation of the lateral ventricle, gives rise to two fountainheads: a medial fountainhead provides neurons for the marginal zone (MZ) of the rostral cortex and rostral hippocampal rudiment, while multiple cell streams migrate from a lateral fountainhead into the MZ of the paleocortex and insula. The latero‐medial gradient of neuronal packing density in the neocortical MZ indicates that migration extends farther into the neocortex. Neurons express CR already in the retrobulbar ventricular zone; they express reelin only as they approach the MZ of the paleocortex and rostral archicortex. At 16/17 GW, large numbers of CR‐immunoreactive granule cells originate from the same fountainheads, and then direct medially, toward the surface of the anterior perforated substance, and laterally, into the paleocortical MZ, from where they continue into the neocortical SGL following a ventrolateral to dorsomedial gradient. From 13 to 18 GW, reelin is expressed by a subpopulation of granule cells and by Cajal–Retzius‐like neurons. By 22 GW, the paleocortical ventricle undergoes regression and no longer supplies the SGL. Our results show that the paleocortical ventricle gives rise to a stream of neurons which extends over the cortical MZ as the subpial granular layer. The fact that SGL derivatives express reelin suggests that this transient cell layer may play a significant role in the establishment of the complex cytoarchitecture of the cerebral cortex.
Prior short‐term synaptic disinhibition facilitates long‐term potentiation and suppresses long‐term depression at CA1 hippocampal synapses
Authors: Hsu Kuei‐Sen , Ho Wen‐Chia , Huang Chiung‐Chun , Tsai Jing‐Jane
Published: March 2003

Long‐term potentiation (LTP) and long‐term depression (LTD) are two main forms of activity‐dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral‐CA1 synapses. Here, we show that prior short‐term synaptic disinhibition induced by type A γ‐aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L‐type voltage‐operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N‐methyl‐d‐aspartate (NMDA) receptor antagonist d‐2‐amino‐5‐phosphopentanoic acid (D‐APV). Moreover, this picrotoxin‐induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)‐dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9‐(tetrahydro‐2‐furanyl)‐9H‐purin‐6‐amine (SQ 22536) and the PKA inhibitor Rp‐adenosine 3′,5′‐cyclic monophosphothioate (Rp‐cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired‐pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral‐CA1 synapses. The increase in Ca2+ influx through L‐type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.
Abnormal expression of neurofilament proteins in dysmyelinating axons located in the central nervous system of jimpy mutant mice
Authors: Gotow Takahiro , Leterrier Jean F. , Ohsawa Yoshiyuki , Watanabe Tsuyoshi , Isahara Kyoko , Shibata Riichi , Ikenaka Kazuhiro , Uchiyama Yasuo
Published: March 2003

Myelination in the peripheral nervous system is considered to increase the phosphorylation level of neurofilament proteins in the axon, resulting in an increase in axonal calibre. To understand the relationship between myelination and neurofilament proteins in axons, we examined jimpy mutant mice with a point mutation in the proteolipid protein gene and dysmyelination in the central nervous system. The jimpy mice exhibited a characteristic similarity in neurofilament nature to the myelin‐deficient mice in the peripheral nervous system reported previously. The following novel results were obtained in the jimpy mice: dysmyelinated axons, in which the amount of non‐phosphorylated neurofilament‐H was drastically increased without a significant reduction of the phosphorylated form, compared with the control myelinated axons, did not suffer any decrease in their diameters. Expression levels of all neurofilament subunit proteins and their mRNAs were enhanced in the central nervous system tissue. Because the above biochemical data were obtained from the cytoskeletal fraction, at least some of the increased neurofilament‐H and ‐M proteins appeared to be coassembled into neurofilaments but remained non‐phosphorylated. Axonal neurofilaments of the jimpy were, probably due to this abnormal stoichiometry and phosphorylation state in neurofilaments, more compact and random in alignment with less prominent cross‐bridges than those of the control, providing possible evidence for disturbing the axonal transport of other organelles. These results suggest that myelination regulates both the expression and phosphorylation of neurofilament proteins, and is essential for the cytoplasmic organization of myelinated axons.
Improved auditory spatial acuity in visually deprived ferrets
Authors: King Andrew J. , Parsons Carl H.
Published: March 2003

We have examined the effects on auditory spatial acuity in the horizontal plane of depriving ferrets of patterned visual cues by binocular eyelid suture in infancy or for a comparable period in adulthood. Minimum audible angles (MAAs) were measured for 500‐, 100‐ and 40‐ms broadband noise bursts at the midline and at 45° to one side. A logistic regression analysis revealed no consistent difference between the midline MAAs of normal and infant lid‐sutured ferrets. However, the lateral field MAAs of the infant‐deprived group were significantly smaller and showed less inter‐subject variability than those of normal‐sighted ferrets. The animals deprived in adulthood were tested in the lateral field only, firstly 6 months after binocular eyelid suture and again after a further 10 months. For the first test, the MAAs achieved by these animals with 500‐ and 100‐ms noise bursts were significantly smaller than the normal values and no different from those of the infant‐deprived group. A significant improvement in performance at the two shortest stimulus durations (100 and 40 ms) was observed when the adult‐deprived animals were re‐tested. Their second‐test MAAs did not differ from those of the infant‐deprived group at any of the three stimulus durations used, and both groups achieved significantly better scores than the normal‐sighted control animals. These results show that prolonged visual deprivation in both juvenile and adult ferrets can lead to a significant improvement in auditory spatial acuity in the lateral sound field. This is consistent with reports that congenitally blind humans can localize peripheral sounds more accurately than normal controls.
Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in mice lacking the neurotrophin receptor p75
Authors: Kinkelin Ilka , Stucky Cheryl L. , Koltzenburg Martin
Published: March 2003

Merkel cells are specialized epidermal cells which are abundantly found in touch‐sensitive areas and which are innervated by slowly adapting mechanosensitive afferent fibres with large myelinated (Aβ) axons. The role of Merkel cells in mechanosensation, their developmental regulation and their influence on sensory neuron function are, however, incompletely understood. Here, we used mice lacking the neurotrophin receptor p75 which is expressed on Merkel cells to investigate their postnatal development and that of their innervating sensory neurons. Using morphological studies we now show that Merkel cells develop normally in both hairy and glabrous skin in these animals until 2 weeks old, but are progressively lost thereafter and have almost completely disappeared 2 months after birth. Using standard extracellular electrophysiological recording techniques we find that despite the profound loss of Merkel cells there is no corresponding reduction in the number of myelinated slowly adapting afferent fibres. Moreover, the mean mechanical threshold of these neurons and their average stimulus response function to suprathreshold mechanical stimuli does not change during the time period when more than 99% of Merkel cells are lost. We conclude that Merkel cells require p75 during the late postnatal development. However, neither the survival nor the mechanical sensitivity of slowly adapting mechanoreceptive Aβ‐fibres depends on the presence of Merkel cells.
Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety
Authors: Ouagazzal Abdel‐Mouttalib , Kenny Paul J. , File Sandra E.
Published: March 2003

The present study investigated the role of nicotinic receptors in the lateral septum in the modulation of anxiety. The effects of direct injections of nicotine into the lateral septum were first investigated in two tests of anxiety, social interaction and elevated plus‐maze tests. Intra‐septal injection of nicotine (1 and 4 μg) induced consistent anxiogenic effects in both tests. The reversal of nicotinic effects with mecamylamine was then studied in the social interaction test. Intra‐septal injection of mecamylamine at a low dose (15 ng) induced an anxiolytic effect, suggesting the presence of intrinsic cholinergic tone increasing anxiety. At higher doses (30–50 ng), mecamylamine was without effect in the social interaction test, but blocked the anxiogenic effects of nicotine (4 μg). These findings provide further evidence for the role of the lateral septum in the modulation of anxiety and suggest that cholinergic projections to this brain area facilitate anxiety through nicotinic receptors.
Neuroactive steroids and the constraint of memory
Authors: Slot L. A. Bruins , Piazza P. V. , Colpaert F. C.
Published: March 2003

Different normo‐ and pathophysiological conditions are associated with large variations in plasma and brain concentrations of neuroactive steroids. In an attempt to specify the possible role of these steroids in memory processes, we examined the ability of pregnanolone, a positive modulator of the γ‐aminobutyric acid type A (GABAA) receptor complex, to sustain state dependence in rats. Animals treated with either saline or different doses of pregnanolone were trained to complete a fixed ratio 10 (FR10) schedule of lever presses for milk reward within 120 s, and were tested for the retention of this response 48 h later while treated with the same or a different treatment. The data indicate that saline‐to‐drug as well as drug‐to‐saline state changes produced robust failures to recall the response. Furthermore, animals trained with pregnanolone showed transfer of the response when tested with the benzodiazepine chlordiazepoxide and vice versa. The partial benzodiazepine inverse agonist N‐methyl‐β‐carboline‐3‐carboxamide (FG‐7142) antagonized the states produced by both pregnanolone and chlordiazepoxide. State changes constitute a mechanism of action that may operate endogenously; the release of neuroactive steroids in response to various physiological conditions may act to contain but also to constrain memories associated with these events, rendering these memories inaccessible on other occasions. The apparent memory impairment that can so be produced may render the effects of past experience available in a manner that is appropriately selective.
The cerebellum and cognition: cerebellar lesions do not impair spatial working memory or visual associative learning in monkeys
Authors: Nixon Philip D. , Passingham Richard E.
Published: March 2003

Anatomical studies in non‐human primates have shown that the cerebellum has prominent connections with the dorsal, but not the ventral, visual pathways of the cerebral cortex. Recently, it has been shown that the dorsolateral prefrontal cortex (DPFC) and cerebellum are interconnected in monkeys. This has been cited in support of the view that the cerebellum may be involved in cognitive functions, e.g. working memory. Six monkeys (Macaca fascicularis) were therefore trained on a classic test of working memory, the spatial delayed alternation (SDA) task, and also on a visual concurrent discrimination (VCD) task. Excitotoxic lesions were made in the lateral cerebellar nuclei, bilaterally, in three of the animals. When retested after surgery the lesioned animals were as quick to relearn both tasks as the remaining unoperated animals. However, when the response times (RT) for each task were directly compared, on the SDA task the monkeys with cerebellar lesions were relatively slow to decide where to respond. We argue that on the SDA task animals can prepare their responses between trials whereas this is not possible on the VCD task, and that the cerebellar lesions may disrupt this response preparation. We subsequently made bilateral lesions in the DPFC of the control animals and retested them on the SDA task. These monkeys failed to relearn the task. The results show that, unlike the dorsal prefrontal cortex, the cerebellum is not essential for working memory or the executive processes that are necessary for correct performance, though it may contribute to the preparation of responses.
The spatial representation of chemical structures in the antennal lobe of honeybees: steps towards the olfactory code
Authors: Sachse Silke , Rappert Angelika , Galizia C. Giovanni
Published: March 2003

Odours are represented by specific ensembles of activated glomeruli in a combinatorial manner within the olfactory bulb of vertebrates or the antennal lobe (AL) of insects. Here, we optically measured glomerular calcium activities in vivo in the honeybee Apis mellifera during olfactory stimulation with 36 pure chemicals differing systematically in carbon chain length (C‐5–10) and functional group (aldehyde, ketone, alcohol, carboxylic acid and alkane). We show their glomerular representations in 38 morphologically identified glomeruli out of the honeybee's 160. We measured the molecular receptive range of identified glomeruli averaging up to 21 individuals. Of the 38 glomeruli measured, 23 show maximal activity in a specific range of chain length. Glomeruli preferentially responding to a functional group are also always broadly tuned to particular chain lengths. Furthermore, glomeruli with similar response spectra are often direct neighbours. The results allow conclusions about the interactions between olfactory receptors and odour molecules, and about the AL network.
Human striosomes are enriched in 5‐HT2A receptors: autoradiographical visualization with [3H]MDL100,907, [125I](±)DOI and [3H]ketanserin
Authors: López‐Giménez Juan F. , Mengod Guadalupe , Palacios José M. , Vilaró M. Teresa
Published: March 2003

5‐HT2A receptors have been visualized with [3H]MDL100,907 in selected human brain areas by autoradiography. These areas included caudate and putamen, nucleus dentatus of the cerebellum, substantia nigra, nucleus raphe dorsalis, locus coeruleus and inferior olive. In the striatum [3H]MDL100,907 labelling was compared with the pattern obtained with [125I](±)DOI and [3H]ketanserin. [3H]MDL100,907 and [125I](±)DOI showed an identical patchy distribution which was hardly observed with [3H]ketanserin. In the remaining regions, [3H]MDL100,907 and [3H]ketanserin autoradiographical signals and percentage of specific binding were compared. Whereas the pattern of distribution was identical for both radioligands, [3H]MDL100,907 presented a much lower percentage of nonspecific binding compared with [3H]ketanserin. These results confirm the presence of 5‐HT2A receptors in human striosomes and in those areas where [3H]ketanserin presented a high nonspecific binding, and they highlight the advantage of using [3H]MDL100,907 to visualize these receptors.
AMPA‐receptor involvement in c‐fos expression in the medial prefrontal cortex and amygdala dissociates neural substrates of conditioned activity and conditioned reward
Authors: Mead Andy N. , Vasilaki Anna , Spyraki Christina , Duka Theodora , Stephens David N.
Published: March 2003

Exposure to an environment, previously conditioned to amphetamine (1 mg/kg, i.p.), induced locomotor activity and c‐fos expression (a marker for neuronal activation) in the mouse medial prefrontal cortex (mPFC) and amygdala; acute or repeated amphetamine (1 mg/kg, i.p.) administration induced c‐fos expression additionally in the nucleus accumbens. An α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)‐receptor antagonist, 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo(f)quinoxaline (NBQX), blocked expression of conditioned activity, and prevented the increase in c‐fos expression in mPFC, implicating mPFC AMPAergic transmission in the conditioned component of behavioural sensitization to amphetamine. NBQX failed to block the expression of amphetamine‐conditioned place preference, a measure of conditioned reward, or conditioned c‐fos expression in the amygdala, an area implicated in the expression of conditioned place preference. These findings indicate that the conditioned components of behavioural sensitization depend on AMPA‐receptor‐mediated activation in mPFC, but that conditioned reward does not.
Role of the corpus callosum in the somatosensory activation of the ipsilateral cerebral cortex: an fMRI study of callosotomized patients
Authors: Fabri Mara , Polonara Gabriele , Quattrini Angelo , Salvolini Ugo , Del Pesce Maria , Manzoni Tullio
Published: March 2003

To verify whether the activation of the posterior parietal and parietal opercular cortices to tactile stimulation of the ipsilateral hand is mediated by the corpus callosum, a functional magnetic resonance imaging (fMRI, 1.0 tesla) study was performed in 12 control and 12 callosotomized subjects (three with total and nine with partial resection). Eleven patients were also submitted to the tactile naming test. In all subjects, unilateral tactile stimulation provoked a signal increase temporally correlated with the stimulus in three cortical regions of the contralateral hemisphere. One corresponded to the first somatosensory area, the second was in the posterior parietal cortex, and the third in the parietal opercular cortex. In controls, activation was also observed in the ipsilateral posterior parietal and parietal opercular cortices, in regions anatomically corresponding to those activated contralaterally. In callosotomized subjects, activation in the ipsilateral hemisphere was observed only in two patients with splenium and posterior body intact. These two patients and another four with the entire splenium and variable portions of the posterior body unsectioned named objects explored with the right and left hand without errors. This ability was impaired in the other patients. The present physiological and anatomical data indicate that in humans activation of the posterior parietal and parietal opercular cortices in the hemisphere ipsilateral to the stimulated hand is mediated by the corpus callosum, and that the commissural fibres involved probably cross the midline in the posterior third of its body.
Experience‐dependent increase in cAMP‐responsive element binding protein in synaptic and nonsynaptic mitochondria of the rat hippocampus
Authors: Bevilaqua Lia R. M. , Cammarota Martín , Paratcha Gustavo , De Stein Miguelina Levi , Izquierdo Iván , Medina Jorge H.
Published: March 2003

Cyclic AMP‐responsive element binding protein (CREB) plays a pivotal role in the formation of long‐term memory in Drosophila, Aplysia, mice and rats. Recently, we were able to demonstrate that CREB and its serine 133 phosphorylated form p‐CREB are localized in synaptic and nonsynaptic mitochondria of the rat brain. Here we report on the effect of a one‐trial inhibitory avoidance training procedure on mitochondrial CREB from the rat hippocampus. This aversively motivated training task is associated with a time‐dependent increase (34–35%) in both p‐CREB and CREB immunoreactivities detected in synaptic mitochondria of the hippocampus. In nonsynaptic mitochondria, p‐CREB levels increased in both trained and shocked animals. In addition to CREB, two CRE‐element binding repressors, CREB‐2 and CREM‐1, were also detected in purified brain mitochondria. No changes were observed in CREB‐2 and CREM‐1 immunoreactivities in hippocampal synaptic mitochondria after an inhibitory avoidance training. Taken together the present findings represent the first evidence showing that brain mitochondrial CREB may participate in plasticity‐dependent changes associated with a behavioural training procedure.