bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats
Authors: Zhou X. ‐F. , Deng Y. ‐S. , Xian C. J. , Zhong J. ‐H.
Published: March 2003

Injury to peripheral nerves often results in chronic pain which is difficult to relieve. The mechanism underlying the pain syndrome remains largely unknown. In previous studies we showed that neurotrophins are up‐regulated in satellite cells around sensory neurons following sciatic nerve lesion. In the present study, we have examined whether the neurotrophins in the dorsal root ganglia play any role in allodynia after nerve injury. Antibodies to different neurotrophins, directly delivered to injured dorsal root ganglia, significantly reduced (with different time sequences) the percentage of foot withdrawal responses evoked by von Frey hairs. The antibodies to nerve growth factor acted during the early phase but antibodies to neurotrophin‐3 and brain‐derived neurotrophic factor were effective during the later phase. Exogenous nerve growth factor or brain‐derived neurotrophic factor, but not neurotrophin‐3, directly delivered to intact dorsal root ganglia, trigger a persistent mechanical allodynia. Our results showed that neurotrophins within the dorsal root ganglia after peripheral nerve lesion are involved in the generation of allodynia at different stages. These studies provide the first evidence that ganglia‐derived neurotrophins are a source of nociceptive stimuli for neuropathic pain after peripheral nerve injury.
Mechanisms of human motion perception: combining evidence from evoked potentials, behavioural performance and computational modelling
Authors: Patzwahl Dieter R. , Zanker Johannes M.
Published: March 2003

Based on single cell recordings in monkey, it has been suggested that neural activity can be related directly to psychophysically measured threshold behaviour. Here, we investigated in humans whether evoked potentials correlate with behavioural measurements like discrimination thresholds and reaction time. Subjects were asked to report the perceived direction of object motion stimuli which contained variable amounts of coherent motion. Simultaneously, we recorded evoked potentials with a multielectrode array, or measured the reaction time. We show here that motion coherence had a strong influence on both amplitude and latency of the evoked potential. Stronger motion signals evoked stronger and faster cortical responses. The latency reduction of the motion onset response with increasing coherence correlated very well with the concurrent decrease in reaction time. Taken together, these results suggest that temporal integration is an important step in analysing motion signals to generate a reliable behavioural response. We stimulated a two‐dimensional array of correlation‐type motion detectors with the same motion sequences, and analysed the distribution of local motion signals according to signal detection theory. Performance resembled that of human subjects when the decision strategy was optimized so as to exclude small signals and, in particular, when the ideal observer had some knowledge about a region of interest in which the object was to be expected.
Cellular and synaptic effect of substance P on neonatal phrenic motoneurons
Authors: Ptak Krzysztof , Konrad Martin , Di Pasquale Eric , Tell Fabien , Hilaire Gérard , Monteau Roger
Published: March 2003

Experiments were carried out on the in vitro brainstem–spinal cord preparation of the newborn rat to analyse the effects of substance P (SP) on phrenic motoneuron (PMN) activity. In current‐clamp mode, SP significantly depolarized PMNs, increased their input resistance, decreased the rheobase current and shifted the firing frequency–intensity relationships leftwards, but did not affect spike frequency adaptation or single spike configuration. The neurokinin receptor agonist NK1 had SP‐mimetic effects, whereas the NK3 and NK2 receptor agonists were less effective and ineffective, respectively. In a tetrodotoxin‐containing aCSF, only SP or the NK1 receptor agonist were still active. No depolarization was observed when the NK1 receptor agonist was applied in the presence of muscarine. In voltage‐clamp mode, SP or the NK1 receptor agonist produced an inward current (ISP) which was not significantly reduced by extracellular application of tetraethylammonium, Co2+, 4‐aminopyridine or Cs+. In aCSF containing tetrodotoxin, Co2+ and Cs+, ISP was blocked by muscarine. No PMN displayed any M‐type potassium current but only a current showing no voltage sensitivity over the range −100 to 0 mV, reversing near the expectedEK+, hence consistent with a leak current. SP application to the spinal cord only (using a partitioned chamber) significantly increased the phrenic activity. Pretreatment with the NMDA receptor antagonist dl‐2‐amino‐5‐phosphonovaleric acid (AP5) decreased the C4 discharge duration and blocked the effect of SP, thus exhibiting an NMDA potentiation by SP. In conclusion, SP modulates postsynaptically the response of phrenic motoneurons to the inspiratory drive through the reduction of a leak conductance and the potentiation of the NMDA component of the synaptic input.
Neurophysiological correlates of face gender processing in humans
Authors: Mouchetant‐Rostaing Yolande , Giard Marie‐Hélène , Bentin Shlomo , Aguera Pierre‐Emmanuel , Pernier Jacques
Published: March 2003

Event‐related potentials (ERPs) were recorded while subjects were involved in three gender‐processing tasks based on human faces and on human hands. In one condition all stimuli were only of one gender, preventing any gender discrimination. In a second condition, faces (or hands) of men and women were intermixed but the gender was irrelevant for the subject's task; hence gender discrimination was assumed to be incidental. In the third condition, the task required explicit gender discrimination; gender processing was therefore assumed to be intentional. Gender processing had no effect on the occipito‐temporal negative potential at ≈ 170 ms after stimulation (N170 component of the ERP), suggesting that the neural mechanisms involved in the structural encoding of faces are different from those involved in the extraction of gender‐related facial features. In contrast, incidental and intentional processing of face (but not hand) gender affected the ERPs between 145 and 185 ms from stimulus onset at more anterior scalp locations. This effect was interpreted as evidence for the direct visual processing of faces as described in Bruce and Young's model [Bruce, V. & Young, A. (1986) Br. J. Psychol., 77, 305–327]. Additional gender discrimination effects were observed for both faces and hands at mid‐parietal sites around 45–85 ms latency, in the incidental task only. This difference was tentatively assumed to reflect an early mechanism of coarse visual categorization. Finally, intentional (but not incidental) gender processing affected the ERPs during a later epoch starting from ≈ 200 ms and ending at ≈ 250 ms for faces, and ≈ 350 ms for hands. This later effect might be related to attention‐based gender categorization or to a more general categorization activity.
Bone morphogenetic protein‐7 enhances dendritic growth and receptivity to innervation in cultured hippocampal neurons
Authors: Withers G. S. , Higgins D. , Charette M. , Banker G.
Published: March 2003

Members of the bone morphogenetic protein (BMP) family of growth factors are present in the central nervous system during development and throughout life. They are known to play an important regulatory role in cell differentiation, but their function in postmitotic telencephalic neurons has not been investigated. To address this question, we examined cultured hippocampal neurons following treatment with bone morphogenetic protein‐7 (BMP‐7, also referred to as osteogenic protein‐1). When added at the time of plating, BMP‐7 markedly stimulated the rate of dendritic development. Within 1 day, the dendritic length of BMP‐7‐treated neurons was more than twice that of controls. By three days the dendritic arbors of BMP‐7‐treated neurons had attained a level of branching similar to that of 2‐week‐old neurons cultured under standard conditions. Several findings indicate that BMP‐7 selectively enhances dendritic development. While dendritic length was significantly increased in BMP‐7‐treated neurons, the length of the axon was not. In addition, the mRNA encoding the dendritic protein MAP2 was significantly increased by BMP‐7 treatment, but the mRNA for tubulin was not. Finally, BMP‐7 did not enhance cell survival. Because dendritic maturation is a rate‐limiting step in synapse formation in hippocampal cultures, we examined whether BMP‐7 accelerated the rate at which neurons became receptive to innervation. Using two separate experimental paradigms, we found that the rate of synapse formation (assessed by counting synapsin I‐positive presynaptic vesicle clusters) was increased significantly in neurons that had been exposed previously to BMP‐7. Because BMP‐7 and related BMPs are expressed in the hippocampus in situ, these factors may play a role in regulating dendritic branching and synapse formation in both development and plasticity.
Intrathecally injected neurotrophins and the release of substance P from the rat isolated spinal cord
Authors: Malcangio Marzia , Ramer Matt S. , Boucher Tim J. , McMahon Stephen B.
Published: March 2003

The aim of this study was to investigate the effects of intrathecally delivered trophic molecules nerve growth factor (NGF), neurotrophin‐3 (NT‐3) and glial cell line‐derived neurotrophic factor (GDNF) on substance P (SP) release and content in the rat spinal cord and SP content in sciatic nerve. SP release was assayed with an in vitro dorsal roots‐attached spinal cord preparation, in which the roots were stimulated at A‐ or C‐fibre strength, and SP levels were measured by radioimmunoassay (RIA). NGF but not NT‐3 and GDNF treatment caused a significant increase in basal SP outflow; NGF, NT‐3 but not GDNF increased C‐fibre stimulation‐evoked SP release, and capsaicin superfusion‐induced SP release. The increase in C‐fibre stimulation‐evoked SP release over basal outflow was greater in NGF‐ than NT‐3‐treated cords, and nociceptive threshold testing showed that intrathecal NGF, but not NT‐3 or GDNF treatment was associated with thermal hyperalgesia. There was no detectable A‐fibre stimulation‐induced SP release from any group as well as no change in SP content in the sciatic nerve and spinal cord. Systemic treatment with the NGF‐sequestering fusion protein trkA‐IgG significantly inhibited electrically or capsaicin‐evoked SP release without affecting basal outflow and SP content in spinal cord and sciatic nerve. These results suggest that: (i) NGF tonically regulates the central synaptic function of SP‐containing primary afferents; (ii) increased SP‐release from the spinal cord is not necessarily associated with behavioural hyperalgesia as in NT‐3‐treated rats there was increased SP release but no detectable hyperalgesia; and (iii) because A‐fibre stimulation failed to increase SP release in any group, these neurotrophins are unlikely to be responsible for the de novo upregulation of SP in large afferents seen after peripheral inflammation or nerve injury.
Endogenous and exogenous nitric oxide enhance the DNA strand scission induced by tert‐butylhydroperoxide in PC12 cells via peroxynitrite‐dependent and independent mechanisms, respectively
Authors: Sestili Piero , Clementi Emilio , Guidarelli Andrea , Sciorati Clara , Cantoni Orazio
Published: March 2003

A short‐term exposure to tert‐butylhydroperoxide (tB‐OOH) promoted a concentration‐dependent formation of DNA single‐strand breaks in PC12 cells. These events were paralleled by an increase in the cytosolic concentration of Ca2+ that was in part cleared by the mitochondria. Unlike the extent of Ca2+ mobilization and/or mitochondrial Ca2+ clearance, the DNA strand scission evoked by the hydroperoxide was markedly reduced by the nitric oxide (NO) scavenger 2‐phenyl‐4,4,5,5‐tetramethylimidazolin‐1‐oxyl‐3‐oxide (PTIO) or by the NO synthase inhibitor N‐nitro‐l‐arginine methylester (L‐NAME). Inhibitors of electron transport (rotenone and myxothiazol), ruthenium red (RR, a polycation which inhibits the calcium uniporter of mitochondria), or peroxynitrite scavengers (Trolox and l‐methionine) were as effective as PTIO or L‐NAME in inhibiting the DNA‐damaging response mediated by tB‐OOH. Rotenone, RR or peroxynitrite scavengers did not further reduce the residual DNA cleavage observed following treatment with tB‐OOH in L‐NAME‐supplemented cells. Exogenous NO also increased the DNA damage caused by tB‐OOH in L‐NAME‐supplemented cells and this response was blunted by RR or by inhibitors of electron transport but was insensitive to peroxynitrite scavengers. We conclude that both endogenous and exogenous NO enhance the DNA cleavage generated by tB‐OOH in PC12 cells. However, only endogenous NO set the bases for an involvement of peroxynitrite in this DNA‐damaging response.
Differential signalling of the chemokine receptor CXCR4 by stromal cell‐derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes
Authors: Lazarini Françoise , Casanova Philippe , Tham To Nam , De Clercq Erik , Arenzana‐Seisdedos Fernando , Baleux Françoise , Dubois‐Dalcq Monique
Published: March 2003

CXCR4 is the Gi protein‐linked seven‐transmembrane receptor for the alpha chemokine stromal cell‐derived factor 1 (SDF‐1), a chemoattractant for lymphocytes. This receptor is highly conserved between human and rodent. CXCR4 is also a coreceptor for entry of human immunodeficiency virus (HIV) in T cells and is expressed in the CNS. To investigate how these CXCR4 ligands influence CNS development and/or function, we have examined the expression and signalling of this chemokine receptor in rat neurons and astrocytes in vitro. CXCR4 transcripts and protein are synthesized by both cell types and in E15 brain neuronal progenitors. In these progenitors, SDF‐1, but not gp120 (the HIV glycoprotein), induced activation of extracellular signal regulated kinases (ERKs) 1/2 and a dose‐dependent chemotactic response. This chemotaxis was inhibited by Pertussis toxin, which uncouples Gi proteins and the bicyclam AMD3100, a highly selective CXCR4 antagonist, as well as by an inhibitor of the MAP kinase pathway. In differentiated neurons, both SDF‐1 and the glycoprotein of HIV, gp120, triggered activation of ERKs with similar kinetics. These effects were significantly inhibited by Pertussis toxin and the CXCR4 antagonist. Rat astrocytes also responded to SDF‐1 signalling by phosphorylation of ERKs but, in contrast to cortical neurons, no kinase activation was induced by gp120. Thus neurons and astrocytes can respond differently to signalling by SDF‐1 and/or gp120. As SDF‐1 triggers directed migration of neuronal progenitors, this alpha chemokine may play a role in cortex development. In differentiated neurons, both natural and viral ligands of CXCR4 activate ERKs and may therefore influence neuronal function.
Spontaneous and locomotor‐related GABAergic input onto primary afferents in the neonatal rat
Authors: Fellippa‐Marques Silvia , Vinay Laurent , Clarac François
Published: March 2003

The in vitro brain stem–spinal cord preparation of neonatal rats (0–5 days old) was used to examine the contribution of GABAA (γ‐aminobutyric acid) receptors to the spontaneous and locomotor‐related antidromic firing in the dorsal roots of neonatal rats. Spontaneous bursts of antidromic discharges were generated by the underlying afferent terminal depolarizations reaching spiking threshold. The number of antidromic action potentials increased significantly in saline solution with Cl– concentration reduced to 50% of control. Bath application of the GABAA receptor antagonist bicuculline, at low concentrations (1–2 μm), or picrotoxin blocked the antidromic discharges in the dorsal roots almost completely. The increase in Cl– conductance was therefore mediated by an activation of GABAA receptors. Increasing the concentration of bicuculline to 10–20 μm never blocked these discharges further. On the contrary, in half of the preparations, the number of antidromic action potentials was higher in the presence of high concentrations of bicuculline (10–20 μm) than in the presence of picrotoxin or low concentrations of bicuculline. This suggests that bicuculline, at high concentrations, may have other effects, in addition to blocking GABAA receptors. Dorsal root firing was observed during fictive locomotion induced by bath application of excitatory amino acids and serotonin. A rhythmical pattern was often demonstrated. Bicuculline at low concentrations caused a decrease of the antidromic discharge whereas, at high concentrations, bursts of discharges appeared. A double‐bath with a barrier built at the L3 level was then used to separate the mechanisms which generate locomotion from those mediating primary afferent depolarizations. Excitatory amino acids and serotonin were perfused in the rostral pool only. Decreasing the concentration of chloride in the caudal bath caused a sharp increase in the number of antidromic action potentials recorded from the L5 dorsal root. These discharges, which were modulated in phase with the locomotor rhythm, were blocked by bicuculline. These data demonstrate the existence of a locomotor‐related GABAergic input onto primary afferent terminals in the neonatal rat.
Evaluation of simple and complex sensorimotor behaviours in rats with a partial lesion of the dopaminergic nigrostriatal system
Authors: Barnéoud Pascal , Descombris Eric , Aubin Nadine , Abrous Djoher N.
Published: March 2003

We have examined the behavioural consequences of a partial unilateral dopaminergic denervation of the rat striatum. This partial lesion was obtained by an intrastriatal 6‐hydroxy‐dopamine injection (6‐OHDA, 20 or 10 μg divided between two injection sites) and was compared with a unilateral complete lesion resulting from an injection of 6‐OHDA (2 × 6 μg) into the medial forebrain bundle. Quantification of striatal dopamine (DA) and its metabolites, and the immunohistochemical evaluation of the nigrostriatal DA system confirmed the complete and partial lesions. Animals with complete striatal denervation displayed both apomorphine‐ and amphetamine‐induced rotations whereas the partial denervation elicited amphetamine‐induced rotations only. However, the rates of amphetamine‐induced rotation were not correlated with the size of the lesion. In contrast, the paw‐reaching impairments were significantly correlated with the striatal dopaminergic depletion. When evaluated in the staircase test, animals with partial denervation were impaired exclusively for the paw contralateral to the side of the lesion. This motor deficit (50–75%) included all components of the skilled paw use (i.e. attempt, motor coordination and success) and was observed at least 12 weeks after the lesion. However, these animals were able to perform normal stepping adjustments with the impaired paw, indicating that the partial lesion induced a coordination deficit of the paw rather than a deficit of movement initiation. After a complete lesion, stepping adjustments of the contralateral paw were dramatically impaired (by 80%), an akinesia which almost certainly accounted for the great deficit in skilled paw use. The paw‐reaching impairments resulting from the partial striatal denervation are proposed as a model of the early symptoms of Parkinson's disease and may be useful for the development of restorative therapies.
Precise matching of olivo‐cortical divergence and cortico‐nuclear convergence between somatotopically corresponding areas in the medial C1 and medial C3 zones of the paravermal cerebellum
Authors: Apps R. , Garwicz M.
Published: March 2003

The paravermal cerebellar cortex contains three spatially separate zones (the C1, C3 and Y zones) which form a functionally coupled system involved in the control of voluntary limb movements. A series of ‘modules’ has been postulated, each defined by a set of olivary neurons with similar receptive fields, the cortical microzones innervated by these neurons and the group of deep cerebellar nuclear neurons upon which the microzones converge. A key feature of this modular organization is a correspondence between cortical input and output, irrespective of the zonal identity of the microzone. This was tested directly using a combined electrophysiological and bi‐directional tracer technique in barbiturate‐anaesthetized cats. During an initial operation, small injections of a mix of retrograde and anterograde tracer material (red beads combined with Fluoro‐Ruby or green beads combined with biotinylated dextran amine or Fluoro‐Emerald) were made into areas of the medial C1 and medial C3 zones in cerebellar lobule V characterized by olivo‐cerebellar input from the ventral forelimb. The inferior olive and the deep cerebellar nuclei were then scrutinized for retrogradely labelled cells and anterogradely labelled axon terminals, respectively. For individual experiments, the degree of C1–C3 zone terminal field overlap in the nucleus interpositus anterior was plotted as a function of either the regional overlap of single‐labelled cells or the proportion of double‐labelled cells in the dorsal accessory olive. The results were highly positively correlated, indicating that cortico‐nuclear convergence between parts of the two zones is in close proportion to the corresponding olivo‐cerebellar divergence, entirely consistent with the modular hypothesis.
Different spatiotemporal expression of DOC2 genes in the developing rat brain argues for an additional, nonsynaptic role of DOC2B in early development
Authors: Korteweg Niki , Denekamp Francien A. , Verhage Matthijs , Burbach J. Peter H.
Published: March 2003

DOC2A and DOC2B are two homologous genes implicated in synaptic vesicle exocytosis. Their complementary, nonoverlapping expression patterns in adult rat brain suggest that they exert similar functions in different neurons. We have analysed the expression pattern of the two genes in the developing rat brain by in situ hybridization. Unexpectedly, we found no parallel expression of the two genes during development. DOC2B mRNA was highly expressed as early as embryonic day 12 (E12) throughout the neuroepithelium, long before synaptic transmission is functional, and the expression remained abundant from E12 onwards. In contrast, faint expression of DOC2A transcripts was first detected at E17 in ventral brain areas, and it extended gradually to other brain structures in the sequence of their ontology, i.e. structures that had formed first also expressed DOC2A first. At postnatal day 3, both genes were highly expressed throughout the brain. This overlapping expression diverged to the complementary distribution of the adult brain. The temporal and spatial differences in expression point to a functional divergence between these homologous genes during brain development: the pattern of DOC2A is consistent with its proposed synaptic function, whereas that of DOC2B suggests an additional, nonsynaptic role in proliferating cells.
Clonidine blocks stress‐induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons
Authors: Shaham Yavin , Highfield David , Delfs Jill , Leung Shirley , Stewart Jane
Published: March 2003

Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug‐taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha‐2 adrenergic receptor agonist that decreases NE cell firing and release, on stress‐induced reinstatement of heroin seeking. Rats were trained to self‐administer heroin (0.1 mg/kg per infusion, IV, three 3‐h sessions per day) for 9–10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10–40 μg/kg, i.p.) or directly into the lateral or fourth ventricles (1–3 μg). Clonidine (1–2 μg per site) or its charged analogue, 2‐[2,6‐diethylphenylamino]‐2‐imidazole (ST‐91, 0.5–1 μg per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress‐induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST‐91 consistently altered stress‐induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress‐induced reinstatement. 6‐Hydroxydopamine (6‐OHDA) lesions performed after training for heroin self‐administration had no effect on extinction of heroin‐taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress‐induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress‐induced reinstatement of heroin seeking.
Age‐related impairment in LTP is accompanied by enhanced activity of stress‐activated protein kinases: analysis of underlying mechanisms
Authors: O'Donnell Eamonn , Vereker Emily , Lynch M. A.
Published: March 2003

The age‐related impairment in long‐term potentiation in the rat dentate gyrus is coupled with an increase in the proinflammatory cytokine, interleukin‐1β (IL‐1β). It is possible that this increase in IL‐1β might be a consequence of the age‐related increase in reactive oxygen species production in hippocampal tissue. In this study we set out to identify the underlying cause of the age‐related increase in reactive oxygen species production and to establish whether any consequences of such a change might impact on the ability of aged rats to sustain long‐term potentiation (LTP). We report that there was an age‐related increase in the activity of superoxide dismutase but no parallel increases in activities of glutathione peroxidase or catalase, while age‐related decreases in the concentration of the scavengers, vitamins E and C and glutathione were also observed. We propose that these compromises in antioxidative strategies may result in an increase in reactive oxygen species production. The data described indicate that IL‐1β and H2O2 increase the activity of two stress‐activated mitogen‐activated protein kinases, c‐Jun NH2‐terminal kinase (JNK) and p38 in vitro, while age‐related increases in both kinases were observed. We propose that the endogenous increase in these parameters which occurs with age induces the increase in activity of the stress‐activated kinases, which in turn impacts on the ability of the aged rat to sustain LTP.
Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements
Authors: Vila M. , Périer C. , Féger J. , Yelnik J. , Faucheux B. , Ruberg M. , Raisman‐Vozari R. , Agid Y. , Hirsch E. C.
Published: March 2003

Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6‐hydroxydopamine (6‐OHDA) in rats. In parallel, the time‐dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6‐OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity.
Metabotropic glutamate receptors and blockade of glial Krebs cycle depress glycinergic synaptic currents of mouse hypoglossal motoneurons
Authors: Hülsmann Swen , Oku Yoshitaka , Zhang Weiqi , Richter Diethelm W.
Published: March 2003

Metabotropic glutamate receptors are known to depress synaptic transmission by inhibiting transmitter release from presynaptic nerve terminals. This study reports the effects of presynaptic metabotropic glutamate receptor activation on inhibitory synaptic transmission in hypoglossal motoneurons in brainstem slice preparations of neonatal mice. Whole‐cell patch‐clamp recordings were performed on hypoglossal motoneurons of 2–6‐day‐old mice. Monosynaptic glycinergic currents were elicited by electrical stimulation of the nucleus of Roller. Application of the specific metabotropic glutamate receptor agonists (±)‐1‐aminocyclopentane‐trans‐1,3,dicarboxylic acid (t‐ACPD), (2 s,2′r,3′r)‐2‐(2′,3′‐dicarboxylcyclopropyl)‐glycine (DCG‐IV) or l‐2‐amino‐4‐phosphonobutyric acid (L‐AP4) depressed stimulus‐evoked glycinergic inhibitory postsynaptic currents (IPSCs) by an average of 39.5, 59.4 and 39.2%, respectively. In the presence of t‐ACPD, glycinergic miniature IPSCs were reduced in frequency but not in amplitude, which is indicative of a presynaptic mechanism. A similar reduction of IPSC amplitude was observed in the presence of elevated extracellular glutamate or during application of d,l‐threo‐hydroxyaspartate (THA), a blocker of glutamate transport, respectively. The data suggest that uptake of glutamate, which is predominately carried out by glial cells, can prevent spill‐over of glutamate and activation of metabotropic glutamate receptors. A reduction of IPSCs was also observed following application of monofluoroacetic acid, a substance acting specifically on glial cells. Our results suggest that glial regulation of extracellular glutamate uptake can prevent spill‐over of glutamate, and glutamatergic depression of glycinergic inhibition in hypoglossal motoneurons.
Different forms of LTD in the CA1 region of the hippocampus: role of age and stimulus protocol
Authors: Kemp Nicola , McQueen Jane , Faulkes Suzanna , Bashir Zafar I.
Published: March 2003

In this study, we have investigated the developmental range over which different stimulus protocols induce long‐term depression (LTD). Low‐frequency stimulation (LFS; 900 stimuli, 1 Hz) produced LTD in hippocampal slices from rats younger than ∼ 40 days old, but not in animals aged between ∼ 40 days and 16 weeks. We demonstrate, however, that different stimulus protocols can result in LTD in the adult hippocampus. Whilst one paired‐pulse low‐frequency stimulus protocol [PP‐LFS; 50 ms paired‐pulse interval (PPI), 900 pairs of stimuli] produced N‐methyl‐ d‐aspartate (NMDA) receptor‐independent LTD, another PP‐LFS protocol (200 ms PPI; 900 pairs) produced NMDA receptor‐dependent LTD. Furthermore, the saturation of NMDA receptor‐dependent LTD did not prevent the induction of further NMDA receptor‐independent LTD. This lack of occlusion suggests that different mechanisms of expression may underlie each of the above forms of LTD in the adult hippocampus. In contrast to the adult hippocampus, NMDA receptor‐dependent LTD was induced by both LFS and PP‐LFS (50 ms PPI) in slices from young animals (12–20 days). Although they share a common induction mechanism, LTD induced by PP‐LFS may be expressed through other mechanisms in addition to those underlying LFS‐induced LTD in the young hippocampus. In conclusion, the results in this study demonstrate that mechanisms of long‐term synaptic depression within the hippocampus can alter radically with development of the central nervous system and with the use of different induction protocols.
The architecture of the colour centre in the human visual brain: new results and a review *
Authors: Bartels A. , Zeki S.
Published: March 2003

We have used the technique of functional magnetic resonance imaging (fMRI) and a variety of colour paradigms to activate the human brain regions selective for colour. We show here that the region defined previously [Lueck et al. (1989) Nature, 340, 386–389; Zeki et al. (1991) J. Neurosci., 11, 641–649; McKeefry & Zeki (1997) Brain, 120, 2229–2242] as the human colour centre consists of two subdivisions, a posterior one, which we call V4 and an anterior one, which we refer to as V4α, the two together being part of the V4‐complex. The posterior area is retinotopically organized while the anterior is not. We discuss our new findings in the context of previous studies of the cortical colour processing system in humans and monkeys. Our new insight into the organization of the colour centre in the human brain may also account for the variability in both severity and degree of recovery from lesions producing cerebral colour blindness (achromatopsia).
Reversible protein kinase C activation in PC12 cells: effect of NGF treatment
Authors: Dupont Jean‐Luc , Janoshazi Agnes , Bellahcene Mohamed , Mykita Serge , De Barry Jean
Published: March 2003

Although protein kinase C (PKC) is a key enzyme in the signal transduction process, there is little information on the mechanism leading to PKC activation in living cells. Using a new fluorescence imaging method, we studied this mechanism and correlated PKC conformational changes with intracellular Ca2+ concentration. PC12 cells were simultaneously loaded with Fura‐2‐AM and Fim‐1, two fluorescent probes, which recognize Ca2+ and PKC, respectively. KCl and carbachol (an agonist to muscarinic receptors) applications induced dose‐dependent increases of fluorescence for both probes. Both Ca2+ and PKC responses were observed within seconds following KCl or carbachol application, and were reversible upon stimulus withdrawal. PKC activation kinetics was slightly more rapid than the Ca2+ response after KCl application. After nerve growth factor (NGF) treatment of the cells, the amplitude of the KCl‐induced PKC responses was larger indicating an increase in the activated PKC‐pool in these cells. This difference between control and NGF‐treated cells was not observed following carbachol application, suggesting the involvement of different PKC pools. While the Ca2+ response uniformly occurred in the cytosol, the PKC response displayed a patch pattern with higher intensities in the peripheral zone near the plasma membrane. This heterogeneous distribution of PKC activation sites was similar to the immunocytological localization of Ca2+‐dependent and independent PKC isoforms, which suggested that at least several PKC isoforms interacted with intracellular elements. Upon repeated stimulation, the PKC response rapidly desensitized.
Scale‐invariant superiority of foveal vision in perceptual categorization
Authors: Jüttner Martin , Rentschler Ingo
Published: March 2003

The recognition of objects is exceedingly difficult in indirect view. This complication cannot be explained in terms of retino‐cortical magnification, as size scaling fails to establish position invariance both for character recognition [Strasburger, H. & Rentschler, I. (1996) Eur. J. Neurosci., 8 1787–1791] and pattern classification [Jüttner, M. & Rentschler, I. (1996) Vision Res., 36, 1007–1021]. Thus we compared, for two tasks of discrimination learning and category learning with respect to a common set of grey‐level patterns, how humans perform in foveal and extrafoveal vision. Observers learnt to discriminate (size‐scaled) images equally well in foveal and extrafoveal view, whereas they displayed profound deficiencies in extrafoveal category learning for the same patterns. From the behavioural learning data, internal representations of the learning signals were reconstructed by means of computer simulations. For foveal view, these representations were found to be veridical to their physical counterparts for both learning tasks. For extrafoveal view, they were severely distorted for category learning but not for discrimination learning. A variance reduction of the pattern classes by a factor of 100 reduced the dissociation between extrafoveal categorization and discrimination but did not remove it. These observations suggest a scale‐invariant superiority of foveal vision for learning object categories. This implies a high degree of space variance of visual cognition which is vastly underestimated by classical measures of visual performance, e.g. acuity, visual field and contrast sensitivity.
A novel carboxypeptidase B that processes native β‐amyloid precursor protein is present in human hippocampus
Authors: Matsumoto Akira , Itoh Kyoko , Matsumoto Reiko
Published: March 2003

The processing of β‐amyloid precursor protein (APP) and generation of β‐amyloid (Aβ) are associated with the pathophysiology of Alzheimer's disease (AD). As the proteases responsible for the process in the human brain have yet to be clarified, we have searched for activities capable of cleaving native brain APP in the human hippocampus. A 40‐kDa protein with proteolytic activity that degrades native brain APP in vitro was purified and characterized; molecular analysis identified it as a novel protease belonging to the carboxypeptidase B (CPB) family. PC12 cells overexpressing the cDNA encoding this protease generate a major 12‐kDa β‐amyloid‐bearing peptide in cytosol, a peptide which has also been detected in a cell‐free system using purified brain APP as substrate. Although the protease is homologous to plasma CPB synthesized in liver, it has specific domains such as C‐terminal 14 amino acid residues. Western analysis, cDNA‐cloning process and Northern analysis suggested a brain‐specific expression of this protease. An immunohistochemical study showed that the protease is expressed in various neuronal perikarya, including those of pyramidal neurons of the hippocampus and ependymal‐choroid plexus cells, and in a portion of the microglia of normal brains. In brains of patients with sporadic AD, there is decreased neuronal expression of the protease, and clusters of microglia with protease immunoreactivity associated with its extracellular deposition are detected. These findings suggest that brain CPB has a physiological function in APP processing and may have significance in AD pathophysiology.
Comparison of the selectivity of postsynaptic potentials and spike responses in cat visual cortex
Authors: Volgushev Maxim , Pernberg Joachim , Eysel Ulf T.
Published: March 2003

Intracellular recordings were made from neurons in the cat visual cortex (area 17) to compare the orientation and direction selectivities of the output of a cell with those of the input the cell receives. The input to a cell was estimated from the PSPs (postsynaptic potentials) evoked by visual stimulation, and the output estimated from the number of spikes generated during the same responses. For the whole sample, selectivity of the output of cells was significantly higher than selectivity of their input. Upon PSP to spike transformation, the selectivity index was, on average, doubled. However, the degree of the selectivity improvement in individual cells was very different, varying from cases in which highly selective output was created from a poorly selective input and thus selectivity was greatly improved, to little or no improvement in other neurons. The improvement of selectivity was not correlated with resting membrane potential, threshold for action potential generation, background discharge rate or amplitude of optimal PSP response. Further, no systematic difference was found between simple and complex cells in the input–output relations, indicating that the ‘tip of the iceberg’ effect on shaping the response selectivity was cell specific, but not cell type specific. This supports the notion that multiple mechanisms are responsible for generation of the response selectivity, and that the contribution of any particular mechanism may vary from one cell to the other. The heterogeneity of the input–output relations in visual cortical cells could indicate different functions of cells in the cortical network; some cells are creating selectivity de novo, the function of other neurons probably being repetition and amplification of the selected signal and arrangement of the output of a whole column.
Substantia nigra pars reticulata units in 6‐hydroxydopamine‐lesioned rats: responses to striatal D2 dopamine receptor stimulation and subthalamic lesions
Authors: Tseng Kuei Y. , Riquelme Luis A. , Belforte Juan E. , Pazo Jorge H. , Murer M. Gustavo
Published: March 2003

In order to increase our understanding of Parkinson's disease pathophysiology, we studied the effects of intrastriatally administered selective dopamine receptor agonists on single units from the substantia nigra pars reticulata of 6‐hydroxydopamine (6‐OHDA)‐lesioned rats with or without an additional subthalamic nucleus lesion. Nigral pars reticulata units of 6‐OHDA‐lesioned rats were classified into two types, showing regular and bursting discharge patterns, respectively (‘non‐burst’ and ‘burst’ units). Non‐burst and burst units showed distinct responses to intrastriatal quinpirole (the former were excited and burst units inhibited). Furthermore, subthalamic nucleus lesions significantly decreased the number of nigral units showing a spontaneous bursting pattern, and reduced the proportion of units that responded to quinpirole. In contrast, subthalamic lesions did not alter the proportion of nigral units that responded to SKF38393, although the lesions changed some response features, e.g. response type and magnitude. Burst analysis showed that quinpirole did not modify the discharge pattern of burst units, whereas SKF38393 produced a shift to regular firing in 62% of the burst units tested. In conjunction, our results support that: (i) the subthalamic nucleus has an important influence on output nuclei firing pattern; (ii) striatal D2 receptors have a strong influence on nigral firing rate, and a less relevant role in controlling firing pattern; (iii) burst and non‐burst units differ in their response to selective stimulation of striatal dopamine receptors; (iv) the effects of striatal D2 receptors on nigral units are mainly, though not exclusively, mediated by the subthalamic nucleus; and (v) nigral responses to SKF38393 involve the subthalamic nucleus.
Involvement of a basolateral amygdala complex–nucleus accumbens pathway in glucocorticoid‐induced modulation of memory consolidation
Authors: Setlow Barry , Roozendaal Benno , McGaugh James L.
Published: March 2003

Systemic or intracerebral administration of glucocorticoids modulates memory consolidation in several tasks. Previously, we have shown that these memory‐modulatory effects depend on an intact basolateral complex of the amygdala (BLC) and efferents from the BLC that run through the stria terminalis. It is currently unknown, however, what BLC efferent structures mediate these effects. The present experiments were designed to determine whether the nucleus accumbens (NA), which receives BLC efferents through the stria terminalis and is involved in several BLC‐dependent behaviours, is involved in glucocorticoid‐induced modulation of memory consolidation. In experiment 1, rats with bilateral sham or N‐methyl‐ d‐aspartate (NMDA)‐induced lesions of the NA were trained on a one‐trial, footshock‐motivated inhibitory avoidance task, and given immediate post‐training injections of either the synthetic glucocorticoid dexamethasone (0.3 or 1.0 mg/kg, s.c.) or vehicle. Testing 48 h later revealed that dexamethasone significantly enhanced retention in sham‐lesioned rats but that the enhancing effect was blocked in NA‐lesioned rats. An asymmetrical, or crossed‐lesion design was employed in experiment 2. Rats with a unilateral NMDA‐induced lesion of the BLC and a unilateral lesion of either the ipsilateral or contralateral NA were trained as in experiment 1. Testing 48 h later revealed that dexamethasone enhanced retention in ipsilaterally lesioned rats, but that this effect was blocked in contralaterally lesioned rats. These findings indicate that an intact BLC–NA pathway is critical for the enhancing effects of glucocorticoids on memory consolidation, and are consistent with the view that the BLC regulates memory consolidation in other brain regions.
L‐type Ca2+ channels and purinergic P2X2 cation channels participate in calcium‐tyrosine kinase‐mediated PC12 growth cone arrest
Authors: Schindelholz Benno , Reber Bernhard F. X.
Published: March 2003

During development and regeneration of the nervous system, growth cones of the various nerve cells navigate and direct neurite elongation by detecting and responding to cues in the environment. To investigate changes in growth cone behaviour due to calcium influx we used nerve growth factor (NGF)‐induced growth cones of PC12 (rat pheochromocytoma cells) cells as a model. High external concentrations of potassium and ATP depress growth cone motility, induce club‐shaped growth cones and reduce filopodia length and the number and relative F‐actin contents of single growth cones (r.a.c.), respectively. The cellular responses are mediated by a sustained increase in the intracellular free Ca2+ concentrations ([Ca2+]i) as monitored by calcium‐sensitive fluorescent dyes and confocal microfluorimetry. The responses are not detectable in the presence of the protein tyrosine kinase inhibitor genistein. Immunocytochemistry revealed an increased level of tyrosine‐phosphorylated proteins in cell bodies and growth cones but not in cell nuclei. Paxillin, a cytoskeleton‐associated protein located in neurites and growth cones, was detected among the phosphotyrosine proteins. The sustained (> 30 s) Ca2+ influx through voltage‐gated L‐type but not N‐ or P‐type Ca2+ channels induced the F‐actin loss and tyrosine phosphorylation. Ca2+ entry through P2X2 ligand‐gated channels caused the same effects. Our data suggest the following mechanism: increased [Ca2+]i levels activate tyrosine kinases located close to the ion channels which then leads to changes in morphology due to tyrosine phosphorylation of proteins, e.g. paxillin.