bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of STN lesions on simple vs choice reaction time tasks in the rat: preserved motor readiness, but impaired response selection
Authors: Baunez Christelle , Humby Trevor , Eagle Dawn M. , Ryan Lawrence J. , Dunnett Stephen B. , Robbins Trevor W.
Published: March 2003

The subthalamic nucleus (STN) is a key structure within the basal ganglia, inactivation of which is a current strategy for treating parkinsonism. We have previously shown that bilateral lesions of the STN or pharmacological inactivation of this structure in the rat induce multiple deficits in serial reaction time tasks. The aim of the present study was to investigate further a possible role for the STN in response preparatory processes by using simple (SRT) and choice (CRT) reaction time tasks. In contrast to the CRT procedure, the information related to the location of where the response had to be made was given in advance in the SRT procedure. Accurate performance on these tasks requires not only the selection of the correct response (i.e. which response), but also preparation in order to perform when required. A comparison between the two tasks allows assessment of whether STN lesions affect which response (‘which’) or when to perform it (‘when’). As previously observed in these procedures, the responses were faster as a function of the variable foreperiod preceding the trigger stimulus. This well‐known effect, termed ‘motor readiness’, was maintained after STN lesions, suggesting that STN lesions did not affect the ‘when’ phase of action preparation. However, while performance on the SRT was faster than on the CRT task preoperatively, STN lesions slowed RTs and abolished the beneficial effect of advance information, suggesting a deficit in the selection (‘which’) phase of response preparation. This deficit in the selection phase was further supported by deficits in accuracy of responding after STN lesions, as well as increases in mislocated premature responding in the SRT condition. Together, these results suggest that the STN plays an important role in response preparatory processes, including response selection and inhibitory control processes.
Hippocampus and homing in pigeons: left and right hemispheric differences in navigational map learning
Authors: Gagliardo Anna , Ioalè Paolo , Odetti Francesca , Bingman Verner P. , Siegel Jennifer J. , Vallortigara Giorgio
Published: March 2003

One‐month‐old, inexperienced homing pigeons, prior to any opportunity to learn a navigational map, were subjected to either right or left unilateral ablation of the hippocampal formation (HF). These pigeons were then held together with a group of age‐matched control birds in an outdoor aviary, where they were kept for about 3 months with the opportunity to learn a navigational map. When subsequently tested for navigational map learning at about 4 months of age posthatching, control and right HF‐ablated pigeons were equally good at orienting homeward from distant, unfamiliar locations, indicating successful navigational map learning. By contrast, left HF‐ablated pigeons were impaired in orienting homeward, indicating a failure to learn a navigational map. Interestingly, both right and left HF‐ablated pigeons displayed impaired homing performance relative to controls. These results suggest that different aspects of homing pigeon navigation may be lateralized to different hemispheres, and in particular, the HF of the different hemispheres. The left HF appears critical for navigational map learning, i.e. determining an approximate direction home from distant, unfamiliar locations. The right HF, and possibly the left HF as well, appear to play an important role in local navigation near the loft, which is likely based on familiar landmarks.
Sindbis viral‐mediated expression of Ca2+‐permeable AMPA receptors at hippocampal CA1 synapses and induction of NMDA receptor‐independent long‐term potentiation
Authors: Okada Takashi , Yamada Nobuaki , Kakegawa Wataru , Tsuzuki Keisuke , Kawamura Meiko , Nawa Hiroyuki , Iino Masae , Ozawa Seiji
Published: March 2003

Gene manipulation in order to artificially express a particular gene in neurons in the central nervous system is a powerful tool for the analysis of brain function. Sindbis viral vectors have been developed to express high levels of foreign genes in postmitotic brain neurons with little transfection of glial cells. In this study, we expressed the gene encoding the unedited GluR2 (GluR‐B) subunit of the AMPA‐type glutamate receptor that forms inwardly rectifying and Ca2+‐permeable channels, in rat CA1 hippocampal neurons in slice cultures using Sindbis viral vectors. The pyramidal cell layer of the CA1 region was injected with recombinant Sindbis viruses encoding both enhanced green fluorescent protein (GFP) and unedited GluR2. The GFP fluorescence from CA1 neurons could be detected as early as 6 h and reached a maximal level about 48 h postinfection. The inwardly rectifying and Ca2+‐permeable AMPA receptors were expressed in most CA1 pyramidal cells expressing GFP. These AMPA receptors expressed by gene transfer were involved in fast excitatory neurotransmission elicited by electrical stimulation of the Schaffer collaterals in the stratum radiatum. Tetanic stimulation of Schaffer collaterals induced NMDA receptor‐independent, long‐term potentiation due to Ca2+ influx through the newly expressed AMPA receptors in the area densely stained with GFP. Thus, the combined use of Sindbis viral vectors with the GFP reporter allowed physiological examination of the roles of a specific gene product in synaptic function in well‐characterized brain neurons.
Modifications of intracellular Ca2+ signalling during nerve growth factor‐induced neuronal differentiation of rat adrenal chromaffin cells
Authors: Jiménez Nicolás , Hernández‐Cruz Arturo
Published: March 2003

Postnatal sympathetic neurons (SNs) and chromaffin cells (CCs) derive from neural crest precursors. CCs can differentiate in vitro into SN‐like cells after nerve growth factor (NGF) exposure. This study examines changes of intracellular Ca2+ homeostasis and dynamics of CCs under conditions that promote a neuronal phenotype. Spontaneous Ca2+ fluctuations, a frequent observation in early cultures of CCs, diminished after > 10 days in vitro in control cells and ceased in NGF‐treated ones. At the same time, Ca2+ rises resulting from entry upon membrane depolarization, gradually increased both their size and peak d[Ca2+]i/dt, resembling those recorded in SNs. Concomitantly, caffeine‐induced Ca2+ rises, resulting from Ca2+ release from intracellular stores, increased their size and their peak d[Ca2+]i/dt by > 1000%, and developed transient and sustained release components, similar to those of SNs. The transient component, linked to regenerative Ca2+ release, appeared after > 10 days of NGF treatment, suggesting a delayed steep enhancement of Ca2+‐induced Ca2+ release (CICR). Immunostaining showed that proteins coded by the three known isoforms of ryanodine receptors (RyRs) are present in CCs, but that only RyR2 increased significantly after NGF treatment. Since the transient release component increased more steeply than RyR2 immunostaining, we suggest that the development of robust CICR requires both an increased expression of RyRs and more efficient functional coupling among them. NGF‐induced transdifferentiation of chromaffin cells involves the enhancement of both voltage‐gated Ca2+ influx and Ca2+ release from intracellular stores. These modifications are likely to complement the extensive morphological and functional reorganization required for the replacement of the endocrine phenotype with the neuronal one.
Protein kinase Cα and β1 isoforms are regulators of α‐secretory proteolytic processing of amyloid precursor protein in vivo
Authors: Roßner S. , Mendla K. , Schliebs R. , Bigl V.
Published: March 2003

We have recently shown that in utero treatment of guinea pigs with the DNA methylating substance methylazoxymethanol acetate (MAM) results in neocortical microencephalopathy, increased protein kinase C (PKC) activity and altered processing of the amyloid precursor protein (APP) in neocortex of offspring. Here we show that PKCα and PKCβ1 are the key regulators of α‐secretory APP processing in guinea pig neocortex under these experimental conditions in vivo. This conclusion is based on the selective translocation of PKCα and PKCβ1 isoforms to the cell membrane in MAM‐treated guinea pigs, as revealed by Western blot analysis and by immunocytochemistry. Additionally, we observed that [3H]phorbol ester binding to protein kinase C increased by 38% and enhanced basal PKC activity by 58% in the neocortex of microencephalic guinea pigs. Inhibition of PKCα/PKCβ1 by Gö6976 abolished this difference, suggesting that constitutive overactivation of these PKC isoforms accounts for the increase in total PKC activity. We also observed a strong positive correlation between levels of α‐secretase‐processed APP and PKC activity in the neocortex of individual animals, providing further evidence for a significant role of classical PKC isoforms in nonamyloidogenic APP processing.
Nitric oxide up‐regulates ferritin mRNA level in snail neurons
Authors: Xie Mingqiang , Hermann Anton , Richter Klaus , Engel Edwin , Kerschbaum Hubert H.
Published: March 2003

We cloned and sequenced the ferric ion‐binding protein, ferritin, from the nervous system of the pulmonate snail, Helix pomatia. Helix H‐ferritin cDNA contains a 519‐bp open reading frame (ORF) and predicts an iron‐responsive element (IRE) at the 5′‐untranslated region (5′‐UTR) of the ferritin mRNA. The deduced amino acid sequence revealed 86% similarity with Lymnaea stagnalis ferritin and about 70% similarity with vertebrate H‐ferritin. While secreted ferritin isoforms contain a signalling sequence at their N‐terminal end, Helix ferritin does not contain this sorting signal indicating that it is restricted to the cytoplasm. The amino acid ligands at positions Glu25, Tyr30, Glu59, Glu60, His63, Glu105 and Gln139 indicate an active ferroxidase site in Helix ferritin. In situ hybridization visualized ferritin mRNA in neuronal cell bodies but not in the neuropil. In contrast, ferritin‐immunoreactive protein was localized in cell bodies and neurites. We further demonstrate that the NO donors S‐nitroso‐N‐acetylpenicillamine (SNAP), or hydroxylamine (HA), increase the intracellular ferritin mRNA level by about 55%. In conclusion, our findings show that Helix neurons express an intracellular H‐ferritin isoform and suggest that iron and NO metabolism are coupled.
Neural correlates of religious experience
Authors: Azari Nina P. , Nickel Janpeter , Wunderlich Gilbert , Niedeggen Michael , Hefter Harald , Tellmann Lutz , Herzog Hans , Stoerig Petra , Birnbacher Dieter , Seitz Rüdiger J.
Published: March 2003

The commonsense view of religious experience is that it is a preconceptual, immediate affective event. Work in philosophy and psychology, however, suggest that religious experience is an attributional cognitive phenomenon. Here the neural correlates of a religious experience are investigated using functional neuroimaging. During religious recitation, self‐identified religious subjects activated a frontal–parietal circuit, composed of the dorsolateral prefrontal, dorsomedial frontal and medial parietal cortex. Prior studies indicate that these areas play a profound role in sustaining reflexive evaluation of thought. Thus, religious experience may be a cognitive process which, nonetheless, feels immediate.
Multiple‐site optical recording reveals embryonic organization of synaptic networks in the chick spinal cord
Authors: Mochida Hiraku , Sato Katsushige , Arai Yoshiyasu , Sasaki Shinichi , Yazawa Itaru , Kamino Kohtaro , Momose‐Sato Yoko
Published: March 2003

We examined embryonic expression of postsynaptic potentials in stages 26–31 (E5 to E7) chick spinal cord slices. Slow optical signals related to the postsynaptic potentials which were evoked by electrical stimulation of afferent fibers were identified in the dorsal grey matter and the ventral motoneuronal area. In cervical spinal cord (C13) preparations, the dorsal slow signal appeared from stage 28 (E6), whilst the ventral slow signal was recognized from stage 29. At stages 26 and 27 (E5), no slow signal was observed in either the dorsal or ventral regions. On the other hand, in lumbosacral spinal cord (LS5) preparations, the dorsal, as well as ventral, slow signals appeared from stage 29; at stage 28 no slow signal was detected in the dorsal or ventral regions. These results suggest that there are differences in the ontogenetic expression of synaptic functions between the dorsal and ventral regions, and between the cervical and lumbosacral spinal cords. In embryos older than stage 29, removal of Mg2+ from the bathing solution markedly enhanced the amplitude and incidence of the ventral slow signal. In addition, in C13 preparations at stage 28, removal of Mg2+ elicited small slow signals in the ventral region in which no synaptic response was evoked in normal Ringer's solution. The slow signals induced in the Mg2+‐free solution were blocked by 2‐amino‐5‐phosphonovaleric acid (APV), showing that they are attributable to N‐methyl‐d‐aspartate (NMDA) receptors. These results suggest that functional synaptic connections via polysynaptic pathways are already generated on motoneurons, but are suppressed by a Mg2+ block on the NMDA receptors at developmental stages when synaptic transmission from the primary afferents to the dorsal interneurons is initially expressed in the dorsal region.
Regulation of SSAT expression by synaptic activity
Authors: Ingi Tatsuya , Worley Paul F. , Lanahan Anthony A.
Published: March 2003

Neuronal activity is a requirement for the plasticity and normal development of the central nervous system. We have used differential cloning techniques to identify an immediate‐early gene (IEG) that is rapidly induced in neurons by activity in both adult and developmental models of plasticity. Here we describe the key regulatory enzyme of polyamine catabolism, spermidine/spermine N1‐acetyltransferase (SSAT), as a neuronal IEG. In the rat brain, kainate‐induced seizures result in a 5.5‐fold increase in the amount of SSAT mRNA above basal levels and the enzymatic activity is increased twofold. Expression of SSAT mRNA is rapidly and transiently upregulated in the cerebral cortex and hippocampus by seizure‐induced neuronal activation. In hippocampal neurons, SSAT expression is dynamically responsive to synaptic activity in the long‐term potentiation (LTP) paradigm. In developing brain, region‐specific expression of SSAT mRNA is first detected at postnatal day 9 (P9) and subsequently increases through days P15, P20, before reaching maximal level in adult animals. This dynamic transcriptional and translational control suggests that SSAT may play a role in activity‐dependent neuronal plasticity and development.
Novelty enhances retrieval: molecular mechanisms involved in rat hippocampus
Authors: Izquierdo L. A. , Viola H. , Barros D. M. , Alonso M. , Vianna M. R. M. , Furman M. , Levi de Stein M. , Szapiro G. , Rodrigues C. , Choi H. , Medina J. H. , Izquierdo I.
Published: March 2003

Rats exposed to a novel environment just prior to or 1–2 h, but not 4 or 6 h, before retention testing exhibited an enhanced retrieval of a one‐trial inhibitory avoidance training. The bilateral intrahippocampal infusion of PD098059, an inhibitor of mitogen‐activated protein kinase (MAPK), the specific upstream activator of p42 and p44 MAPKs, given 10 min before the exposure to the novel environment, blocked the enhancing effect of novelty on memory retrieval. In addition, prenovelty infusion of dl‐2‐amino‐5‐phosphonovalerate (APV), an antagonist of glutamate NMDA receptors, produced similar effects. The exposure to the novel environment is associated with an activation of p42 and p44 MAPKs and an increase in the phosphorylation state of the transcription factor cAMP response element binding protein (CREB). No changes were observed in cAMP‐dependent protein kinase (PKA) activity or in α‐CAMKII activation. Taken together, our results indicate that novelty activates hippocampal MAPKs, which are necessary, along with glutamate NMDA receptors, for the enhancing effect of novelty on retrieval.
Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala
Authors: Hall Jeremy , Thomas Kerrie L. , Everitt Barry J.
Published: March 2003

Fear memory retrieval has been shown to induce a protein‐synthesis dependent re‐consolidation of memories within the amygdala. Here, using immunocytochemistry, we investigated the molecular basis of this process in the rat and show that retrieval of a cued fear memory induces the activation, by phosphorylation, of the transcription factor CREB within the basal and lateral nuclei of the amygdala, as well as expression of the CREB‐regulated immediate‐early gene, c‐fos, in the basal amygdala. We also show an increase in CREB phosphorylation within the central nucleus of the amygdala following behavioural testing, with an accompanying increase in Fos‐immunoreactive nuclei in animals retrieving the cued association. There were no changes in either phosphorylated CREB or Fos in the hippocampus following exposure to discrete fear stimuli. These results show that activation of CREB, which has been shown to be involved in the formation of long‐term fear memories, also accompanies memory retrieval, and also suggest a role for CREB phosphorylation in memory re‐consolidation following retrieval.
Kindling of claustrum and insular cortex: comparison to perirhinal cortex in the rat
Authors: Mohapel Paul , Zhang Xia , Gillespie Greg W. , Chlan‐Fourney Jennifer , Hannesson Darren K. , Corley Shannon M. , Li Xin‐Min , Corcoran Michael E.
Published: March 2003

The perirhinal cortex has recently been implicated in the kindling of limbic generalized seizures. The following experiments in rats tested the selectivity of the perirhinal cortex's epileptogenic properties by comparing its kindling profile with those of the adjacent insular cortex, posterior (dorsolateral) claustrum and amygdala. The first experiment examined the kindling and EEG profiles, and found that both the claustrum and insular cortex demonstrated rapid epileptogenic properties similar to the perirhinal cortex, including very rapid kindling rates and short latencies to convulsion. Furthermore, electrical stimulation of all three structures led to a two‐phase progression through stage‐5 seizures which had characteristics of both neocortical and amygdaloid kindling. In a second experiment rats were suspended in a harness to allow for more detailed documentation of both forelimb and hindlimb convulsions. With this procedure we were able to detect subtle yet unique differences in convulsion characteristics from each of the kindled sites and stage‐5 seizure phases. Some of these convulsive parameters were correlated with changes in FosB/ΔFosB protein and BDNF mRNA expression measured two hours after the last convulsion. Overall, it appears that the perirhinal cortex is not unique in its property of rapid epileptogenesis. Moreover, the posterior claustrum exhibited the fastest kindling and most vigorous patterns of clonus, suggesting that it may be even more intimately associated with the motor substrates responsible for limbic seizure generalization than is the perirhinal cortex.
For whales and seals the ocean is not blue: a visual pigment loss in marine mammals*
Authors: Peichl Leo , Behrmann Günther , Kröger Ronald H. H.
Published: March 2003

Most terrestrial mammals have colour vision based on two spectrally different visual pigments located in two types of retinal cone photoreceptors, i.e. they are cone dichromats with long‐to‐middle‐wave‐sensitive (commonly green) L‐cones and short‐wave‐sensitive (commonly blue) S‐cones. With visual pigment‐specific antibodies, we here demonstrate an absence of S‐cones in the retinae of all whales and seals studied. The sample includes seven species of toothed whales (Odontoceti) and five species of marine carnivores (eared and earless seals). These marine mammals have only L‐cones (cone monochromacy) and hence are essentially colour‐blind. For comparison, the study also includes the wolf, ferret and European river otter (Carnivora) as well as the mouflon and pygmy hippopotamus (Artiodactyla), close terrestrial relatives of the seals and whales, respectively. These have a normal complement of S‐cones and L‐cones. The S‐cone loss in marine species from two distant mammalian orders strongly argues for convergent evolution and an adaptive advantage of that trait in the marine visual environment. To us this suggests that the S‐cones may have been lost in all whales and seals. However, as the spectral composition of light in clear ocean waters is increasingly blue‐shifted with depth, an S‐cone loss would seem particularly disadvantageous. We discuss some hypotheses to explain this paradox.
Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson's disease
Authors: Kirik Deniz , Georgievska Biljana , Rosenblad Carl , Björklund Anders
Published: March 2003

Here we studied the effects of glial cell line‐derived neurotrophic factor (GDNF) in a rat model that represents the symptomatic stages of Parkinson's disease. GDNF was infused starting 2 weeks after an intrastriatal 6‐hydroxydopamine (6‐OHDA) lesion in order to halt the ongoing degeneration of the nigrostriatal dopaminergic neurons. GDNF or vehicle was infused in the striatum or the lateral ventricle via an osmotic minipump over a total 4‐week period (2–6 weeks postlesion). Motor function was evaluated by the stepping, paw reaching and drug‐induced motor asymmetry tests before the pump infusion was initiated, and was repeated once during (5 weeks postlesion) and twice after the withdrawal of the minipumps (7 and 11 weeks postlesion). We found that within two weeks following the lesion ≈ 40% of the nigral TH‐positive neurons were lost. In the vehicle infusion groups there was an additional 20% cell loss between 2 and 12 weeks after the lesion. This latter cell loss occurred mainly in the caudal part of the SN whereas the cell loss in the rostral SN was almost complete within the first two weeks. Ventricular GDNF infusion completely blocked the late degenerating neurons in the caudal SN and had long lasting behavioural effects on the stepping test and amphetamine rotation, extending to 6 weeks after withdrawal of the factor. Striatal infusion affected the motor behaviour transiently during the infusion period but the motor performance of these animals returned to baseline upon cessation of the GDNF delivery, and the delayed nigral cell loss was marginally affected. We conclude that intraventricular GDNF can successfully block the already initiated degenerative process in the substantia nigra, and that the effects achieved via the striatal route, when GDNF is given acutely after the lesion, diminish as the fibre terminal degeneration proceeds.
Behavioural profiling of a murine Charcot–Marie–Tooth disease type 1A model
Authors: Norreel J. C. , Jamon M. , Riviere G. , Passage E. , Fontes M. , Clarac F.
Published: March 2003

Different features of motor behaviour were studied on a transgenic mouse model of Charcot–Marie–Tooth's disease (CMT). Mutants with 4 or 7 copies of the human PMP22 gene leading to a phenotype significantly close to CMT's disease type 1A were compared with control animals. The aim of the study was to validate this transgenic model and to characterise the impairments occurring in the various lines. Three main types of analysis were performed in 2‐month‐old mice without any peculiar visible deficit: (i) a study of standardised clinical tests (SHIRPA protocol) demonstrated that only a few motor deficits were expressed; (ii) a measurement of general spontaneous activity by means of a commercial video‐tracking system was performed and revealed that the main spontaneous activities were identical in the three lines with, however, some slight localised modifications; and, (iii) by contrast, the three lines respond very differently to the footprints, grip strength, splay test and rotarod test. Even in lines with a significantly limited copy number of the transgene, we observed and quantified impairments. In conclusion, mutants of CMT1A seem to be a very pertinent model of this human pathology and will certainly be useful for therapeutic procedures and for theoretical studies on this disease.
Cannabinoid receptor activation and elevated cyclic AMP reduce glutamate neurotoxicity
Authors: Hampson A. J. , Grimaldi M.
Published: March 2003

Cannabinoid receptor activation in vivo reduces ischemic injury, a phenomenon that has not been successfully reproduced in vitro. Because cyclic adenosine monophosphate (cAMP) levels are radically elevated during ischemic reperfusion, but cannabinoid receptor activation reduces cAMP levels, we hypothesized that cannabinoids might prevent in vitro glutamate toxicity if reperfusion was simulated by cAMP supplementation after glutamate removal. Although neuronal cultures were unaffected by the single addition of either cannabinoid or dibutyryl cAMP (dbcAMP), glutamate toxicity was reduced by 20% when cannabinoid was present during glutamate exposure and either dbcAMP or forskolin was added after glutamate removal. Further studies revealed that cannabinoid receptor activation reduces glutamate toxicity by attenuating calcium influx through N‐ and P/Q‐type calcium channels. The effect of glutamate exposure on neuronal cAMP levels was also examined. Glutamate exposure significantly reduced neuronal cAMP levels, although suppression was even greater when cannabinoid was present. Because neurological outcome after ischemia is poor when cAMP levels during reperfusion are low, it is hypothesized that cAMP elevation after glutamate exposure may offset excitotoxic and/or cannabinoid receptor‐induced cAMP depletion. Cannabinoids protect against ischemic injury in vivo, but only reduce toxicity in vitro when cAMP levels are elevated, possibly suggesting that cAMP elevation during reperfusion reduces brain injury by off‐setting the effect of Gi/o protein‐coupled systems on adenylate cyclase.
Contribution of intralaminar thalamic nuclei to spike‐and‐wave‐discharges during spontaneous seizures in a genetic rat model of absence epilepsy
Authors: Seidenbecher Thomas , Pape Hans‐Christian
Published: March 2003

In an epileptic rat model of generalized absence epilepsies, the genetic absence epilepsy rats from Strasbourg (GAERS), simultaneous recordings of bilateral epidural electroencephalogram (EEG) of the prefrontal cortex and unit activity of neurons in the intralaminar centrolateral (CL) and paracentral thalamic nucleus (PC) were performed under neurolept‐anaesthesia (fentanyl–dehydrobenzperidol analgesia). Spike‐and‐wave (SW) seizures in these rats are characterized by generalized 7–10 Hz spike‐and‐wave discharges (SWDs) on the EEG. All neurons recorded in intralaminar thalamic nuclei during spontaneous SWDs showed high‐frequency (average 368 Hz, range 200–500 Hz), burst‐like activity, which occurred in a highly synchronized fashion with every SWD or with alternating SWD‐complexes. Burst discharges in intralaminar neurons were delayed by 13.1 ms (CL) and 12.7 ms (PC), with respect to the spike component of a given SWD on the EEG, whereas burst discharges in the ventrobasal thalamus (VB) and in the rostral nucleus reticularis thalami (rRT) preceded the spike component by 17.8 ms and 8.3 ms, respectively. The onset of SWDs on the EEG was preceded by a tonic firing pattern (20–50 Hz) in about one third of CL and PC neurons. Microiontophoretic application of the γ‐aminobutyric acid (GABA)A receptor antagonist bicuculline aggravated, whereas, the glutamate receptor antagonists DNQX and APV dampened, SWD‐related discharges in PC and CL; the GABAB receptor antagonist CGP 35347 had no measurable effect. These data indicate that intrathalamic nuclei are recruited rhythmically during SWDs, through mechanisms that seem to rely on a delayed glutamatergic excitation modulated by GABAergic influences, rather than a GABA‐mediated rebound burst activity typical of relay cells. The finding of a temporal delay of SWD‐related activity in intrathalamic, compared with ‘specific’ thalamic relay nuclei, does not support the notion of a leading or pacemaker role in SWD generation. It is, however, rather suggestive of a function of intrathalamic neurons during synchronization and maintenance of neuronal oscillations, and these intrathalamic neurons may be recruited through glutamatergic corticofugal inputs.
The cortical connections of area V6: an occipito‐parietal network processing visual information
Authors: Galletti Claudio , Gamberini Michela , Kutz Dieter F. , Fattori Patrizia , Luppino Giuseppe , Matelli Massimo
Published: March 2003

The aim of this work was to study the cortical connections of area V6 by injecting neuronal tracers into different retinotopic representations of this area. To this purpose, we first functionally recognized V6 by recording from neurons of the parieto‐occipital cortex in awake macaque monkeys. Penetrations with recording syringes were performed in the behaving animals in order to inject tracers exactly at the recording sites. The tracers were injected into the central or peripheral field representation of V6 in different hemispheres. Irrespective of whether injections were made in the centre or periphery, area V6 showed reciprocal connections with areas V1, V2, V3, V3A, V4T, the middle temporal area /V5 (MT/V5), the medial superior temporal area (MST), the medial intraparietal area (MIP), the ventral intraparietal area (VIP), the ventral part of the lateral intraparietal area and the ventral part of area V6A (V6AV). No labelled cells or terminals were found in the inferior temporal, mesial and frontal cortices. The connections of V6 with V1, and with all the retinotopically organized prestriate areas, were organized retinotopically. The connection of V6 with MIP suggests a visuotopic organization for this latter. Labelling in V6A and VIP after either central or peripheral V6 injections was very similar in location and extent, as expected on the basis of the nonretinotopic organization of these areas. We suggest that V6 plays a pivotal role in the dorsal visual stream, by distributing the visual information coming from the occipital lobe to the sensorimotor areas of the parietal cortex. Given the functional characteristics of the cells of this network, we suggest that it could perform the fast form and motion analyses needed for the visual guiding of arm movements as well as their coordination with the eyes and the head.
GABAA receptor subunit interactions important for benzodiazepine and zinc modulation: a patch‐clamp and single cell RT‐PCR study
Authors: Alsbo Carsten W. , Kristiansen Uffe , Møller Flemming , Hansen Suzanne L. , Johansen Flemming Fryd
Published: March 2003

The expression of mRNAs for the GABAA receptor subunits α1, α6, β2, β3, γ2 and δ in single mouse cerebellar granule cells and cortical interneurons were analysed by RT‐PCR and correlated to their midazolam and zinc modulation of agonist‐induced receptor currents. The registration of molecular and electrophysiological data from each cell allowed us to estimate the significance of individual subunits and their two‐factor interaction for modulation. The presence of α6 decreased midazolam modulation, but statistical analysis also suggested interactions of α6 with β3 and γ2 with respect to midazolam modulation. Zinc modulation was decreased by the presence of γ2, and analysis points to an β3 effect as well as an interaction between γ2 and δ in zinc modulation. Thus, our model confirmed, in single native cells, the known effects of α6 in midazolam and γ2 in zinc modulation, and additionally pointed to significant subunit interactions that need to be further tested in recombinant receptors. The present study offers a method to identify subunit interactions in heteromeric receptor complexes.
Human brain carboxypeptidase B, which cleaves β‐amyloid peptides in vitro, is expressed in the endoplasmic reticulum of neurons
Authors: Matsumoto Akira , Itoh Kyoko , Seki Tsuneyoshi , Motozaki Kenjiro , Matsuyama Shogo
Published: March 2003

Intracellular localization of novel human brain carboxypeptidase B (HBCPB) was investigated in human hippocampus, using immunohistochemistry by confocal laser microscopy and biochemical purification of the homogenate by density gradient ultracentrifugation. The former revealed that the majority of HBCPB was expressed in the endoplasmic reticulum, in which the HBCPB‐specific C14‐module immunoreactivity was colocalized with GRP78 immunoreactivity, a stress 70 heat shock protein specifically expressed in the endoplasmic reticulum. The latter showed that anti‐C14‐module immunoreactivity and prepro‐HBCPB immunoreactivity were both enriched in the microsome fraction, especially in that of the endoplasmic reticulum‐density fraction of normal human hippocampal homogenates from various sources. However, HBCPB prepared from human hippocampus showed exopeptidase activity for synthetic β‐amyloid 1–42 peptide, in which Aβ X‐42 C‐terminus immunoreactivity was decreased in a fashion dose‐dependent of the amount of the protease added. These findings indicate that HBCPB, which is expressed in the endoplasmic reticulum of a group of neuronal perikarya, may play an important physiological role in degradation of β‐amyloid 1–42, which is specifically generated in the endoplasmic reticulum of human and rodent neurons and is also regarded as the most pathogenic and aggregatable species among all β‐amyloid peptides.
An activity‐dependent switch from facilitation to inhibition in the control of excitotoxicity by group I metabotropic glutamate receptors
Authors: Bruno Valeria , Battaglia Giuseppe , Copani Agata , Cespédes Virtudes M. , Galindo María F. , Ceña Valentín , Sánchez‐Prieto Jose , Gasparini Fabrizio , Kuhn Rainer , Flor Peter J. , Nicoletti Ferdinando
Published: March 2003

Activation of group I metabotropic glutamate receptors (mGlu1 or ‐5 receptors) is known to either enhance or attenuate excitotoxic neuronal death depending on the experimental conditions. We have examined the possibility that these receptors may switch between two different functional modes in regulating excitotoxicity. In mixed cultures of cortical cells, the selective mGlu1/5 agonist, 3,5‐dihydroxyphenylglycine (DHPG), amplified neurodegeneration induced by a toxic pulse of NMDA. This effect was observed when DHPG was either combined with NMDA or transiently applied to the cultures prior to the NMDA pulse. However, two consecutive applications of DHPG consistently produced neuroprotection. Similar effects were observed with DHPG or quisqualate (a potent agonist of mGlu1/5 receptors) in pure cultures of cortical neurons virtually devoid of astrocytes. In cultures of hippocampal pyramidal neurons, however, only protective effects of DHPG were seen suggesting that, in these particular cultures, group I mGlu receptors were endogenously switched into a ‘neuroprotective mode’. The characteristics of the activity‐dependent switch from facilitation to inhibition were examined in mixed cultures of cortical cells. The switch in the response to DHPG was observed when the two applications of the drug were separated by an interval ranging from 1–45 min, but was lost when the interval was extended to 90 min. In addition, this phenomenon required the initial activation of mGlu5 receptors (as indicated by the use of subtype‐selective antagonists) and was mediated by the activation of protein kinase C. We conclude that group I mGlu receptors are subjected to an activity‐dependent switch in regulating excitotoxic neuronal death and, therefore, the recent ‘history’ of these receptors is critical for the response to agonists or antagonists.
Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons
Authors: Guo Xin , Dawson Valina L. , Dawson Ted M.
Published: March 2003

Immunosuppressant drugs, like FK506, and nonimmunosuppressant compounds like, GPI1046 and L685818, are immunophilin ligands that specifically bind to immunophilins, like FK506 binding protein 12 (FKBP12). Several lines of evidence show that these ligands exert neurotrophic properties in neural injury models and in PC12 cells. However, the mechanism of the neurotrophic function of the immunophilin ligands is poorly known. In the present study, we use MPP+ and 6‐OHDA toxicity models to examine both neuroprotective and neuroregenerative effects of immunophilin ligands on primary cultures of midbrain dopaminergic neurons. We find that FK506, GPI1046 and L685818 at concentrations from 0.01 to 1 μm partially, but significantly, protect dopaminergic neurons against both MPP+ and 6‐OHDA toxicity. By Western blot analysis, we also find that all three compounds prevent tyrosine hydroxylase (TH) loss induced by MPP+ and 6‐OHDA treatments. Morphologic analysis of dopaminergic neurons, by immunocytochemistry, shows that MPP+ and 6‐OHDA cause the retraction and loss of neuronal processes, while FK506, GPI1046 and L685818 promote regeneration of these processes as indicated by increases in process number and length. To examine if FKBP12 is required for neurotrophic effects of immunophilin ligands, we cultured dopaminergic neurons from FKBP12 knockout mice and find that FK506 still protects dopaminergic neurons against MPP+ toxicity. These results suggest that FKBP12 is not essential for the neurotrophic properties of immunophilin ligands, and immunophilin ligands are a new class of neuroprotective and neuroregenerative agents that may have therapeutic potential in a variety of neurological disorders.
Gene expression profiles during long‐term memory consolidation
Authors: Cavallaro Sebastiano , Schreurs Bernard G. , Zhao Weiqin , D'Agata Velia , Alkon Daniel L.
Published: March 2003

Changes in gene expression have been postulated to occur during long‐term memory (LTM). We used high‐density cDNA microarrays to assess changes in gene expression 24 h after rabbit eye blink conditioning. Paired animals were presented with a 400 ms, 1000 Hz, 82 dB tone conditioned stimulus that coterminated with a 100 ms, 60 Hz, 2 mA electrical pulse unconditioned stimulus. Unpaired animals received the same conditioned and unconditioned stimuli but presented in an explicitly unpaired manner. Differences in expression levels between paired and unpaired animals in the hippocampus and cerebellar lobule HVI, two regions activated during eye blink conditioning, indicated the involvement of novel genes as well as the participation of previously implicated genes. Patterns of gene expression were validated by in situ hybridization. Surprisingly, the data suggest that an underlying mechanism of LTM involves widespread decreased, rather than increased, gene expression. These results demonstrate the feasibility and utility of a cDNA microarray system as a tool for dissecting the molecular mechanisms of associative memory.
Electroencephalographic activity during perception of motion in childhood
Authors: Cochin S. , Barthelemy C. , Roux S. , Martineau J.
Published: March 2003

The purpose of the present study was to relate observations of biological motion to cortical activity by evaluation of the association of quantified electroencephalogram (qEEG) parameters with a video film projection. Thirty right‐handed healthy children (2–8‐year‐olds) viewed a video film showing still shots and moving shots with human movement or object movement. The EEG was recorded while children watched the video movie and was then subjected to spectral analysis; the spectral powers for theta, alpha and beta bands were matched with corresponding sequences of video film. The power values of each frequency band were analysed in a four‐way repeated‐measuresanova(Age × Hemisphere × Electrode × Sequence). Three main results were obtained: (i) younger children (2–4‐year‐olds) had higher power spectral values than older children (5–8‐year‐olds); (ii) greater EEG desynchronization of the left hemisphere was observed; (iii) observation of biological movement was related to a significant decrease in theta 1 and theta 2 power values of EEG in fronto‐temporal and central regions of the left hemisphere compared with visual perception of still shots or nonhuman movement. These results indicated some support for the theory that the sensori‐motor cortex and Broca's area are activated during visual observation of human motion.
Dissociable contributions of the orbitofrontal and lateral prefrontal cortex of the marmoset to performance on a detour reaching task
Authors: Wallis J. D. , Dias R. , Robbins T. W. , Roberts A. C.
Published: March 2003

To gain insight into the nature and neural specificity of the relationship between simple problem solving, inhibitory control and prefrontal cortex, comparison of the effects of excitotoxic lesions of the orbitofrontal and lateral prefrontal cortex were examined on the performance of common marmosets on a detour reaching task. Monkeys were required to inhibit reaching directly for food reward in a transparent box and instead make a detour reach around to the side of the box either having had (i) no prior experience on the task (experiment 1) or (ii) previous experience in reaching around the sides of an opaque box (experiment 2). Whilst monkeys with orbitofrontal lesions had difficulty in inhibiting direct reaches to visible food reward (experiment 1), they could resist this prepotent response tendency following extensive prior experience of detour reaching with an opaque box (experiment 2). In marked contrast, monkeys with lateral prefrontal lesions exhibited no difficulty in inhibiting reaching to visible food reward or acquiring detour reachingper se(experiment 1). However, having been given the opportunity to acquire an efficient detour reaching strategy to hidden food reward these lateral prefrontal lesioned monkeys were impaired at transferring this strategy to the new context in which the food reward was made visible (experiment 2). This double dissociation between the effects of orbitofrontal and lateral prefrontal lesions on detour reaching provides evidence for a clear distinction in the level of control over responding exerted by the orbitofrontal and lateral prefrontal cortex, consistent with hierarchical ordering of response control processes within prefrontal cortex.
Respiratory function in adult mice lacking the µ‐opioid receptor: role of δ‐receptors
Authors: Morin‐Surun Marie‐Pierre , Boudinot Eliane , Dubois Christelle , Matthes Hans W. , Kieffer Brigitte L. , Denavit‐Saubié Monique , Champagnat Jean , Foutz Arthur S.
Published: March 2003

Mice lacking the µ‐opioid receptor (MOR) provide a unique model to determine whether opioid receptors are functionally interactive. Recent results have shown that respiratory depression produced by δ‐opioid receptor agonists is suppressed in mice lacking the µ‐opioid receptor. Here we investigated the involvement of µ‐ and δ‐opioid receptors in the control of ventilation and µ/δ receptor interactions in brainstem rhythm‐generating structures. Unrestrained MOR–/– and wild‐type mice showed similar ventilatory patterns at rest and similar chemosensory responses to hyperoxia (100% O2), hypoxia (10% O2) or hypercapnia (5%CO2−95%O2). Blockade of δ‐opioid receptors with naltrindole affected neither the ventilatory patterns nor the ventilatory responses to hypoxia in MOR–/– and wild‐type mice. In‐vitro, respiratory neurons were recorded in the pre‐Bötzinger complex of thick brainstem slices of MOR–/– and wild‐type young adult mice. Respiratory frequency was not significantly different between these two groups. The δ2 receptor agonist deltorphin II (0.1–1.0 µm) decreased respiratory frequency in both groups whereas doses of the δ1 receptor agonist enkephalin[D‐Pen2,5] (0.1–1.0 µm) which were ineffective in wild‐type mice significantly decreased respiratory frequency in MOR–/– mice. We conclude that deletion of the µ‐opioid receptor gene has no significant effect on ensuing respiratory rhythm generation, ventilatory pattern, or chemosensory control. In MOR–/– mice, the loss of respiratory‐depressant effects of δ2‐opioid receptor agonists previously observed in vivo does not result from a blunted response of δ receptors in brainstem rhythm‐generating structures. These structures show an unaltered response to δ2‐receptor agonists and an augmented response to δ1‐receptor agonists.
Bimanual organization of manipulative forces: evidence from erroneous feedforward programming of precision grip
Authors: Serrien Deborah J. , Wiesendanger Mario
Published: March 2003

The objective of the present study was to investigate grip–load force regulation during a bimanual lifting task with two hand‐held objects. Various conditions were included during which the weight of one or both objects was changed in an unpredictable order every fourth trial. Results showed that force control of heavy weight movements preceded by light weight movements was not strongly influenced across trials. Conversely, force responses of light weight movements preceded by heavy weight movements were overestimated due to an augmented degree of grip force. However, successful updating of force output occurred after one trial. Furthermore, bimanual interactions between the grasping forces were observed, suggestive of a coordinative command that assimilated the individual response specifications. The latter also became apparent from a similar grip–load force ratio for both hands when the objects' physical properties had become predictable, independent of the forces that were produced according to the individual weight requirements. These data indicate that the grip–load force ratio is the controlled variable for bimanual manipulative behaviour.
Dendritic attenuation of synaptic potentials in the CA1 region of rat hippocampal slices detected with an optical method
Authors: Inoue Masashi , Hashimoto Yoshinori , Kudo Yoshihisa , Miyakawa Hiroyoshi
Published: March 2003

We directly measured fast excitatory postsynaptic potentials (EPSPs) along the dendrites of hippocampal CA1 pyramidal neurons by employing an optical method to study how synaptic potentials spread along the dendrites. Rat hippocampal slices were stained with a fluorescent voltage‐sensitive dye JPW1114 and optical signals were monitored with a 16 × 16 photodiode array system. A stimulating electrode was placed either at stratum lacunosum moleculare to activate perforant fibers that make synaptic contacts to the distal apical dendrites or at stratum oriens to induce EPSPs at the basal dendrites of CA1 pyramidal cells. CNQX‐sensitive components of the optical signals, which were assumed to be population EPSPs, were isolated. Propagation and attenuation of the CNQX components were successfully observed with the optical method. At the cell body layer, the peak of the CNQX‐sensitive component was delayed by 17.08 ± 1.64 ms from the input sites. Additionally we performed a simulation study to estimate the passive membrane parameters of the apical dendrites. Estimated apparent specific internal axial resistance (Ri) following stratum lacunosum moleculare stimulation was 76.0 ± 4.2 Ω·cm and apparent specific membrane resistance (Rm) was 27.8 ± 2.1 kΩ·cm2 (assuming the specific membrane capacitance of dendrites Cm = 1.6 µF/cm2). These values are comparable to those previously reported. When synaptic inputs were applied at stratum oriens, these apparent passive membrane parameters were different (high Ri and low Rm), suggesting that nonuniform dendritic membrane conductance or voltage‐dependent conductances which are active near the resting potential may contribute to the measured passive membrane properties.