bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of the predicted time of stimuli eliciting movements on responses of tonically active neurons in the monkey striatum
Authors: Sardo Pierangelo , Ravel Sabrina , Legallet Eric , Apicella Paul
Published: March 2003

Changes in activity of tonically active neurons of the primate striatum are determined both by the behavioural significance of stimuli and the context in which stimuli are presented. We investigated how the responses of these neurons are modified by the temporal predictability of stimuli eliciting learned behavioural reactions. Single neurons were recorded from the caudate nucleus and putamen of two macaque monkeys performing a visual reaction time task under conditions in which the timing of the trigger stimulus was made more or less predictable. The monkeys' ability to predict the trigger onset was assessed by measuring arm movement reaction times and saccadic ocular reactions. Of 171 neurons responding to the unsignalled presentation of the trigger stimulus, 32% lost their response when an instruction cue preceded the trigger by a highly practised 1.5 s interval, and the response reappeared when this interval was varied randomly from 1 to 2.5 s or prolonged to 3 or 4.5 s. Although 43% of the neurons remained responsive irrespective of task condition, the responses were stronger with longer intervals than with the accustomed 1.5 s interval. In addition, a number of neurons responding to the instruction lost their response when the trigger appeared more distant from the instruction. These findings demonstrate that neuronal responses to a movement‐triggering signal become more numerous and pronounced when the degree of temporal predictability of that signal was decreased. We conclude that tonic striatal neurons are sensitive to temporal aspects of stimulus prediction.
The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by β‐amyloid
Authors: Bastianetto Stéphane , Ramassamy Charles , Doré Sylvain , Christen Yves , Poirier Judes , Quirion Rémi
Published: March 2003

Substantial evidence suggests that the accumulation of β‐amyloid (Aβ)‐derived peptides, and to a lesser extent free radicals, may contribute to the aetiology and/or progression of Alzheimer's disease (AD). Ginkgo biloba extract (EGb 761) is a well‐defined plant extract containing two major groups of constituents, i.e. flavonoids and terpenoids. It is viewed as a polyvalent agent with a possible therapeutic use in the treatment of neurodegenerative diseases of multifactorial origin, e.g. AD. We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Aβ)‐derived peptides (Aβ25−35, Aβ1−40 and Aβ1−42) on hippocampal primary cultured cells, this area being severely affected in AD. A co‐treatment with EGb 761 concentration‐dependently (10–100 μg/mL) protected hippocampal neurons against toxicity induced by Aβ fragments, with a maximal and complete protection at the highest concentration tested. Similar, albeit less potent protective effects were seen with the flavonoid fraction of the extract (CP 205), while the terpenes were ineffective. Most interestingly, EGb 761 (100 μg/mL) was even able to protect (up to 8 h) hippocampal cells from a pre‐exposure to Aβ25−35 and Aβ1−40. EGb 761 was also able to both protect and rescue hippocampal cells from toxicity induced by H2O2 (50–150 μm), a major peroxide possibly involved in mediating Aβ toxicity. Moreover, EGb 761 (10–100 μg/mL), and to a lesser extent CP 205 (10–50 μg/mL), completely blocked Aβ‐induced events, e.g. reactive oxygen species accumulation and apoptosis. These results suggest that the neuroprotective effects of EGb 761 are partly associated with its antioxidant properties and highlight its possible effectiveness in neurodegenerative diseases, e.g. AD via the inhibition of Aβ‐induced toxicity and cell death.
SEK1/MKK4, c‐Jun and NFΚB are differentially activated in forebrain neurons during postnatal development and injury in both control and p75NGFR‐deficient mice
Authors: Ward Nicole L. , Hagg Theo
Published: March 2003

The common neurotrophin receptor (p75NGFR) can signal in vitro through activation of the c‐Jun N‐terminal kinase (JNK) pathway and nuclear translocation of NFΚB. Activation of JNK and its substrate c‐Jun can lead to apoptosis. We investigated these activities in vivo by comparing immunoreactivity for phosphorylated(p) SEK‐1 (or MKK4, which activates JNK), c‐Jun (ser63, ser73) and nuclear translocation of NFΚB‐p50 in tissue sections through the forebrain of control and p75NGFR‐deficient mice. During postnatal development, SEK1p‐immunoreactivity was detectable in p75NGFR‐positive cholinergic neurons and p75NGFR‐negative neurons throughout the forebrain in control mice. During development, few cells contained c‐Junp, although many neurons contained c‐Jun. No obvious c‐Jun immunostaining was present in the adult forebrain. At any age, NFΚB‐p50 immunoreactivity was seen in nuclei of most cells throughout the forebrain. Following fimbria fornix transection in adult mice, few basal forebrain neurons contained SEK1p while many axotomized choline acetyltransferase (ChAT)‐positive neurons contained c‐Junp and nuclear NFΚB‐p50. The immunostaining patterns of SEK1p, c‐Junp and NFKB during development and following injury were largely similar in p75NGFR‐deficient mice. During development, cells throughout the forebrain had TdT‐mediated dUTP‐biotin nick end labelling (TUNEL)‐labelling (a potential marker for apoptosis), however, their presence was not predicted by number of neurons stained for SEK1p or c‐Junp. These results suggest that the expected activation of the JNK pathway by p75NGFR, as well as the expected relationship between SEK1 and downstream activation of c‐Jun do not occur in the mammalian forebrain. Also, these results suggest that this activation does not necessarily lead to cell death.
Expression of Fos‐related antigens in the nucleus accumbens and associated regions following exposure to a cocaine‐paired environment
Authors: Franklin Teresa R. , Druhan Jonathan P.
Published: March 2003

This study examined whether conditioned hyperactivity measured in a cocaine‐paired environment was associated with increased expression of Fos‐related antigens (FRA) within the nucleus accumbens (NAc) and associated forebrain regions of rats. Three groups of rats were given repeated injections of either cocaine in the test environment and saline in the colony room (group Paired), saline in the test environment and cocaine in the colony room (group Unpaired), or saline in both environments (group Control). All rats were subsequently given a drug‐free test for conditioned hyperactivity in the test environment, and their brains were removed so that FRA immunohistochemistry could be conducted. Rats in the Paired group showed conditioned hyperactivity during the conditioning test, and this behavioural response was associated with increased FRA expression within the caudal NAc, the medial prefrontal cortex and the lateral septum relative to the Unpaired and Control groups. Paired rats also showed increased FRA expression within the orbital prefrontal cortex, the claustrum, the caudal amygdala (basolateral and central regions), the paraventricular thalamic nucleus, the subiculum of the hippocampus, and the lateral habenula relative to the Control group. However, the FRA levels in these latter sites were not significantly increased relative to those of Unpaired rats, indicating that genomic responses in these regions were not entirely context dependent. The correspondence between conditioned hyperactivity and enhanced FRA expression within the caudal NAc, the medial prefrontal cortex and lateral septum suggests that these regions may participate in the expression of conditioned responses to cocaine‐related stimuli.
Depolarization‐dependent survival of cultured mouse cerebellar granule neurons is strain‐restrained
Authors: Fujikawa Naoto , Tominaga‐Yoshino Keiko , Okabe Masaru , Ogura Akihiko
Published: March 2003

Cerebellar granule neurons (CGNs) isolated from the rat are often used as a model system for the analysis of activity‐dependent survival of neurons. These cells do not survive in culture without addition of a depolarizing agent (KCl or glutamate) to the medium. However, it has been reported that mouse CGN behave differently. Here we found that the requirement for depolarization for the survival of the mouse CGN was strain‐dependent, which may be important for future analyses using transgenic animals. CGNs from the Balb/C mouse could survive without KCl addition, whereas CGNs from the C57Bl/6 mouse could not (similar to the rat CGN). The survival‐promoting activity of the Balb/C mouse CGNs was transferable by coculturing. However, the medium of the Balb/C mouse CGN culture was ineffective, suggesting that the neurotrophic substance that is supposed to be released is labile. Although we are yet to specify the substance, it might be independent of neurotrophins. It is necessary to select the strain of mouse in the production of transgenic animals for the analyses of activity‐dependent neuronal survival.
X‐ray kinematic analysis of forelimb movements during target reaching and food taking in the cat
Authors: Boczek‐Funcke A. , Kuhtz‐Buschbeck J. ‐P. , Paschmeyer B. , Illert M.
Published: March 2003

We have used a three‐dimensional X‐ray cinematographic approach to investigate the kinematics of the forelimb during target reaching and food taking in five cats. Measurements of the trajectory of the limb during the reaching movement showed that the movement paths of the metacarpophalangeal joint (MCP) and the wrist were sigmoidal with a long nearly linear segment. The elbow followed a bent movement path with maximal inflection in the middle. The path of the humerus had an ascending parabola‐like characteristic. The velocity profiles of the MCP and wrist were nearly bell‐shaped and skewed to the left, whereas the profiles of the elbow joint were more or less double peaked with the second peak occurring 60–40 ms before object contact. Several different velocity peaks reflecting specific aspects of the task existed when the bell‐shaped velocity profiles were divided in their vectorial components. Angular motion of the elbow consisted of a flexion–extension sequence during the reach and a flexion during the subsequent retraction. After an initial flexion during lift‐off the wrist was extended. It kept this extended position during orienting towards the food container. During the retraction phase it was further extended. The angle between the wrist axis and the parasagittal plane changed during the movement. It first increased, then decreased during the last 100 ms before the object was reached. During the retraction it increased again to support the object weight against gravity. The position of the wrist was established by radio‐ulnar supination and movements of the whole arm around the shoulder joint. We hypothesize that the position of the wrist axis is the controlled variable during protraction and retraction, regardless of whether it is achieved by radio‐ulnar supination or by movements around the shoulder.
Reciprocal actions of interleukin‐6 and brain‐derived neurotrophic factor on rat and mouse primary sensory neurons
Authors: Murphy P. G. , Borthwick L. A. , Altares M. , Gauldie J. , Kaplan D. , Richardson P. M.
Published: March 2003

In low‐density, serum‐free cultures of neurons from embryonic rat dorsal root ganglia, interleukin‐6 supports the survival of less than one third of the neurons yet virtually all of them bear interleukin‐6 α‐receptors. A finding that might explain this selectivity is that interleukin‐6 acts on sensory neurons in culture through a mechanism requiring endogenous brain‐derived neurotrophic factor. Antibodies or a trkB fusion protein that block the biological activity of brain‐derived neurotrophic factor synthesized by dorsal root ganglion neurons also block the survival‐promoting actions of interleukin‐6 on these neurons. Two results indicate that interleukin‐6 influences synthesis of brain‐derived neurotrophic factor in adult dorsal root ganglion neurons. Intrathecal infusion of interleukin‐6 in rats increases the concentration of brain‐derived neurotrophic factor mRNA in rat lumbar dorsal root ganglia. The induction of brain‐derived neurotrophic factor in dorsal root ganglion neurons that is seen after nerve injury in rats or wild‐type mice is severely attenuated in mice with null mutation of the interleukin‐6 gene. In brief, the ability of interleukin‐6 to support the survival of embryonic sensory neurons in vitro depends upon the presence of endogenous brain‐derived neurotrophic factor and the induction of brain‐derived neurotrophic factor in injured adult sensory neurons depends upon the presence of endogenous interleukin‐6.
Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti‐inflammatory drug: implication in Alzheimer's disease
Authors: Scali Carla , Prosperi Costanza , Vannucchi Maria Giuliana , Pepeu Giancarlo , Casamenti Fiorella
Published: March 2003

Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and nonsteroidal anti‐inflammatory drugs have a protective effect in the disease. The aim of this study was to characterize in vivo in the rat brain the inflammatory reaction in response to excitotoxic insult and to investigate the efficacy of nimesulide treatment. Quisqualic acid was injected into the right nucleus basalis of rats. The excitotoxin induced cholinergic degeneration, an intense glial reaction and the production of inflammatory mediators. Three hours after injection, a five‐fold elevation in the concentration of interleukin‐1β in the injected area was observed. This elevation was reduced by 50% by nimesulide (10 mg/kg, i.m.) pretreatment. Electron microscope examination and immunocytochemical staining revealed an intense activation of microglia and astrocytes at both 24 h and 7 days after injection. Cyclooxygenase‐2‐immunoreactivity was induced in the blood vessels of the injected hemisphere in perivascular microglial and endothelial cells 24 h after injection. Seven days postinjection, a cyclooxygenase‐2‐positive signal was induced in the parenchymal microglia and large amounts of prostaglandin‐E2 were measured in the injected area. Twenty‐four hours and 7 days after injection, many inducible nitric oxide synthase‐positive cells and a high level of nitrite were detected at the injection site. Seven days of nimesulide (10 mg/kg/day, i.m.) treatment strongly attenuated the microglial reaction, reduced the number of inducible nitric oxide synthase‐positive cells and completely abolished the increase in prostaglandin‐E2 formation. These data provide valuable support in vivo for the potential efficacy of cyclooxygenase‐2 inhibitors in Alzheimer's disease therapy.
Syntaxin 13 is a developmentally regulated SNARE involved in neurite outgrowth and endosomal trafficking
Authors: Hirling Harald , Steiner Pascal , Chaperon Catherine , Marsault Robert , Regazzi Romano , Catsicas Stefan
Published: March 2003

In addition to its role in exocytosis, SNAP‐25 is essential for axonal outgrowth. In order to identify SNARE proteins involved in neurite growth we have used SNAP‐25 antibodies to affinity‐purify protein complexes enriched in developing rat brain membrane extracts. We have identified a complex between SNAP‐25 and syntaxin 13 predominantly present in brain at embryonic or early postnatal stages. We show that syntaxin 13 is developmentally regulated with a decrease in adult brain. In differentiated neuroendocrine PC12 cells as well as primary cortical neurons the protein is localized to a punctated and tubular staining in the perinuclear region and along processes with high levels in the central region of growth cones. Carboxy‐terminally tagged syntaxin 13 was also detected on the plasma membrane by in vivo surface‐labelling where it colocalized with SNAP‐25. Syntaxin 13 has recently been shown to be implicated in early endosomal trafficking. In our study, colocalization with internalized transferrin in the cell body and along neurites confirmed endosomal location in both compartments. Finally, overexpression of full‐length syntaxin 13 enhanced neurite outgrowth in NGF‐stimulated PC12 cells, whilst it had no effect on regulated secretion. The data suggest that a syntaxin 13‐dependent endocytic trafficking step plays a limiting role in membrane expansion during neuronal development.
Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats
Authors: Ferencz I. , Leanza G. , Nanobashvili A. , Kokaia M. , Lindvall O.
Published: March 2003

Intraventricular administration of the immunotoxin 192 IgG‐saporin in rats has been shown to cause a selective loss of cholinergic afferents to the hippocampus and cortical areas, and to facilitate seizure development in hippocampal kindling. Here we demonstrate that this lesion also accelerates seizure progression when kindling is induced by electrical stimulations in the amygdala. However, whereas intraventricular 192 IgG‐saporin facilitated the development of the initial stages of hippocampal kindling, the same lesion promoted the late stages of amygdala kindling. To explore the role of various parts of the basal forebrain cholinergic system in amygdala kindling, selective lesions of the cholinergic projections to either hippocampus or cortex were produced by intraparenchymal injections of 192 IgG‐saporin into medial septum/vertical limb of the diagonal band or nucleus basalis, respectively. Cholinergic denervation of the cortical regions caused acceleration of amygdala kindling closely resembling that observed after the more widespread lesion induced by intraventricular 192 IgG‐saporin. In contrast, removal of the cholinergic input to the hippocampus had no effect on the development of amygdala kindling. These data indicate that basal forebrain cholinergic neurons suppress kindling elicited from amygdala, and that this dampening effect is mediated via cortical but not hippocampal projections.
Polysorbate‐80 coating enhances uptake of polybutylcyanoacrylate (PBCA)‐nanoparticles by human and bovine primary brain capillary endothelial cells
Authors: Ramge Peter , Unger Ronald E. , Oltrogge Jens B. , Zenker Dietmar , Begley David , Kreuter Jörg , Von Briesen Hagen
Published: March 2003

Certain drugs such as dalargin, loperamide or tubocurarine are not transported across the blood–brain barrier (BBB) and therefore exhibit no effects on the central nervous system. However, effects on the central nervous system can be observed when these drugs are loaded onto polybutylcyanoacrylate (PBCA)‐nanoparticles and coated with polysorbate 80. The mechanism by which these complexed nanoparticles cross the BBB and exhibit their effects has not been elucidated. Cultured microvessel brain endothelial cells of human and bovine origin were used as an in vitro model for the BBB to gain further insight into the mechanism of uptake of nanoparticles. With cells from these species we were able to show that polysorbate 80‐coated nanoparticles were taken up by brain endothelial cells much more rapidly and in significantly higher amounts (20‐fold) than uncoated nanoparticles. The process of uptake was followed by fluorescence and confocal laser scanning microscopy. The results demonstrate that the nanoparticles are taken up by cells and that this uptake occurs via an endocytotic mechanism.
Local GABAergic modulation of acetylcholine release from the cortex of freely moving rats
Authors: Giorgetti Marco , Bacciottini Lucia , Giovannini Maria Grazia , Colivicchi Maria Alessandra , Goldfarb Joseph , Blandina Patrizio
Published: March 2003

Cortical perfusion with GABA agonists and antagonists modulates the spontaneous release of cortical acetylcholine and GABA in freely moving rats. Twenty‐four hours after implantation of a dialysis fibre, cerebral cortex spontaneously released acetylcholine (3.8 ± 0.2 pmol/10 min) and GABA (6.6 ± 0.4 pmol/10 min) at a stable rate. Local administration of GABA (1 or 5 mm) or the GABAA agonist muscimol (25 or 50 μm) had no effect on the spontaneous release of acetylcholine. However, bicuculline (1–25 μm), a GABAA antagonist, added to the dialysis perfusate, elicited a concentration‐dependent increase of acetylcholine release to approximately double that of control. This effect of bicuculline (25 μm) was completely prevented by coperfusion with muscimol (50 μm). Local administration of the GABAB receptor agonist baclofen (10 or 50 μm) elicited a concentration‐dependent increase in spontaneous acetylcholine release with a maximal increase of about 60%. Intracortical administration of baclofen also decreased the spontaneous release of GABA. The GABAB receptor antagonist CGP 35348 (1 mm), administered alone for 20 min through the dialysis fibre, was without effect on spontaneous acetylcholine release; however, it completely blocked both the baclofen‐induced increase in acetylcholine release and the decrease in GABA release. These results suggest that cortically released GABA exerts a tonic influence on cholinergic activity.
Modulation of synaptic transmission in the rat ventral septal area by the pharmacological activation of metabotropic glutamate receptors
Authors: Tolchard Stephen , Clarke Geoff , Collingridge Graham L. , Fitzjohn Stephen M.
Published: March 2003

The ventral septal area (VSA) is considered to be critically involved in the control of the height and duration of fever. The major excitatory input to this region of the brain is glutamatergic, and the aim of this study was to investigate possible modulation of this synapse by metabotropic glutamate (mGlu) receptors. Whole‐cell patch recordings were made from individual VSA neurons voltage‐clamped at −60 mV. Activation of either group I or group II mGlu receptors (by bath application of 3,5‐dihydroxyphenylglycine (DHPG) or (2S,2′R,3′R)‐2‐(2′,3′‐dicarboxycyclopropyl)glycine (DCG‐IV), respectively) produced a long‐lasting depression of synaptic transmission which in both cases was insensitive to the N‐methyl‐ d‐aspartate (NMDA) receptor antagonist D‐2‐amino‐5‐phosphonopentanoate (D‐AP5). In contrast, application of (S)‐2‐amino‐4‐phosphonobutyric acid (L‐AP4), a group III mGlu receptor agonist, had a biphasic effect on synaptic transmission in the VSA, first eliciting a transient depression of transmission during drug application, followed by a marked and sustained potentiation of synaptic transmission upon drug washout. The response elicited by L‐AP4 was dependent on NMDA receptor activation, as in the presence of D‐AP5 the potentiation was replaced by an underlying long‐term depression (LTD) of transmission. These data provide the first evidence that metabotropic glutamate receptor agonists can induce both NMDA receptor‐dependent and ‐independent modulation of synaptic transmission in the VSA.
Increased responsivity of glutamate release from the substantia nigra pars reticulata to striatal NMDA receptor blockade in a model of Parkinson's disease. A dual probe microdialysis study in hemiparkinsonian rats
Authors: Marti M. , Sbrenna S. , Fuxe K. , Bianchi C. , Beani L. , Morari M.
Published: March 2003

Dual probe microdialysis was employed in freely moving 6‐hydroxydopamine (6‐OHDA) hemilesioned rats to investigate the effects of blockade of N‐methyl‐D‐aspartate (NMDA) receptors in the dorsolateral striatum on glutamate (Glu) release from the ipsilateral substantia nigra pars reticulata (SNr). Perfusion for 60 min with the NMDA antagonist dizocilpine (0.1 and 1 μm) in the dopamine (DA)‐denervated striatum stimulated nigral Glu release (peak effect of 139 ± 7% and 138 ± 9%, respectively). The lower (0.01 μm) and higher (10 μm) concentrations were ineffective. In sham‐operated rats, dizocilpine failed to affect nigral Glu release up to 1 μm but induced a prolonged stimulation at 10 μm (153 ± 9% at the end of perfusion). The present results show that DA‐deficiency in the striatum of hemiparkinsonian rats is associated with increased responsivity of nigral Glu release to striatal NMDA receptor blockade. This suggests that changes of NMDA receptor mediated control of the striatofugal pathways occur during Parkinson's disease (PD).
Organization of connections of the basal and accessory basal nuclei in the monkey amygdala
Authors: Bonda Eva
Published: March 2003

The present study investigated the intrinsic connections of the basal and accessory basal nuclei of the Macaca fascicularis monkey by means of the anterograde tracers Phaseolus vulgaris‐leucoagglutinin (PHA‐L) and biotinylated dextran amine (BDA). Analysis of the intranuclear connections of the basal nucleus indicates that there are five modules: dorsal, intermediate, ventral lateral, ventral medial and periamygdaloid sulcal cortex. The dorsal division projects to the intermediate division. Laterally, the intermediate division projects to the ventral lateral division and dorsal parts of the ventral medial division. Ventrally, the ventral lateral division projects to the ventral medial division and periamygdaloid sulcal cortex, which appears to constitute a medial extension of the basal nucleus onto the cortical surface of the amygdala. Medially, the ventral medial division projects to the intermediate and dorsal divisions. Thus, the connections between these modules form functional microcolumns within the nucleus with distinct patterns of information flow that are dorsal to ventral laterally, lateral to medial ventrally, and ventral to dorsal medially. Observations on the intranuclear connections of the accessory basal nucleus suggest that they are organized into two relatively distinct domains: the dorsal division projects to the ventral division and the ventral division projects primarily to the ventromedial division. Projections to other amygdaloid areas originate in select divisions of the basal and accessory basal nuclei, and are topographically distributed. The organization of intrinsic connections of the basal nuclei correlates with specific amygdalo‐cortical connections and suggests that extensive convergence of information takes place within the amygdala, which potentially influences activity at both the temporal and parietal pathways and hippocampal fields.
Suppression of the rat microglia Kv1.3 current by src‐family tyrosine kinases and oxygen/glucose deprivation
Authors: Cayabyab Francisco S , Khanna Rajesh , Jones Owen T , Schlichter Lyanne C
Published: March 2003

Microglia activate following numerous acute insults to the brain, including oxygen/glucose deprivation (OGD), and both protein tyrosine kinases (PTKs) and K+ channels have been implicated in their activation. We identified Kv1.3 (voltage‐gated potassium channel) protein in cultured rat microglia and confirmed that the native current is biophysically and pharmacologically similar to Kv1.3. To explore whether src‐family PTKs regulate the microglial Kv current, we first heterologously expressed Kv1.3 in a microglia‐like cell line derived from neonatal rat brain (MLS‐9). The resulting large Kv1.3 current was eliminated by co‐transfecting the constitutively active PTK, v‐src, then rapidly restored by the PTK inhibitor, lavendustin A. Acute activation of endogenous src kinases by a peptide activator significantly reduced the current, an effect that was mimicked by OGD. Similarly, in primary cultures of rat microglia, the endogenous Kv1.3‐like current was inhibited by activating endogenous src‐family PTKs and by OGD. Biochemical analysis showed that OGD increased the tyrosine phosphorylation of native Kv1.3 protein, which was alleviated by PTK inhibitors or reactive oxygen species (ROS) scavengers. Conversely, the basal level of Kv1.3 phosphorylation was decreased by PTK inhibitors or scavengers of ROS. Together, our results point to a post‐insertional downregulation of the microglial Kv1.3‐like current by oxidative stress and tyrosine phosphorylation. This interaction may be facilitated by a multiprotein complex because, in cultured microglia, the endogenous Kv1.3 and src proteins both bind to the scaffolding protein, post‐synaptic density protein 95 (PSD‐95). By associating with, and phosphorylating Kv1.3, src is well positioned to regulate microglial responses to oxidative stress.
A new class of neurotoxin from wasp venom slows inactivation of sodium current
Authors: Sahara Yoshinori , Gotoh Masamichi , Konno Katsuhiro , Miwa Akiko , Tsubokawa Hiroshi , Robinson Hugh P. C. , Kawai Nobufumi
Published: March 2003

The effects of α‐pompilidotoxin (α‐PMTX), a new neurotoxin isolated from the venom of a solitary wasp, were studied on the neuromuscular synapses in lobster walking leg and the rat trigeminal ganglion (TG) neurons. Paired intracellular recordings from the presynaptic axon terminals and the innervating lobster leg muscles revealed that α‐PMTX induced long bursts of action potentials in the presynaptic axon, which resulted in facilitated excitatory and inhibitory synaptic transmission. The action of α‐PMTX was distinct from that of other known facilitatory presynaptic toxins, including sea anemone toxins and α‐scorpion toxins, which modify the fast inactivation of Na+ current. We further characterized the action of α‐PMTX on Na+ channels by whole‐cell recordings from rat trigeminal neurons. We found that α‐PMTX slowed the Na+ channels inactivation process without changing the peak current–voltage relationship or the activation time course of tetrodotoxin (TTX)‐sensitive Na+ currents, and that α‐PMTX had voltage‐dependent effects on the rate of recovery from Na+ current inactivation and deactivating tail currents. The results suggest that α‐PMTX slows or blocks conformational changes required for fast inactivation of the Na+ channels on the extracellular surface. The simple structure of α‐PMTX, consisting of 13 amino acids, would be advantageous for understanding the functional architecture of Na+ channel protein.
Glycine triggers an intracellular calcium influx in oligodendrocyte progenitor cells which is mediated by the activation of both the ionotropic glycine receptor and Na+‐dependent transporters
Authors: Belachew Shibeshih , Malgrange Brigitte , Rigo Jean‐Michel , Rogister Bernard , Leprince Pierre , Hans Gregory , Nguyen Laurent , Moonen Gustave
Published: March 2003

Using fluo‐3 calcium imaging, we demonstrate that glycine induces an increase in intracellular calcium concentration ([Ca2+]i) in cortical oligodendrocyte progenitor (OP) cells. This effect results from a calcium entry through voltage‐gated calcium channels (VGCC), as it is observed only in OP cells expressing such channels, and it is abolished either by removal of calcium from the extracellular medium or by application of anl‐type VGCC blocker. Glycine‐triggered Ca2+influx in OP cells actually results from an initial depolarization that is the consequence of the activation of both the ionotropic glycine receptor (GlyR) and Na+‐dependent transporters, most probably the glycine transporters 1 (GLYT1) and/or 2 (GLYT2) which are colocalized in these cells. Through this GlyR‐ and transporter‐mediated effect on OP intrcellular calcium concentration [Ca2+]i, glycine released by neurons may, as well as other neurotransmitters, serve as a signal between neurons and OP during development.
Protein kinase C activity modulates dendritic differentiation of rat Purkinje cells in cerebellar slice cultures
Authors: Metzger Friedrich , Kapfhammer Josef P.
Published: March 2003

The molecular mechanisms underlying dendritic differentiation in neurons are currently poorly understood. We used slice cultures from rat cerebellum of postnatal day 8 to investigate the effect of protein kinase C (PKC) activity on dendritic development of Purkinje cells. After 12 days in culture under control conditions, Purkinje cells had developed a typical dendritic tree consisting of a few long primary dendrites with shorter side branches. Following treatment with the PKC agonist, phorbol‐12‐myristate‐13‐acetate (PMA), the dendritic tree area was strongly reduced to 32% of control and primary dendrites were short with only a few side branches. Delayed addition of PMA after 6 days resulted in a retraction of existing dendrites, whereas discontinuation of PMA treatment after 6 days resulted in a recovery of the dendritic tree to almost control values. In the presence of the PKC inhibitor, 2‐[1‐(3‐dimethylaminopropyl)indol‐3‐yl]‐3‐(indol‐3‐yl)maleimide (GF109203X), the dendritic tree area was increased to 158% of control with much more ramified branches after 12 days. The overall morphology of the cultures and the survival of Purkinje cells were unaffected by PKC modulators. Our data show that increased activity of PKC inhibits, and reduced activity of PKC promotes dendritic growth. This suggests that PKC activity is a critical regulator of dendritic growth and differentiation in cerebellar Purkinje cells.
Spatio‐temporal characterizations of non‐linear changes in intracranial activities prior to human temporal lobe seizures
Authors: Le Van Quyen M. , Adam C. , Martinerie J. , Baulac M. , Clémenceau S. , Varela F.
Published: March 2003

Recent studies have shown that non‐linear analysis of intracranial activities can detect a ‘pre‐ictal phase’ preceding the epileptic seizure. Nevertheless, the dynamical nature of the underlying neuronal process and the spatial extension of this pre‐ictal phase still remain unknown. In this paper, we address these aspects using a new non‐linear measure of dynamic similarity between different parts of intracranial recordings of nine patients with medial temporal lobe epilepsy recorded during transitions to seizure. Our results confirm that non‐linear changes in neuronal dynamics allow, in most cases (16 out of 17), a seizure anticipation several minutes in advance. Furthermore, we show that the spatial distribution of pre‐ictal changes often involves an extended network projecting beyond the limits of the epileptogenic region. Finally, the pre‐ictal phase could frequently (13 out of 17) be characterized with a marked shift toward slower frequencies in upper delta or theta frequency range.
Involvement of the direct striatonigral pathway in levodopa‐induced sensitization in 6‐hydroxydopamine‐lesioned rats
Authors: Bordet Régis , Ridray Sophie , Schwartz Jean‐Charles , Sokoloff Pierre
Published: March 2003

Induction of dopamine D3receptor gene expression in 6‐hydroxydopamine‐lesioned rats by repeated administration of levodopa had been suggested to be responsible for behavioural sensitization developing in these animals. Using double in situ hybridization techniques, we show that D3receptor mRNA induction after repeated administration of levodopa took place mainly in dynorphin/substance P‐expressing neurons of the direct striatonigral pathway. In agreement, induction of D3receptor binding sites was evidenced, using 7‐[3H]hydroxy‐N,N‐di‐propyl‐2‐aminotetralin ([3H]7‐OH‐DPAT), in substantia nigra pars reticulata, the projection area of the direct nigrostriatonigral pathway. Changes in D3receptor binding and behavioural sensitization during intermittent administration of levodopa paralleled changes in prodynorphin/preprotachykinin rather than preproenkephalin/prodynorphin and preproenkephalin/preprotachykinin mRNA ratios. Behavioural sensitization, induction of D3receptor binding and changes in prodynorphin/preprotachykinin ratio were all prevented together when levodopa was continuously delivered or intermittently delivered in combination withr‐(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine (SCH 23390), a selective D1receptor antagonist. Our results indicate that functional changes of the direct striatal output pathway, possibly through an interaction between D1and D3receptors at the level of terminals in the substantia nigra pars reticulata, are important for the development of behavioural sensitization.
Interleukin‐10 modulates neuronal threshold of vulnerability to ischaemic damage
Authors: Grilli Mariagrazia , Barbieri Ilaria , Basudev Harsha , Brusa Rossella , Casati Carlo , Lozza Gianluca , Ongini Ennio
Published: March 2003

Interleukin‐10 (IL‐10) is a powerful suppressor of cellular immune responses, with a postulated role in brain inflammation. First, we have evaluated the role of this cytokine in ischaemic brain damage using IL‐10 knockout (IL‐10–/–) mice. The middle cerebral artery (MCA) was occluded in either IL‐10–/– or wild‐type animals of corresponding strain (C57Bl/6) and age. Infarct volume was assessed 24 h later in serial brain sections. Brain infarct produced by MCA occlusion was 30% larger in the IL‐10–/– than in wild‐type mice (21.8 ± 1.2 vs. 16.9 ± 1.0 mm3, respectively; P < 0.01; Student's t‐test). To further characterize these findings, studies were extended to in vitro models. Primary neuronal cortical cultures derived from IL‐10–/– animals were more susceptible to both excitotoxicity and combined oxygen–glucose deprivation compared with cell cultures from wild‐type mice. Moreover, when added to the culture medium, recombinant murine IL‐10 (0.1–100 ng/mL) exerted a concentration‐dependent prevention of neuronal damage induced by excitotoxicity in both cortical and cerebellar granule cell cultures taken from either strain. The accordance of in vivo and in vitro data allows us to suggest a potential neuroprotective role of IL‐10 against cerebral ischaemia when administered exogenously or made available from endogenous sources.
Role of desensitization of AMPA receptors on the neuronal viability and on the [Ca2+]i changes in cultured rat hippocampal neurons
Authors: Ambrósio António F. , Silva Ana P. , Malva João O. , Mesquita José F. , Carvalho Arsélio P. , Carvalho Caetana M.
Published: March 2003

We investigated the role of desensitization of α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐4‐propionate (AMPA) receptors on the neurotoxicity and on the [Ca2+]i changes induced by kainate or by AMPA in cultured rat hippocampal neurons. The neuronal viability was evaluated either by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, or by analysis of cell morphology. Short‐term exposure of the neurons to kainate or AMPA (30 min) was not toxic, but the exposure for 24 h to the excitotoxic drugs caused a concentration‐dependent neurotoxic effect which was prevented by LY 303070, a noncompetitive AMPA receptor antagonist. In the presence of cyclothiazide (CTZ), kainate or AMPA was toxic (30 min exposure), or the toxic effect was significantly enhanced (24 h exposure), but in this case LY 303070 did not completely protect the cells against kainate‐induced toxicity. The alterations in the [Ca2+]i caused by kainate or AMPA showed a great cell‐to‐cell variability. LY 303070 completely or partially inhibited the responses stimulated by kainate. CTZ differentially affected the responses evoked by kainate or AMPA. In the majority of hippocampal neurons, CTZ did not potentiate, or only slightly potentiated, the kainate‐stimulated responses but in 11% of neurons there was a great potentiation. In AMPA‐stimulated neurons, the responses were slightly or greatly potentiated in the majority of neurons, but not in all of them. The results show that AMPA and kainate may be toxic, depending on the time of exposure and on the blockade of the desensitization of the AMPA receptors. Overall, our results clearly show that there exist different populations of hippocampal neurons with different sensitivities to kainate, AMPA, CTZ and LY 303070. Moreover, the effects of CTZ on both [Ca2+]i alterations and neurotoxicity are not fully correlated.
Glial cell line‐derived neurotrophic factor modulates ischemia‐induced tyrosine hydroxylase expression in rat hippocampus
Authors: Miyazaki Hiroyuki , Ono Takashi , Okuma Yasunobu , Nagashima Kazuo , Nomura Yasuyuki
Published: March 2003

Recently, we have reported that glial cell line‐derived neurotrophic factor (GDNF), which supports the survival of dopaminergic neurons, prevents delayed neuronal death in the hippocampal CA1 region induced by transient forebrain ischemia. In the present study, we examined the role of GDNF in the expression of tyrosine hydroxylase (TH) mRNA induced by transient forebrain ischemia in rats. The expression of TH mRNA was increased in a time‐dependent manner, with a significant increase in 24 h to 7 days, in the hippocampus after induction of transient forebrain ischemia, as determined using the reverse transcription and polymerase chain reaction method. Although it has been suggested that the increase of dopamine β‐hydroxylase mRNA expression correlates with the activation of noradrenergic neurons, no increase of dopamine β‐hydroxylase mRNA in the hippocampus was observed in our system. Western blot analysis revealed that TH protein, but not dopamine β‐hydroxylase protein, was produced in a time‐dependent manner in the hippocampus during the ischemia. Interestingly, the induction level of TH mRNA was reduced by intrahippocampal microinjection of GDNF (1.0 μg), and this local GDNF treatment also reduced the increase of TH‐like immunohistochemistry‐positive terminals in the hippocampus. In contrast, local GDNF treatment of normal rats increased the TH mRNA expression at 6–12 h. These findings suggest that GDNF protects against neuronal degeneration including delayed neuronal death in the hippocampal CA1 region by modulating the expression levels of TH mRNA and protein.
Corticothalamic axons contact blood vessels as well as nerve cells in the thalamus
Authors: Feig Sherry L. , Guillery R. W.
Published: March 2003

Corticothalamic axons in cats and rats were studied after labelling by intracortical injections of axonally transported markers. Individual axons were traced to their terminal branches. Many preterminal segments had a tightly spiral or winding course which was often closely adjacent to a thalamic blood vessel. Electron micrographs of such axons showed them lying immediately adjacent to the vascular basement membrane, without the astrocytic cytoplasm that generally separates neural processes from the basement membrane of vessels. The functional nature of this neurovascular relationship remains to be explored.
Synaptic interactions increase optic flow specificity
Authors: Horstmann Wolfram , Egelhaaf Martin , Warzecha Anne‐Kathrin
Published: March 2003

Representations of optic flow are encoded in fly tangential neurons by pooling the signals of many retinotopically organized local motion‐sensitive inputs as well as of other tangential cells originating in the ipsi‐ and contralateral half of the brain. In the so called HSE cell, a neuron involved in optomotor course control, two contralateral input elements, the H1 and H2 cells, mediate distinct EPSPs. These EPSPs frequently elicit spike‐like depolarizations in the HSE cell. The synaptic transmission between the H2 and the HSE cell is analysed in detail and shown to be very reliable with respect to the amplitude and time‐course of the postsynaptic potential. As a consequence of its synaptic input, the HSE cell responds best to wide‐field motion, such as that generated on the eyes when the animal turns about its vertical body axis. It is shown that the specificity of the HSE cell for this type of optic flow is much enhanced if rapid membrane depolarizations, such as large‐amplitude EPSPs or spike‐like depolarizations, are taken into account rather than the average membrane potential.
The activity‐dependent plasticity of segmental and intersegmental synaptic connections in the lamprey spinal cord
Authors: Parker David , Grillner Sten
Published: March 2003

Activity‐dependent synaptic plasticity has been proposed as a contributory factor in the patterning of rhythmic network activity. However, its role has not been examined in detail. Here, paired or triple intracellular recordings have been made from identified neurons in the lamprey locomotor network to examine the potential relevance of activity‐dependent synaptic plasticity in segmental and intersegmental spinal networks. Segmental inputs from glutamatergic excitatory interneurons (EIN) to ipsilateral glycinergic crossed caudal (CC) interneurons were facilitated or depressed during spike trains at 5–20 Hz. Connections between EINs were depressed. Glycinergic inputs from small ipsilateral inhibitory interneurons were depressed in motor neurons, but were facilitated in CC interneurons. Excitatory inputs from small crossing interneurons to motor neurons were depressed, whereas inhibitory inputs were unaffected. With the exception of connections between EINs, significant effects occurred with stimulation that mimicked interneuron spiking during network activity. Intersegmental EIN synaptic properties were also investigated. EIN inputs did not differ significantly when examined from zero to four segments rostral to motor neurons or CC interneurons. However, caudally located EINs evoked greater activity‐dependent facilitation than did rostral EINs. Whilst the amplitude or plasticity of EIN inputs in the rostral or mid‐trunk regions of the spinal cord did not differ, EINs in the caudal trunk region evoked greater facilitation. Synaptic transmission between locomotor network neurons thus exhibits activity‐dependent plasticity in response to physiologically relevant stimulation. Activity‐dependent plasticity could thus contribute to the patterning of the rhythmic network output.
Facial nerve injury‐induced disinhibition in the primary motor cortices of both hemispheres
Authors: Farkas Tamás , Perge János , Kis Zsolt , Wolff Joachim‐R. , Toldi József
Published: March 2003

Unilateral facial nerve transection induces plastic reorganization of the somatotopic order in the primary motor cortex area (MI). This process is biphasic and starts with a transient disinhibition of connections between cortical areas in both hemispheres. Little is known about the underlying mechanisms. Here, cortical excitability has been studied by paired pulse electrical stimulation, applied either within the MI or peripherally to the trigeminal nerve, while the responses were recorded bilaterally in the MI. The ratios between the amplitudes of the second and first evoked potentials (EPs or fEPSPs) were taken as measures of the inhibitory capacity in the MI ipsilateral or contralateral to the nerve injury. A skin wound or unilateral facial nerve exposure immediately caused a transient facilitation, which was followed by a reset to some level of inhibition in the MI on both sides. After facial nerve transection, the first relatively mild reduction of inhibition started shortly (within 10 min) after denervation. This was followed by a second step, involving a stronger decrease in inhibition, 40–45 min later. Previous publications have proved that sensory nerve injury (deafferentation) induces disinhibition in corresponding areas of the sensory cortex. It is now demonstrated that sham operation and, to an even greater extent, unilateral transection of the purely motoric facial nerve (deefferentation), each induce extended disinhibition in the MIs on both sides.
Arm trajectory and representation of movement processing in motor cortical activity
Authors: Schwartz Andrew B. , Moran Daniel W.
Published: March 2003

We review experiments in which single‐cell primary motor cortical activity was recorded from Rhesus monkeys (Macaca mulatta) while they performed reaching and drawing tasks. The directional tuning curves generated during reaching were modulated by the speed of movement and this was reflected in the magnitude of population vectors calculated from firing rates of a large population of cells. Directional and speed representation in the firing rates of these cells is robust across both reaching and drawing. Several behavioural invariants related to the speed of drawing were represented in the time‐series of population vectors. This high fidelity neural representation of velocity found in motor cortex can be used to visualize the dynamics of motor cortical activity during drawing and suggests that the cost function governing the rate of drawing is bound by neural processing.