bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scorpion α and α‐like toxins differentially interact with sodium channels in mammalian CNS and periphery
Authors: Gilles Nicolas , Chen Haijun , Wilson Harry , Le Gall Frédéric , Montoya Gonzalo , Molgo Jordi , Schönherr Roland , Nicholson Graham , Heinemann Stefan H. , Gordon Dalia 
Published: March 2003

AbstractScorpion α‐toxins from Leiurus quinquestriatus hebraeus, LqhII and LqhIII, are similarly toxic to mice when administered by a subcutaneous route, but in mouse brain LqhII is 25‐fold more toxic. Examination of the two toxins effects in central nervous system (CNS), peripheral preparations and expressed sodium channels revealed the basis for their differential toxicity. In rat brain synaptosomes, LqhII binds with high affinity, whereas LqhIII competes only at high concentration for LqhII‐binding sites in a voltage‐dependent manner. LqhII strongly inhibits sodium current inactivation of brain rBII subtype expressed in HEK293 cells, whereas LqhIII is weakly active at 2 μm, suggesting that LqhIII affects sodium channel subtypes other than rBII in the brain. In the periphery, both toxins inhibit tetrodotoxin‐sensitive sodium current inactivation in dorsal root ganglion neurons, and are strongly active directly on the muscle and on expressed μI channels. Only LqhII, however, induced repetitive end‐plate potentials in mouse phrenic nerve–hemidiaphragm muscle preparation by direct effect on the motor nerve. Thus, rBII and sodium channel subtypes expressed in peripheral nervous system (PNS) serve as the main targets for LqhII but are mostly not sensitive to LqhIII. Toxicity of both toxins in periphery may be attributed to the direct effect on muscle. Our data elucidate, for the first time, how different toxins affect mammalian central and peripheral excitable cells, and reveal unexpected subtype specificity of toxins that interact with receptor site 3.
Coupling between lumbar and sacral motor networks in the neonatal rat spinal cord
Authors: Cazalets Jean‐René , Bertrand Sandrine 
Published: March 2003

AbstractWe have studied the rhythm‐generating capabilities of the lumbar, sacral and coccygeal (Co) areas using an isolated spinal cord preparation of the newborn rat. The bath‐application of a mixture of N‐methyl‐ d‐l‐aspartate (NMA) and serotonin (5‐HT) on the whole spinal cord induced a coordinated rhythmic activity that could be recorded from the lumbar to the coccygeal ventral roots. The phase relationships and mean burst duration between the activity in the rostral lumbar segments and the activity in the sacral segments was analysed. The direct activation of the sacral network, by using sections or by selective pharmacological activation, showed that these caudal segments possess their own rhythmogenic capability. By combining section experiments and compartmentation of the spinal cord, we demonstrated that a strong coupling exists between the lumbar and sacral motor networks. In addition, we found that in an intact spinal cord the activity of the sacral networks is driven by the lumbar networks. We have found that different modes of coordination between the lumbar and the sacral activity may occur. Finally, we have shown that the coupling between the lumbar and sacral networks can be modified by sensory inputs, suggesting that the spinal machinery could modulate and adapt the coupling of these two spinal networks.
Synchronization of circadian firing rhythms in cultured rat suprachiasmatic neurons
Authors: Shirakawa Tetsuo , Honma Sato , Katsuno Yumiko , Oguchi Haruhisa , Honma Ken‐ichi 
Published: March 2003

AbstractThe circadian clock in mammals is located in the suprachiasmatic nucleus (SCN) which consists of multiple oscillating neurons. Integration of the cellular oscillations is essential for the generation of a single circadian period in the SCN. By using a multielectrode dish (MED), we measured circadian firing rhythms in individual SCN neurons for more than 2 weeks continuously, and examined the involvement of synaptic communication in the synchronization of circadian rhythms. Cross‐correlation analysis of spontaneous action potentials revealed that a neuron pair was functionally connected by synapses when their circadian rhythms were synchronized. No correlation was found between the paired neurons whose circadian rhythms were not synchronized. Calcium (Ca2+)‐dependent synaptic transmission in the cellular communication was indicated by dose‐dependent lengthening of an intercellular spike interval and loss of spike correlation with a Ca2+ channel blocker. Approximately 60% of the SCN neurons in culture were immunoreactive to antibodies against γ‐aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD). Spontaneous firing of all the neurons tested was either increased or decreased by bicuculline, the GABAA receptor antagonist. These findings indicate that synaptic communication plays a critical role in the synchronization of circadian rhythms in individual SCN neurons and the GABAergic transmission is involved in the synchronization mechanism.
Cellular uptake and spread of the cell‐permeable peptide penetratin in adult rat brain
Authors: Bolton Sarah J. , Jones Declan N. C. , Darker John G. , Eggleston Drake S. , Hunter A. Jacqueline , Walsh Frank S. 
Published: March 2003

AbstractInvestigation of normal and pathological diseases of the central nervous system (CNS) has been hampered by the inability to effectively manipulate protein function in vivo. In order to address this important topic, we have evaluated the ability of penetratin, a novel cell‐permeable peptide consisting of a 16‐amino acid sequence derived from a Drosophila homeodomain protein, to act as a carrier system to introduce a cargo into brain cells. Fluorescently tagged penetratin was injected directly into rat brain, either into the striatum or the lateral ventricles, and rats were perfusion‐fixed 24 h later in order to assess the brain response to the peptide. Immunohistochemistry following intrastriatal injection showed that injection of 10 μg penetratin caused neurotoxic cell death and triggered recruitment of inflammatory cells in a dose‐dependent fashion. Doses of 1 μg or less resulted in reduced toxicity and recruitment of inflammatory cells, but interestingly, there was some spread of the penetratin. Injections of an inactive peptide sequence, derived from the same homeodomain, caused little toxicity but could still, however, trigger an inflammatory response. Intraventricular injections showed extensive inflammatory cell recruitment but minimal spread of either peptide. These results suggest that a dose of 1 μg of penetratin peptide is suitable for directing agents to small, discrete areas of the brain and as such is an interesting new system for analysing CNS function.
The HIV‐1 coat protein gp120 and some of its fragments potently activate native cerebral NMDA receptors mediating neuropeptide release
Authors: Gemignani Anita , Paudice Paolo , Pittaluga Anna , Raiteri Maurizio 
Published: March 2003

AbstractThe objective of this study was to investigate the effects of the HIV‐1 envelope protein gp120 and its peptide fragments on the function of N‐methyl‐ d‐aspartate (NMDA) receptors mediating release of cholecystokinin (CCK) and somatostatin (SRIF). These are nonconventional NMDA receptors recently found to be activated by glycine or d‐serine ‘only’. The release of cholecystokinin‐like immunoreactivity (CCK‐LI) and of somatostatin‐like immunoreactivity (SRIF‐LI) elicited by 12 mm K+ from superfused rat neocortex synaptosomes was potently increased by gp120, its cyclic V3 loop and the linear V3 sequence BRU‐C‐34‐A, but not by RP‐135 (a central portion of BRU‐C‐34‐A). The EC50 values of gp120 were 0.02 nm (CCK‐LI release) and 0.01 nm (SRIF‐LI release). The releasing effect of gp120 was prevented by blocking the glycine site or the ion channel of NMDA receptors, but not the glutamate recognition site; in addition, the gp120 effect was strongly inhibited by nanomolar concentrations of Zn2+ ions and by low micromolar concentrations of ifenprodil. It is concluded that gp120 acts as a very potent agonist at the glycine site of NMDA receptors sited on CCK‐ and SRIF‐releasing nerve endings; the protein is able to activate the receptor channel in the absence of glutamate. Gp120 activates the receptors through its V3 loop as peptide fragments related to V3 retain near‐maximal activity. The sensitivity of the gp120 effect to both Zn2+ and ifenprodil would not be incompatible with the idea that these NMDA receptors contain the triple subunit combination NR1/NR2A/NR2B.
The circadian cycle of mPER clock gene products in the suprachiasmatic nucleus of the Siberian hamster encodes both daily and seasonal time
Authors: Nuesslein‐Hildesheim Barbara , O'brien John A. , Ebling Francis J. P. , Maywood Elizabeth S. , Hastings Michael H. 
Published: March 2003

AbstractThe circadian clock in the hypothalamic suprachiasmatic nuclei (SCN) regulates the pattern of melatonin secretion from the pineal gland such that the duration of release reflects the length of the night. This seasonally specific endocrine cue mediates annual timing in photoperiodic mammals. The aim of this study was to investigate how changes in photoperiod influence the cyclic expression of recently identified clock gene products (mPER and mTIM) in the SCN of a highly seasonal mammal, the Siberian hamster (Phodopus sungorus). Immunocytochemical studies indicate that the abundance of both mPER1 and mPER2 (but not mTIM) in the SCN exhibits very pronounced, synchronous daily cycles, peaking approximately 12 h after lights‐on. These rhythms are circadian in nature as they continue approximately under free‐running conditions. Their circadian waveform is modulated by photoperiod such that the phase of peak mPER expression is prolonged under long photoperiods. mPER1 protein is also expressed in the pars tuberalis of Siberian hamsters. In hamsters adapted to long days, the expression of mPER1 is elevated at the start of the light phase. In contrast, there is no clear elevation in mPER1 levels in the pars tuberalis of hamsters held on short photoperiods. These results indicate that core elements of the circadian clockwork are sensitive to seasonal time, and that encoding and decoding of seasonal information may be mediated by the actions of these transcriptional modulators.
Photoperiod differentially regulates the expression of Per1 and ICER in the pars tuberalis and the suprachiasmatic nucleus of the Siberian hamster
Authors: Messager Sophie , Hazlerigg David G. , Mercer Julian G. , Morgan Peter J. 
Published: March 2003

AbstractPrevious studies demonstrated that the clock gene Per1 and the transcription factor ICER are expressed rhythmically in the suprachiasmatic nucleus (SCN) and in the pars tuberalis (PT). In the Syrian hamster the duration of photoperiod affects the amplitude of gene expression in the PT, and melatonin administered before lights‐on suppressed the peak of Per1/ICER expression; these effects were not seen in the SCN. It was speculated that the inefficacy of melatonin was due to the low density of melatonin receptors in the SCN of this species. The aim of the present study was to determine whether this phenomenon also occurs in the Siberian hamster, which expresses a higher density of melatonin receptors in the SCN. Male Siberian hamsters were housed in long days (16 h light : 8 h dark) or short days (8 h light : 16 h dark) and expression of Per1 and ICER mRNA was studied by in situ hybridization. The expression of Per1 and ICER mRNA in the PT peaked 3 h following lights‐on (ZT3) under both photoperiods. The amplitudes of these peaks were greatly attenuated under short photoperiod. In the SCN, the duration of Per1 gene expression was proportional to the length of the light phase, but only a modest amplitude effect was observed. Injections of melatonin (25 μg) 1 h before lights‐on significantly reduced the expression of both genes in the PT at ZT3, but had no effect in the SCN. These data demonstrate that photoperiod‐dependent amplitude modulation of Per1 and ICER gene expression in the PT is conserved across species, and reinforce the argument that this phenomenon is driven by melatonin.
Differential modulation of AMPA receptors by cyclothiazide in two types of striatal neurons
Authors: Vorobjev Vladimir S. , Sharonova Irina N. , Haas Helmut L. , Sergeeva Olga A. 
Published: March 2003

AbstractThe modulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazol‐propionate (AMPA) receptor‐mediated currents by cyclothiazide was investigated in acutely isolated cells from rat striatum with whole‐cell patch‐clamp recording. Single‐cell reverse transcriptase‐polymerase chain reaction (RT‐PCR) was used to identify medium spiny and giant aspiny neurons and to determine their AMPA receptor subunit composition mostly in separate experiments. After pretreatment with cyclothiazide, kainate‐induced AMPA responses were more strongly potentiated in medium spiny than in giant aspiny neurons; cyclothiazide induced a ninefold leftward shift in the kainate concentration–response curve for medium spiny neurons (not giant aspiny neurons). The EC50s for the cyclothiazide potentiation did not differ substantially between medium spiny neurons and giant aspiny neurons. The recovery of kainate‐activated currents from modulation by cyclothiazide was slower for medium spiny neurons than for giant aspiny neurons. Medium spiny neurons expressed GluR‐A, GluR‐B and GluR‐C, but not GluR‐D subunits in both flip and flop splice variants. All giant aspiny neurons expressed GluR‐A and GluR‐D, exclusively in the flop form, half of them also expressed GluR‐B and GluR‐C. This is in keeping with slow and fast desensitization kinetics in medium spiny neurons and giant aspiny neurons, respectively, and differences in cyclothiazide modulation. The rate of cyclothiazide dissociation from the AMPA receptor, activated by glutamate, was ∼ 90 times slower in medium spiny neurons than in giant aspiny neurons. In giant aspiny neurons (not medium spiny neurons) this rate was strongly dependent on the presence of an agonist; 1 mm glutamate increased it 30‐fold. Thus, two major cell groups in the striatum display distinct AMPA receptor compositions carrying specific properties of glutamate responses. Excitatory transmission will thus be differentially affected by cyclothiazide‐type compounds.
Postnatal handling alters the activation of stress‐related neuronal circuitries
Authors: Ábrahám István M. , Kovács Krisztina J. 
Published: March 2003

AbstractPostnatal handling, as a crucial early life experience, plays an essential role in the development of hypothalamo‐pituitary–adrenal axis responses to stress. The impact of postnatal handling on the reactivity of stress‐related neuronal circuitries was investigated in animals that were handled for the first 21 days of life and as adults they were exposed to physical (ether) or emotional (restraint) challenge. To assess neuronal activation we relied on the induction of immediate‐early gene product c‐Fos and analysed its spatial and temporal distribution at various time intervals after stress. Ether and restraint commonly activated parvocellular neurons in the hypothalamic paraventricular nucleus, and resulted in activation of brain areas providing stress‐related information to the hypothalamic effector neurons and/or in regions governing autonomic and behavioural responses to stress. Beyond these areas, the strength and timing of c‐Fos induction showed stressor specificity in olfactory and septal region, basal ganglia, hypothalamus, hippocampal formation, amygdala and brainstem. Handled rats displayed a lower number of c‐Fos‐positive cell nuclei and weaker staining intensity than non‐handled controls in the hypothalamic paraventricular nucleus, bed nucleus of stria terminalis, central nucleus of amygdala, hippocampus, piriform cortex and posterior division of the cingulum. Significant differences were revealed in timing of c‐Fos induction as a function of stressor and early life experience. Together, these data provide functional anatomical evidence that environmental enrichment in the early postnatal period attenuates the reactivity of stress‐related neuronal circuitries in the adult rat brain.
Human area V5 and motion in the ipsilateral visual field
Authors: Ffytche D. H. , Howseman A. , Edwards R. , Sandeman D. R. , Zeki S. 
Published: March 2003

AbstractWe have studied area V5 of the human brain with visually‐evoked potential (VEP) and functional magnetic resonance imaging (fMRI) methods, using hemifield motion stimuli. Our results confirmed the presence of an ipsilateral field representation in V5 and found: (i) a delay in the ipsilateral response in V5, irrespective of the hemifield stimulated; (ii) a longer ipsilateral delay for left hemifield than for right hemifield stimulation; and (iii) in a patient with a section of the splenium, an absent ipsilateral response for right but not left hemifield stimulation. Together with neurophysiological and anatomical evidence in the monkey, our non‐invasive spatial and temporal imaging studies in man reveal that ipsilateral V5 is activated by motion signals transferred from contralateral V5. The asymmetry of ipsilateral delay in normal subjects and the asymmetrical loss of ipsilateral response following splenial section imply that signals related to visual motion are transferred from one V5 to the other through two segregated pathways.
A modulatory role for protein phosphatase 2B (calcineurin) in the regulation of Ca2+ entry
Authors: Burley J. Russell , Sihra Talvinder S. 
Published: March 2003

AbstractThe Ca2+/calmodulin‐dependent protein phosphatase 2B (PP2B) also known as calcineurin (CN) has been implicated in the Ca2+‐dependent inactivation of Ca2+ channels in several cell types. To study the role of calcineurin in the regulation of Ca2+‐channel activity, phosphatase expression was altered in NG108‐15 cells by transfection of sense and antisense plasmid constructs carrying the catalytic subunit of human PP2Bβ3. Relative to mock‐transfected (wild‐type) controls, cells overexpressing calcineurin showed dramatically reduced high‐voltage‐activated Ca2+ currents which were recoverable by the inclusion of 1 μm FK506 in the patch pipette. Conversely, in cells with reduced calcineurin expression, high‐voltage‐activated Ca2+ currents were larger relative to controls. Additionally in these cells, low‐voltage‐activated currents were significantly reduced. Analysis of high‐voltage‐activated Ca2+ currents revealed that the kinetics of inactivation were significantly accelerated in cells overexpressing calcineurin. Following the delivery of a train of depolarizing pulses in experiments designed to produce large‐scale Ca2+ influx across the cell membrane, Ca2+‐dependent inactivation of high‐voltage‐activated Ca2+ currents was increased in sense cells, and this increase could be reduced by intracellular application of 1 mm BAPTA or 1 μm FK506. These data support a role of calcineurin in the negative feedback regulation of Ca2+ entry through voltage‐operated Ca2+ channels.
Differences in the effect of chronic and acute caffeine on self‐administration of cocaine in mice
Authors: Kuzmin A. , Johansson B. , Semenova S. , Fredholm B. B. 
Published: March 2003

AbstractWe have compared the ability of an acute injection of caffeine (3 mg/kg, i.p.) and long‐term peroral caffeine consumption for 10 days (≈ 150 mg/kg/day in tap water) to affect cocaine self‐administration in mice. The peak plasma and brain levels of caffeine and its metabolites were similar in the two experimental set‐ups. Moreover, the levels reached are close to those obtained in humans upon coffee ingestion. Neither type of caffeine administration affected the reinforcing effect of cocaine, defined as a selective increase in nose‐poke responses in mice self‐administering cocaine compared to their yoked controls. However, caffeine injection increased the amount of cocaine self‐administered whereas caffeine drinking reduced it. A low dose of cocaine, by itself essentially ineffective, produced an increase in c‐fos and NGFI‐A mRNA in the cerebral cortex in mice that had been drinking caffeine. An acute caffeine injection also enhanced the immediate early gene response to cocaine, but to a lesser degree. Cocaine and caffeine also synergistically increased NGFI‐A expression in caudate‐putamen. Thus, regular caffeine drinking decreased the cocaine intake without significantly affecting its reinforcing properties, perhaps because it enhanced the activation of the predominantly inhibitory frontal cortical areas produced by low doses of cocaine.
Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse
Authors: Bezard Erwan , Jaber Mohamed , Gonon François , Boireau Alain , Bloch Bertrand , Gross Christian E. 
Published: March 2003

AbstractAlthough several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.