bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of neurosteroid synthesis by NMDA receptors in isolated rat retina: a potential early event in excitotoxicity
Authors: Guarneri P. , Russo D. , Cascio C. , De Leo G. , Piccoli F. , Guarneri R. 
Published: March 2003

AbstractHere we investigated the possible regulation of neurosteroidogenesis by N‐methyl‐d‐aspartic acid (NMDA) receptor activation and addressed the hypothesis that neurosteroid synthesis may be involved in acute excitotoxicity. In the isolated retina, exposure to NMDA modified pregnenolone and pregnenolone sulphate formation. This effect was dose and time dependent, the synthesis being increased by relatively moderate NMDA doses (1–100 μm) within 30 min exposure and reduced to its control value by 60 min or by raising drug concentrations. NMDA‐stimulated neurosteroid synthesis was blocked by (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine hydrogen maleate (MK‐801) and 3(2‐carboxypiperazine‐4‐yl)propyl‐1‐phosphonic acid (CPP), depended on extracellular calcium and reproduced by glutamate. Lactate dehydrogenase (LDH) release and morphological analysis revealed that retinal cell viability was not significantly affected after 30 min exposure to 50 μm NMDA, but severe cell damage occurred by 60 min. When the GABAA (γ‐aminobutyric acid) receptor agonist muscimol (1–1000 μm), known to activate retinal neurosteroidogenesis, was added together with NMDA, no additional increase in neurosteroid synthesis was observed, and NMDA‐induced LDH release remained unchanged. However, exposure to a high concentration of muscimol alone (500 μm) provoked a similar degree of toxicity to NMDA. By contrast, bicuculline abolished the increase in neurosteroidogenesis and LDH release. Similarly, pretreatment with R (+)‐p‐aminoglutethimide (AMG), an inhibitor of cholesterol side‐chain cleavage cytochrome P450, attenuated acute retinal cell damage. The inhibitory nature of AMG on NMDA‐stimulated neurosteroidogenesis was confirmed in the observation that drug treatment reduced pregnenolone content and did not affect the bindings of [3H] MK‐801 and [3H] muscimol. The results demonstrate that NMDA receptors regulate neurosteroidogenesis through a transneuronal mechanism, which implies GABAA receptor activation. The early NMDA‐mediated stimulation of neurosteroid synthesis seems to play a critical role in acute excitotoxicity; consequently, its inhibition is likely to delay neuronal cell death.
GFRα‐3, a protein related to GFRα‐1, is expressed in developing peripheral neurons and ensheathing cells
Authors: Widenfalk Johan , Tomac Andreas , Lindqvist Eva , Hoffer Barry , Olson Lars 
Published: March 2003

AbstractWe report here the identification of a gene, termed GFRα‐3 (glial cell line‐derived neurotrophic factor family receptor alpha‐3), related to GFRα‐1 and GFRα‐2 (also known as GDNFR‐α and GDNFR‐β), and describe distribution of GDNFα‐3 in the nervous system and other parts of the mouse body during development and in the adult. GFRα‐3 in situ hybridization signals were found mainly in the peripheral nervous system, with prominent signals in developing dorsal root and trigeminal ganglia. Sympathetic ganglia were also positive. Developing nerves manifested strong GFRα‐3 mRNA signals, presumably generated by the Schwann cells. Olfactory ensheathing cells were also positive. Other non‐neuronal cells appearing positive during development included chromaffin cells in the adrenal gland and small clusters of cells in the intestinal epithelium. In the central nervous system no robust signals could be detected at any stage investigated with the present probes. Compared with the previously described GFRα‐1 and GFRα‐2 mRNAs, which are widely distributed in the central nervous system and peripheral organs, the expression of GFRα‐3 mRNA is much more restricted. The prominent expression in Schwann cells during development suggests a key role for GFRα‐3 in the development of the peripheral nervous system. As Schwann cells are known to lack expression of the transducing RET receptor, we propose that a possible function of GFRα‐3 during development could be to bind Schwann cell‐derived GDNF‐like ligands, thus presenting such molecules to growing axons.
Functional Ca2+ and Na+ channels on mouse Schwann cells cultured in serum‐free medium: regulation by a diffusible factor from neurons and by cAMP
Authors: Beaudu‐Lange Claire , Despeyroux Sophie , Marcaggi Païkan , Coles Jonathan A. , Amédée Thierry 
Published: March 2003

AbstractRegulation of expression of functional voltage‐gated ion channels for inward currents was studied in Schwann cells in organotypic cultures of dorsal root ganglia from E19 mouse embryos maintained in serum‐free medium. Of the Schwann cells that did not contact axons, 46.5% expressed T‐type Ca2+ conductances (ICaT). Two days or more after excision of the ganglia, and consequent disappearance of neurites, ICaT were detectable in only 10.9% of the cells, and the marker 04 disappeared. On Schwann cells deprived of neurons, T‐ (but not L‐) type Ca2+ conductances were re‐induced by weakly hydrolysable analogues of cAMP, and by forskolin (an activator of adenylyl cyclase) after long‐term treatment (4 days). With CPT cAMP (0.1–2 mm), 8Br cAMP, db cAMP or forskolin (0.01 or 0.1 mm), the proportion of cells with ICaT was not significantly different from the proportion in the cultures with neurons. These agents also induced expression in some cells of tetrodotoxin‐resistant Na+ currents, which were rarely induced by neurons, but 04 was not re‐induced by cAMP analogue treatments that re‐induced ICaT. Inward currents (Ba2+ or Na+) were partly restored (P < 0.05) on Schwann cells cultured for 6–7 days beneath a filter bearing cultured neurons. In contrast, addition of neuron‐conditioned medium was ineffective. The results suggest that neurons activate, via diffusible and degradable factors, a subset of Schwann cell cAMP pathways leading to expression of ICaT, and activate additional non‐cAMP pathways that lead to expression of 04.
Calcium influx through N‐ and P/Q‐type channels activate apamin‐sensitive calcium‐dependent potassium channels generating the late afterhyperpolarization in lamprey spinal neurons
Authors: Wikström  , Manira A. El 
Published: March 2003

AbstractLamprey spinal neurons exhibit a fast afterhyperpolarization and a late afterhyperpolarization (AHP) which is due to the activation of apamin‐sensitive SK Ca2+‐dependent K+ channels (KCa) activated by calcium influx through voltage‐dependent channels during the action potential (Hill et al. 1992, Neuroreport, 3, 943–945). In this study we have investigated which calcium channel subtypes are responsible for the activation of the KCa channels underlying the AHP. The effects of applying specific calcium channel blockers and agonists were analysed with regard to their effects on the AHP. Blockade of N‐type calcium channels by ω‐conotoxin GVIA resulted in a significant decrease in the amplitude of the AHP by 76.2 ± 14.9% (mean ± SD). Application of the P/Q‐type calcium channel blocker ω‐agatoxin IVA reduced the amplitude of the AHP by 20.3 ± 10.4%. The amplitude of the AHP was unchanged during application of the L‐type calcium channel antagonist nimodipine or the agonist (±)‐BAY K 8644, as was the compound afterhyperpolarization after a train of 10 spikes at 100 Hz. The effects of calcium channel blockers were also tested on the spike frequency adaptation during a train of action potentials induced by a 100–200 ms depolarizing pulse. The N‐ and P/Q‐type calcium channel antagonists decreased the spike frequency adaptation, whereas blockade of L‐type channels had no effect. Thus in lamprey spinal cord motor‐ and interneurons, apamin‐sensitive KCa channels underlying the AHP are activated primarily by calcium entering through N‐type channels, and to a lesser extent through P/Q‐type channels.
Hyperpolarization induces a rise in intracellular sodium concentration in dopamine cells of the substantia nigra pars compacta
Authors: Knöpfel T. , Guatteo E. , Bernardi G. , Mercuri N. B. 
Published: March 2003

SummaryWe investigated the effect of changes in membrane‐voltage on intracellular sodium concentration ([Na+]i) of dopamine‐sensitive neurons of the substantia nigra pars compacta in a slice preparation of rat mesencephalon. Whole‐cell patch‐clamp techniques were combined with microfluorometric measurements of [Na+]i using the Na+‐sensitive probe, sodium‐binding benzofuran isophthalate (SBFI). Hyperpolarization of spontaneouslyactive dopamine neurons (recorded in current‐clamp mode) caused the cessation of action potential firing accompanied by an elevation in [Na+]i. In dopamine neurons voltage‐clamped at a holding potential of −60 mV elevations of [Na+]i were induced by long‐lasting (45–60 s) voltage jumps to more negative membrane potentials (–90 to −120 mV) but not by corresponding voltage jumps to −30 mV. These hyperpolarization‐induced elevations of [Na+]i were depressed during inhibition of Ih, a hyperpolarization‐activated inward current, by Cs+. Hyperpolarization‐induced elevations in [Na+]i might occur also in other cell types which express a powerful Ih and might signal lack of postsynaptic activity.
Efferent‐mediated protection of the cochlear base from acoustic overexposure by low doses of lithium
Authors: Horner Kathleen C. , Higueret Denise , Cazals  
Published: March 2003

AbstractMany studies on anaesthetized animals and a few on awake animals have suggested that the cholinergic olivocochlear efferent feedback to outer hair cells can participate in the protection of the cochlea from acoustic overexposure. Lithium is known to stimulate acetylcholine synthesis and release in the brain and it is likely to act similarly at the level of the cochlear efferent synapses. We demonstrate here that, in the awake guinea‐pig with a chronically implanted electrode on the round window of the cochlea, the temporary threshold shift induced by 1 minute exposure to different pure tones at around 90 dB sound pressure level (SPL) was reduced by as much as 40 dB, when exposure occurred after lithium treatment. The protection effect was not observed in anaesthetized animals. The effect was seen across the test frequency range of 6.4–12.5 kHz, suggesting that both ‘fast’ and ‘slow’ efferent effects are likely to be mediated by acetylcholine. Together our results provide new evidence that the olivocochlear efferents can provide a more efficient protection from acoustic overexposure when animals are awake.
The response of cat visual cortex to flicker stimuli of variable frequency
Authors: Rager Günter , Singer Wolf 
Published: March 2003

AbstractWe examined the possibility that neurons or groups of neurons along the retino‐cortical transmission chain have properties of tuned oscillators. To this end, we studied the resonance properties of the retino‐thalamo‐cortical system of anaesthetized cats by entraining responses with flicker stimuli of variable frequency (2–50 Hz). Responses were assessed from multi‐unit activity (MUA) and local field potentials (LFPs) with up to four spatially segregated electrodes placed in areas 17 and 18. MUA and LFP responses were closely related, units discharging with high preference during LFP negativity. About 300 ms after flicker onset, responses stabilized and exhibited a highly regular oscillatory patterning that was surprisingly similar at different recording sites due to precise stimulus locking. Fourier transforms of these steady state oscillations showed maximal power at the inducing frequency and consistently revealed additional peaks at harmonic frequencies. The frequency‐dependent amplitude changes of the fundamental and harmonic response components suggest that the retino‐cortical system is entrainable into steady state oscillations over a broad frequency range and exhibits preferences for distinct frequencies in the θ‐ or slow α‐range, and in the β‐ and γ‐band. Concomitant activation of the mesencephalic reticular formation increased the ability of cortical cells to follow high frequency stimulation, and enhanced dramatically the amplitude of first‐ and second‐order harmonics in the γ‐frequency range between 30 and 50 Hz. Cross‐correlations computed between responses recorded simultaneously from different sites revealed pronounced synchronicity due to precise stimulus locking. These results suggest that the retino‐cortical system contains broadly tuned, strongly damped oscillators which altogether exhibit at least three ranges of preferred frequencies, the relative expression of the preferences depending on the central state. These properties agree with the characteristics of oscillatory responses evoked by non‐temporally modulated stimuli, and they indicate that neuronal responses along the retino‐cortical transmission chain can become synchronized with precision in the millisecond range not only by intrinsic interactions, but also by temporally structured stimuli.
Melanocortin receptors and δ‐opioid receptor mediate opposite signalling actions of POMC‐derived peptides in CATH.a cells
Authors: René Frédérique , Muller André , Jover Emmanuel , Kieffer Brigitte , Koch Bernard , Loeffler Jean‐Philippe 
Published: March 2003

AbstractThe locus cœruleus is innervated by proopiomelanocortin (POMC)‐derived peptide immunoreactive fibres. The biological effects of α melanocyte‐stimulating hormone (αMSH) and β‐endorphin on second messengers (cAMP, inositol phosphates) and gene transcription were studied in the locus cœruleus‐derived cell line CATH.a. RT‐PCR analysis revealed the presence of four MSH receptor subtypes (1, 3, 4 and 5). Activation of these receptors by diacetyl αMSH stimulated cAMP accumulation in a dose‐dependent manner (EC50: 4 × 10–9m). Diacetyl αMSH stimulated transcription from reporter genes driven by the c‐fos or tyrosine hydroxylase promoter. This effect was abolished when protein kinase A was inactivated with a dominant inhibitory mutant. RT‐PCR analyses revealed the presence of δ‐, but not μ‐and κ‐opioid receptor. Pharmacological analysis showed that β‐endorphin (EC50: 2.5 × 10–8m), but not N‐acetyl β‐endorphin, antagonized the biological effect of diacetyl αMSH on cAMP production and gene transcription. Since N‐acetylation regulates the biological activity of αMSH and β‐endorphin in an opposite manner, we propose a model where the rate of secretion dictated by the bioelectric activity of the presynaptic neuron modulates POMC‐derived peptide maturation and the resulting biological signal sensed by the postsynaptic plate.
Functional connectivity within the visual cortex of the rat shows state changes
Authors: van der Togt Chris , Lamme Victor A. F. , Spekreijse Henk 
Published: March 2003

AbstractThe aim of this study was to investigate the dynamics of the horizontal functional connectivity within the visual cortex during spontaneous activity or during visual stimulation. Two arrays of 16 electrodes were inserted in the visual cortex of a rat. From these electrodes a depth profile was obtained of the local spiking activity. The cross‐correlations between all electrodes were estimated. Three types of cross‐correlation peaks were identified and classified as;‘thin peaks’, ‘fast waves’ and ‘slow waves’. Partialization was applied, a mathematical method to reduce the amount of common input in correlations, and its effect on the three types of correlation peaks was studied. Slow waves were found to be the most vulnerable to partialization and thin peaks the least. From these observations it was concluded that the three types of peaks represent synchronous neuronal assemblies of different magnitude; slow waves large, fast waves intermediate and thin peaks assemblies composed of small numbers of neurons.Large changes were observed in the types of cross‐correlations and their spatial distribution within the set of interarray combinations of electrodes. These changes were spontaneous, and could not be related to the visual stimulation. Two states were identified; the ‘thin‐peak’ state and the ‘slow‐wave’ state. The ‘thin‐peak’ state is interpreted as occurring at a light level of anaesthesia and is characterized by the presence of thin peaks in all combinations of electrodes. Thin peaks with the largest strength were found in the upper interarray electrode combinations. The ‘slow‐wave’ state is interpreted as occurring at a deep level of anaesthesia and is characterized by the presence of exclusively slow waves, which were limited mostly to the middle and lower interarray combinations of electrodes. Activation of the cortex is thus associated with the appearance of synchrony between small groups of neurons (thin peaks) which, in contrast to the slow‐wave state, include the upper layers of the cortex.
Mesolimbic dopaminergic mechanisms underlying individual differences in sugar consumption and amphetamine hyperlocomotion in Wistar rats
Authors: Sills Terrence L. , Onalaja Ava O. , Crawley Jacqueline N. 
Published: March 2003

AbstractIndividual differences within strains of rats have been demonstrated for dopamine‐mediated behaviours and responses to dopaminergic drugs. Differences in mesolimbic dopamine function may underlie individual differences in some of these behaviours, including sugar consumption and amphetamine hyperlocomotion. The present study addressed two potential mechanisms for these differences in dopamine‐mediated behaviours. The possibility of functional differences in dopamine receptor subtypes was tested in LOW and HIGH sugar feeders. LOW and HIGH feeders did not differ in their response to the partial D1 agonist SKF‐38393. The highest dose (2.5 mg/kg) of the D2 agonist quinpirole stimulated locomotor activity to a greater degree in a subset of HIGH sugar feeders as compared with LOW feeders. All doses of amphetamine induced a greater locomotor response in HIGH feeders as compared with LOW feeders, and HIGH feeders exhibited higher levels of extracellular dopamine in the nucleus accumbens than LOW feeders following exposure to sugar and treatment with amphetamine. These results support the interpretation that LOW and HIGH feeders exhibit differences in presynaptic nucleus accumbens dopamine function that account for the expression of individual differences in sugar consumption and response to amphetamine treatments. A subset of HIGH feeders may also exhibit greater D2 receptor function.
NMDA‐induced superoxide production and neurotoxicity in cultured rat hippocampal neurons: role of mitochondria
Authors: Sengpiel Bernd , Preis Elke , Krieglstein Josef , Prehn Jochen H. M. 
Published: March 2003

AbstractExcitotoxic mechanisms are believed to be involved in the death of neurons after trauma, epileptic seizures and cerebral ischaemia. We investigated the role of mitochondrial superoxide production in excitotoxic cell death of cultured rat hippocampal neurons. Brief exposure to the selective glutamate agonist N‐methyl‐d‐aspartate (NMDA; 100–300 μm, 10 min) induced significant neuronal death, which was sensitive to cycloheximide (1 μm) and the caspase‐1 inhibitor, acetyl‐Tyr‐Val‐Ala‐Asp‐chloromethylketone (10 μm). Intracellular superoxide production was monitored semiquantitatively on sister cultures from the same platings using the oxidation‐sensitive probe, hydroethidine. Brief exposures to toxic NMDA concentrations induced significant increases in superoxide production which correlated with the degree of neuronal injury. However, subtoxic NMDA exposures also produced moderate, yet statistically significant increases in superoxide production. Both NMDA‐induced superoxide production and neurotoxicity were reduced by inhibition of mitochondrial electron transport using either sodium cyanide (1 mm), or a combination of rotenone (2 μm) and oligomycin (2 μm). The mitochondrial uncoupler carbonyl cyanide p‐trifluoromethoxy‐phenylhydrazone (FCCP, 1 μm) mimicked the effect of NMDA on mitochondrial superoxide production. Both NMDA‐induced superoxide production and neurotoxicity were potentiated by FCCP (1 μm). Exposure to FCCP alone (1–10 μm, 10 min), however, failed to produce any toxicity. Our data suggest that mitochondrial superoxide production per se is not sufficient to trigger the degeneration of cultured hippocampal neurons, but that manipulation of mitochondrial activity alters NMDA‐induced superoxide production and neurotoxicity.
Identification and characterization of a novel member of the fibroblast growth factor family
Authors: Greene J. M. , Li Y. L. , Yourey P. A. , Gruber J. , Carter K. C. , Shell B. K. , Dillon P. A. , Florence C. , Duan D. R. , Blunt A. , Ornitz D. M. , Ruben S. M. , Alderson R. F. 
Published: March 2003

AbstractA new member of the fibroblast growth factor (FGF) family, FGF‐13, has been molecularly cloned as a result of high throughput sequencing of a human ovarian cancer cell library. The open reading frame of the novel human gene (1419 bp) encodes for a protein of 216 a.a. with a molecular weight of 22 kDa. The FGF‐13 sequence contains an amino‐terminal hydrophobic region of 23 a.a. characteristic of a signal secretion sequence. FGF‐13 is most homologous, 70% similarity at the amino acid level, to FGF‐8. Northern hybridization analysis demonstrated prominent expression of FGF‐13 in human foetal and adult brain, particularly in the cerebellum and cortex. In proliferation studies with BaF3 cells, FGF‐13 preferentially activates cell clones expressing either FGF receptor variant, 3‐IIIc or 4. The signal transduction pathways of FGF‐13 and FGF‐2 were compared in rat hippocampal astrocytes. The two FGFs induce an equivalent level of tyrosine phosphorylation of mitogen‐activated protein kinase (MAPK) and c‐raf activation. However, FGF‐13 is more effective than FGF‐2 in inducing the phosphorylation of phospholipase C‐gamma (PLC‐γ). Treatment of neuronal cultures from rat embryonic cortex with FGF‐13 increases the number of glutamic acid decarboxylase immunopositive neurons, the level of high‐affinity gamma‐aminobutyric acid (GABA) uptake, and choline acetyltransferase enzyme activity. The GABAergic neuronal response to FGF‐13 treatment is rapid with a significant increase occurring within 72 h. We have identified a novel member of the FGF family that is expressed in the central nervous system (CNS) and increases the number as well as the level of phenotypic differentiation of cortical neurons in vitro.
Serotonin is not synthesized, but specifically transported, in the neurons of the hypothalamic dorsomedial nucleus
Authors: Vanhatalo Sampsa , Soinila Seppo 
Published: March 2003

AbstractA small group of neurons in the hypothalamic dorsomedial nucleus (DMN) have been reported to contain serotonin after pharmacological treatments enhancing brain serotonin levels. This study aimed at elucidating whether these neurons are able to synthesize serotonin de novo, and whether they possess a specific serotonin transport mechanism. Serotonin content in these neurons was raised by administration of l‐tryptophan and pargyline. Double immunostaining for serotonin and tryptophan hydroxylase (TpOH), the serotonin synthesizing enzyme, revealed that none of the serotonin‐containing neuronal somata expressed TpOH. Intracerebro‐ventricular colchicine treatment did not result in TpOH‐IR in these neurons. Fluoxetine, a specific serotonin transport inhibitor, prevented the accumulation of serotonin in these neurons. The present results thus indicate that the serotonin‐containing DMN neurons are not able to synthesize serotonin. Instead, they take up exogenous serotonin via a specific serotonin transport mechanism. As serotonin and DMN are associated with various physiological functions, such as regulation of food intake and modulation of fear and anxiety, the mechanisms revealed in the present study may participate in these clinically important brain functions.