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PubMed2001

Modulation of [3H]quinpirole binding at striatal D2 dopamine receptors by a monoamine oxidaseA-like site: evidence from radioligand binding studies and D2 receptor- and MAO(A)-deficient mice.

[3H]Quinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptors. A variety of monoamine oxidase inhibitors (MAOIs) inhibit equilibrium binding of [3H]quinpirole binding in rat striatal membranes suggesting that MAOIs interact with a novel binding site that is labeled by [3H]quinpirole or that allosterically modulates [3H]quinpirole binding. To determine whether the D2 receptor is essential for [3H]quinpirole binding and/or modulation of [3H]quinpirole binding by MAOIs, D2 receptor-deficient mice were studied. [3H]Quinpirole binding was decreased in D2 receptor-deficient mice to 3% of that observed in wild-type controls indicating that [3H]quinpirole binding is associated with the D2 dopamine receptors. Then, in an attempt to label the site mediating the modulation of [3H]quinpirole binding, binding of the MAOI [3H]Ro 41-1049 was characterized in rat striatal membranes. [3H]Ro-41-1049 labeled a single binding site with a pharmacological profile with respect to MAOIs that was similar to both [3H]quinpirole binding (Spearman r=0.976) and MAO(A) activity. To determine whether MAO(A) plays a role in the modulation of [3H]quinpirole binding by MAOIs, MAO(A)-deficient mice were examined. In these mice, [3H]Ro-41-1049 binding was decreased to 7% of wild-type control. [3H]Spiperone binding was unaltered. Spiperone-displaceable [3H]quinpirole binding was decreased to 43% of wild-type control; however, the remaining [3H]quinpirole binding in MAO(A)-deficient animals was inhibited by Ro 41-1049 similar to wild-type. [3H]Ro-41-1049 binding was not decreased in D2 receptor-deficient mice. These data suggest that [3H]Ro-41-1049 labels multiple sites and that MAOIs modulate [3H]quinpirole binding to the D2 receptor via interactions at a novel, non-MAO binding site with MAO(A)-like pharmacology.

Animals↗
PubMed1998

Xenobiotics and xenoestrogens in fish: modulation of cytochrome P450 and carcinogenesis.

As is the case with mammals, an ever-increasing number of cytochromes P450 (CYPs) are being characterized from fish. The focus of work on fish CYPs has been primarily on environmental induction of CYP1A by pollutants such as the polycyclic aromatic hydrocarbons, polychlorinated biphenyls, dioxins and dibenzofurans. This response has been the basis for a sensitive biomonitoring tool of ecosystem health for a number of years. Studies have documented a correlation between CYP1A induction, pollutant levels and tumor incidence, especially in bottom-dwelling species. The rainbow trout has been utilized as a tumor model to document the role of CYP1A modulation in the inhibition or promotion of cancer. Fish are also very responsive to the class of chemicals known as xenoestrogens. Recent evidence is presented documenting the modulation of CYPs by xenoestrogens and their potential role as modulators of the tumor response. In this paper, we summarize the current knowledge concerning the occurrence of CYPs in fish and focus on the role of CYP1A induction in environmental monitoring of various genotoxic carcinogens and in the modulation of cancer in the trout model. Finally, the important class of aquatic pollutants known as xenoestrogens have now been shown to modulate CYP levels perhaps leading to alterations in tumor response or other adverse effects.

Animals↗
PubMed1999

Modulation of synaptic transmission and differential localisation of mGlus in cultured hippocampal autapses.

Metabotropic glutamate receptors (mGlus) are known to modulate synaptic transmission in various pathways of the central nervous system, but the exact mechanisms by which this modulation occurs remain unclear. Here we utilise electrophysiological and immunocytochemical techniques on cultured autaptic hippocampal neurones to investigate the mechanism of action and distribution of mGlus. Agonists at all three groups of mGlus depressed glutamatergic transmission, whereas only agonists at group I mGlus depressed GABAergic transmission. Agonists at all mGlus failed to modulate Ca2+ and K+ channels in glutamatergic autapses whereas an agonist at group III mGlus did depress the frequency of miniature excitatory postsynaptic currents (mEPSCs). Agonists failed to modulate Ca2+ or K+ channels and miniature inhibitory postsynaptic currents (mIPSCs) in GABAergic autapses. Distribution studies using selective antibodies revealed punctate staining for group III mGlus that co-localised with the synaptic marker, synaptophysin. Staining for the remaining mGlus was more diffuse throughout the soma and processes with little co-localisation with synaptophysin. The distribution of the group III receptors is consistent with the direct 'downstream' modulation of mEPSCs, although the exact mechanism of action for the remaining receptors remains unclear.

Animals↗
PubMed2000

The contributions of GluR2 to allosteric modulation of AMPA receptors.

Native AMPA receptor complexes in the CNS are composed of hetero-oligomers of the GluR1-4 subunits, and generally contain the GluR2 subunit. To determine the contributions of GluR2 to pharmacological properties of receptor complexes, the effect of hetero-oligomerization with GluR2 on allosteric modulation of recombinant AMPA receptors was studied. The study of homo-oligomeric GluR2 was facilitated with a site-directed mutant of the pore, GluR2(R607Q), which allowed robust currents from this normally low-conducting subunit. The efficacy of the allosteric modulators was tested on homo-oligomeric GluR1-4, and then compared with hetero-oligomeric GluR1/GluR2, GluR3/GluR2 and GluR4/GluR2. Two selective allosteric modulators were tested, a positive modulator, cyclothiazide, and a negative modulator, LY300164. The results show that the pharmacological properties of homo-oligomeric GluR2 are not significantly different from those of GluR1, GluR3 or GluR4. The apparent affinity of cyclothiazide is not significantly changed upon hetero-oligomerization. However, the extent of potentiation of kainate responses by cyclothiazide is significantly decreased upon hetero-oligomerization. Hetero-oligomerization increases the apparent affinity of LY300164, a (-) isomer of the 2,3-benzodiazepine LY293606. These data indicate that although GluR2 has a dominant effect on the permeation properties, this subunit does not have a similarly dominant effect on pharmacological properties of native receptors. However, the state of hetero-oligomerization can alter the pharmacological properties of AMPA receptors.

Allosteric Regulation↗
PubMed2002

Expectation-based attentional modulation of visual extinction in spatial neglect.

Visual extinction, the failure of patients with unilateral focal brain damage to report the contralesional of two simultaneously presented stimuli, may be modulated by characteristics of the display such as similarity, collinearity, or connectedness. Since these factors affect the perceptual configuration of stimuli, the modulation of extinction is believed to reflect low-level perceptual grouping. In the present study, patient AG did not show any modulation of contralesional detection when the ipsilesional and contralesional stimulus grouped by colour, by form, or both (Experiment 1). In contrast, identification of the contralesional stimulus was facilitated when the stimuli grouped (Experiment 2), suggesting a modulation of extinction by specific task demands. Experiment 3 used a cueing procedure to demonstrate modulation of extinction by expectation biases. Prior to stimulus presentation, AG was cued to attend to a particular feature (e.g. colour). After stimulus exposure he was prompted to identify the expected feature on valid trials and the unexpected feature on invalid trials. AG showed a significant validity effect for contralesional stimuli i.e. he identified the expected feature (e.g. colour) significantly better than the unexpected feature (e.g. form). These results suggest that competition for selection between visual stimuli may not only be influenced by perceptual characteristics of the display, but also by high-level factors such as the response criterion or expectation biases.

Attention↗
PubMed2002

Thermo-optical modulation of ultrasonic surface waves for NDE.

The well-known thermo-elastic effect of laser irradiation can be exploited to produce strong localized stresses when an expanded, long pulse, low-intensity laser beam is used to irradiate the specimen. These stresses will produce a parametric modulation of the received ultrasonic signals, that is somewhat similar to the acousto-elastic effect often used in nonlinear ultrasonic studies. It is shown in this paper that otherwise hidden small cracks in fatigue-damaged aluminum and titanium specimens can be readily detected by exploiting this optically induced thermo-elastic modulation during ultrasonic surface wave inspection since they are susceptible to crack closure and therefore exhibit strong parametric modulation. The temporal and spatial variations of the ultrasonic signals due to laser irradiation were evaluated numerically and experimentally. Based on these results, the direct temperature modulation of the ultrasonic velocity can be separated from the thermo-elastic stress modulation present only in cracked specimens. It was found that this method can be used to selectively increase the sensitivity of ultrasonic flaw detection to small fatigue cracks by more than one order of magnitude.

Journal Article↗
PubMed1997

The peripheral flicker effect: desensitization of the luminance pathway by static and modulated light.

Previous studies have shown that luminance flicker, presented peripheral to a foveal test target, increases thresholds for target detection: the peripheral flicker (PF) effect. These studies have also shown that thresholds are elevated more for luminance targets, relative to chromatic targets. In the present study we examined the specificity of the PF effect on the luminance mechanism and assessed the contribution of modulated stray-light to the test field, as well as longer range spatial interactions. We found that the presence of a foveal luminance pedestal, as well as PF, caused a notch to appear in the spectral sensitivity function around 570 nm. This result confirms the hypothesis that the PF effect decreases the sensitivity of the luminance pathway. To assess the contribution of stray-light to the PF effect, we modulated a luminance pedestal without the presence of PF in order to simulate the stray-light effect in isolation. A decrease in sensitivity for wavelengths around 570 nm occurred with modulated stray-light, suggesting that modulated stray-light contributes substantially to this effect. We then minimized the modulated stray-light by phase-reversing a checkerboard pattern in the periphery. A significant, though smaller, threshold elevation to mid-spectrum stimuli was obtained, suggesting that long range spatial effects are also active in the PF effect. We conclude that the PF effect causes a desensitization of foveal luminance pathways via local and more long range spatial interactions. Our results are consistent with previous data which suggest that the PF effect is due to selective adaptation of cells in the magnocellular pathway (M-cells). Our data imply that local network adaptation may be a property of the magnocellular pathway.

Color Perception↗
PubMed1999

Sensitivity to modulations of luminance and contrast in visual white noise: separate mechanisms with similar behaviour.

Human vision can detect spatiotemporal information conveyed by first-order modulations of luminance and by second-order, non-Fourier modulations of image contrast. Models for second-order motion have suggested two filtering stages separated by a rectifying nonlinearity. We explore here the encoding of stationary first-order and second-order gratings, and their interaction. Stimuli consisted of 2-D binary, broad-band, static, visual noise sinusoidally modulated in luminance (LM, first-order) or contrast (CM, second-order). Modulation thresholds were measured in a two-interval forced-choice staircase procedure. Sensitivity curves for LM and CM had similar shape as a function of spatial frequency, and as a function of the size of a circular Gaussian blob of modulation. Weak background gratings present in both intervals produced order-specific facilitation: LM background facilitated LM detection (the dipper function) and CM facilitated CM detection. LM did not facilitate CM, nor vice-versa, neither in-phase nor out-of-phase, and this is strong evidence that LM and CM are detected via separate mechanisms. This conclusion was further supported by an experiment on the detection of LM/CM mixtures. From a general mathematical model and a specific computer simulation we conclude that a single mechanism sensitive to both LM and CM cannot predict the pattern of results for mixtures, while a model containing separate pathways for LM and CM, followed by energy summation, does so successfully and is quantitatively consistent with the finding of order-specific facilitation.

Contrast Sensitivity↗
PubMed2000

Spatial frequency tuned covariance channels for red-green and luminance-modulated gratings: psychophysical data from human adults.

Both chromatic and luminance-modulated stimuli are served by multiple spatial-frequency-tuned channels. This experiment investigated the independence versus interdependence of spatial frequency channels that serve the detection of red-green chromatic versus yellow-black luminance-modulated stimuli at low spatial frequencies. Contrast thresholds for both chromatic and luminance-modulated gratings were measured within 12 individual subjects using a repeated-measures design. Spatial frequencies ranged from 0.27 to 2.16 c/deg. A covariance structure analysis of individual differences was applied to the data. We computed statistical sources of individual variability, used them to define covariance channels, and determined the number and frequency tuning of these channels. For luminance-modulated gratings, two covariance channels were found, including one above and one below 1 c/deg [cf. Peterzell, & Teller (1996). Individual differences in contrast sensitivity functions: the coarsest spatial pattern analyzer. Vision Research, 36, 3077-3085]. For chromatic gratings, correlations between thresholds for most spatial frequencies were uniformly high, yielding a single covariance channel covering all but the highest spatial frequency tested. A combined analysis of both data sets recovered the same three covariance channels, and showed that detection thresholds for low-frequency red-green chromatic and luminance-modulated stimuli are served by separate, statistically independent processes.

Adult↗
PubMed1996

Solution structure of the link module: a hyaluronan-binding domain involved in extracellular matrix stability and cell migration.

Link modules are hyaluronan-binding domains found in proteins involved in the assembly of extracellular matrix, cell adhesion, and migration. The solution structure of the Link module from human TSG-6 was determined and found to consist of two alpha helices and two antiparallel beta sheets arranged around a large hydrophobic core. This defines the consensus fold for the Link module superfamily, which includes CD44, cartilage link protein, and aggrecan. The TSG-6 Link module was shown to interact with hyaluronan, and a putative binding surface was identified on the structure. A structural database search revealed close similarity between the Link module and the C-type lectin domain, with the predicted hyaluronan-binding site at an analogous position to the carbohydrate-binding pocket in E-selectin.

Amino Acid Sequence↗
PubMed1999

Central alpha1-adrenoceptors: their role in the modulation of attention and memory formation.

Adrenoceptors presently are classified into three main subclasses: alpha1-, alpha2-, and beta-receptors, each with three (perhaps more) subtypes. All three alpha1-adrenoceptor subtypes are present in rat brain. The purpose of this review is to assess the role of alpha1-adrenoceptors in the modulation of synaptic transmission and plasticity, as well as their ability to modulate higher cerebral functions, such as attentional and memory processes. However, since there are no truly subtype-specific agonists or antagonists available at present, it is virtually impossible to allocate a particular central effect to one or other of the subtypes. The activation of alpha1-adrenoceptors reduces the firing probability and glutamate release in the cornu ammonis of the hippocampus. Alpha1-Adrenoceptors may flexibly modulate weak and strong activation of the pyramidal neurones in the neocortex. Alpha1-Adrenoceptors play only a minor role in the modulation of long-term potentiation in the hippocampus, and may influence many brain functions also via non-neuronal mechanisms. since glial cells can express alpha1-adrenoceptors. At the behavioural level, the activation of alpha1-adrenoceptors promotes vigilance and influences working memory and behavioural activation, while having only a minor role in the modulation of long-term memory.

Animals↗
PubMed2000

Conformal irradiation of concave-shaped PTVs in the treatment of prostate cancer by simple 1D intensity-modulated beams.

BACKGROUND: In the case of concave-shaped PTVs including prostate (P) and seminal vesicles (SV), intensity-modulated radiation therapy (IMRT) should improve the therapeutic ratio of the treatment of prostate cancer. PURPOSE: Comparing IMRT by simple 1D modulations with conventional 3D conformal therapy (i.e. non-IMRT) in the treatment of concave-shaped PTVs including P+SV. MATERIALS AND METHODS: For five patients having a concave-shaped PTV (P+SV) previously treated at our Institute with conformal radiotherapy, conventional 3- and 4-fields conformal plans were compared with IMRT plans in terms of biological indices. IMRT plans were generated by using five equi-spaced beams with a partial shielding of the rectum obtainable with our single-absorber modulation technique (Fiorino C, Lev A, Fusca M, Cattaneo GM, Rudello F, Calandrino R. Dynamic beam modulation by using a single dynamic absorber. Phys. Med. Biol. 1995;40:221-240). The modulation was one-dimensional and the shape of the beams was at single minimum in correspondence with the 'core' of the rectum; the beam intensity in the minimum was set equal to 20 or 40% of the open beam intensity. All plans were simulated on the CADPLAN TPS using a pencil-beam based algorithm (with 18 MV X-rays). Tumour control probability (TCP) and normal tissue complication probabilities (NTCPs) (for rectum, bladder and femoral head) were calculated for all situations when varying the isocentre dose from 60 to 90 Gy. Dose distributions were corrected taking dose fractionation into account through the linear-quadratic model; for the TCP/NTCP estimations the Webb-Nahum and the Lyman-Kutcher models were respectively applied. Three different scores were considered: (a) increase of TCP while keeping rectum NTCP equal to 5% (TCP(5%)); (b) increase of the uncomplicated tumour control probability (P+); (c) increase of the biological-based scoring function (S+), developed by Mohan et al. (Mohan R, Mageras GS, Baldwin B, Clinically relevant optimization of 3D conformal treatments. Med. Phys. 1992;19:933-944). The impact of the uncertainty in the knowledge of the parameters of the biological models was investigated for TCP(5%). RESULTS: (a) The average gain in TCP(5%) when considering IMRT against non-IMRT conformal plans was 7.3% (range 5.0-13.5%); (b) the average increase of P+ was 3.4% (range: 1. 0-8.5%); and (c) the average increase of S+ was 5.4% (range 2.9-12. 4%). The largest gain was found for one patient (patient 5) showing a significantly larger overlapping between PTV and rectum. CONCLUSIONS: Simple 1D-IMRT may clearly improve the therapeutic ratio in the treatment of concave-shaped PTVs including P and SV. In the range of clinically suitable values, the impact of the uncertainty of the parameters n and sigma(alpha) does not significantly alter the main results concerning the gain in TCP(5%). The reported gain in terms of P+ and S+ should be considered with great caution because of the intrinsic uncertainties of the model's parameters and, for bladder, because the 'true' DVH (considering variations of the shape and dimension due to variable filling) may be very different from the DVH calculated on a single CT scan. Further investigations should consider inversely-optimised 1D and 2D-IMRT plan in order to compare them in terms of cost-benefit.

Algorithms↗
PubMed1998

Modulated electron beams using multi-segmented multileaf collimation.

BACKGROUND AND PURPOSE: Conformal radiation therapy by modulation of photon and electron beams has been described for many techniques. Modulation of electron beams with the use of either bolus or altered scanned beams is reported. Our institution previously investigated the use of MLC for fixed static electron fields. The results were dismal due to the wide penumbra associated with multileaf collimated electrons scattered from foils. The purpose of this study was to decipher whether multi-segmented electron beams using MLC would provide a useful and practical modulated beam by taking advantage of matching the diffuse beam edges. MATERIALS AND METHODS: We started by planning simple target shapes, such as wedged and parabolic shapes. We optimized the segment widths, weights, gaps between segments and energies. We then irradiated phantoms using film to confirm the calculations. The study was limited to single-plane irradiation. We also planned and measured isodoses for a parotid target volume that possessed varying depths from surface to medial aspect. RESULTS: We found that we could optimize distributions by using the treatment depth and points of inflection to derive optimal segments. The planned treatments using a simple CET (coefficient of equivalent thickness) algorithm were confirmed with reasonable success. A 24 cm wide target was treated with nine segments in under 5 min, while most cases, including the parotid volume, were treated in under 3 min. CONCLUSIONS: We have developed a technique to complement a photon modulation program by treating lesions close to the surface. The debate as to whether this technique is optimal and more efficient than a bolus technique continues. We are currently devising methods for optimizing modulated electron MLC beams in multiple planes.

Electrons↗
PubMed1999

The in vivo effect of the administration of resistance-modulating agents on rhodamine 123 distribution in mice thymus and lymph nodes.

P-glycoprotein (Pgp) has been widely associated with the multidrug resistance phenotype. Nevertheless, this protein has been detected in many normal tissues and cells, including liver, kidney, endothelial cells that constitute the hematological barrier of the brain and testes, and cells from the immune system. Many in vitro models have been used to study drugs that modulate Pgp activity and the multidrug resistance phenomenon. In the present work, we investigate the in vivo effects of resistance-modulating agents on lymphoid organs. Rhodamine 123 (Rho123), a well-known Pgp substrate, was administered to mice, and the fluorescence level in thymus and lymph node cells measured. The fluorescence level on these organs showed a dose-dependent response. Cyclosporin A (CSA), Verapamil (VP) and Trifluoperazine (TFP), three resistance-modulating agents, were administered to mice 1 h prior to 1 mg/kg Rho123 administration. Surprisingly, VP (10 mg/kg) and TFP (750 microg/kg) did not modulate Rho123 retention by thymus and lymph node cells. CSA (50 mg/kg) was the only drug that increased the fluorescence level in both organs. These results point out to the need of a wider study on the in vivo effects of resistance-modulating agents in different organs and systems.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Endogenous mechanisms of sensory modulation.

We provide evidence supporting the idea that the relationship between tissue damage, or the threat of tissue damage, and the response to such stimuli is variant and dependent on neuronal networks by which attentional, emotional and cognitive components of pain experience activate endogenous descending modulatory systems. Most previous studies have focused on responses to transient noxious stimuli with little information on the influence of descending modulation on behavioral responses to persistent pain and hyperalgesia after tissue or nerve injury. Utilizing correlative behavioral and neuronal studies we have demonstrated that (1) behavioral context modulates neuronal activity in nociceptive and non-nociceptive somatosensory pathways, supporting the hypothesis that responses in these pathways are not immutable; (2) descending modulation influences behavior and neuronal activity at spinal cord levels after inflammation and persistent pain; and (3) there are descending facilitatory as well as inhibitory influences on behavior and spinal cord neuronal activity that may impact on persistent pain particularly of deep muscle and visceral origin. Cortical as well as subcortical pathways are available by which dorsal horn activity can be modulated by attentional, motivational and cognitive factors. It appears that the same neuronal mechanisms in the forebrain and brain stem are available for behavioral modulation in a learned task involving the threat of tissue damage (transient noxious stimuli) as are available in the development and amplification of persistent pain produced by inflammation. These parallel brain mechanisms emphasize the saliency of pain experience as an important learned behavior for the survival of the organism, similar to sequential goal-directed behaviors in an operant task.

Animals↗
PubMed2002

FMRFamide modulates potassium currents in circadian pacemaker neurons of Bulla gouldiana.

The peptide FMRFamide (Phe-Met-Arg-Phe-NH(2)) is known to modulate the circadian pacemaker found in the eye of the marine snail Bulla gouldiana. In the present study, we investigated the cellular mechanisms underlying this modulation by examining the effects of FMRFamide on the membrane properties of the circadian pacemaker cells, known as basal retinal neurons in this preparation. Bath application of FMRFamide (0.1-1 microM) increased the membrane conductance, and hyperpolarized the membrane potential of these neurons. Next, perforated-patch recordings were used to demonstrate that FMRFamide reversibly increased the outward current amplitude due to an augmentation of a non-inactivating calcium-independent current. Reversal potential of the tail currents and its dependence on extracellular potassium concentration suggested potassium ions as the charge carrier for this current. The peptide-modulated outward current was blocked by 54% after bath application of the potassium channel blocker tetraethylammonium chloride and completely blocked by substituting cesium for intracellular potassium. Voltage dependence, activation kinetics and tail current kinetics of the FMRFamide-modulated current were consistent with values found for the delayed rectifier current.Overall, our data suggest that FMRFamide modulates a delayed rectifier potassium current and at least one other, less voltage-dependent conductance. This provides a mechanistic explanation for FMRFamide's ability to both shift the phase and attenuate light-induced phase shifts of the circadian pacemaker in B. gouldiana.

Action Potentials↗
PubMed2003

Modulation by C2 ceramide of the nicotinic transmission within the coeliac ganglion in the rabbit.

We have investigated the modulation by ceramide of the nicotinic activation of the prevertebral sympathetic neurons. Our study was performed in vitro in rabbit isolated coeliac ganglion, using intracellular recording techniques. We have used C(2) ceramide, a permeant analog of ceramide. The effects of C(2) ceramide were first assessed when nicotinic activation was elicited without modulatory mechanisms (fast excitatory postsynaptic potentials triggered by stimulation of the thoracic splanchnic nerves with a single pulse). In all the neurons tested, C(2) ceramide triggered an increase in the amplitude of the fast excitatory postsynaptic potentials demonstrating a direct facilitatory effect on the nicotinic activation. We then investigated the effects of C(2) ceramide on modulatory mechanisms of this activation. These mechanisms occur when a train of pulses of supramaximum intensity is applied on the splanchnic nerves. During the train, a gradual depression of fast nicotinic activation occurred: the pulses failed to systematically elicit action potentials. We have previously demonstrated that this regulatory phenomenon is partly modulated by nitric oxide which exerts a dual effect: facilitation or inhibition of the nicotinic activation. In all the neurons tested, C(2) ceramide decreased the number of action potentials fired during a train of pulses, demonstrating an indirect inhibitory effect on the nicotinic activation. The use of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (nitric oxide scavenger) suppressed the inhibitory effect of C(2) ceramide, demonstrating that this effect is mediated through the nitric oxide pathway. C(2) dihydro-ceramide, an inactive analog of ceramide, was without effect on the nicotinic activation of the ganglionic neurons. These results demonstrate that ceramide exerts a complex modulation of the nicotinic activation of the prevertebral neurons: direct facilitation and indirect inhibition involving the nitric oxide pathway. In fact, C(2) ceramide plays a key gating role in the dual effect of the nitric oxide pathway by activating the inhibitory effect. The existence of this gating mechanism involving ceramide and nitric oxide opens new perspectives in terms of our understanding of the modulation of synaptic transmission within the prevertebral ganglia. Our study demonstrates that sphingolipids are involved in complex modulations of the synaptic activation within the prevertebral ganglia, and thus contribute to their integrative properties.

Animals↗
PubMed1998

Periodically-modulated inhibition of living pacemaker neurons--III. The heterogeneity of the postsynaptic spike trains, and how control parameters affect it.

Codings involving spike trains at synapses with inhibitory postsynaptic potentials on pacemakers were examined in crayfish stretch receptor organs by modulating presynaptic instantaneous rates periodically (triangles or sines; frequencies, slopes and depths under, respectively, 5.0 Hz, 40.0/s/s and 25.0/s). Timings were described by interspike and cross-intervals ("phases"); patterns (dispersions, sequences) and forms (timing classes) were identified using pooled graphs (instant along the cycle when a spike occurs vs preceding interval) and return maps (plots of successive intervals). A remarkable heterogeneity of postsynaptic intervals and phases characterizes each modulation. All cycles separate into the same portions: each contains a particular form and switches abruptly to the next. Forms differ in irregularity and predictability: they are (see text) "p:q alternations", "intermittent", "phase walk-throughs", "messy erratic" and "messy stammering". Postsynaptic cycles are asymmetric (hysteresis). This contrasts with the presynaptic homogeneity, smoothness and symmetry. All control parameters are, individually and jointly, strongly influential. Presynaptic slopes, say, act through a postsynaptic sensitivity to their magnitude and sign; when increasing, hysteresis augments and forms change or disappear. Appropriate noise attenuates between-train contrasts, providing modulations are under 0.5 Hz. Postsynaptic natural intervals impose critical time bases, separating presynaptic intervals (around, above or below them) with dissimilar consequences. Coding rules are numerous and have restricted domains; generalizations are misleading. Modulation-driven forms are trendy pacemaker-driven forms. However, dissimilarities, slight when patterns are almost pacemaker, increase as inhibition departs from pacemaker and incorporate unpredictable features. Physiological significance-(1) Pacemaker-driven forms, simple and ubiquitous, appear to be elementary building blocks of synaptic codings, present always but in each case distorted typically. (2) Synapses are prototype: similar behaviours should be widespread, and networks simulations benefit by nonlinear units generating all forms. (3) Relevant to periodic functions are that few variables need be involved in form selection, that distortions are susceptible to noise levels and, if periods are heterogeneous, that simple input cycles impose heterogeneous outputs. (4) Slow Na inactivations are necessary for obtaining complex forms and hysteresis. Formal significance--(1) Pacemaker-driven forms and presumably their modulation-driven counterparts, pertain to universal periodic, intermittent, quasiperiodic and chaotic categories whose formal properties carry physiological connotations. (2) Only relatively elaborate, nonlinear geometric models show all forms; simpler ones, show only alternations and walk-throughs. (3) Bifurcations resemble those of simple maps that can provide useful guidelines. (4) Heterogeneity poses the unanswered question of whether or not the entire cycle and all portions have the same behaviours: therefore, whether trajectories are continuous or have discontinuities and/or singular points.

Action Potentials↗