We study a physiologically realistic implementation of internal stochasticity in a four-dimensional Hodgkin-Huxley type model of mammalian cold receptors. We show that in a deterministically tonic firing regime, this stochasticity can drive the neuron into a state of complex bursting behaviour. An explanation of the mechanism behind this effect is given in terms of phase space dynamics.

The effects of bi-directional gap junction coupling of two model neurons with subthreshold oscillations have been examined when the individual neurons are operating at different dynamical states either in the tonic or bursting firing mode. Our simulations indicate that intermediate coupling strengths mostly lead to highly variable, often chaotic impulse patterns whereas transition to completely synchronized activity at high coupling strengths is generally going along with transitions to regular limit cycle activity. The synchronized activity pattern, however, can be completely different from the original pattern of the uncoupled neurons.

Hyperammonemia (HA) is thought to be responsible for alterations in cognitive functions in patients with liver failure and the congenital deficiencies of the urea cycle enzymes. Acute HA leads to cell damage via overactivation of glutamate NMDA receptors and hyperproduction of free radicals, while chronic HA results in an irreversible impairment of NMDA receptor function. Hippocampal long-term potentiation (LTP) is an NMDA receptordependent form of synaptic plasticity presumably involved in the mechanisms of learning and memory. With the objective to examine whether it is impaired by ammonia and if this impairment can be reversed by taurine, hippocampal slices from 812 week-old male C57BL16 mice were preincubated in either standard medium or in the medium containing 1 mM ammonium chloride, alone or in combination with 1 mM taurine or some other antioxidants and osmolytes. Significant impairment of LTP was found in the ammonia-preincubated slices: the mean increase in the CA1 field EPSP slope 60 min after high-frequency stimulation of Schaffer collaterals was 16.6I4.7% vs 32.2.I3.7% in the control (p<0.01). This deficit in hippocampal LTP was reversed by treatment with taurine (3 1.6I6.9%), but not ascorbate (5.5I9.0%), carnosine (17.1I10.6%), or betaine (10.5I6.2%). Thus taurine rescues hippocampal LTP from ammonia-induced impairemt by mechanisms seemingly not associated with its antioxidant or osmolytic capacities. Supported by SFB 575lC3. We recorded extracellular impulse activity of thermosensitive hypothalamic neurons (n=55) in PVN, SON and ARC during application of ethanol (EtOH, 0.1-0.8% (1 7137 mM)) at constant temperatures and during sinusoidal temperature changes (37113+/2113, f=O.OlHz). Most cells (>SO%) showed a triphasic change in their firing rate during EtOH application. In phase 1, immediately after EtOH application, the firing increases for a short time (1-5 minutes). Phase 2 is charactererized by a decrease, mostly down to Zero (for 2-20 minutes). In phase 3, during ongoing EtOH application, the neuron spontaneously recovers. It again starts to generate action potentials and reaches a constant firing rate which is higher than before EtOH application. The different states are more pronounced at higher concentrations. When EtOH application is stopped the firing rate gradually declines to almost the same level as before. When sinusoidal temperature changes are applied, the neurons' responses are enhanced by EtOH application. Both these sensitization effects and the triphasic responses are fully reversible and could be reproduced in subsequent trials. Our data suggest that EtOH on central neurons has different effects on different transduction mechanisms with different time delays and thresholds. We assume that several types of ion channels are involved as well as changes of membrane fluidity.

Calcitonin-gene-related peptide and adrenomedullin have similar and potent vascular effects, which appear to be mediated by the G protein-coupled calcitonin receptor-like (CRL) receptor. Using immunohistochemical and Western blot analyses, we have obtained novel evidence that CRL receptor is expressed in the rat vascular endothelium using an antibody to rat CRL receptor that we have raised and fully characterised. These results are an important basis for further studies aimed at determining the so far ill-defined functional significance of the extensive distribution of CRL receptor in the vascular endothelium.

Modulation of neuronal impulse pattern is examined by means of a simplified Hodgkin-Huxley type computer model which refers to experimental recordings of cold receptor discharges. This model essentially consists of two potentially oscillating subsystems: a spike generator and a subthreshold oscillator. With addition of noise the model successfully mimics the major types of experimentally recorded impulse patterns and thereby elucidate different resonance behaviors. (1) There is a range of rhythmic spiking or bursting where the spike generator is strongly coupled to the subthreshold oscillator. (2) There is a pacemaker activity of more complex interactions where the spike generator has overtaken part of the control. (3) There is a situation where the two subsystems are decoupled and only resonate with the help of noise.

These in vitro studies aimed to characterize the pattern and the kinetics of endoproteolysis of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) and related peptides by native ectopeptidases. Peptides were incubated with isolated rat or pig kidney brush-border microvilli membranes, which are a rich source of the ectopeptidases that are responsible for the post-secretory metabolism of peptide hormones. The proteolytic products were separated by reversed-phase HPLC column chromatography and characterised by molecular mass and primary structure. The relative importance of specific peptidases was established by measuring the effects of specific peptidase inhibitors on the kinetics of proteolysis. Dipeptidyl-peptidase-IV was found to be rate-limiting in the endoproteolysis of GLP-1. GLP-1 homologs, exendins-3 and -4, exhibited exceptional stability in the presence of isolated kidney microvilli membranes. Our finding that exendin-4 is several orders of magnitude more stable than GLP-1 and Ser-8-GLP-1 is especially noteworthy given this peptide's widely reported insulinotropic potency.

Background/Aims: Pharmacological and morphological studies suggest that the gut mucosal immune system and local neuropeptide-containing neurones interact. We aimed to determine whether gut immune cells are targets for calcitonin gene-related peptide (CGRP), which has potent immune regulatory properties. Methods: Using density gradient centrifugation, rat lamina propria mononuclear cells (LP-MNCs) and intra-epithelial lymphocytes (IELs) were isolated. RT-PCR was employed for the detection of mRNA of rat calcitonin receptor-like receptor (CRLR), which is considered to represent the pharmacologically defined CGRP receptor-1 subtype, as well as mRNA of the receptor activity-modifying proteins, which are essential for CRLR function and determine ligand specificity. A radioreceptor assay was employed for the detection of specific CGRP binding sites. Results: RT-PCR and DNA sequencing showed that LP-MNCs and IELs express CRLR. Incubation of isolated LP-MNCs with radiolabelled αCGRP revealed the existence of specific binding sites for CGRP. Conclusion: These novel data indicate that mucosal immune cells of the rat gut are a target for CGRP and provide significant evidence that CGRP functions as an immune regulator in the gut mucosa.

We used a minimal Hodgkin-Huxley type model of cold receptor discharges to examine how noise interferes with the non-linear dynamics of the ionic mechanisms of neuronal stimulus encoding. The model is based on the assumption that spike-generation depends on subthreshold oscillations. With physiologically plausible temperature scaling, it passes through different impulse patterns which, with addition of noise, are in excellent agreement with real experimental data. The interval distributions of purely deterministic simulations, however, exhibit considerable differences compared to the noisy simulations especially at the bifurcations of deterministically period-one discharges. We, therefore, analyzed the effects of noise in different situations of deterministically regular period-one discharges: (1) at high-temperatures near the transition to subthreshold oscillations and to burst discharges, and (2) at low-temperatures close to and more far away from the bifurcations to chaotic dynamics. The data suggest that addition of noise can considerably extend the dynamical behavior of the system with coexistence of different dynamical situations at deterministically fixed parameter constellations. Apart from well-described coexistence of spike-generating and subthreshold oscillations also mixtures of tonic and bursting patterns can be seen and even transitions to unstable period-one orbits seem to appear. The data indicate that cooperative effects between low- and high-dimensional dynamics have to be considered as qualitatively important factors in neuronal encoding.

Healthy sleep consists of several stages: deep sleep, light sleep, and rapid eye movement (REM) sleep. Here we show that these sleep stages can be characterized and distinguished by correlations of heart rates separated by n beats. Using the detrended fluctuation analysis (DFA) up to fourth order we find that long-range correlations reminiscent to the wake phase are present only in the REM phase. In the non-REM phases, the heart rates are uncorrelated above the typical breathing cycle time, pointing to a random regulation of the heartbeat during non-REM sleep.

Intrinsic oscillations at the level of the membrane potential are a widespread feature of nerve cells. Several evidences exist that, in particular, sensory neurons combine their oscillatory membrane potentials with intrinsic, membrane and/or synaptic noise to obtain sensitive encoding properties. An interesting example are mammalian cold receptors where stimulus transduction results from modulation of intrinsic receptor oscillations with essential contribution of noise thereby generating a rich spectrum of impulse patterns. To further explore the dynamics of these receptors we here investigate an HH-type model for oscillations and spike initiation in cold receptors. By use of a biophysically plausible temperature scaling and with addition of noise, the model successfully mimicks the principle temperature-dependence of stationary impulse patterns of real cold receptors. Our results suggest that interactions between stochastic and deterministic dynamics are of functional importance for the encoding charcteristics of cold receptors.

Heart rate and heart rate variability are under the control of the autonomous nervous system. It can be assumed that during sleep internal influences dominate the autonomous nervous system. During the different sleep stages heart rate regulation differs in normal subjects. Obstructive sleep apnea is a disorder which has its origin in sleep and has strong modulating effects on the autonomous nervous system with prominent heart rate variations in consequence. In order to separate the influences of sleep stages and sleep apnea on heart rate variability we applied detrended fluctuation analysis in 12 healthy subjects and 20 patients with sleep apnea. We could show that the differences between sleep stages observed in healthy subjects were still present in subjects with sleep apnea despite their cyclical variation in heart rate. We conclude, that detrended fluctuation analysis is able to separate the influences of sleep stages and sleep apnea on heart rate variability.

In the field of psychoneuroimmunology it has become obvious that the immune system is governed by multiple influences from the central nervous system. One approach to verify these interactions can be seen in stress research. While the phenomenon of stress-induced changes in immunological processes is widely accepted, more recent studies focus on possible moderators and mechanisms of these responses. Within this research strategy it became evident that catecholamine increases upon stress are of major importance for the frequently observed mild leukocytosis. The present study was conducted to investigate whether the often observed stress-induced increases in the number of peripheral lymphocyte subsets depends on the amount of epinephrine or norepinephrine release. Moreover, the question was addressed whether high or low catecholamine release is related to subjective ratings on discomfort. Using a "public speaking paradigm", we were able to replicate previous findings of high increases in the absolute number of CD8+ and CD56+ cells in peripheral blood. Moreover, when dividing subjects into high and low catecholamine responders, the amount of change was significantly larger in catecholamine responders irrespective of whether norepinephrine or epinephrine was used for grouping the subjects. However, high and low catecholamine responders did not differ with respect to subjective ratings on discomfort. The data are discussed with respect to underlying mechanisms in catecholamine-induced lymphocyte migration and possible reasons for the mismatch between objective and subjective indicators of stressor efficacy.

Transitions between different types of impulse patterns, according to experimentally recorded cold-receptor discharges, can successfully be mimicked with a minimal Hodgkin–Huxley-type simulation, here referred to as the Huber/Braun cold-receptor model. The model consists of two sets of simplified de- and repolarizing ionic conductances responsible for spike generation and slow-wave potentials, respectively. Over a broad temperature range, spike patterns are determined by the periodicity of subthreshold oscillations. At low temperatures, however, the periodicity of the pattern is destroyed and then appears again but with different patterns of different rhythmicity. We demonstrate that these complex transitions originate from the interactions between slow-wave and spike-generating currents.