Hippocampal type 1 (movement-related) theta rhythm positively correlates with serotonergic activity.

To investigate the relationship between the hippocampal [symbol: see text] activity (or Rhythmical Slow Activity, RSA) and the hippocampal serotonergic activity during spontaneous behavior, simultaneous recordings of i) hippocampal EEG, ii) sleep-wake activity, and iii) hippocampal levels of the serotonin (5-HT) metabolite 5-hydroxyndolacetic acid (5-HIAA--measured by in vivo voltammetry and infrared telemetry) were performed. The results show that hippocampal type 1 RSA recorded during wakefulness and voluntary movements (such as walking), is positively correlated to hippocampal 5-HIAA levels. Since in the experimental conditions used in the study, 5-HIAA levels are a reliable index of 5-HT release, the results support the hypothesis that hippocampal type 1 RSA is generated by a serotonergic mechanism. In contrast, hippocampal type 2 RSA recorded during desynchronized sleep is negatively correlated with 5-HT release, suggesting a different neurochemical mechanism for its production. These results also show that, in the experimental condition of this study, hippocampal RSA power spectrum has a main peak frequency of 3.5 during wakefulness, and of 6.5 Hz during desynchronized sleep.     

The spinal antinociceptive effect of FR140423 in mice involvement of the descending noradrenergic and serotonergic systems.

In this study, we investigated the role of descending monoaminergic systems in the antinociceptive activity of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methyl sulfinyl)phenyl]pyrazole, by using the tail-pinch test in mice and various monoamine depletors. The antinociceptive effects of FR140423 given p.o. and i.t. with ED50 values of 22 mg/kg and 3.5 microg/mouse, respectively, in the tail-pinch test were antagonized by reserpine, 6-hydroxydopamine plus nomifensine, and p-chlorophenylalanine treatment, whereas the antinociceptive action of morphine in this assay was attenuated by reserpine and 6-hydroxydopamine plus nomifensine but not by p-chlorophenylalanine treatment. These results suggest that both descending noradrenergic and serotonergic systems are involved in the antinociceptive activity of spinally and systemically administered FR140423 against mechanical noxious stimuli. The mechanisms underlying the suppressive action of FR140423 on the nociceptive response may differ from those of morphine in mice.     

Simulation of the hippocampal theta rhythm

Centre of Theoretical and Computational Neuroscience, University of Plymouth, UK Basing on the hypothesis about the mechanisms of the theta rhythm generation, the article presents mathematical and computational models of theta activity in the hippocampus. The problem of the theta rhythm modeling is nontrivial because the slow theta oscillations (about 5 Hz) should be generated by a neural system composed of frequently firing neural populations. We studied a model of neural pacemakers in the septum. In this model, the pacemaker follows the frequency of the external signal if this frequency does not deviate too far from the natural frequency of the pacemaker, otherwise the pacemaker returns to the frequency of its own oscillations. These results are in agreement with the experimental records of medial septum neurons. Our model of the septal pacemaker of the theta rhythm is based on the hypothesis that the hippocampal theta appears as a result of the influence of the assemblies of neurons in the medial septum which are under control of pacemaker neurons. Though the model of the pacemaker satisfies many experimental facts, the synchronization of activity in different neural assemblies of the model is not as strong as it should be. Another model of the theta generation is based on the anatomical data about the existence of the inhibitory GABAergic loop between the medial septum and the hippocampus. This model shows stable oscillations at the frequency of the theta rhythm in a broad range of parameter values. It also provides explanation to the experimental data about the variation of the frequency and the amplitude of the theta rhythm under different external stimulations of the system. The role of the theta rhythm for information processing in the hippocampus is discussed.     

Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergic and noradrenergic modulatory systems.

Experimental results consistently show that the respiratory control system is plastic, such that environmental factors and experience can modify its performance. Such plasticity may represent basic neurobiological principles of learning and memory, whereby intermittent sensory stimulation produces long-term alterations (i.e. facilitation or depression) in synaptic transmission depending on the timing and intensity of the stimulation. In this review, we propose that intermittent chemosensory stimulation produces long-term changes in respiratory motor output via specific neuromodulatory systems. This concept is based on recent data suggesting that intermittent hypoxia produces a net long-term facilitation of respiratory output via the serotonergic system, whereas intermittent hypercapnia produces a net long-term depression by a mechanism associated with the noradrenergic system. There is suggestive evidence that, although both respiratory stimuli activate both modulatory systems, the balance is different. Thus, these opposing modulatory influences on respiratory motor control may provide a 'push-pull' system, preventing unchecked and inappropriate fluctuations in ventilatory drive.     

Mechanisms and functional significance of tumour-induced dendritic-cell defects

The failure of the immune system to provide protection against tumour cells is an important immunological problem. It is now evident that inadequate function of the host immune system is one of the main mechanisms by which tumours escape from immune control, as well as an important factor that limits the success of cancer immunotherapy. In recent years, it has become increasingly clear that defects in dendritic cells have a crucial role in non-responsiveness to tumours. This article focuses on the functional consequences and recently described mechanisms of the dendritic-cell defects in cancer.     

Cortical hypometabolism in injured brain: New correlations with the noradrenergic and serotonergic systems and with behavioral deficits

Changes with time after injury in behavioral deficits, as determined by the Morris swim test, and the in vivo specific binding of HEAT, a selective ₁-adrenoreceptor ligand, were compared with the time-course of development of cortical hypometabolism in rats with focal freezing lesions. In our trauma model, cortical hypometabolism was detectable in the lesioned hemisphere at 4 hr, became maximal (50% of normal) at 3 days and diminished towards normal on days 5 and 10 post-injury. Progressive impairment of acquisition of the Morris water maze task was demonstrated up to day 3 post-lesion with improvement thereafter. On day 3 the latency to reach criterion was 60% longer in lesioned animals than in corresponding sham-operated ones. An increase in the volume of distribution of HEAT, limited to cortical areas of the lesioned hemisphere, was demonstrable at 4 hr post-lesion and reached its maximum on day 3 (200% of normal) with subsequent return toward normal on days 5 and 10. Several types of drugs were shown previously to modify the cortical hypometabolism associated with cerebral injury. The present data indicate that the same drugs also modify the in vivo binding of HEAT and the behavioral deficits induced by brain lesions. Ibuprofen, a non-steroidal anti-inflammatory drug, p-chlorophenylalanine, an inhibitor of serotonin synthesis, ketanserin, a specific 5HT₂-receptor antagonist, and prazosin, an ₁-adrenergic receptor blocker all normalized the in vivo binding of HEAT in the cortical areas of the lesioned hemisphere. All groups of animals treated with these drugs also showed subtle, but statistically highly significant improvements in latency to locate the platform in the Morris water maze. Taken together these results show good correlation between behavioral deficits, changes in ₁-noradrenergic receptor binding and cortical hypometabolism in injured brain. This supports the hypothesis that post-injury cortical hypometabolism is a reflection of cortical functional depression in which both the serotonergic and noradrenergic neurotransmitter systems play a role, compatible with their inhibitory effects in the cortex and their postulated involvement in cortical information processing.Special issue dedicated to Dr. Leon S. Wolfe.     

Mechanisms of respiratory rhythm generation.

In mammals, a three-phasic respiratory rhythm is generated by a network of various types of neurons in the lower brainstem. The cellular mechanisms of rhythmogenesis involve cooperative interactions between synaptic processes and specific membrane properties. The network seems to be driven by extrinsic sources in mature animals, whereas in the immature network pacemaker neurons might be involved.     

Interrelation of heart rhythm disorders in acute myocardial ischemia with the activity of the limbic and noradrenergic systems

Experiments on white rats were made to study the time-course of the electric activity in the limbic structures and Locus Coeruleus (LC) under ligation of the coronary artery, and the effect of the coagulation of these structures on heart rhythm disorders in acute myocardial ischemia. It was established that during the period that preceded the development of heart rhythm disorders, the most conspicuous changes were seen in the electric activity of the anterior amygdaline nucleus and LC, whereas the coagulation of the amygdalae prevented to a considerable measure development of different forms of arrhythmia. The authors suggest that in acute myocardial ischemia, these structures are directly related to heart rhythm disorders, while the LC is likely to play a role of the hyperactive determinant structure.     

The modelling of theta rhythm regulation by an increasing afferent inflow in septal slices in vitro

The aim of the work was the modelling in vitro of the condition of increased afferent inflow, which in the intact septum results in an increase of population of theta-bursting units, their synchronization and shift to a higher frequency of the bursts, with corresponding changes in the hippocampal electrical activity. Neuronal activity was recorded extracellularly in the medial septal nucleus and vertical limb of the nucleus of diagonal band (MS-DB) in guinea pig septal slices. Electrical stimulation in the medial part of horizontal limb of DB evokes initial period of suppression of spontaneous activity in 85% of the neurones. This low-threshold, rapid inhibition has variable duration (20-280 ms) in different units at low intensities of the stimulating current. With increased intensities of stimulation this inhibitory phase in majority of units is gradually or by steps shortened, though in some units with initial short inhibition it is not changed. As a result the variability of initial inhibitory period between units is decreased and centered around 30-60 ms. Many units with single-spike background activity developed postinhibitory burst responses at various levels of stimulating current. The spontaneously bursting MS-DB units always responded by resetting of their background bursts. In total 58% of all recorded neurones generated evoked bursts under condition of increased afferent inflow.     

Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex

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Mechanisms of induction of adenosine receptor genes and its functional significance

Adenosine is a metabolite generated and released from cells, particularly under injury or stress. It elicits protective or damaging responses via signaling through the adenosine receptors, including the adenylyl cyclase inhibitory A(1) and A(3), and the adenylyl cyclase stimulatory A(2A) and A(2B). Multiple adenosine receptor types, including stimulatory and inhibitory, can be found in the same cell, suggesting that a careful balance of adenosine receptor expression in a particular cell is necessary for a specific adenosine-induced response. This balance could be controlled by differential expression of the adenosine receptor genes under different stimuli. Here, we have reviewed an array of studies that have characterized basal or induced expression of the adenosine receptors and common as well as distinct mechanisms of effect, in hopes that ongoing studies on this topic will further elucidate detailed mechanisms of adenosine receptor regulation, leading to potential therapeutic applications.     

Mechanisms of DNA-binding specificity and functional gene regulation by transcription factors

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An approach to recognizing the functional states of the systems regulating the heart rhythm

A new approach is suggested to quantity assessment of functional state of cardiac rhythm regulation systems. Using this approach, three automatic systems were elaborated, which are realized functional system assessment of organism and cardiac rhythm.