Synaptic activation of GABA(B) receptors regulates neuronal network activity and entrainment

In the mammalian central nervous system, GABA(B) receptors mediate slow pre- and postsynaptic inhibition. Using rat hippocampal slices we investigated the role of synaptic GABA(B) receptors in regulating kainate-induced subthreshold neuronal network oscillations in the gamma frequency range (25-80 Hz). The GABA(B) receptor agonist baclofen largely eliminated gamma oscillations. The GABA(B) receptor antagonist CGP55845 reversed this action of baclofen but alone did not alter the power or frequency of ongoing oscillations. To examine the role of synaptically released GABA on network activity, we electrically stimulated stratum radiatum of CA3 whilst recording gamma oscillations from stratum pyramidale. Single stimuli produced a pronounced transient (up to 1 s in duration) inhibition of gamma frequency oscillations. This stimulus-induced shutdown of network activity was enhanced by the GABA uptake inhibitor tiagabine and largely inhibited by CGP55845. Multiple stimuli delivered at frequencies of 1-3 Hz resulted in an activity-dependent fatigue of the inhibition of gamma activity, such that, after a number of stimuli, oscillations could be detected tens of milliseconds after the stimulus. Interestingly, this activity-dependent fatigue of inhibition uncovered a stimulus-dependent temporal entrainment of the gamma oscillations. Furthermore, the amount of repetitive synaptic input that was required to cause this entrainment was dramatically reduced by GABA(B) receptor antagonism such that it was evident within just a few stimuli. These data suggest that convergent afferent synaptic activity can alter the precise temporal arrangement of neuronal network activity. Furthermore, the flow of such information into a functioning neuronal network is highly regulated by GABA(B) receptor-mediated synaptic inhibition.     

The thermophysiological cascade leading to sleep initiation in relation to phase of entrainment

This article reviews circadian thermoregulation in relation to sleep induction and phase of entrainment in the light of the comprehensive thermophysiological and chronobiological concepts of Jürgen Aschoff. The idea that temperature and sleep are interrelated is based on evolutionary history. Mammalian sleep developed in association with endothermy, and all species, independent of temporal niche, usually sleep during the circadian trough of their core body temperature (CBT) rhythm. The circadian pattern of CBT results from the balance between heat production and heat loss, the latter being relevant for sleep induction. Sleep under entrained conditions is typically initiated on the declining portion of the CBT curve when its rate of change and body heat loss is maximal. Body heat loss before lights off, via selective vasodilatation of distal skin regions, promotes sleepiness and the rapid onset of sleep. This thermophysiological effect represents the cement between the circadian clock and the sleep-wake cycle, and in turn determines phase of entrainment (Psi) and sleep onset latency (SOL). These interrelationships have been recently studied in a particular subset of the general population, mainly women, who suffer from cold hands and feet (the so-called vasospastic syndrome, VS). Women with VS exhibit not only a lower capacity to lose heat during the daytime but also a prolonged SOL, a disturbed Psi of the circadian clock with respect to the sleep-wake cycle and psychologically, a disposition to turn experienced anger inwards. This naturalistic model leads us to a more general conclusion that regulation of distal skin blood flow may have clinical relevance for insomnia, in particular sleep onset insomnia.     

Adipose tissue, adipocytes and the circadian timing system

Circadian clocks time the daily occurrence of multiple aspects of behaviour and physiology. Through studies of chronic misalignment between our internal clocks and the environment (e.g. during shift work), it has long been postulated that disruption of circadian rhythms is detrimental to human health. Recent advances in understanding of the cellular and molecular basis of mammalian circadian timing mechanisms have identified many key genes involved in circadian rhythm generation and demonstrated the presence of clocks throughout the body. Furthermore, clear links between sleep, circadian rhythms and metabolic function have been revealed, and much current research is studying these links in more detail. Here, we review the evidence linking circadian rhythms, clock genes and adipose biology. We also highlight gaps in our understanding and finally suggest avenues for future research.     

Synchrony through twice-frequency forcing for sensitive and selective auditory processing

Male mosquitoes detect flying females using antennal hearing organs sensitive to nanoscale mechanical displacements and that harbor motile mechanosensory neurons. The mechanisms supporting neuronal motility, and their function in peripheral sensory processing, remain, however, puzzling. The mechanical and neural responses reveal a transition that unmasks the onset of synchronization between sensory neurons. This synchronization constitutes an unconventional, mechanically driven, process of communication between sensory neurons. Enhancing auditory sensitivity and selectivity, synchronization between mechanosensors in the mosquito arises from entrainment to twice-frequency forcing and is formally analogous to injection-locking in high-power laser technology. This discovery opens up the enticing possibility that other sensory systems, even nonsensory cell ensembles, coordinate their actions through mechanical signaling.     

The effect of brainstem stimulation on the evoked potentials in the intergeniculate leaflet

We have investigated the effect of the laterodorsal tegmental (LDTg) stimulation on evoked potentials in the intergeniculate leaflet (IGL) of the rat, in order to characterize how non-specific systems of the brain, whose activity indicates the influence of non-photic information, impact the activity of the IGL. IGL responses were evoked by electrical stimulation of contralateral suprachiasmatic nuclei (SCN). The amplitude of the evoked potentials was, in all experiments, significantly reduced after the LDTg stimulation. This effect indicated strong neuronal integration between the brainstem reticular formation and the IGL. These results are discussed in relation to the putative role of GABAergic projection.     

Electrophysiology of Postinfarction Ventricular Tachycardia:

Sustained monomorphic ventricular tachycardia (VT) is a paradigm of a stable reentrant rhythm. The hallmark of stable reentry is the presence of an excitable gap, which in reentrant VT composes 15% to 45% of the tachycardia cycle length. Resetting allows definition of the extent and pattern of the excitable gap. Site-specific resetting responses suggest that the VT circuit has both functionally and anatomically derived characteristics. Entrainment provides information regarding the effects of overdrive pacing on properties of the tissue composing the circuit rather than on properties of the tachycardia itself. These data help us to understand the mechanisms of pharmacologic agents and to direct ablation of reentrant VT.     

The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei

The suprachiasmatic nuclei (SCN) contain a major circadian pacemaker, which is regulated by photic and nonphotic stimuli. Although enkephalins are present in the SCN, their role in phase regulation of the pacemaker is largely unknown. The opioid agonist fentanyl, a homologue of morphine, is an addictive drug that induces phase shifts of circadian rhythms in hamsters. We observed that these phase shifts are blocked by naloxone, which is a critical test for true opioid receptor involvement, and conclude that opioid receptors are the sole mediators of the actions of fentanyl on the circadian timing system. A strong interaction between opioids and light input was shown by the ability of fentanyl and light to completely block each other's phase shifts of behavioural activity rhythms. Neuronal ensemble recordings in vitro provide first evidence that SCN cells show direct responses to fentanyl and react with a suppression of firing rate. Moreover, we show that fentanyl induces a strong attenuation of light-induced Syrian hamster Period 1 (shPer1) gene expression during the night. During the subjective day, we found no evidence for a role of shPer1 in mediation of fentanyl-induced phase shifts. Based on the present results, however, we cannot exclude the involvement of shPer2. Our data indicate that opioids can strongly modify the photic responsiveness of the circadian pacemaker and may do so via direct effects on SCN electrical activity and regulation of Per genes. This suggests that the pathways regulating addictive behaviour and the circadian clock intersect.     

Prevalence of a shared isthmus in postinfarction patients with pleiomorphic, hemodynamically tolerated ventricular tachycardias

INTRODUCTION: Multiple forms of ventricular tachycardia (VT) after myocardial infarction may result from multiple reentrant circuits that share an isthmus or from separate reentrant circuits. The prevalence of a shared isthmus in patients with multiple hemodynamically tolerated VTs has not been determined. METHODS AND RESULTS: Criteria for a shared isthmus consisted of (1) concealed entrainment of >1 VT at a single pacing site; (2) concealed entrainment during VT and a perfect pace map of another VT at the same pacing site; or (3) concealed entrainment of VT of a given morphology that had at least two cycle lengths that varied by at least 100 msec. In a series of 19 patients (16 men and 3 women; age 65+/-14 years, ejection fraction 0.25+/-0.09) with 54 VTs (mean cycle length 494+/-98 msec), there was evidence of a shared isthmus in 23 VTs (43%) at 11 sites in 9 patients. Concealed entrainment of two different VTs was observed at 4 of 11 sites. At 5 of 11 sites there was concealed entrainment of one VT and a perfect pace map of another VT. At the remaining 2 of 11 sites, there was concealed entrainment of a VT that had two different cycle lengths. Nineteen of the 23 VTs were ablated successfully with radiofrequency energy applications at 11 sites. CONCLUSION: In postinfarction patients with pleiomorphic, hemodynamically stable VT, a shared isthmus may be present in approximately 40% of VTs.     

Demonstration of Entrainment and Presence of Slow Conduction During Ventricular Tachycardia in Arrhythmogenic Right Ventricular Dysplasia

During VT in two cases with arrhythmogenic right ventricular dysplasia, entrainment criteria, constant fusion beats except for the last entrainment beat, progressive fusion, and a localized conduction block associated with interruption of VT, were demon strated with rapid ventricular pacing performed during VT. Furthermore, a long conduction interval was present during entrainment from the pacing site to the earliest activation site during VT. indicating the presence of a slow conduction area. VT in these cases was, thus, due to reentry with an area of slow conduction within the circuit.