THE COORDINATION OF POTENTIAL PACEMAKERS IN THE HYDROID TUBULARIA

Sectioning experiments and electrical recording indicate thatthere are many potential pacemakers in polyps of the hydroidTubularia. Functionally the pacemakers are organized primarilyinto pacemaker systems, groups within which there is tight coupling.The different pacemaker systems of a polyp are loosely coupledto one another. There are two principal systems in Tubularia,one in the polyp neck (the NP system) and one in the hydranth(the HP system). In addition, there are pacemakers controllingactivities of individual tentacles. Activity in the NP systemis usually not associated with observable polyp behavior. HPsystem activity is correlated with behavioral responses termedconcerts. Concerts are probably digestive activities; they resultin the mixing of food being digested and the distribution ofthe products of this digestion. The NP systems of polyps ona colony are loosely coupled to one another through one of thethree conducting systems found in Tubularia stalks. The loosecoupling between NP systems of polyps on a colony and the loosecoupling between NP and HP systems within single polyps resultsin there being some coordination of concert activity throughouta colony.     

PACEMAKER INTERACTION IN HYDRA

Previous reports have described in detail the characteristicsof two pacemaker systems in hydras. Each of these, the rhythmicpotential (RP) system located near the base of the polyp, andthe contraction burst (CB) system at the sub-hypostome, hasits own conducting system running the length of the animal,so that the impulses originated at either end spread throughoutthe organism. It has been postulated that these conducted impulsesof each system can reach and influence both the pacemakers ofits own, and those of the other, system. The over-all behaviorof the hydra would thus be the integrated responses of the effectorsresponding to these interdependent coordinating systems. Certain evidence favoring this hypothesis is presented. It isevident that there are interactions between the two systems,especially in the control of contraction burst initiation. Duringperiods in which RP impulses are appearing at short, regularintervals, contraction bursts are characteristically absent.Paradoxically when RP frequency is low, CB firing is also minimal.Normal CB activity levels are associated with intermediate RPfrequencies. There is also a frequency correlation between RP rate and theonset of individual contraction bursts. The interval betweenRP impulses is longer just before the first CB pulse than itis midway between bursts. It is shortest just following theburst. The longest RP intervals occur during contraction bursts.It appears that the initiation of endogenous CB activity isinfluenced by RP frequency in a manner comparable to the triggeringof the distinctive locomotor CB after RP pacemaker stimulation. Comparable work with other coelenterates has stressed the importanceboth of endogenous rhythmicity and ordered interaction betweenseparate pacemaker-driven coordinating systems. Hydras are notexceptional to this pattern, but they do show distinctive featurescompared to strictly sessile polyps. Further investigation maydisclose how the so-far unique RP pattern of repeated individualpulses and the absence of pulse bursts or trains is responsiblefor hydras' distinctive behavior.     

Differential control of active and silent phases in relaxation models of neuronal rhythms

Rhythmic bursting activity, found in many biological systems, serves a variety of important functions. Such activity is composed of episodes, or bursts (the active phase, AP) that are separated by quiescent periods (the silent phase, SP). Here, we use mean field, firing rate models of excitatory neural network activity to study how AP and SP durations depend on two critical network parameters that control network connectivity and cellular excitability. In these models, the AP and SP correspond to the network's underlying bistability on a fast time scale due to rapid recurrent excitatory connectivity. Activity switches between the AP and SP because of two types of slow negative feedback: synaptic depression—which has a divisive effect on the network input/output function, or cellular adaptation—a subtractive effect on the input/output function. We show that if a model incorporates the divisive process (regardless of the presence of the subtractive process), then increasing cellular excitability will speed up the activity, mostly by decreasing the silent phase. Reciprocally, if the subtractive process is present, increasing the excitatory connectivity will slow down the activity, mostly by lengthening the active phase. We also show that the model incorporating both slow processes is less sensitive to parameter variations than the models with only one process. Finally, we note that these network models are formally analogous to a type of cellular pacemaker and thus similar results apply to these cellular pacemakers. Action Editor: Misha Tsodyks     

The circadian program of algae

The endogenous circadian program enables organisms to cope with the temporal ecology of their environment. It is driven by a molecular pacemaker, which is found in animals as well as plants at the level of the single cell. Unicellular organisms are, therefore, ideal model systems for the study of circadian systems because rhythms can be investigated in single cells at the molecular, physiological, behavioral and environmental level. In this review, we discuss the possible driving forces for the evolution of circadian rhythmicity in unicellular marine organisms. The current knowledge about the cellular and molecular mechanisms involved in the different components of the circadian system (input, oscillator and output) are described primarily with reference to the marine dinoflagellate,Gonyaulax polyedra. Light is the most important and best described environmental signal synchronizing the endogenous rhythms to the 24-hour solar day. However, little is known about the nature of circadian light receptors, which appear to be distinct from those that control behavioral light responses such as phototaxis. It has recently been shown inGonyaulaxthat nutrients, namely nitrate, can act as a non-photic zeitgeber for the circadian system. In this alga, bioluminescence is under circadian control, and the molecular mechanisms of this circadian output have been investigated in detail. The circadian program turns out to be more complex than simply consisting of an input pathway, a pacemaker and the driven rhythms. Different rhythms appear to be controlled by separate pacemakers, even in single cells, and both circadian inputs and outputs contain feedback loops. The functional advantages of this complexity are discussed. Finally, we outline the differences between the circadian program under laboratory and natural conditions.     

In vivo Microdialysis of 5-Hydroxyindoleacetic Acid and Glutamic Acid in the Hamster Suprachiasmatic Nuclei

SYNOPSIS. The technique of in vivo brain microdialysis rapidlyis becoming a popular tool for research on the neurochemicalbasis of physiological and behavioral functions. The presentstudy describes the application of microdialysis to investigatethe endogenous release of 5-hydroxyindoleacetic acid (5-HIAA)and glutamic acid in the suprachiasmatic nuclei (SCN) of hamsters.There were apparent circadian patterns of release of both ofthese neurosecretions, with peak levels occurring during thedark phase. Pharmacological manipulations of serotonin releaseand reuptake, using tetrodotoxin and citalopram, respectively,provided evidence that the nocturnal increase in 5-HIAA reflectsan increase in serotonergic synaptic activity, rather than intraneuronalmetabolism of unreleased serotonin. These results illustratethe usefulness of the microdialysis technique for studies onthe neurochemistry of central pacemaker function.     

Morphine challenges in levo-alpha-acetylmethadol (LAAM) post-addict rats

LAAM dependence was established in female Sprague-Dawley rats over a two week period by a series of twice daily oral intubations. LAAM was then withdrawn. These LAAM post-addict rats along with controls were challenged with 10 mg/kg of i.p. morphine at 15 days, one month, three months, and six months post-withdrawal. In control rats morphine challenges produced, as expected, a biphasic response consisting of 60–90 minutes of EEG slow-wave bursts and behavioral depression followed by 60–90 minutes of EEG and behavioral arousal. In LAAM post-addict rats on day 15 of abstinence morphine challenges produced primarily EEG and behavioral arousal for two to three hours with little or no depression. At one and three months of LAAM abstinence morphine challenges still produced more immediate and sustained EEG and behavioral arousal during the initial two hours than in control rats. At six months in LAAM post-addict rats responses to morphine challenges were biphasic and were similar to those seen in control rats. These results are indicative of protracted abstinence in LAAM post-addict rats, and these results are analogous to those previously reported from our laboratory for morphine post-addict rats.     

Noise effects on robust synchronization of a small pacemaker neuronal ensemble via nonlinear controller: electronic circuit design

In this paper, we report on the synchronization of a pacemaker neuronal ensemble constituted of an AB neuron electrically coupled to two PD neurons. By the virtue of this electrical coupling, they can fire synchronous bursts of action potential. An external master neuron is used to induce to the whole system the desired dynamics, via a nonlinear controller. Such controller is obtained by a combination of sliding mode and feedback control. The proposed controller is able to offset uncertainties in the synchronized systems. We show how noise affects the synchronization of the pacemaker neuronal ensemble, and briefly discuss its potential benefits in our synchronization scheme. An extended Hindmarsh–Rose neuronal model is used to represent a single cell dynamic of the network. Numerical simulations and Pspice implementation of the synchronization scheme are presented. We found that, the proposed controller reduces the stochastic resonance of the network when its gain increases.     

Spontaneous contractions and nerve net activity in the sea anemone calliactis parasitica

Suction electrodes attached to tentacles of the sea anemone Calliactis parasitica record regular bursts of activity associated with the through‐conducting nerve net. Most bursts consist of 10–15 pulses at a frequency of 1 every 4 sec to 1 every 10 sec. The interval between bursts is usually 10–20 min. Regularity in pulse number and frequency in successive bursts suggests that the activity originates from a pacemaker. Bursts are always followed by slow contraction of endodermal longitudinal (parietal) muscles after a short delay, and endo‐dermal circular muscles after a long delay. A simple model for nervous pacemaker control of rhythmic contractions cannot be proposed as slow contractions can also occur in the absence of recorded nerve net activity.     

Persistent sodium current is a nonsynaptic substrate for long-term associative memory

Although synaptic plasticity is widely regarded as the primary mechanism of memory [1], forms of nonsynaptic plasticity, such as increased somal or dendritic excitability or membrane potential depolarization, also have been implicated in learning in both vertebrate and invertebrate experimental systems [2], [3], [4], [5], [6] and [7]. Compared to synaptic plasticity, however, there is much less information available on the mechanisms of specific types of nonsynaptic plasticity involved in well-defined examples of behavioral memory. Recently, we have shown that learning-induced somal depolarization of an identified modulatory cell type (the cerebral giant cells, CGCs) of the snail Lymnaea stagnalis encodes information that enables the expression of long-term associative memory [8]. The Lymnaea CGCs therefore provide a highly suitable experimental system for investigating the ionic mechanisms of nonsynaptic plasticity that can be linked to behavioral learning. Based on a combined behavioral, electrophysiological, immunohistochemical, and computer simulation approach, here we show that an increase of a persistent sodium current of this neuron underlies its delayed and persistent depolarization after behavioral single-trial classical conditioning. Our findings provide new insights into how learning-induced membrane level changes are translated into a form of long-lasting neuronal plasticity already known to contribute to maintained adaptive modifications at the network and behavioral level [8].     

Comparison of the anticonvulsant effects of opioid peptides and etorphine in rats after icv administration

The effect of acute icv administration of β-endorphin (5–160 μg), D-ala²-D-leu⁵-enkephalin (DADL; 5–160 μg), D-ala²-met-enkephalinamide (DAME; 10–160 μg), and etorphine (0.05–1.6 μg) on brain excitability was studied by measuring flurothyl seizure thresholds in rats. Each test compound produced a behavioral stupor characterized by muscle rigidity, exophthalmos, and the absence of spontaneous movement. Wet-dog shakes occured only after injection of the opioid peptides. All four compounds produced a dose-related increase in seizure threshold. Naloxone antagonized the behavioral and anticonvulsant effects; the increase in seizure threshold induced by β-endorphin was the most resistant to naloxone. These results indicate that the opioid peptides, in addition to their known EEG epileptogenic potential, are also anticonvulsant in the rat, thus raising the possibility of a dual action for the opioid peptides on central nervous system excitability.     

Mathematical models for excitable systems in biology and medicine.

The excitable systems play a very important role in Biology and Medicine. Phenomena such as the transmission of impulses between neurons, the cardiac arrhythmia, the aggregation of amoebas, the appearance of organized structures in the cortex of egg cells, all derive from the activity of excitable media. In the first part of this work a general definition of excitable system is given; we then analyze some cases of excitability, distinguishing between electrical and chemical excitability and comparing experimental observations with simulations carried out by appropriate mathematical models. Such models are almost always formulated by partial differential equations of "reaction-diffusion" type and they have the characteristic to describe propagations of electrical waves (neurons, pacemaker cardiac cells, pancreatic b-cells) or chemical and mechanical waves (propagation of Ca++ waves or mechanical waves in the endoplasmic reticulum). The aim is to put in evidence that the biological systems can show not only excitability of electrical type, but also excitability of chemical nature, which can be observed in the first steps of development of egg cells or, for example, in the formation of pigments in vertebrate skin or in clam shells.     

Central projections of peripheral mechanosensory cells with increased excitability in Drosophila mosaics

The formation and maintenance of the central projections of identified bristle mechanosensory neurons with altered excitability were examined in Drosophila mosaics. Two mutants, eag (ether à go-go) and Sh (Shaker), are known to increase excitability of both nerve and muscle cells and enhance synaptic transmission by affecting different types of K+ currents. The eag Sh double mutant produces a synergistic effect, resulting in a greatly increased level of spontaneous neuronal activity and extreme behavioral phenotypes. By constructing mosaic flies containing small patches of doubly mutant cuticle, it was possible to alter the excitability of only one or two identified sensory cells without affecting the surrounding tissue. In these mosaic flies, the doubly mutant sensory cells were more responsive to tactile stimulation. A CoCl2 backfilling technique was utilized in staining the sensory cell projections. Both qualitative and quantitative comparisons were made between projections of cells having normal and increased levels of excitability. The length, branching characteristics, and number of terminal varicosities were analyzed for each sensory cell projection. Results indicate that, at the light microscopy level, these characteristics were not obviously altered by an increased level of excitability.     

Neuromuscular Systems in Neurogenic Arthropod Hearts

Neuromuscular transmission has been studied in detail by variousauthors in neurogenic hearts of decapod and stomatopod crustaceans,horseshoe crabs, and spiders. In these hearts, bursts of impulsesgenerated in the cardiac ganglion at regular intervals producedepolarizations of the muscle fibers. Each depolarization isassociated with a heart contraction. The depolarization is composedof many excitatory junction potentials (ejp's), each producedby a single nerve impulse. There is no evidence in Homarus,Squilla, or Limulus hearts that single ejp's or composites ofejp's give rise to regenerative membrane responses; in thesehearts, spontaneous depolarizations never overshoot the zeroreference level. Overshooting occurs in certain crab and crayfishhearts, and it is possible that muscle fibers of these heartsproduce regenerative membrane events. The muscle fibers of Limulus, Tachypleus and Homarus heartsare polyneuronally innervated. Pulse stimuli applied to nerve branches evoke ejp's that facilitatein hearts of Squilla and Homarus. In addition to facilitationin Homarus, there is also depression; at certain frequenciesof stimulation both facilitation and depression can be observed.Experiments in tarantula, Limulus, and Homarus hearts show thatL-glutamic acid mimics the natural transmitter substance.     

Atrial Pacing to Control Heart Rate and Rhythm in Acute Cardiac Conditions

Increasing the heart rate by a bedside atrial pacing technique was successfully utilized to treat serious cardiac arrhythmia or failure in 13 patients. Nine of these had ventricular arrhythmia refractory to drugs. Seven had evidence of sinus node depression or disease since their sinus pacemaker was below 70 beats per minute under decompensated conditions. In five, coronary artery disease was associated with the bradycardia and in two, digitalis toxicity was related to depression of the intrinsic pacemaker rate. Two patients in the coronary group required implantation of a permanent demand ventricular pacemaker. Hemodynamic studies were performed in seven patients. Only one patient had no increase in cardiac output with pacing rates above his resting rate. The other six patients showed an increase in cardiac output from 22 to 81% at paced rates between 70 and 125/minute. The duration of pacing ranged from one hour to 14 days and averaged five days.     

Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine

Pacemaker potentials were recorded in situ from myenteric interstitial cells of Cajal (ICC-MY) in the murine small intestine. The nature of the two components of pacemaker potentials (upstroke and plateau) were investigated and compared with slow waves recorded from circular muscle cells. Pacemaker potentials and slow waves were not blocked by nifedipine (3 µM). In the presence of nifedipine, mibefradil, a voltage-dependent Ca²⁺ channel blocker, reduced the amplitude, frequency, and rate of rise of upstroke depolarization (dV/dt_max) of pacemaker potentials and slow waves in a dose-dependent manner (1–30 µM). Mibefradil (30 µM) changed the pattern of pacemaker potentials from rapidly rising, high-frequency events to slowly depolarizing, low-frequency events with considerable membrane noise (unitary potentials) between pacemaker potentials. Caffeine (3 mM) abolished pacemaker potentials in the presence of mibefradil. Pinacidil (10 µM), an ATP-sensitive K⁺ channel opener, hyperpolarized ICC-MY and increased the amplitude and dV/dt_max without affecting frequency. Pinacidil hyperpolarized smooth muscle cells and attenuated the amplitude and dV/dt_max of slow waves without affecting frequency. The effects of pinacidil were blocked by glibenclamide (10 µM). These data suggest that slow waves are electrotonic potentials driven by pacemaker potentials. The upstroke component of pacemaker potentials is due to activation of dihydropyridine-resistant Ca²⁺ channels, and this depolarization entrains pacemaker activity to create the plateau potential. The plateau potential may be due to summation of unitary potentials generated by individual or small groups of pacemaker units in ICC-MY. Entrainment of unitary potentials appears to depend on Ca²⁺ entry during upstroke depolarization. pacemaker activity; slow waves; gastrointestinal motility; calcium channel     

Pacemaker activity in hydra is modulated by glycine receptor ligands

In the mammalian central nervous system, the neurotransmitter, glycine, acts both on an inhibitory, strychnine-sensitive receptor (GlyR) and an excitatory, strychnine-insensitive site at the NMDA receptor. Here we present electrophysiological evidence that the strychnine-sensitive glycine agonists, glycine and taurine, and the antagonist, strychnine, affect the endodermal rhythmic potential (RP) system and that the ectodermal contraction burst (CB) pacemaker system is modulated by glycine and strychnine in hydra. The RP and CB pacemaker systems are responsible for the respective elongation and contraction of hydra's body column. Activity of the CB system, quantified by the rate of contraction bursts (CBs), the number of pulses per contraction burst (P/CB), and the duration of bursts, was decreased by glycine. Glycine, coadministered with the strychnine-insensitive glycine site blocker, indole-2-carboxylic acid (I2CA), decreased RPs but not CBs or P/CB. The effect was mimicked by taurine. Strychnine increased the duration of RP production, and decreased CB duration. The effect of glycine with I2CA was counteracted by strychnine. The results support the idea that a vertebrate-like GlyR may be involved in modulating activity of the endodermal RP system and suggest that a glycine site on an NMDA receptor may be involved in the CB system.     

Androgens alter electric organ discharge pulse duration despite stability in electric organ discharge frequency.

Weakly electric fish in the genus Sternopygus emit a sinusoidal, individually distinct, and sexually dimorphic electric organ discharge (EOD) that is used in electrolocation and communication. Systemically applied androgens decrease EOD frequency, which is set by a medullary pacemaker nucleus, and increase pulse duration, which is determined by the cells of the electric organ (the electrocytes), in a coordinated fashion. One possibility is that androgens broaden the EOD pulse duration by acting on the pacemaker neurons, thereby effecting a change in pacemaker firing frequency, and that the change in EOD pulse duration is due to an activity-dependent process. To determine whether androgens can alter pulse duration despite a stable pacemaker nucleus firing frequency, we implanted small doses of dihydrotestosterone in the electric organ. We found that androgen implants increased EOD pulse duration, but did not influence EOD frequency. In addition, using immunocytochemistry, we found that electrocytes label positively with an androgen receptor antibody. While it is not known on which cells androgens act directly, together these experiments suggest that they likely act on the electrocytes to increase EOD pulse duration. Since pulse duration is determined by electrocyte action potential duration and ionic current kinetics, androgens may therefore play a causative role in influencing individual variation and sexual dimorphism in electrocyte electrical excitability, an important component of electrocommunicatory behavior.     

Clotrimazole-sensitive K+ currents regulate pacemaker activity in interstitial cells of Cajal

Interstitial cells of Cajal (ICC) are pacemaker cells for gut peristaltic motor activity. Compared with cardiac pacemaker cells, little is known about mechanisms that regulate ICC excitability. The objective of the present study was to investigate a potential role for clotrimazole (CTL)-sensitive K currents (I(CTL)) in the regulation of ICC excitability and pacemaker activity. ICC were studied in situ and in short-term culture by using the whole cell patch-clamp configuration. In situ, ICC exhibited spontaneous transient inward currents followed by transient outward currents. CTL blocked outward currents, thereby increasing the net inward currents, and depolarized ICC, thereby establishing CTL-sensitive channels as regulators of ICC pacemaker activity. In short-term culture, a I(CTL) was identified that showed increased conductance when depolarized from the resting membrane potential to 0 mV and subsequent inward rectification at further depolarized potentials. The I(CTL) markedly increased with increasing intracellular calcium and was insensitive to the ether-à-go-go-related K channel blocker E-4031 and the large-conductance calcium-activated K channel blocker iberiotoxin. I(CTL) contributed 3-9 nS to the whole cell conductance at 0 mV membrane potential under physiological conditions; it was fast activating (tau = 88 ms), showed little time-dependent inactivation, and exhibited a deactivation time constant of 38 ms. The nitric oxide donor sodium nitroprusside (SNP) increased I(CTL). Single-channel activity, activated by calcium and SNP, was inhibited by CTL, with a single-channel conductance of approximately 38 pS. In summary, ICC generate a I(CTL) on depolarization through an intermediate-conductance calcium-activated K channel that regulates pacemaker activity and ICC excitability.     

Neurophysiology of Ganglia of Auerbach's Plexus

The enteric plexuses of the automatic nervous system may beconsidered, on the basis of both function and morphology, tobe a simple integrative nervous system of vertebrate animals.Microelectrcde studies of single unit activity within entericganglia reveal four distinct types of ganglion cells distinguishedon the basis of pattern of spike discharge. These are (i) burst-typeunits which spontaneously discharge bursts of spikes at periodicintervals; (ii) fast- and slowly-adapting mechanoreceptors;(iii) tonic-type units which respond to mechanical stimulationwith prolonged, all-or-nothing trains of spikes; (iv) single-spikeunits which spontaneously discharge single action potentialsat variable intervals. The enteric plexuses are adapted forcontrol of the intestinal musculature which behaves as an electricalsyncytium activated by myogenic pacemaker potentials. The mechanismof neural control is integration of continuous neurogenic inhibitionof the inherently excitable musculature.