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PubMed1996

Oscillatory and burst discharge across electrosensory topographic maps.

1. Three parallel maps of the distribution of tuberous electroreceptor inputs are found in the medullary electrosensory lateral line lobe (ELL) of weakly electric fish. Pyramidal cells in each map are known to respond differentially to the frequency of amplitude modulations (AMs) of external electric fields in vivo. We used an in vitro ELL slice preparation of Apteronotus leptorhynchus to compare the characteristics of spontaneously active single units across the three tuberous maps. It was our objective to determine whether spontaneous bursting activity of pyramidal cells in each map correlates with the known AM frequency selectivities of pyramidal cells in vivo. 2. Single-unit discharges were recorded from the pyramidal cell layer of the centromedial segment (CMS), centrolateral segment (CLS), and lateral segment (LS) of the ELL. Stochastic analysis of interspike intervals (ISIs) was used to identify bursting and nonbursting unit activity, and to separately analyze intra- and interburst ISIs. Four ISI patterns were identified as 1) bursting, 2) regular spiking, 3) irregular spiking, and 4) highly irregular spiking. This work focuses primarily on the characteristics of bursting units across the ELL segments. 3. Spontaneous bursting discharge was identified in all three maps (68 of 97 units), with several characteristics changing in a gradual manner across the maps. The coefficient of variation (CV) of ISIs and intraburst ISIs decreased significantly from the CMS to the LS, whereas the CV of burst periods increased significantly from the CMS to the LS. Autocorrelations and power spectral density analysis identified units discharging in an oscillatory manner with the following ratio: CMS, 75%; CLS, 4%; LS, 8%. 4. The mean period of spike bursts decreased significantly across the segments (CMS, 2.7 s; CLS, 1.2 s; LS, 1.1 s) primarily because of a shortening of mean burst duration (CMS, 1.0 s; CLS, 0.1 s; LS, 0.05 s). The average number of spikes per burst decreased significantly across the maps (CMS, 61; CLS, 8; LS, 8), whereas the average frequency of spikes per burst increased (CMS, 90 Hz; CLS, 130 Hz; LS, 178 Hz), mainly through an increase in the maximal frequencies attained by units within each map. 5. Bursts in the CMS were unstructured in that the intraburst ISIs were serially independent, whereas for many units in the CLS and especially the LS there were serial dependencies of successive spikes, with alternating short and long ISIs during the burst. 6. These data reveal that the characteristics of bursting unit activity differ between the CMS, CLS, and LS maps in vitro, implying a modulation of the factors underlying burst discharge across multiple sensory maps. Because the pattern of change in burst activity between these maps parallels that of pyramidal cell AM frequency selectivity in vivo, oscillatory and burst discharge may represent the cellular mechanism used to tune these cells to specific frequencies of afferent input during electrolocation and electrocommunication.

Action Potentials↗

PubMed2003

Task-dependent presynaptic inhibition.

This study compares the level of presynaptic inhibition during two rhythmic movements in the cat: locomotion and scratch. Dorsal rootlets from L6, L7, or S1 segments were cut, and their proximal stumps were recorded during fictive locomotion occurring spontaneously in decerebrate cats and during fictive scratch induced by d-tubocurarine applied on the C1 and C2 segments. Compared with rest, the number of antidromic spikes was increased (by 12%) during locomotion, whereas it was greatly decreased (31%) during scratch, and the amplitude of dorsal root potentials (DRPs), evoked by stimulating a muscle nerve, was slightly decreased (7%) during locomotion but much more so during scratch (53%). When compared with locomotion, the decrease in the number of antidromic spikes (45%) and the decrease in DRP amplitude (43%) during scratch were of similar magnitude. Also, the amplitude of primary afferent depolarization (PAD), recorded with micropipettes in axons (n = 13) of two cats, was found to be significantly reduced (60%) during scratch compared with rest. During both rhythms, there were cyclic oscillations in dorsal root potential the timing of which was linearly related to the timing of rhythmic activity in tibialis anterior. The amplitude of these oscillations was significantly smaller (34%) during locomotion compared with scratch. These results suggest that the reduction in antidromic activity during scratch was attributable to a task-dependent decrease in transmission in PAD pathways and not to underlying potential oscillations related to the central pattern generator. It is concluded that presynaptic inhibition and antidromic discharge may have a more important role in the control of locomotion than scratch.

Animals↗

PubMed1996

Quantitative differences in the circadian rhythm of locomotor activity and vasopressin and vasoactive intestinal peptide gene expression in the suprachiasmatic nucleus of tau mutant compared to wildtype hamsters.

The activity profiles of homozygous tau mutant hamsters bred in our colony exhibit several differences when compared to wildtype golden hamsters. In addition, tau mutant hamsters respond to saturating white light pulses presented between circadian time (CT) 11 and CT 16 with extremely large phase shifts (type 0 resetting) after prolonged time in constant darkness. We measured five parameters of the activity rhythm early during exposure to constant darkness (DD) (cycles 5-9), and after 44-48 cycles in DD, and we confirmed the tau mutants' unusual phase shifting response to light. Next we determined whether neurotransmitter peptide mRNA levels in the SCN differed between wildtype and tau mutant hamsters exhibiting these divergent activity patterns and responses to light. After 49 circadian cycles in DD, tau mutant hamsters responded to a 1 h light pulse at CT 15 with phase shifts averaging 10.19 +/- 0.35 h. Among wildtype hamsters the mean phase shift was 1.22 +/- 0.34 h and the largest phase shift observed was 3.67 h. Total wheel revolutions/circadian cycle were significantly lower in tau mutants (4022 +/- 1103) vs. wildtypes (7528 +/- 458) and there was a significant decrease in wheel-running activity after prolonged exposure to DD, particularly among the wildtype hamsters (tau = 3045 +/- 972, wildtype = 4362 +/- 388 rev/circadian cycle). When analyzed by 5 min segments throughout the circadian cycle, the highest intensity wheel-running activity did not differ between groups and there was no significant effect of length of time in DD on this measure (tau = 38.5 +/- 6.3 and 38.4 +/- 4.7 rev/min, wildtype = 46.8 +/- 1.7 and 41.4 +/- 2.7 rev/min early or late in DD, respectively). The precision of activity onset differed greatly between groups with tau mutants exhibiting a much higher daily deviation from mean tau (1.00 +/- 0.24 h) than wildtypes (0.14 +/- .02 h). Activity onset became significantly less precise with increased time in DD: tau = 1.66 +/- 0.21 h, wildtype = 0.45 +/- 0.14 h after 44-48 circadian cycles. The length of the active period, alpha, was significantly shorter in tau mutants than in wildtypes (7.2 +/- 0.2 h vs. 8.0 +/- 0.2 h) but alpha was a similar percentage of tau in the two groups (tau mutant = 36%, wildtype = 33%). After 48 circadian cycles in DD, alpha measured 7.2 +/- 0.5 h in tau mutants and 8.9 +/- 0.6 h in wildtypes, thus there was no significant effect of time in DD on this parameter. Activity records of tau mutant animals appear more fragmented to the eye and we quantitated this with a computer-aided analysis of the number of bouts of wheel-running per active period. Wildtype hamsters exhibited 2.8 +/- 0.2 bouts of wheel-running activity early in DD and 3.1 +/- 0.2 bouts per circadian cycle later in DD. The activity records of tau mutant hamsters were significantly more fragmented but this group actually showed some consolidation of bouts per circadian cycle after prolonged time in DD (4.7 +/- 0.3 vs. 3.9 +/- 0.3 bouts per cycle). Wildtype and tau mutant hamsters were killed after 66-71 cycles in DD at either CT 4 or CT 16 and in situ hybridization was performed for vasopressin (AVP) and vasoactive intestinal peptide (VIP). Levels of AVP and VIP mRNA were significantly lower in tau mutant than wildtype hamsters at CT 16. We conclude that the tau mutation causes these differences in gene expression and we speculate that differences in the peptidergic output of the clock may have some relevance for the differences in the quantitative aspects of the activity rhythm and the response to light pulses exhibited by these animals.

Animals↗

PubMed2002

A functional asymmetry in the Leech Heartbeat Timing Network is revealed by driving the network across various cycle periods.

We tested predictions of a computational model (Hill et al., 2002) of the leech heartbeat timing network. The timing network consists of two segmental oscillators located in the third (G3) and fourth (G4) segmental ganglia. Each oscillator consists of two reciprocally inhibitory oscillator interneurons along with the coordinating interneuron fibers that link them. In the model, the network was driven to cycle periods around the normal period of the network by repeatedly stimulating one of the paired oscillator interneurons in G3 or G4. Here we replicate these experiments in the biological system. The model predicts that the G3 and G4 oscillators can entrain the timing network to periods faster but not slower than the inherent period of the nondriven ("follower") oscillator and that they can do so symmetrically. The biological system can be driven to periods both faster (such that the driven oscillator leads in phase) and slower (such that the driven oscillator lags in phase) than the inherent period of the timing network. Although both oscillators can entrain the network, the G4 oscillator does so over a narrower range of periods. Two differences between the assumptions of the model and the properties of the biological network, spike frequency adaptation in coordinating interneurons and asymmetry in the connections from the oscillator interneurons to the coordinating interneurons, may account for these discrepancies. Individual coordinating interneurons were also able to entrain the oscillators but with little effect of the phase relationship between the oscillators, suggesting that phase relations are determined by properties inherent to the oscillator interneurons.

Action Potentials↗

PubMed2006

Target width scaling in a repetitive aiming task: switching between cyclical and discrete units of action.

An aiming task was used to identify the processes whereby the motor system adapted a repetitive aiming action to systematic changes in ID (ID = log(2 )(2A/W), Fitts in J Exp Psychol 47:381-391, 1954) within a single trial. Task ID was scaled in a trial by moving the outside edge of two stationary targets to produce nine different target IDs in a trail. The ID within a trial was scaled in one of two directions: (1) an increasing ID condition, starting with an ID = 3.07 and ending with an ID = 5.91; and (2) a decreasing ID condition, starting with an ID = 5.91 and ending with an ID = 3.07. An index of movement harmonicity (Guiard in Acta Psychol 82:139-159, 1993) revealed that the repetitive aiming action was harmonic in nature when task ID was 3.07, and consisted of a series of discrete segments when task ID was 5.91. This finding provides evidence for the existence of discrete and cyclical units of action that are irreducible and that may be employed independently to assemble longer continuous actions. The scaling of ID within a trial promoted a transition in repetitive aiming motions assembled from discrete and cyclical units of action. A variety of kinematic measures (e.g., movement harmonicity, time spent accelerating the limb) revealed a critical ID (ID(c)) region (4.01-4.91) separating aiming motions governed by the different units of action. Enhancement of fluctuations before the transition were found in the movement harmonicity data and in the distance traveled to peak velocity data, with variability in these measures highest in the ID(c) region. The enhancement of fluctuations indicates that loss of stability in the limb's motion acted as a key mechanism underlying the transition between units of action. The loss of stability was associated with the transition from cyclical to discrete actions and with the transition from discrete to cyclical actions. The transition between units of action may be conceptualized as a transition from a limit cycle attractor (cyclical unit of action) to a shift between two fixed-point attractors (discrete unit of action) when ID was increased, with the transition occurring in the opposite direction when ID was decreased.

Adaptation, Physiological↗

PubMed2002

Myogenic tone, reactivity, and forced dilatation: a three-phase model of in vitro arterial myogenic behavior.

Myogenic behavior, prevalent in resistance arteries and arterioles, involves arterial constriction in response to intravascular pressure. This process is often studied in vitro by using cannulated, pressurized arterial segments from different regional circulations. We propose a comprehensive model for myogenicity that consists of three interrelated but dissociable phases: 1) the initial development of myogenic tone (MT), 2) myogenic reactivity to subsequent changes in pressure (MR), and 3) forced dilatation at high transmural pressures (FD). The three phases span the physiological range of transmural pressures (e.g., MT, 40-60 mmHg; MR, 60-140 mmHg; FD, >140 mmHg in cerebral arteries) and are characterized by distinct changes in cytosolic calcium ([Ca(2+)](i)), which do not parallel arterial diameter or wall tension, and therefore suggest the existence of additional regulatory mechanisms. Specifically, the development of MT is accompanied by a substantial (200%) elevation in [Ca(2+)](i) and a reduction in lumen diameter and wall tension, whereas MR is associated with relatively small [Ca(2+)](i) increments (<20% over the entire pressure range) despite considerable increases in wall tension and force production but little or no change in diameter. FD is characterized by a significant additional elevation in [Ca(2+)](i) (>50%), complete loss of force production, and a rapid increase in wall tension. The utility of this model is that it provides a framework for comparing myogenic behavior of vessels of different size and anatomic origin and for investigating the underlying cellular mechanisms that govern vascular smooth muscle mechanotransduction and contribute to the regulation of peripheral resistance.

Animals↗

PubMed2006

High-frequency oscillations during human focal seizures.

Discrete high-frequency oscillations (HFOs) in the range of 100-500 Hz have previously been recorded in human epileptic brains using depth microelectrodes. We describe for the first time similar oscillations in a cohort of unselected focal epileptic patients implanted with EEG macroelectrodes. Spectral analysis and visual inspection techniques were used to study seizures from 10 consecutive patients undergoing pre-surgical evaluation for medically refractory focal epilepsy. Four of these patients had focal seizure onset in the mesial temporal lobe, and in all 12 of their seizures, well-localized, segmental, very high frequency band (VHF: 250-500 Hz) oscillations were visually identified near the time of seizure onset from contacts in this zone. Increased high-frequency band (HF: 100-200 Hz) activity compared with the background was distinguished both visually and with spectral analysis later in the seizures of 3/4 mesial temporal patients, involving contacts in the generator region and, in one patient, areas of contralateral peri-hippocampal propagation. Three patients with well-defined neocortical seizure-onset areas also demonstrated focal HF or VHF oscillations confined to the seizure-onset channels during their eight seizures. No discrete HF or VHF activity was present in the poorly localized seizures from the remaining three patients. These results show that discrete HFOs can be recorded from human focal epileptic brain using depth macroelectrodes, and that they occur mostly in regions of primary epileptogenesis and rarely in regions of secondary spread. Absent high-frequency activity seems to indicate poor localization, whereas the presence of focal HFOs near the time of seizure onset may signify proximity to the epileptogenic focus in mesial temporal lobe and neocortical seizures. We postulate that focal HFOs recorded with depth macroelectrodes reflect the partial synchronization of very local oscillations such as those previously studied using microelectrodes, and result from interconnected small neuronal ensembles. Our finding that localized HFOs occur in varying anatomical structures and pathological conditions perhaps indicates commonality to diverse epileptogenic aetiologies.

Adult↗

PubMed2000

Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkinsonism.

To investigate the role of the basal ganglia in parkinsonian tremor, we recorded hand tremor and simultaneous activity of several neurons in the external and internal segments of the globus pallidus (GPe and GPi) in two vervet monkeys, before and after systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and development of parkinsonism with tremor of 5 and 11 Hz. In healthy monkeys, only 11% (20/174) of the GPe cells and 3% (1/29) of the GPi cells displayed significant 3-19 Hz oscillations. After MPTP treatment, 39% (107/271) of the GPe cells and 43% (26/61) of the GPi cells developed significant oscillations. Oscillation frequencies of single cells after MPTP treatment were bimodally distributed around 7 and 13 Hz. For 10% of the oscillatory cells that were recorded during tremor periods, there was a significant tendency for the tremor and neuronal oscillations to appear simultaneously. Cross-correlation analysis revealed a very low level of correlated activity between pallidal neurons in the normal state; 95.6% (477/499) of the pairs were not correlated, and oscillatory cross-correlograms were found in only 1% (5/499) of the pairs. After MPTP treatment, the correlations increased dramatically, and 40% (432/1080) of the cross-correlograms had significant oscillations, centered around 13-14 Hz. Phase shifts of the cross-correlograms of GPe pairs, but not of GPi, were clustered around 0 degrees. The results illustrate that MPTP treatment changes the pattern of activity and synchronization in the GPe and GPi. These changes are related to the symptoms of Parkinson's disease and especially to the parkinsonian tremor.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

Slow oscillatory activity of rat globus pallidus neurons in vitro.

The neurons in the external segment of the pallidum in the primate develop a characteristic firing pattern consisting of alternately occurring long, 2-20 s, strongly active phases and long completely silent phases when the subthalamo-pallidal excitatory inputs are blocked. The induction of the activity might be a factor in the development of dyskinesias after the loss of subthalamic output. In this study, we used globus pallidus (GPe) slice preparations obtained from juvenile rats to examined the conditions that support the alternatively occurring long depolarized and hyperpolarized phases which we refer to as the slow oscillation (SO). SO was not induced by the blockade of glutamatergic inputs but was induced by treatments that depolarized dendrites and, at the same time, hyperpolarized the somata with current injections. The treatments included elevation of extracellular K(+), application of K-current blockers and the lowering of extracellular Ca(2+). Application of TTX or intracellular BAPTA injection blocked the SO, while the SO could be maintained in hyperpolarization-activated inward current blockers, organic Ca-current blockers and up to 200 microm CdCl(2). These results suggest that Na currents play a major role in the generation of SO in vitro. It can be speculated that Na currents are involved in the development of active phases observed in the GPe after blockade of the glutamatergic inputs in vivo and that the unique property of GPe neurons in maintaining strong activity after the elimination of the glutamatergic driving force contributes to the development of motor disorders such as dyskinesia.

Action Potentials↗

PubMed2001

Results of a standardized protocol for sentinel node imaging in breast cancer with Tc-99m labeled nanocolloidal albumin.

AIM: Of this study was to evaluate the results of a standardized protocol for sentinel node (SN) detection in breast cancer using Tc-99m labeled nanocolloidal albumin and a combined intra- and subdermal injection technique. METHODS: One hundred and fifty-five women with proven breast cancer (disease stages Tis-T2) were included. Four injections of 10 to 15 MBq of Tc-99m nanocolloid in 0.1 ml physiologic saline were administered intra- and subdermally at the 3, 6, 9 and 12 o'clock positions in the skin overlying the tumor. Planar scintigraphic images in lateral and anterior projections were obtained once between 2.5 and 18 hours after tracer administration. Guided by a gamma probe, all radioactive lymph nodes in the axilla were resected, then complete dissection followed. RESULTS: In 151 of the 155 women (97.4%), nodal tracer uptake (range 1-7 foci, average 2.2) was scintigraphically revealed. In one of these cases, drainage was only to the internal mammary lymphatic chain. Three of the 4 women with detection failure presented with histologically proven tumor infiltration of the lymphatics and axillary involvement. In 49 of the patients with visualized axillary lymph nodes (32.7%), at least one SN was metastatic. In 21 cases, this SN was the only positive node. The remaining 101 patients with negative SN included 4 cases with axillary involvement. The sensitivity of the SN with respect to the histological status of the entire axilla was thus 92.5%, the negative predictive value was 96.0%. The overall accuracy of the method was 97.3%. There was a significant difference between the number of totally detected radioactive nodes in the groups with and without nodal metastases (3.49 vs. 2.57, p < 0.01). CONCLUSION: The described protocol represents an easy reproducible and reliable method for SN detection in breast cancer that additionally allows flexible timing of surgery. Further, we found evidence that the number of scintigraphically visualized nodes also reflects the histological status of the axilla.

Biopsy↗

PubMed2006

Quantitative multichannel EEG measure predicting the optimal weaning from ventilator in ICU patients with acute respiratory failure.

OBJECTIVE: The objective of this study was to develop a novel quantitative multichannel EEG (qEEG) based analysis method, called Global Field Damping Time (GFDT), in order to detect potential EEG changes of patients admitted to the ICU with acute respiratory failure, and correlate them to the patients' recovery outcome predicting the optimal time-point to disconnect the patient from mechanical ventilation. METHODS: Twenty-nine adult patients with acute respiratory failure out of 98 admitted to the Intensive Care Unit of Saint Paul General Hospital were enrolled, and among them only 15 completed the study. The patients were classified in 3 groups according to their outcome after 3 months follow-up. The patients were intubated with fraction of inspired oxygen (FiO2) of 100%. Neurological Deficit Scores (NDS) were measured 24 h after intubation to assess patients' neurological condition. Twenty-four hours after patient's intubation, FiO2 was decreased to 40% (weaning session), followed by a 5 min early recovery session, a 5 min recovery 1 session and a 5 min recovery 2 session. EEG recordings were performed during this experimental procedure. Multichannel EEG segments were processed and fitted into a multivariate autoregressive (mAR) model, and single channel EEG segments into a scalar autoregressive (sAR) model. The mAR and the sAR models of arbitrary order p were decomposed into mp and p oscillators and relaxators, respectively. Damping time of each oscillator and each relaxator, and the Global Field Damping Time (GFDT) as a weighted damping time were estimated for both mAR and sAR models. RESULTS: A statistically significant increase of mAR model's GFDT during the weaning session was observed in the subjects of all groups. Comparing the 3 patients' groups, statistically significant differences for mAR model's GFDT were observed for the weaning and early recovery session. Linear regression analysis between NDS and mean mAR model's GFDT showed statistical significance during weaning session, early recovery session, and recovery 1 session. There was no statistical significance for SaO2 in the regression analysis with NDS. The sAR model's GFDT presented worst results in comparison with the mAR modelling GFDT in the identification of hypoxic conditions during weaning session and in the discrimination of patients with acute respiratory failure according to their neurological outcome. CONCLUSIONS: Global Field Damping Time as correlated to the patients' neurological outcome appears to be a simple, compact, and substantial novel indicator of cerebral hypoxia and a potential predictor of the optimal time-point to disconnect the patient from the ventilator. SIGNIFICANCE: Quantitative EEG seems to be an important tool for ICU clinicians assisting them to decide for the patients' optimal time-point to disconnect the patient from the ventilator.

Acute Disease↗

PubMed2005

Oscillatory ROP GTPase activation leads the oscillatory polarized growth of pollen tubes.

Oscillation regulates a wide variety of processes ranging from chemotaxis in Dictyostelium through segmentation in vertebrate development to circadian rhythms. Most studies on the molecular mechanisms underlying oscillation have focused on processes requiring a rhythmic change in gene expression, which usually exhibit a periodicity of >10 min. Mechanisms that control oscillation with shorter periods (<10 min), presumably independent of gene expression changes, are poorly understood. Oscillatory pollen tube tip growth provides an excellent model to investigate such mechanisms. It is well established that ROP1, a Rho-like GTPase from plants, plays an essential role in polarized tip growth in pollen tubes. In this article, we demonstrate that tip-localized ROP1 GTPase activity oscillates in the same frequency with growth oscillation, and leads growth both spatially and temporally. Tip growth requires the coordinate action of two ROP1 downstream pathways that promote the accumulation of tip-localized Ca2+ and actin microfilaments (F-actin), respectively. We show that the ROP1 activity oscillates in a similar phase with the apical F-actin but apparently ahead of tip-localized Ca2+. Furthermore, our observations support the hypothesis that the oscillation of tip-localized ROP activity and ROP-dependent tip growth in pollen tubes is modulated by the two temporally coordinated downstream pathways, an early F-actin assembly pathway and a delayed Ca2+ gradient-forming pathway. To our knowledge, our report is the first to demonstrate the oscillation of Rho GTPase signaling, which may be a common mechanism underlying the oscillation of actin-dependent processes such as polar growth, cell movement, and chemotaxis.

Actin Cytoskeleton↗

PubMed2004

An electrical description of the generation of slow waves in the antrum of the guinea-pig.

This paper provides an electrical description of the generation of slow waves in the guinea-pig gastric antrum. A short segment of a circular smooth muscle bundle with an attached network of myenteric interstitial cells of Cajal (ICC-MY) and longitudinal muscle sheet was modelled as three electrical compartments with resistive connexions between the ICC-MY compartment and each of the smooth muscle compartments. The circular smooth muscle layer contains a proportion of intramuscular interstitial cells of Cajal (ICC-IM), responsible for the regenerative component of the slow wave. Hence the equivalent cell representing the circular muscle layer incorporated a mechanism, modelled as a two stage reaction, which produces an intracellular messenger. The first stage of the reaction is proposed to be activated in a voltage-dependent manner as described by Hodgkin and Huxley. A similar mechanism was incorporated into the equivalent cell describing the ICC-MY network. Spontaneous discrete transient depolarizations, termed unitary potentials, are detected in records taken from either bundles of circular smooth muscle containing ICC-IM or from ICC-MY. In the simulation the mean rate of discharge of unitary potentials was allowed to vary with the concentration of messenger according to a conventional dose-effect relationship. Such a mechanism, which describes regenerative potentials generated by the circular muscle layer, also simulated the plateau component of the pacemaker potential in the ICC-MY network. A voltage-sensitive membrane conductance was included in the ICC-MY compartment; this was used to describe the primary component of the pacemaker potential. The model generates a range of membrane potential changes with properties similar to those generated by the three cell types present in the intact tissue.

Animals↗

PubMed1997

Repetitive firing and oscillatory activity of pyramidal-like bursting neurons in the rat subiculum.

Electrophysiological characterization of neurons within the rat subiculum was carried out with intracellular recordings in an in vitro slice preparation. Subicular neurons responded to threshold pulses of depolarizing current delivered at a resting membrane potential (RMP) of 45.7+/-5.8 mV (mean+/-SD, n=85) with an initial burst of three to five fast action potentials that rode on a depolarizing envelope and was terminated by an afterhyperpolarization (burst AHP) (duration 113+/-35 ms; peak amplitude 2.7+/-0.6 mV, n=10). Tonic firing replaced the bursting mode at membrane potential less negative than -55 mV. Suprathreshold depolarizing pulses evoked at RMP both an initial burst and successive tonic firing. Intracellular staining with biocytin showed morphological features typical of pyramidal cells (n=8). The relationship between frequency of repetitive firing and injected current (f-I) revealed that the burst firing frequency (250-300 Hz) was only slightly influenced by the amount of injected current. By contrast, the f-I curve of the tonic firing phase depended upon current intensity: it displayed an initial segment that increased at first linearly and then turned into a plateau for both the early and the late inter-spike intervals. The frequency of the tonic firing declined only slightly with time, thus suggesting a lack of adaptation. During tonic firing, each single action potential was followed by a fast AHP and a depolarizing afterpotential. Termination of repetitive firing was followed by an AHP (spike-train AHP; duration 223+/-101 ms, peak amplitude 5.6+/-2.4 mV, n=17). Fast spike-train and burst AHPs were reduced by bath application of the Ca2+-channel blockers Co2+ (2 mM) and Cd2+ (1 mM) (n=8), thus suggesting the participation of Ca2+-dependent K+ conductances in these AHPs. Subicular bursting neurons generated persistent, subthreshold voltage oscillations at 5.3+/-1 Hz (n=20) during steady depolarization positive to -60 mV; at values positive to -55 mV, the oscillatory activity could trigger clusters of single action potentials with a periodicity of 0.9-2 Hz. Oscillations were not prevented by application of excitatory amino acid receptor and GABA(A) receptor antagonists (n=5), Ca2+-channel blockers (n=5), or Cs+ (3 mM; n=4), but were abolished by the Na+-channel blocker tetrodotoxin (1 microM; n=6). Our findings demonstrate that pyramidal-like subicular neurons generate both bursting and non-adapting tonic firing, depending upon their membrane potential. These neurons also display oscillatory activity in the range of theta frequency that depends on the activation of a voltage-gated Na+ conductance. These electrophysiological properties may play a role in the process of signals arising from the hippocampal formation before being funnelled towards other limbic structures.

Action Potentials↗

PubMed2006

Heterogeneous three-dimensional anatomical and electrophysiological model of human atria.

Investigating the mechanisms underlying the genesis and conduction of electrical excitation in the atria at physiological and pathological states is of great importance. To provide knowledge concerning the mechanisms of excitation, we constructed a biophysical detailed and anatomically accurate computer model of human atria that incorporates both structural and electrophysiological heterogeneities. The three-dimensional geometry was extracted from the visible female dataset. The sinoatrial node (SAN) and atrium, including crista terminalis (CT), pectinate muscles (PM), appendages (APG) and Bachmann's bundle (BB) were segmented in this work. Fibre orientation in CT, PM and BB was set to local longitudinal direction. Descriptions for all used cell types were based on modifications of the Courtemanche et al. model of a human atrial cell. Maximum conductances of Ito, IKr and ICa,L were modified for PM, CT, APG and atrioventricular ring to reproduce measured action potentials (AP). Pacemaker activity in the human SAN was reproduced by removing IK1, but including If, ICa,T, and gradients of channel conductances as described in previous studies for heterogeneous rabbit SAN. Anisotropic conduction was computed with a monodomain model using the finite element method. The transversal to longitudinal ratio of conductivity for PM, CT and BB was 1:9. Atrial working myocardium (AWM) was set to be isotropic. Simulation of atrial electrophysiology showed initiation of APs in the SAN centre. The excitation spread afterwards to the periphery near to the region of the CT and preferentially towards the atrioventricular region. The excitation extends over the right atrium along PM. Both CT and PM activated the right AWM. Earliest activation of the left atrium was through BB and excitation spread over to the APG. The conduction velocities were 0.6ms-1 for AWM, 1.2ms-1 for CT, 1.6ms-1 for PM and 1.1ms-1 for BB at a rate of 63bpm. The simulations revealed that bundles form dominant pathways for atrial conduction. The preferential conduction towards CT and along PM is comparable with clinical mapping. Repolarization is more homogeneous than excitation due to the heterogeneous distribution of electrophysiological properties and hence the action potential duration.

Action Potentials↗

PubMed1995

An effector site that stimulates G-protein GTPase in photoreceptors.

Heterotrimeric G-proteins mediate between receptors and effectors, acting as molecular clocks. G-protein interactions with activated receptors catalyze the replacement of GDP bound to the alpha-subunit with GTP. alpha-Subunits then modulate the activity of downstream effectors until the bound GTP is hydrolyzed. In several signal transduction pathways, including the cGMP cascade of photoreceptor cells, the relatively slow GTPase activity of heterotrimeric G-proteins can be significantly accelerated when they are complexed with corresponding effectors. In the phototransduction cascade the GTPase activity of photoreceptor G-protein, transducin, is substantially accelerated in a complex with its effector, cGMP phosphodiesterase. Here we characterize the stimulation of transducin GTPase by a set of 23 mutant phosphodiesterase gamma-subunits (PDE gamma) containing single alanine substitutions within a stretch of the 25 C-terminal amino acid residues known to be primarily responsible for the GTPase regulation. The substitution of tryptophan at position 70 completely abolished the acceleration of GTP hydrolysis by transducin in a complex with this mutant. This mutation also resulted in a reduction of PDE gamma affinity for transducin, but did not affect PDE gamma interactions with the phosphodiesterase catalytic subunits. Single substitutions of 7 other hydrophobic amino acids resulted in a 50-70% reduction in the ability of PDE gamma to stimulate transducin GTPase, while substitutions of charged and polar amino acids had little or no effect. These observations suggest that the role of PDE gamma in activation of the transducin GTPase rate may be based on multiple hydrophobic interactions between these molecules.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

The redusome hypothesis of aging and the control of biological time during individual development.

The redusome hypothesis of aging and the control of biological time in individual development is proposed. Redusomes are hypothetical perichromosomal particles arising in differentiation events during morphogenesis of an organism. The linear molecule of DNA covered with proteins in the redusome is assumed to be a copy of a segment of chromosomal DNA. Redusomes are located mainly in subtelomeric regions of chromosomes. The redusome does not leave the body of a chromosome even in the course of cellular divisions, being kept in its chromosomal nest. Like telomeric DNA, redusome linear DNA is shortened step by step. Thus, tiny redusomes progressively decrease in size; it is from here their name originates. Together with loss of the length of DNA in a redusome, the number of different genes contained in it also decreases. Shortening of the redusomal DNA molecules (and, coupled to it, changes of the sets of genes in redusomes) is responsible for age-dependent shifts in the level of expression of different chromosomal genes. Owing to this, redusome DNA shortening serves as a key means of measuring biological time in individual development. The main part of DNA of most redusomes is postulated to be occupied by noncoding genes. Low-molecular-weight RNAs (micro RNAs and fountain RNAs, or fRNAs) are assumed to be transcribed from them. These RNAs are involved in regulation of various chromatin repackings that are specific to certain differentiations, while others modulate the levels of expression of chromosomal genes. Hypothetical fountain RNAs can quantitatively regulate the expression levels of chromosomal genes, forming specific complexes with fions. Fions are suggested to be specific sites of a chromosomal DNA which are complementary to different fRNAs. Fions reside in the vicinity of usual chromosomal genes. A complex of the fRNA-fion, specifically interacting with a closed gate of the corresponding ion channel of the internal nuclear membrane, initiates the opening of the gate for a very short time, thus organizing activity of an ion fountain which appears to be automatically aimed at the chromosomal gene nearest to the fion involved. The ion fountain creates, depending on specificity of matching fRNA, fion, and ion channel, a distinctive ionic environment near certain structural genes. Ion fountains exert their action on the configuration of corresponding segments of chromatin and on the transcriptional efficiency of chromosomal genes in a topographically specific manner. Hence, the fountain system of the nucleus is able to regulate the quantitative traits both of cells and organism; it can control dominance of alleles and plays a role in individual development. Significant and escalating truncation of the redusome DNA causes cell aging due to an arising and increasing deficit of fRNAs and, for this reason, the lack of required ions near certain structural genes. Progressive shortening of DNA of redusomes is proposed to result in cellular aging because of a constantly growing shortage of low-molecular-weight RNAs transcribed from redusomal genes. Two types of redusomes are postulated: chronosomes and printosomes. Linear molecules of DNA in these two types of redusomes are called chronomeres and printomeres, respectively. Chronosomes are responsible for measurement of biological time in nondividing cells of the CNS. Printosomes remember positions of cells in the course of interpretation of the positional information in morphogenesis. In accordance with the position of a cell in a morphogenetic field, printomeres do change cellular properties and remember the change made (this is a so-called printomere mechanism of interpretation of positional information). Besides, printomeres participate in maintaining the achieved state of cellular differentiation. Normally, the chronomere is shortened only on the maximum of infradian hormonal rhythm (T-rhythm) which initiates the act of a superhigh velocity of its transcription that is finished with truncation of the end of a chronomere (an effect called scrupting). Theprintomere can be shortened due to the effect of DNA end underreplication and owing to scrupting. The effect of the end underreplication of DNA in doubling cells occurs simultaneously both in printomeres and telomeres. Shortening of telomeres is just a bystander process of aging of cells, whereas the true cause of biological aging is only the shortening of redusome DNA. Processing of certain redusomes in terminally differentiating cells is a cause of a proliferation arrest. Linkage of genes in a eukaryotic chromosome is determined by the distances between genes and redusomes.

Aging↗