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S B Khalsa

Publications and source records attributed to S B Khalsa.

At least 19 recordsLinked to original sources
PubMed2001

Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects.

The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.

Adolescent↗
PubMed1999

Time course of sleep inertia dissipation in human performance and alertness.

Alertness and performance on a wide variety of tasks are impaired immediately upon waking from sleep due to sleep inertia, which has been found to dissipate in an asymptotic manner following waketime. It has been suggested that behavioural or environmental factors, as well as sleep stage at awakening, may affect the severity of sleep inertia. In order to determine the time course of sleep inertia dissipation under normal entrained conditions, subjective alertness and cognitive throughput were measured during the first 4 h after habitual waketime from a full 8-h sleep episode on 3 consecutive days. We investigated whether this time course was affected by either sleep stage at awakening or behavioural/environmental factors. Sleep inertia dissipated in an asymptotic manner and took 2-4 h to near the asymptote. Saturating exponential functions fitted the sleep inertia data well, with time constants of 0.67 h for subjective alertness and 1.17 h for cognitive performance. Most awakenings occurred out of stage rapid eye movement (REM), 2 or 1 sleep, and no effect of sleep stage at awakening on either the severity of sleep inertia or the time course of its dissipation could be detected. Subjective alertness and cognitive throughput were significantly impaired upon awakening regardless of whether subjects got out of bed, ate breakfast, showered and were exposed to ordinary indoor room light (approximately 150 lux) or whether subjects participated in a constant routine (CR) protocol in which they remained in bed, ate small hourly snacks and were exposed to very dim light (10-15 lux). These findings allow for the refinement of models of alertness and performance, and have important implications for the scheduling of work immediately upon awakening in many occupational settings.

Adult↗
PubMed1999

EEG and ocular correlates of circadian melatonin phase and human performance decrements during sleep loss.

The aim of this study was to quantify the associations between slow eye movements (SEMs), eye blink rate, waking electroencephalogram (EEG) power density, neurobehavioral performance, and the circadian rhythm of plasma melatonin in a cohort of 10 healthy men during up to 32 h of sustained wakefulness. The time course of neurobehavioral performance was characterized by fairly stable levels throughout the first 16 h of wakefulness followed by deterioration during the phase of melatonin secretion. This deterioration was closely associated with an increase in SEMs. Frontal low-frequency EEG activity (1-7 Hz) exhibited a prominent increase with time awake and little circadian modulation. EEG alpha activity exhibited circadian modulation. The dynamics of SEMs and EEG activity were phase locked to changes in neurobehavioral performance and lagged the plasma melatonin rhythm. The data indicate that frontal areas of the brain are more susceptible to sleep loss than occipital areas. Frontal EEG activity and ocular parameters may be used to monitor and predict changes in neurobehavioral performance associated with sleep loss and circadian misalignment.

Adult↗
PubMed1997

Circadian rhythms in mouse suprachiasmatic nucleus explants on multimicroelectrode plates.

The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus functions as a circadian pacemaker. This study used multimicroelectrode plates to measure extracellular action potential activity simultaneously from multiple sites within the cultured mouse SCN. Neurons within the isolated mouse SCN expressed a circadian rhythm in spontaneous firing rate for weeks in culture.

Action Potentials↗
PubMed1997

The role of extracellular sodium in the mechanism of a neuronal in vitro circadian pacemaker.

In evaluation of whether extracellular ion concentrations or fluxes are involved in the mechanism of the circadian pacemaker in Bulla retinal neurons, previous studies have ruled out obligatory requirements for extracellular calcium and chloride. In this study, it is demonstrated that extracellular sodium and magnesium are also not requirements for and do not contribute to the circadian pacemaker mechanism. Since sodium-free solutions inhibit the output rhythm of compound action potential activity, pacemaker motion during long pulse treatments was evaluated retrospectively from the phase of the circadian rhythm subsequent to the treatment. Although some pulses of sodium-free solutions were capable of affecting pacemaker phase in a manner consistent with the stopping of pacemaker motion, these effects were reversed by elevating extracellular pH, suggesting that sodium-free solutions can only affect pacemaker motion indirectly through a previously demonstrated effect of low pH on pacemaker motion.

Action Potentials↗
PubMed1996

Circadian rhythm generation, expression and entrainment in a molluscan model system.

The Bulla ocular pacemaker provides remarkable opportunities for cellular study of circadian pacemaker systems. The demonstration of circadian oscillations within individual neurons maintained in culture provides us with a first occasion to study the biophysical and biochemical properties of bona fide neuronal circadian pacemakers. The ocular clock is robust and shares formal similarity with other circadian systems. The development of molecular techniques that can be applied to single neurons should allow research on the Bulla retina to continue to progress towards a molecular analysis of circadian timekeeping.

Animals↗
PubMed1996

Evidence for a central role of transcription in the timing mechanism of a circadian clock.

The retinal circadian clock in the isolated in vitro eye of the marine mollusc Bulla gouldiana exhibits a phase-dependent requirement for transcription. The transcription-sensitive phase extends through most of the subjective day and therefore is substantially longer than the previously reported translation-sensitive phase. Lower concentrations of transcription inhibitors yield a significant dose-dependent lengthening of circadian period. Clock motion can be stopped by a high concentration of the transcription inhibitor 5,6-dichlorobenz-imidazole riboside (DRB) when applied during the sensitive phase; after withdrawal of the inhibitor, motion resumes from the phase at which it was stopped. In a double-pulse experiment, phase shifts to light pulses applied after DRB pulses, and not during the translation-sensitive phase, indicate that the inhibition of transcription has immediate effects on the phase of the clock. These data suggest that DRB-induced phase shifts are independent of translation, which implies that the rate of transcription itself plays a significant role in the mechanism underlying the generation of the circadian cycle.

Animals↗
PubMed1995

The anesthetic agents pentobarbital and chloralose block phase shifts of a neuronal in vitro circadian pacemaker.

The anesthetic pentobarbital (6 mM) is capable of blocking light or high K(+)-induced phase shifts of the circadian pacemaker in the isolated eye of Bulla. Pentobarbital alone was effective in generating phase shifts consistent with phase response curves obtained to either extracellular low Ca2+ or hyperpolarizing pulses. Patch clamp recordings from the circadian pacemaker cells indicate that pentobarbital reduces the Ca(2+)-dependent K+ current. Together, these data suggest that pentobarbital acts on the pacemaker by reducing an inward Ca2+ current. Chloralose (3 mM) was effective in blocking light, but not high K(+)-induced phase shifts, and did not generate phase shifts when applied alone, suggesting that chloralose may act as a weak Ca2+ channel inhibitor.

Animals↗
PubMed1993

The role of extracellular calcium in generating and in phase-shifting the Bulla ocular circadian rhythm.

Since extracellular calcium is known to be involved in the entrainment of the circadian pacemaker in the retina of Bulla gouldiana, we have assessed the requirement for extracellular calcium in the generation of the circadian rhythm. To enable us to assay the state of the pacemaker during low-calcium treatment, which often obscures rhythmicity, long-duration pulses of low-calcium artificial seawater (no added calcium, 10 mM EGTA, calculated calcium concentration = 4.5 x 10(-10) M) were applied, and the phase of the subsequent rhythm was measured. Pulse treatments started at zeitgeber time (ZT) 6, and durations ranged from 4 to 72 hr. Although no phase shifts followed pulses ending before the next projected dawn (ZT 24), phase delays of up to 4 hr followed pulses ending after projected dawn, and delays of up to 8 hr followed pulses spanning two dawns. Some activity records exhibited unequivocal circadian rhythmicity during the long low-calcium treatments, with phases and periods similar to untreated control eye records; this finding suggests that the phase delays observed following long low-calcium pulses are attributable to the pulsatile nature of the treatment. These data suggest that extracellular calcium is not an essential requirement for the pacemaker in generating the circadian rhythm.

Action Potentials↗
PubMed1993

The effects of lithium on a neuronal in vitro circadian pacemaker.

Previous studies have suggested a causal connection between abnormalities of the circadian system and affective disorders. The effectiveness of lithium or rubidium as a treatment for affective disorders and the ability of lithium or rubidium to influence circadian pacemakers has stimulated research into the mechanism of lithium's action on circadian systems. In this study we used a neuronal in vitro circadian pacemaker preparation, the eye of the mollusc Bulla, to examine the cellular effects of lithium and rubidium. Continuous extracellular LiCl application lengthens the period of the circadian rhythm of the Bulla pacemaker in a concentration-dependent manner. Rubidium was found to be more effective than lithium in period lengthening. Stable phase delays were generated by 2-h pulses of 395 mM LiCl applied extracellularly from zeitgeber time (ZT) 5-7 (mid subjective day). Concomitant continuous application of 16 mM LiCl and light (a depolarizing agent) generated period lengthening substantially greater than the arithmetic sum of the modest period lengthening of each treatment alone. Furthermore, LiCl pulses, applied together with depolarizing extracellular KCl concentrations, yielded an increasing magnitude of phase delays with increasing KCl concentration. These data suggest that LiCl acts intracellularly on the circadian pacemaker cells by entering through a voltage-dependent channel, most likely a sodium channel.

Animals↗
PubMed1992

Stopping the circadian pacemaker with inhibitors of protein synthesis.

The requirement for protein synthesis in the mechanism of a circadian pacemaker was investigated by using inhibitors of protein synthesis. Continuous treatment of the ocular circadian pacemaker of the mollusc Bulla gouldiana with anisomycin or cycloheximide substantially lengthened (up to 39 and 52 hr, respectively) the free-running period of the rhythm. To determine whether high concentrations of inhibitor could stop the pacemaker, long pulse treatments of various durations (up to 44 hr) were applied and the subsequent phase of the rhythm was assayed. The observed phases of the rhythm after the treatments were a function of the time of the end of the treatment pulse, but only for treatments which spanned subjective dawn. The results provide evidence that protein synthesis is required in a phase-dependent manner for motion of the circadian pacemaker to continue.

Action Potentials↗
PubMed1992

Phase shifting of the circadian rhythm in the eye of Bulla by inhibition of chloride conductance.

Inhibition of Cl- conductance has been previously found to shorten the free-running period of the circadian eye rhythm of the marine snail Bulla gouldiana. In this study, we describe a phase-response curve for 6-h pulses of Cl(-)-free seawater, consisting only of phase advances with the largest in the late subjective night (1.5 h) and smaller phase shifts in the late subjective day. Intracellular recordings revealed that at both circadian times retinal pacemaker neurons hyperpolarized in response to the removal of extracellular chloride. Since previous studies indicate that membrane potential generates both phase advances and delays it seems unlikely that the action of chloride removal is mediated exclusively by the change in membrane potential.

Animals↗
PubMed1992

FMRFamide modulates the action of phase shifting agents on the ocular circadian pacemakers of Aplysia and Bulla.

The eye of the marine mollusk Aplysia californica contains a photo-entrainable circadian pacemaker that drives an overt circadian rhythm of spontaneous compound action potentials in the optic nerve. Both light and serotonin are known to influence the phase of this ocular rhythm. The current study evaluated the effect of FMRFamide on both light and serotonin induced phase shifts of this rhythm. The application of FMRFamide was found to block serotonin induced phase shifts but, by itself, FMRFamide did not cause significant phase shifts. Furthermore, the effects of FMRFamide on light-induced phase shifts appeared to be phase dependent (i.e., the application of FMRFamide inhibited light-induced phase delays but actually enhanced the magnitude of phase advances). As in Aplysia, the eye of Bulla gouldiana also contains a circadian pacemaker. In Bulla, FMRFamide prevented light-induced phase advances and delays. Although FMRFamide alone generated phase dependent phase shifts, it did not cause phase shifts at the phases where it blocked the effects of light. These data demonstrate that FMRFamide can have pronounced modulatory effects on phase shifting inputs to the ocular pacemakers of both Aplysia and Bulla.

Animals↗
PubMed1992

Phase-shifting of a neuronal circadian pacemaker in Bulla gouldiana by pentylenetetrazol.

1. The convulsant agent pentylenetetrazol generates compound action potential activity from the circadian pacemaker cells in the Bulla retina. 2. The phase response curve to 3 hr pulses of pentylenetetrazol consists of only phase delays which occur following pulses delivered in the early subjective night. 3. Phase shifts to pentylenetetrazol are independent of extracellular calcium since they persist in a low-calcium EGTA solution.

Action Potentials↗
PubMed1992

Cellular mechanisms of entrainment.

This review summarizes our current understanding of the signal transduction cascade by which light causes phase shifts of the circadian oscillators found in the eye of Bulla and Aplysia. The isolated retina of these marine mollusks contains a circadian oscillator, a photoreceptor, and a light transduction pathway sufficient for entrainment. This preparation offers unique advantages for the cellular analysis of entrainment and the generation of circadian oscillations. There is evidence that similar cellular mechanisms may underlie mammalian and molluscan circadian oscillations. Thus, the models developed to explain entrainment in the molluscan retina are likely to have utility in exploring the mammalian suprachiasmatic nucleus.

Animals↗
PubMed1991

Does low intracellular pH stop the motion of the Bulla circadian pacemaker?

The eye of the mollusk Bulla has proven itself useful as an in vitro neural circadian pacemaker. Here, we report that treatments applied to lower intracellular pH may stop the motion of this circadian pacemaker in a phase-dependent manner. Lowering the extracellular pH of the artificial seawater bath to 6.9, or application of the stilbene derivatives 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) or 4,4-di-isothiocyanostilbene-2,2'-disulfonic acid (DIDS), abolishes the circadian rhythm in optic nerve compound action-potential frequency. Because these treatments are known to lower intracellular pH, these data suggest that the pacemaker may be inhibited by low intracellular pH. In order to assess the state of the pacemaker during low extracellular pH treatment, pulses of seawater at pH 6.8 were applied, and the phase of the rhythm subsequent to the pulse was observed. All pulses started 1 hr after subjective dusk [circadian time (CT) 13] and were applied to eyes in constant darkness; pulse lengths varied from 4 to 47 hr for different preparations. The phases of the eye rhythms following pulses that ended before subjective dawn (about CT 24) were not different from untreated preparations. However, for pulses longer than 11 hr and therefore ending after subjective dawn, the subsequent phase of the rhythm was a function of the ending time of the pulse. These data suggest that the pacemaker's motion was stopped at dawn during the low-pH treatment and resumed following restoration of normal pH. To distinguish between phase and duration dependence of this effect in the above experiment, phase shifts were obtained to 14-hr pulses of pH 6.8 seawater applied at three different phases.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1990

Chloride conductance contributes to period determination of a neuronal circadian pacemaker.

The isolated eye of Bulla gouldiana, a marine mollusc, is a circadian pacemaker. Previous studies have shown that membrane potential changes of neurons at the base of the Bulla retina play a critical role in the expression of the circadian rhythm and that the free-running period can be modified by chronic alteration of the resting membrane potential. We now report that treatments which inhibit CI- conductance shorten the free-running period. Substitution of CI- with the anions SO4(2-), isethionate and glutamate significantly shorten the period of the ocular rhythm in vitro. Furthermore, addition of the CI- channel blocker 9-anthracene-carboxylic acid (9-AC) is also effective at shortening the period of the circadian rhythm. These data suggest that a CI- conductance participates in determining the free-running period of the circadian pacemaker cells. This is the first report of CI- conductance involvement in a circadian system and the effect is remarkable in that few treatments are known which reliably shorten the period of circadian clocks.

Animals↗