Managed care and medication compliance: implications for chronic depression

Syrian hamsters, Mesocricetus auratus, were confined to novel running wheels for a 3-h period, starting at approximately circadian time (CT) 4.5 (i.e., approaching the middle of their subjective day). It can be reliably predicted from the amount of running in this situation whether or not there will be a subsequent phase-shift. Expression of the immediate early genes c-fos and fosB was examined by immunocytochemistry in the suprachiasmatic nucleus (SCN), the intergeniculate leaflet (IGL) of the thalamus, and the medial pretectal area of hamsters that ran vigorously in the novel wheel and would have phase-shifted. c-Fos was increased, compared to levels in a control group left in their home cages, in the IGL, and the pretectum (PT), but decreased in the SCN. No significant changes in FosB were detected in any region examined. An additional experiment argued against the possibility that the changes in c-Fos could be attributed to a rapid advance of the pacemaker to a different phase in the circadian cycle. Counts of c-Fos-positive cells in the IGL were similar in animals given pulses of running starting at CT 4.5 and starting at CT 12.5-16 (i.e., in the subjective night when they would have been active anyway). Altogether the results support the view that activation of the IGL is important in nonphotic clock resetting, and raise the possibility that the PT may also be involved in nonphotic resetting. However, the results also indicate that novelty-induced running does not alter c-Fos induction in a phase-specific manner in the IGL. The inhibition of c-Fos in the SCN by nonphotic phase-shifting events contrasts with the well-known inducing effects of light pulses. These different effects might underlie some of the interactions between nonphotic and photic zeitgebers when both act together on the circadian system.     

Reward and Aversive Stimuli Produce Similar Nonphotic Phase Shifts.

Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patterns of entrainment. To examine whether the motivational significance of a stimulus is important for eliciting nonphotic circadian phase shirts in Syrian hamsters (Mesocricetus auratus), the authors compared responses to a highly rewarding stimulus (lateral hypothalamic brain stimulation reward [BSR]) and a highly aversive stimulus (footshock). Animals were housed on a 14:10-hr light-dark cycle until test day, when they were given a 1-hr BSR session (trained animals) or a 1-mA electric footshock at 1 of 8 circadian times, and were maintained in constant dark thereafter. Both BSR pulses and footshock produced nonphotic phase response curves. These results support the hypothesis that arousal resulting from the motivational significance of a stimulus is a major factor in nonphotic phase shifts. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory bulbectomy impedes social but not photic reentrainment of circadian rhythms in female Octodon degus

Recent studies demonstrated that nonphotic (social) cues markedly accelerate reentrainment to large phase shifts of the light-dark (LD) cycles in female Octodon degus and that such changes are likely effected by chemosensory stimuli. This experiment investigated the effects of olfactory bulbectomies on (1) socially facilitated reentrainment rates of circadian rhythms following a 6-h phase advance of the LD cycle, (2) photic reentrainment rates of circadian rhythms following a 6-h advance of the LD cycle, (3) photic entrainment, and (4) the circadian period (tau) of activity rhythms in constant darkness (DD). olfactory bulbectomies (BX) blocked socially facilitated reentrainment rates but did not alter reentrainment rates of circadian rhythms to photic cues alone. In addition, BX lowered mean daily locomotor activity levels and decreased the amplitude of the activity rhythm in degus housed in entrained (LD 12:12) conditions but did not alter the phase of activity onset or offset, duration (alpha) of activity, or mean daily core body temperature. Bulbectomies also failed to modify tau of free-running activity rhythms. This experiment confirms that the olfactory bulbs and chemosensory cues are necessary for socially facilitated reentrainment. In contrast to their effects in nocturnal rodents, BX do not produce significant circadian photic changes in diurnal degus. This is the first experiment to determine that chemosensory stimuli modulate the circadian system in a diurnal rodent.     

Roles of suprachiasmatic nuclei and intergeniculate leaflets in mediating the phase-shifting effects of a serotonergic agonist and their photic modulation during subjective day

Serotonin (5-HT) has been implicated in the phase adjustment of the circadian system during the subjective day in response to nonphotic stimuli. Two components of the circadian system, the suprachiasmatic nucleus (SCN) (site of the circadian clock) and the intergeniculate leaflet (IGL), receive serotonergic projections from the median raphe nucleus and the dorsal raphe nucleus, respectively. Experiment 1, performed in golden hamsters housed in constant darkness, compared the effects of bilateral microinjections of the 5-HT1A/7 receptor agonist, 8-hydroxydipropylaminotetralin (8-OH-DPAT; 0.5 microgram in 0.2 microliter saline per side), into the IGL or the SCN during the mid-subjective day. Bilateral 8-OH-DPAT injections into either the SCN or the IGL led to significant phase advances of the circadian rhythm of wheel-running activity (p < .001). The phase advances following 8-OH-DPAT injections in the IGL were dose department (p < .001). Because a light pulse administered during the middle of the subjective day can attenuate the phase-resetting effect of a systemic injection of 8-OH-DPAT, Experiment 2 was designed to determine whether light could modulate 5-HT agonist activity at the level of the SCN and/or the IGL. Serotonergic receptor activation within the SCN, followed by a pulse of light (300 lux of white light lasting 30 min), still induced phase advances. In contrast, the effect of serotonergic stimulation within the IGL was blocked by a light pulse. These results indicate that the respective 5-HT projections to the SCN and IGL subserve different functions in the circadian responses to photic and nonphotic stimuli.     

Staphylococcal culture supernates stimulate human phagocytes

c-fos induction was investigated as a potential component in the avian photic entrainment pathway and as a possible means of locating the central pacemaker in birds. In both quail (Coturnix coturnix japonica) and starlings (Sturnus vulgaris) exposure to 1 h of light induced Fos-lir in the visual suprachiasmatic nucleus but not in the medial suprachiasmatic nucleus. However, the degree of c-fos induction in the visual suprachiasmatic nucleus was similar at different circadian times despite the fact that the light pulses caused differential phase shifts in the locomotor rhythm. For golden hamsters the same experiment resulted in significantly different levels of Fos-lir in the suprachiasmatic nucleus, as well as different phase shifts. Starlings and hamsters were also entrained to T-cycles that caused a large daily phase shift (T = 21.5 h in starlings, T = 22.67 hours in hamsters), or no daily phase shift (T = free running period). No difference in the induced levels of Fos-lir in the visual suprachiasmatic nucleus region was observed between the two groups of starlings, but in hamsters there were significantly different levels of Fos-lir in the suprachiasmatic nucleus between the two groups.     

Destruction of serotonergic neurons in the median raphe nucleus blocks circadian rhythm phase shifts to triazolam but not to novel wheel access

Systematic treatment of hamsters with triazolam (TRZ) or novel wheel (NW) access will yield PRCs similar to those for neuropeptide Y. Both TRZ and NW access require an intact intergeniculate leaflet (IGL) to modulate circadian rhythm phase. It is commonly suggested that both stimulus types influence rhythm phase response via a mechanism associated with drug-induced or wheel access-associated locomotion. Furthermore, there have been suggestions that one or both of these stimulus conditions require an intact serotonergic system for modulation of rhythm phase. The present study investigated these issues by making serotonin neuron-specific neurotoxic lesions of the median or dorsal raphe nuclei and evaluating phase response of the hamster circadian locomotor rhythm to TRZ treatment or NW access. The expected effect of TRZ injected at CT 6 h on the average phase advance was virtually eliminated by destruction of serotonin neurons in the median, but not the dorsal, raphe nucleus. No control or lesioned animal engaged in substantial wheel running in response to TRZ. By contrast, all median raphe-lesioned hamsters that engaged in substantial amounts of running when given access to a NW had phase shifts comparable to control or dorsal raphe-lesioned animals. The results demonstrate that serotonergic neurons in the median raphe nucleus contribute to the regulation of rhythm phase response to TRZ and that it is unlikely that these neurons are necessary for phase response to NW access. The data further suggest the presence of separate pathways mediating phase response to the two stimulus conditions. These pathways converge on the IGL, a nucleus afferent to the circadian clock, that is necessary for the expression of phase response to each stimulus type.     

The "seat belt mark" sign: a call for increased vigilance among physicians treating victims of motor vehicle accidents

The light-induced phase-resetting response of the locomotor activity rhythm in the field mouse Mus booduga was studied at two phases of the circadian cycle known to respond to light stimuli of 15 min duration and 1000 lux intensity with maximum advance (at circadian time 20 [CT20]) and maximum delay phase-shifts (at CT15). The phase-shifts evoked by natural daylight stimuli of various illuminations ranging between 0.001 lux and 10,000 lux and lasting 15 min were estimated. The results clearly demonstrate that the relationship between the phase-shifts and the intensities of light stimuli is nonlinear. Furthermore, a single light stimulus of 0.001 lux, or 0.1 lux intensity for a duration of 15 min, administered at CT20, evoked unequivocal responses; phase delays were observed instead of phase advances. The critical intensities needed for light stimuli of 15 min duration to induce saturating response were calculated and were found to be about 100 lux for CT20 and about 500 lux for CT15. These results suggest that a greater intensity of light is required at the phase CT15 to induce a saturating phase shift than is required at a later phase of the circadian cycle (CT20).     

Genetic resistance to parasitic infection

Intraventricular administration of carbachol can induce phase shifts in wheel-running activity in rodents, which depend on circadian phase and are mediated via muscarinic cholinergic receptors in Syrian hamsters. We studied the circadian variation in binding of [3H]-N-methylscopolamine ([3H]NMS), a hydrophilic muscarinic receptor antagonist, in micropunches obtained from the anterior hypothalamus and occipital cortex of Syrian hamsters housed in a 14:10 light:dark cycle. Binding sites were characterized on cells contained within 1 mm punches (obtained from slices 300 microm thick), using a method to selectively detect cell surface (functional) receptors. Atropine sulphate was used to determine nonspecific binding. Cortex showed a significant daily rhythm in [3H]NMS binding with a peak occurring late in the light phase and a trough at lights on, while the hypothalamus showed no detectable rhythm. Following suprachiasmatic nucleus (SCN) ablation or maintenance in constant darkness, the rhythm in the cortex was abolished. These findings suggest that photic information conveyed via the SCN is responsible for the receptor binding rhythm in the cortex. Autoradiographic studies ([3H]NMS; 2 nM, 3 weeks exposure) clearly revealed both M1 and M2 subtypes of muscarinic receptors in the region of the SCN and the visual cortex.     

Conditioned stimulus control in the rat circadian system depends on clock resetting during conditioning.

The authors examined the ability of a conditioned stimulus (CS; mild air disturbance) previously paired with an entraining light pulse to reset the circadian pacemaker in rats. Rats were entrained to a single 30-min light stimulus delivered every 25 hr or 24 hr (T cycle). Each daily light presentation was paired with the CS. After at least 20 days of stable entrainment to each of the T cycles, the rats were allowed to free run and were then presented with the CS at circadian time 15. CS-induced phase shifts in wheel-running activity rhythms were taken as evidence for conditioning. For the most part, conditioning occurred after CS-light pairings on the 25-hr but not 24-hr T cycle. The results suggest that CS control of the circadian clock phase depends on the effect that the entraining light pulse has on the clock during conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Atherosclerosis in the human brachial artery

The hypothalamic suprachiasmatic nucleus (SCN) of the mammal is the circadian pacemaker responsible for generation of circadian rhythms. Several immediate-early genes are expressed in the SCN by light stimuli which induce phase shifts of animal activity rhythms. In the present study, we investigated whether Homer, a PDZ-like protein which is rapidly induced following synaptic activation, mRNA expression is regulated by light in rat SCN. Homer mRNA expression in the SCN of rat killed at 4 h after onset of the light and dark phases was very low. One hour light stimuli during the subjective night dramatically induced Homer mRNA expression in the ventrolateral portion of the SCN, whereas light stimuli during the subjective light phase did not. This finding implies that Homer may be involved in the photic entrainment of the circadian clock.     

Circadian rhythms in cultured mammalian retina

Many retinal functions are circadian, but in most instances the location of the clock that drives the rhythm is not known. Cultured neural retinas of the golden hamster (Mesocricetus auratus) exhibited circadian rhythms of melatonin synthesis for at least 5 days at 27 degrees celsius. The rhythms were entrained by light cycles applied in vitro and were free-running in constant darkness. Retinas from hamsters homozygous for the circadian mutation tau, which shortens the free-running period of the circadian activity rhythm by 4 hours, showed a shortened free-running period of melatonin synthesis. The mammalian retina contains a genetically programmed circadian oscillator that regulates its synthesis of melatonin.     

The tau mutation affects temperature compensation of hamster retinal circadian oscillators

Neural retinas of the golden hamster (Mesocricetus auratus) express circadian rhythms of melatonin synthesis when cultured in constant darkness. Retinas from wild-type hamsters synthesize melatonin with a period close to 24 h, while retinas obtained from hamsters homozygous for the circadian mutation tau, which shortens the free-running period of the circadian activity rhythm by 4 h, synthesize melatonin with a period close to 20 h. The retinal circadian oscillators of both wild-type and tau mutant hamsters are temperature compensated; however, temperature compensation is adversely affected by the mutation.     

Phase control of ultradian feeding rhythms in the common vole (Microtus arvalis): the roles of light and the circadian system

In their ultradian (2- to 3-hr) feeding rhythm, common voles show intraindividual synchrony from day to day, as well as interindividual synchrony between members of the population, even at remote distances. This study addresses the question of how resetting of the ultradian rhythm, a prerequisite for such synchronization, is achieved. Common voles were subjected to short light-dark cycles (1 hr darkness with light varying between 0.7 and 2.5 hr); to T cycles (long light-dark cycles in the circadian range--16 hr darkness and 3-13 hr light); to light pulses (15 min) during different circadian and ultradian phases; and to addition of D2O to the drinking water (25%). Short light-dark cycles and D2O were also applied to voles without circadian rhythmicity, after lesions of the suprachiasmatic nuclei. In these experiments, four hypotheses on synchronization of ultradian rhythmicity were tested: (I) synchronization by a direct response to light; (II) synchronization via the circadian system with multiple triggers, here called "cogs," each controlling a single ultradian feeding bout; and (III and IV) synchronization via the circadian system with a single "cog," which resets an ultradian oscillator and either (III) originates directly from the circadian pacemaker, or (IV) is mediated via the overt circadian activity rhythm. Short light-dark cycles failed to entrain ultradian rhythms, either in circadian-rhythmic or in non-circadian-rhythmic voles; light pulses did not cause phase shifts; and in extreme T cycles no stable phase relationship with light could be demonstrated. Thus, Hypothesis I was rejected. Changes in the circadian period (tau) were generated as aftereffects of light pulses, by entrainment in various T cycles, and by the addition of D2O to the drinking water. These changes in tau did not lead to parallel, let alone proportional, changes in the ultradian period. This excluded Hypothesis II. Both in T-cycle experiments and in the D2O experiments with circadian-rhythmic voles, the phase of ultradian feeding bouts was locked to the end of circadian activity rather than to the most prominent marker of the pacemaker, the onset of circadian activity. This was not expected under Hypothesis III, but was consistent with entrainment via activity (Hypothesis IV). On the basis of these experiments, we conclude that the most likely mechanism of ultradian entrainment is that of a light-insensitive ultradian oscillator, reset every dawn by the termination of the activity phase controlled by the circadian pacemaker, which is itself entrained by the light-dark cycle. Neither in circadian-rhythmic nor in non-circadian-rhythmic voles was the period of the feeding rhythm lengthened by administration of D2O. This insensitivity to deuterium is exceptional among biological rhythms.     

Renal ischemia-reperfusion injury: contribution of nitric oxide and renal blood flow

In nocturnal rodents, the c-fos gene is directly involved in the light mechanism of resetting of the suprachiasmatic nucleus (circadian clock). Light also induces c-fos expression in the retinal ganglion cell layer (GCL), but no attempt has been made to study the retinal responses to the phase-shifting effects of light. The expression of the Fos protein in each of the two populations of the GCL (displaced amacrine cells [DACs] and ganglion cells [GCs]) was analyzed in hamsters after light stimulation delivered early (circadian time [CT13]) and in the middle (CT18) of the subjective night. To evaluate as accurately as possible the number of GCs able to phase shift the locomotor activity rhythm (LAR), neonatal hamsters treated with monosodium glutamate (MSG) were also used, an in vivo model which displays retinal degeneration and LAR normally entrained by light. In nontreated hamsters, the number of Fos-immunoreactive (Fos-ir+) nuclei in the GCL was significantly higher at CT18 than at CT13. In MSG-treated hamsters, the number of Fos-ir+ nuclei was the same at both CTs and nonsignificantly different as those of nontreated hamsters at CT13. MSG treatment destroyed as many Fos-ir+ DACs as Fos-ir- DACs or Fos-ir+ GCs. Fos-ir+ GCs were less sensitive to neurotoxic than other GCs, as only 37% of them were destroyed by treatment versus 92% for Fos-ir- GCs. At CT18, a maximum of 3,500 GCs expressed Fos protein in nontreated hamsters versus only 2,200 in MSG-treated hamsters. This minor subgroup was sufficiently potent to normally synchronize the circadian rhythms to the Light/dark cycle in treated hamsters.     

Nonphotically induced phase shifts of circadian rhythms in the golden hamster: activity-response curves at different ambient temperatures

Running in a novel wheel during the subjective day can shift the circadian activity rhythm of a hamster. The amount of running is thought to be an important variable. We generated a dose-response (activity-phase shift) curve for the amount of wheel running during a 3 h period starting 8 h before normal dark onset in a 14:10 LD cycle. At room temperature (23 degrees C) the relationship was sigmoidal: from 0 to 4000 revolutions resulted in minimal phase advances (up to 50 min). From 4000 to 5000 revolutions the magnitude of the advances increased sharply, and above 5000 revolutions phase advances were asymptotic at about 3 h. The same general relationship held when hamsters were stimulated to be more active in the novel wheel by lowering the ambient temperature to either 11 degrees C or 6 degrees C. However, at these lower temperatures, a significant number of animals did not shift more than the minimal amount of 50 min even though they ran more than 5000 revolutions. This indicates that running per se in a novel wheel was not sufficient to induce phase shifts. Possibly, at room temperature, the amount of wheel running reflects a particular motivational state produced by the rewarding nature of wheel running, although at low ambient temperatures at least some individuals run primarily to meet thermoregulatory needs.     

Reentrainment of motor activity and spontaneous neuronal activity in the suprachiasmatic nucleus of Djungarian hamsters

Neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus exhibit a daily rhythm in spontaneous electrical activity. Essentially two methods have been employed to record this circadian rhythm: (1) an in vitro brain slice technique and (2) in vivo multiunit recordings. Reentrainment of a circadian output to a shifted light:dark cycle commonly takes several cycles (depending on the amount of shift) until completed. Such a resetting kinetic has also been shown to be valid for SCN electrical activity if recorded in vivo. In an in vitro slice preparation, however, pharmacologically induced resetting is much faster and lacks transients; that is, a shift is completed within one cycle. This study was designed to probe for the presence of transients in the neuronal activity of the SCN in a brain slice preparation. The authors exposed Djungarian hamsters to an 8-h advanced or delayed light:dark cycle and monitored wheel-running activity during reentrainment. Additional groups of identically treated hamsters were used to record the pattern of spontaneous neuronal activity within the SCN using the brain slice preparation. Neuronal activity exhibited the usual rhythm with high firing rates during the projected day and low firing rates during the projected night. However, following 1 day of exposure to the 8-h advanced light:dark cycle, this rhythm disappeared in 6 of 7 slices. Rhythmicity was still absent following 3 days of exposure to the advanced light:dark cycle (n = 4). By contrast, 3 of 7 slices prepared from hamsters exposed to a delayed light:dark cycle for 3 days exhibited a daily rhythm in electrical activity. Although pharmacological agents reset the in vitro SCN neuronal activity almost instantaneously and in in vivo studies a stable phase relationship to a shifted light:dark cycle occurs gradually over several cycles, the authors did not detect either of these patterns. Such differences in resetting kinetics (e.g., rapid resetting, gradual reentrainment, temporary lack of measurable rhythmicity) may be due to (a) application of a resetting stimulus in vivo versus in vitro, (b) duration of the resetting stimulus, (c) the nature of the resetting stimulus, or (d) the recording technique employed.     

The role of the intergeniculate leaflet in entrainment of circadian rhythms to a skeleton photoperiod

Mammalian circadian rhythms are synchronized to environmental light/dark (LD) cycles via daily phase resetting of the circadian clock in the suprachiasmatic nucleus (SCN). Photic information is transmitted to the SCN directly from the retina via the retinohypothalamic tract (RHT) and indirectly from the retinorecipient intergeniculate leaflet (IGL) via the geniculohypothalamic tract (GHT). The RHT is thought to be both necessary and sufficient for photic entrainment to standard laboratory light/dark cycles. An obligatory role for the IGL-GHT in photic entrainment has not been demonstrated. Here we show that the IGL is necessary for entrainment of circadian rhythms to a skeleton photoperiod (SPP), an ecologically relevant lighting schedule congruous with light sampling behavior in nocturnal rodents. Rats with bilateral electrolytic IGL lesions entrained normally to lighting cycles consisting of 12 hr of light followed by 12 hr of darkness, but exhibited free-running rhythms when housed under an SPP consisting of two 1 hr light pulses given at times corresponding to dusk and dawn. Despite IGL lesions and other damage to the visual system, the SCN displayed normal sensitivity to the entraining light, as assessed by light-induced Fos immunoreactivity. In addition, all IGL-lesioned, free-running rats showed masking of the body temperature rhythm during the SPP light pulses. These results show that the integrity of the IGL is necessary for entrainment of circadian rhythms to a lighting schedule like that experienced by nocturnal rodents in the natural environment.     

Circadian patterns of locomotor activity and body temperature in blind mole-rats, Spalax ehrenbergi

A wide variety of organisms exhibit circadian rhythms, regulated by internal clocks that are entrained primarily by the alternating cycle of light and darkness. There have been few studies of circadian rhythms in fossorial species that inhabit a microenvironment where day-night variations in most environmental parameters are minimized and where exposure to light occurs only infrequently. In this study, daily patterns of locomotor activity and body temperature (Tb) were examined in adult blind mole-rats (Spalax ehrenbergi). These fossorial rodents lack external eyes but possess rudimentary ocular structures that are embedded in the Harderian glands and covered by skin and fur. Most individual mole-rats exhibited circadian rhythms of locomotor activity, but some animals were arrhythmic. Individuals that did exhibit robust rhythms of locomotor activity also showed rhythms of Tb. In most cases, Tb was highest during the phase of intense locomotor activity. Locomotor activity rhythms could be entrained to light:dark cycles, and several mole-rats exhibited entrainment to non-24-h light cycles (T-cycles) with period lengths ranging from T = 23 h to T = 25 h. Some individuals also showed entrainment to daily cycles of ambient temperature. There was considerable interindividual variation in the daily patterns of locomotor activity among mole-rats in virtually all the conditions of environmental lighting and temperature employed in this study. Thus, whereas it appears likely that photic cues have a significant role in the entrainment of circadian rhythms in mole-rats, the amount of variability in rhythm patterns among individuals appears to be much greater than for most species that have been studied.     

Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2

Traditional T2-based imaging techniques are geared toward imaging long-T2 species. Traditional techniques are, therefore, not optimal in clinical situations where the information of interest lies in the short-T2 species. T2-selective RF excitation (TELEX) is a technique for obtaining a T2-based contrast that highlights short-T2 values while suppressing long-T2 values-opposite to traditional T2 contrast. Previously, TELEX has been demonstrated qualitatively to highlight only very short-T2 values (T2 approximately 0.001 s). When applied to longer T2 values (T2 > or = 0.01 s), TELEX becomes sensitive to deltaB0 non-uniformities. This restricts its application to problems in which the T2 of interest is very short. In this study, TELEX is characterized quantitatively. Furthermore, a bandwidth broadening scheme is developed that reduces the deltaB0 sensitivity of TELEX. This permits the technique to be applied to longer T2 values. The capabilities and limitations of a practical implementation of TELEX are discussed.