The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip study.

Previous studies have demonstrated that macromolecular synthesis in the brain is modulated in association with the occurrence of sleep and wakefulness. Similarly, the spectral composition of electroencephalographic activity that occurs during sleep is dependent on the duration of prior wakefulness. Since this homeostatic relationship between wake and sleep is highly conserved across mammalian species, genes that are truly involved in the electroencephalographic response to sleep deprivation might be expected to be conserved across mammalian species. Therefore, in the rat cerebral cortex, we have studied the effects of sleep deprivation on the expression of immediate early gene and heat shock protein mRNAs previously shown to be upregulated in the mouse brain in sleep deprivation and in recovery sleep after sleep deprivation. We find that the molecular response to sleep deprivation and recovery sleep in the brain is highly conserved between these two mammalian species, at least in terms of expression of immediate early gene and heat shock protein family members. Using Affymetrix Neurobiology U34 GeneChips , we also screened the rat cerebral cortex, basal forebrain, and hypothalamus for other genes whose expression may be modulated by sleep deprivation or recovery sleep. We find that the response of the basal forebrain to sleep deprivation is more similar to that of the cerebral cortex than to the hypothalamus. Together, these results suggest that sleep-dependent changes in gene expression in the cerebral cortex are similar across rodent species and therefore may underlie sleep history-dependent changes in sleep electroencephalographic activity.

Circadian and homeostatic control of rapid eye movement (REM) sleep: promotion of REM tendency by the suprachiasmatic nucleus.

The daily timing of rapid eye movement (REM) sleep reflects an interaction between the circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus (SCN) and a homeostatic process that induces compensatory REM sleep in response to REM sleep loss. Whether the circadian variation in REM sleep propensity is caused by active promotion, inhibition, or passive gating of REM sleep homeostasis by the SCN is unknown. To investigate these possibilities, compensatory responses to 24 hr REM sleep deprivation (RSD) were compared between SCN-lesioned (SCNx) and sham-lesioned rats at different times of day in constant dark. The attempts to enter REM sleep (REM tendency) increased during RSD in all rats and were modulated by circadian phase in sham-lesioned, but not SCNx rats. REM sleep homeostasis interacted with circadian time, such that REM tendency doubled during the rest phase in sham-lesioned rats relative to SCNx rats (F((6,93)) = 17.9; p = 0.0001). However, REM tendency was indistinguishable between SCNx and sham-lesioned rats during the activity phase, suggesting the SCN does not inhibit REM tendency at this time. By contrast, the amount of compensatory REM sleep examined 2, 6, 12, or 24 hr after RSD did not depend on circadian phase. Thus, transitions into REM sleep are facilitated by the SCN during the rest phase, but the amount of REM sleep, once initiated, is determined primarily by homeostatic mechanisms. This work supports a role for the SCN in the active promotion of REM sleep at specific times of day.

Dopaminergic role in stimulant-induced wakefulness.

The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.

Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer's disease: a role for cholinergic transmission.

The Tg2576 mouse model of Alzheimer's disease (AD) exhibits age-dependent amyloid beta (Abeta) deposition in the brain. We studied electroencephalographically defined sleep and the circadian regulation of waking activities in Tg2576 mice to determine whether these animals exhibit sleep abnormalities akin to those in AD. In Tg2576 mice at all ages studied, the circadian period of wheel running rhythms in constant darkness was significantly longer than that of wild type mice. In addition, the increase in electroencephalographic delta (1-4 Hz) power that occurs during non-rapid eye movement sleep after sleep deprivation was blunted in Tg2576 mice relative to controls at all ages studied. Electroencephalographic power during non-rapid eye movement sleep was shifted to higher frequencies in plaque-bearing mice relative to controls. The wake-promoting efficacy of the acetylcholinesterase inhibitor donepezil was lower in plaque-bearing Tg2576 mice than in controls. Sleep abnormalities in Tg2576 mice may be due in part to a cholinergic deficit in these mice. At 22 months of age, two additional deficits emerged in female Tg2576 mice: time of day-dependent modulation of sleep was blunted relative to controls and rapid eye movement sleep as a percentage of time was lower in Tg2576 than in wild type controls. The rapid eye movement sleep deficit in 22 month-old female Tg2576 mice was abolished by brief passive immunization with an N-terminal antibody to Abeta. The Tg2576 model provides a uniquely powerful tool for studies on the pathophysiology of and treatments for sleep deficits and associated cholinergic abnormalities in AD.

Scheduled voluntary wheel running activity modulates free-running circadian body temperature rhythms in Octodon degus.

Entrainment of the circadian pacemaker to nonphotic stimuli, such as scheduled wheel-running activity, is well characterized in nocturnal rodents, but little is known about activity-dependent entrainment in diurnal or crepuscular species. In the present study, effects of scheduled voluntary wheel-running activity on circadian timekeeping were investigated in Octodon degus, a hystricomorph rodent that exhibits robust crepuscular patterns of wakefulness. When housed in constant darkness, O. degus exhibited circadian rhythms in wheel-running activity and body temperature (Tb) with an average period length (tau) of 23.39 +/- 0.11 h. When wheel running was restricted to a fixed 2-h schedule every 24 h, tau increased on average 0.39 +/- 0.09 h but did not result in steady-state entrainment. Instead, relative coordination between the fixed running schedule and circadian timing was observed. Tau was greatest when scheduled wheel running occurred at CT 20.5 (0.4 h greater than DD baseline tau). Scheduled running activity also influenced Tb waveform symmetry, reflecting concomitant changes in the circadian activity-rest ratio (alpha:rho). Aftereffects of the scheduled wheel-running paradigm were also observed. In 2 animals, tau lengthened from 23.20 and 23.80 h to 24.14 and 24.15 h, respectively, and remained relatively stable for approximately 1 month during the wheel schedule. Although behavioral activity appears to be a weak zeitgeber in this species, these data suggest that nonphotic stimuli can phase delay the circadian pacemaker in O. degus at similar times of the day as in nocturnal hamsters and mice, and in humans.

Crepuscular rhythms of EEG sleep-wake in a hystricomorph rodent, Octodon degus.

Sleep-wake circadian rhythms are well documented for nocturnal rodents, but little is known about sleep regulation in diurnal or crepuscular rodent species. This study examined the circadian sleep-wake rhythms in Octodon degus by means of electroencephalogram (EEG) analysis. Recordings were made from animals housed with or without running wheels in the cages. In a 24-h light-dark (LD) cycle (LD 12:12), sleep and wake patterns were highly fragmented under both conditions except for crepuscular timed episodes of waking. Without running wheels, sleep bout lengths averaged 3.7 +/- 0.1 min, and total sleep time was 37.6 +/- 3.7% per 24 h. Although the percentage of total wakefulness was similar during the light phase (63.4 +/- 2.4%) and dark phase (61.5 +/- 2.8%), measures of locomotor activity (LMA) and body temperature were generally greater during the day than during the night. Without running wheels, EEG slow wave activity (SWA) in nonrapid eye movement (NREM) sleep exhibited a circadian waveform that was elevated only during the light phase. SWA peaked at Zeitgeber Time 7 (ZT 7) (several hours after the dominant waking episode at ZT 23), then declined across the later half of the light phase and into the dark phase. Voluntary wheel running did not alter daily total sleep time, the duration of average sleep bouts, or maximum sleep bouts, but it increased the episode of waking, LMA, and body temperature at ZTs 11-12. Under these conditions, NREM sleep and SWA exhibited crepuscular patterns, with elevated SWA during the day and night. Although Octodon degus exhibited no strong preference for sleep during the light or dark phase, these data suggest that in this species homeostatic sleep responses (indicated by SWA) are gated by the dominant crepuscular episode(s) of waking and can be influenced by wheel running.

Activity feedback to the mammalian circadian pacemaker: influence on observed measures of rhythm period length.

In the mouse, activity is precisely timed by the circadian clock and is normally most intense in the early subjective night. Since vigorous activity (e.g., wheel running) is thought to induce phase shifts in rodents, the temporal placement of daily exercise/activity could be a determinant of observed circadian rhythm period. The relationship between spontaneous running-wheel activity and the circadian period of free-running rhythms was studied to assess this possibility. With ad libitum access to a running wheel, mice exhibited a free-running period (tau) of 23.43 +/- 0.08 hr (mean +/- SEM). When running wheels were locked, tau increased (23.88 +/- 0.04 hr, p less than 0.03), and restoration of ad libitum wheel running again produced a shorter period (tau = 23.56 +/- 0.06 hr, p less than 0.05). A survey of free-running activity patterns in a population of 100 mice revealed a significant correlation between the observed circadian period and the time of day in which spontaneous wheel running occurred (r = 0.7314, p less than 0.0001). Significantly shorter periods were observed when running was concentrated at the beginning of the subjective night (tau = 23.23 +/- 0.04), and longer periods were observed if mice ran late in the subjective night (tau = 23.89 +/- 0.04), F (1, 99) = 34.96, p less than 0.0001. It was previously believed that the period of the circadian clock was primarily responsive to externally imposed tonic or phasic events. Systematic influences of spontaneous exercise on tau demonstrate that physiological and/or behavioral determinants of circadian timekeeping exist as well.

Serotonin and the mammalian circadian system: I. In vitro phase shifts by serotonergic agonists and antagonists.

The primary mammalian circadian clock, located in the suprachiasmatic nuclei (SCN), receives a major input from the raphe nuclei. The role of this input is largely unknown, and is the focus of this research. The SCN clock survives in vitro, where it produces a 24-hr rhythm in spontaneous neuronal activity that is sustained for at least three cycles. The sensitivity of the SCN clock to drugs can therefore be tested in vitro by determining whether various compounds alter the phase of this rhythm. We have previously shown that the nonspecific serotonin (5-HT) agonist quipazine resets the SCN clock in vitro, inducing phase advances in the daytime and phase delays at night. These results suggest that the 5-HT-ergic input from the raphe nuclei can modulate the phase of the SCN circadian clock. In this study we began by using autoradiography to determine that the SCN contain abundant 5-HT1A and 5-HT1B receptors, very few 5-HT1C and 5-HT2 receptors, and no 5-HT3 receptors. Next we investigated the ability of 5-HT-ergic agonists and antagonists to reset the clock in vitro, in order to determine what type or types of 5-HT receptor(s) are functionally linked to the SCN clock. We began by providing further evidence of 5-HT-ergic effects in the SCN. We found that 5-HT mimicked the effects of quipazine, whereas the nonspecific 5-HT antagonist metergoline blocked these effects, in both the day and night. Next we found that the 5-HT1A agonist 8-OH-DPAT, and to a lesser extent the 5-HT1A-1B agonist RU 24969, mimicked the effects of quipazine during the subjective daytime, whereas the 5-HT1A antagonist NAN-190 blocked quipazine's effects. None of the other specific agonists or antagonists we tried induced similar effects. This suggests that quipazine acts on 5-HT1A receptors in the daytime to advance the SCN clock. None of the specific agents we tried were able either to mimic or to block the actions of 5-HT or quipazine at circadian time 15. Thus, we were unable to determine the type of 5-HT receptor involved in nighttime phase delays by quipazine or 5-HT. However, since the dose-response curves for quipazine during the day and night are virtually identical, we hypothesize that the nighttime 5-HT receptor is a 5-HT1-like receptor.

Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists.

The suprachiasmatic nuclei (SCN) receive primary afferents from the median and dorsal raphe, but the role of these projections in circadian timekeeping is poorly understood. Studies of the SCN in vitro suggest that quipazine, a general serotonin (5-HT) receptor agonist, can produce circadian time-dependent phase advances and phase delays in circadian rhythms of neuronal activity. The present study addresses whether quipazine and the selective 5-HT1A receptor agonist 8-OH-DPAT are similarly effective in vivo. Drinking and wheel-running patterns of male Wistar rats individually housed in constant darkness were monitored before and after subcutaneous administration of quipazine (5-10 mg/kg) at either circadian time (CT) 6 or CT 18, with and without running wheels available. Dose-dependent phase advances (20-180 min) were produced at CT 6. Significant phase shifts were not observed at CT 18. CT 6 quipazine-treated animals also showed a sustained and significant shortening of rhythm period (tau) following treatment (-0.28 hr; p < 0.002). tau shortening was inconsistently observed in CT 18 quipazine-treated rats. Neither quipazine-induced phase shifts nor tau effects were dependent on wheel-running activity per se. 8-OH-DPAT delivered via intracerebral ventricular treatment into the third ventricle (5 microliters at 100 microM in saline) produced slightly smaller phase advances (20-90 min) at CT 6, but did not produce phase delays at CT 18 or changes in tau. These findings support in vitro evidence that 5-HT-ergic agonists can phase-shift the circadian pacemaker.

Biological rhythmicity in preterm infants prior to discharge from neonatal intensive care.

OBJECTIVE: The study of biological rhythms and the influence of environmental factors in the timing and synchronization of different rhythmic events have important implications for neonatal health. Preterm infants in the neonatal intensive care unit (NICU) are deprived of the patterned influences of maternal sleep, temperature, heart rate, and hormonal cycles. The impact of the NICU and nursing interventions on the development of the circadian system was studied in 17 stable preterm infants in the Intermediate Intensive Care Nursery at Stanford University for three consecutive days at about 35 weeks postconceptional age. OUTCOME MEASUREMENTS: Rectal temperature, abdominal skin temperature, heart rate, and activity were simultaneously recorded at 2-minute intervals during each 3-day study by a small microcomputer (Vitalog). RESULTS: Very low amplitude circadian rhythms were found for rectal and skin temperatures (maximum range 36.8 to 37.0 degrees C); population mean values for heart rate (158 bpm) and activity (3.5 counts per 2-min bin) did not differ significantly as a function of time of day. Rectal temperature, averaged in 6-hour bins over the 24-hour day as a function of both postconceptional age and postnatal age, was significantly higher during the first part of the circadian cycle. In all infants, rhythmicity in each variable was dominated by ultradian periodicities that were coincident with feedings and related interventions; moreover, several physiological variables charted during feeding differed significantly from values obtained during periods in which caregiving interventions did not occur. CONCLUSION: Quantitative data on the preterm infant circadian system may facilitate evaluation of factors that improve therapeutic responses, recovery, and outcome of neonatal intensive care patients.

Biological rhythmicity in normal infants during the first 3 months of life.

OBJECTIVE: The mammalian "biological clock," which resides in the hypothalamic suprachiasmatic nucleus, has an important role in both the timing and organization of sleep and in the coordination of sleep with other physiological rhythms such as temperature regulation and respiratory control. We wished to describe the development of the circadian system in normal infants during the first 3 months of life. METHODS: Ten healthy full term infants were studied in the infant's home for three consecutive days at 1 month and 3 months postnatal age. Rectal temperature, abdominal skin temperature, heart rate, and activity were recorded at 2-minute intervals during each study using a small microcomputer. RESULTS: Circadian periodicity for most variables was seen at 1 month of age and significantly increased at 3 months. Differences in the pattern of rhythmicity during these two developmental periods were highlighted by an increase in activity during the subjective day and a decrease in Trec during the subjective night at 3 months compared to 1 month. Correlational analysis revealed that all pairs of variables, exclusive of Tsk, showed a significantly higher association at 3 months relative to 1 month. The lengthening of the interfeeding interval at 3 months of age corresponded with an increased consolidation of sleep during the night and a relatively lower nocturnal body temperature minima compared to 1 month of age. CONCLUSION: The results of this study underscore the subtle changes in the nature and interaction of several infant variables during this critical developmental period, which may reflect maturation of the circadian system and its coupling with homeostatic effector systems that are developing in parallel.

Circadian timed wakefulness at dawn opposes compensatory sleep responses after sleep deprivation in Octodon degus.

The circadian timing system in mammals is thought to promote wakefulness and oppose sleep drive that accumulates across the activity phase in diurnal and nocturnal species. Whether the circadian system actively opposes compensatory sleep responses in mammals with episodes of alertness consolidated at dawn and dusk is unknown. In the present study, an interaction between circadian timed arousal at dawn and compensatory sleep responses after sleep deprivation (SD) was examined in Octodon degus, a hystricomorph rodent with crepuscular episodes of wakefulness. Recovery sleep was compared after 6 hours and 12 hours of SD ending at either CT 21 or 12, just before the dawn, and just after the dusk crepuscular episodes of consolidated wakefulness, respectively. Total sleep time and NREM sleep after SD increased proportionally to the amount of sleep loss; however, compensatory sleep responses after SD were attenuated at CT 23, a circadian time when a crepuscular event of wakefulness occurs in this species. EEG slow-wave activity (SWA) and body temperature levels in the first two hours after 6 and 12 hours of SD ending at CT 12 were similar. However, both were significantly higher than after 12 hours of SD ending at CT 21, suggesting factors other than the amount of prior wake duration can influence SWA levels. This study provides evidence that the circadian arousal system opposes compensatory sleep responses at dawn by actively promoting wakefulness in this species.

Real-time automated sleep scoring: validation of a microcomputer-based system for mice.

Long-term circadian studies of sleep and wakefulness in rodents have been hindered by the labor required to analyze long polygraph records. To expedite such studies, we have designed and implemented SCORE, a microcomputer-based real-time sleep scoring system for rodents. The electroencephalograph is digitized in 10-s epochs at 100 Hz. Frequency and amplitude information from the waveform are extracted into a 48-dimension vector that is then compared to previously taught vectors representing the canonical features of four arousal states: wakefulness, theta-dominated wakefulness, rapid eye movement (REM) sleep, and nonREM (NREM) sleep. Match values are assigned for each state to each epoch; after excluding states based on wheel-running or drinking activity data, the nonexcluded state with the best match value for the epoch is scored. Analysis of over 23,000 epochs for four mice yielded an overall agreement of 94.0% between two human scorers and the program, compared with a 94.5% agreement between the two human scorers. The SCORE algorithm matched the human concensus best for wakefulness (97.8%) and NREM sleep (94.7%), but was lower for REM sleep (75.2%) and theta-dominated wakefulness (83.3%). Most errors in scoring of REM sleep were in close temporal proximity to human-scored REM epochs. SCORE is capable of scoring arousal states for eight animals simultaneously in real time on a standard IBM PC equipped with a commercially available analog-to-digital conversion board, and should considerably facilitate the performance of long-term studies of sleep and wakefulness in the rodent.

Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms?

Differing conclusions regarding the sleep-promoting effects of melatonin may be the result of the broad range of doses employed (0.1-2000 mg), the differing categories of subjects tested (normal subjects, insomniac patients, elderly, etc.), and the varying times of administration (for daytime vs. nighttime sleep). We conclude that melatonin may benefit sleep by correcting circadian phase abnormalities and/or by a modest direct soporific effect that is most evident following daytime administration to younger subjects. We speculate that these effects are mediated by interactions with specific receptors concentrated in the suprachiasmatic nucleus (SCN) that result in resetting of the circadian pacemaker and/or attenuation of an SCN-dependent circadian alerting process.

Circadian and homeostatic influences on sleep in the squirrel monkey: sleep after sleep deprivation.

A series of sleep deprivation (SD) experiments were performed to examine the relative influence of circadian and homeostatic factors on the timing of sleep in squirrel monkeys free-running in constant illumination. All SDs started at the beginning of subjective night and lasted 0, 1/4, 1/2, 1, 1 1/4, or 1 1/2 circadian cycles. These six lengths represented three pairs: (0.1), (1/4, 1 1/4), (1/2, 1 1/2). Within each pair, SD ended at the same circadian phase but differed by one circadian cycle in duration. Both before and after SD, consolidated sleep (CS) episodes occurred predominantly during subjective night, even after long SDs ending at the beginning of subjective day. CS duration was strongly influenced by circadian phase but had no overall correlation with prior wake duration. Sleep loss incurred during SDs longer than 1/4 cycle was only partially recovered over the next two circadian cycles, though total sleep duration was closer to baseline levels after the second circadian cycle after SD. There was a trend toward a positive correlation between prior wake duration and the amount of NREM and delta activity measures during subjective day. Delta activity was not increased in the first 2 hours of CS after the SD. Relatively high levels of delta activity occurred immediately after the SD ended and again at the time of baseline CS onset. These data indicate that the amount of sleep and delta activity after SD in squirrel monkeys is weakly dependent on prior wake duration. Circadian factors appear to dominate homeostatic processes in determining the timing, duration and content of sleep in these diurnal primates.

Prepro-hypocretin (prepro-orexin) expression is unaffected by short-term sleep deprivation in rats and mice.

The hypocretin/orexin ligand-receptor system has recently been implicated in the sleep disorder narcolepsy. During the dark (active) period, null mutants of the prepro-orexin (prepro-hypocretin) gene have cataplectic attacks and increased levels of both rapid eye movement (REM) and non-REM (NREM) sleep. Intracerebroventricular injection of one of the encoded neuropeptides, orexin-A, early in the light period increases wakefulness and reduces REM sleep in the rat, suggesting that this system may be involved in the normal regulation of sleep and wakefulness. To further test this hypothesis, we measured hypocretin (hcrt) mRNA levels by both Northern hybridization and Taqman analysis in mouse and rat hypothalamus after short-term (6 h) sleep deprivation (SD) and 2-4 hours after recovery from SD. Although our SD procedures effectively induced a sleep debt and increased c-fos mRNA expression in the cortex and hypothalamus as described by other investigators, we found that hcrt mRNA levels were not significantly changed in either species either after SD or after recovery from SD. If the hcrt system is involved in normal regulation of sleep and wakefulness, longer periods of SD may be necessary to affect hcrt mRNA levels or changes may occur at the protein rather than mRNA level. Alternatively, this system may also be involved in another function that counterbalances any SD-induced changes in hcrt mRNA levels.

Nicotine and nicotinic receptors in the circadian system.

Considerable data support a role for cholinergic influences on the circadian system. The extent to which these influences are mediated by nicotinic acetylcholine receptors (nAChRs) has been controversial, as have the specific actions of nicotine and acetylcholine in the suprachiasmatic nucleus (SCN) of the hypothalamus. In this article we review the existing literature and present new data supporting an important role for nAChRs in both the developing and adult SCN. Specifically, we present data showing that nicotine is capable of causing phase shifts in the circadian rhythms of rats. Like light and carbachol, nicotine appears to cause phase delays in the early subjective night and phase advances in the late subjective night. In the isolated SCN slice, however, only phase advances are seen, and, surprisingly, nicotine appears to cause the inhibition rather than the excitation of neurons. Among nAChR subunit mRNAs, alpha 7 appears to be the most abundant subunit in the adult SCN, whereas in the perinatal period, the more typical nAChRs with higher affinity for nicotine predominate in the SCN. This developmental change in subunit expression may explain the dramatic sensitivity of the perinatal SCN to nicotine that we have previously observed. The effects of nicotine on the SCN may contribute to alterations caused by nicotine in other physiological systems. These effects might also contribute to the dependence properties of nicotine through influences on arousal.

Triazolam-induced sleep in the rat: influence of prior sleep, circadian time, and light/dark cycles.

Rats entrained to 12-h on /12-h off light schedule and injected with triazolam 0.4 mg/kg at the mid-point of their activity phase (6 h after lights out: circadian time = CT-18) had a stronger hypnotic response than animals free-running in constant dark injected at the equivalent circadian time. In contrast, entrained rats injected 5 h after lights on (CT-5) showed increased wake after injection relative to baseline, largely due to REM sleep inhibition. Hypnotic efficacy was found to be inversely related to prior accumulated sleep. During the 6 h before injection, entrained rats injected at CT-18 slept significantly less than the free-running rats, which in turn slept significantly less than entrained rats injected at CT-5. Taken together, the results suggest that the amount of prior sleep was a more important influence on the response to triazolam than either light/dark per se or circadian phase. Methodologically, automated sleep scoring was found to be an efficient method for examining drug effects, particularly when corroborated by concurrent independent physiological variables and spectral analysis.

Altered rapid eye movement sleep timing in serotonin transporter knockout mice.

The monoamine neurotransmitter serotonin has long been implicated in development and maintenance of sleep patterns, yet the role of the serotonin transporter (SERT) in these processes has not been evaluated in detail. We report that genetically engineered SERT knockout mice exhibit more REM sleep (REMS) than wild type littermates (11 vs 7% of recording time under baseline conditions) and display more frequent REMS bouts that last longer. This phenotype resembles the previously reported long-term effect of repeated treatment with SERT inhibitor compounds rather than the acute REMS suppressing effect of treatment with such compounds, and is thus likely to reflect neuroadaptations to the absence of SERT, rather than an acute effect of its absence in the adult. While electroencephalographic (EEG) spectra did not differ between SERT knockout and wild type mice during non-REM sleep (NREMS) or REMS, the dynamics of the EEG during the transition from NREMS to REMS differed between the genotypes. The surge in EEG power in both the 6-9 Hz and 10-16 Hz ranges that occurs just prior to the onset of REMS (pre-REMS power surge) is of greater magnitude in SERT knockout mice than in wild type littermate controls. This observation contrasts with the reduced magnitude pre-REMS power surge observed in rats subjected to REMS deprivation relative to yoked controls. These results indicate that the pre-REMS power surge is influenced by REMS history and by monoaminergic transmission. Genetic differences in serotonin systems and developmental exposure to SERT blockers are likely to exert effects on REMS.