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Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to establish groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

Correlational studies show that short sleep is associated with negative daytime outcomes in school-aged children, but there are few experimental sleep manipulation studies to assess whether this is a causal relation. The aim of this study was to determine the impact of mild, cumulative sleep restriction on daytime functioning of typically developing (TD) children and children with attention-deficit/hyperactivity disorder (ADHD).A total of 36 school-aged children (n = 18 TD; n = 18 ADHD), aged 6-11 years participated.Children participated in two sleep conditions (order counter-balanced). The Restricted condition required a 1 h reduction of time in bed for one week, and the Controlled Typical condition was based on participant's average baseline sleep. At the end of each condition, participants attended the sleep lab for overnight polysomnography and daytime functioning assessments.Children successfully reduced time in bed by ~1 h. Due to compensatory changes, total sleep time (TST) was reduced by only ~20 min, as children fell asleep faster and spent less time awake after sleep onset during the Restricted compared to Controlled Typical condition. Many daytime functions were not affected by this very mild sleep restriction, however, both groups showed significant changes in performance on an objective attention task and on a parent-rated emotional lability measure after six nights of minimal reductions in TST. There were no significant differences between groups.Results suggest that a very mild sleep restriction can affect children's attention and emotional regulation, even with evidence of compensatory sleep mechanisms.

Objective: To examine how risk-related decision making might be associated with habitual sleep variables, including sleep variability, sleep duration and perceived sleep need in young adults cross-...

Sleep and circadian rhythm disruptions commonly occur in individuals with schizophrenia. Stable tubule only polypeptide (STOP) knockout (KO) mice show behavioral impairments resembling symptoms of schizophrenia. We previously reported that STOP KO mice slept less and had more fragmented sleep and waking than wild-type littermates under a light/dark (LD) cycle. Here, we assessed the circadian phenotype of male STOP KO mice by examining wheel-running activity rhythms and EEG/EMG-defined sleep/wake states under both LD and constant darkness (DD) conditions. Wheel-running activity rhythms in KO and wild-type mice were similarly entrained in LD, and had similar free-running periods in DD. The phase delay shift in response to a light pulse given early in the active phase under DD was preserved in KO mice. KO mice had markedly lower activity levels, lower amplitude activity rhythms, less stable activity onsets, and more fragmented activity than wild-type mice in both lighting conditions. KO mice also spent more time awake and less time in rapid eye movement sleep (REMS) and non-REMS (NREMS) in both LD and DD conditions, with the decrease in NREMS concentrated in the active phase. KO mice also showed altered EEG features and higher amplitude rhythms in wake and NREMS (but not REMS) amounts in both lighting conditions, with a longer free-running period in DD, compared to wild-type mice. These results indicate that the STOP null mutation in mice altered the regulation of sleep/wake physiology and activity rhythm expression, but did not grossly disrupt circadian mechanisms.

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor symptoms as well as severe deficits in olfactory function and microstructural changes in olfactory brain regions. Because of the evidence of asymmetric neuropathological features in early-stage PD, we examined whether lateralized microstructural changes occur in olfactory brain regions and the substantia nigra in a group of early-stage PD patients. Using diffusion tensor imaging (DTI) and the University of Pennsylvania Smell Identification Test (UPSIT), we assessed 24 early-stage PD patients (Hoehn and Yahr stage 1 or 2) and 26 healthy controls (HC). We used DTI and a region of interest (ROI) approach to study the microstructure of the left and right anterior olfactory structures (AOS; comprising the olfactory bulbs and anterior end of the olfactory tracts) and the substantia nigra (SN). PD patients had reduced UPSIT scores relative to HC and showed increased mean diffusivity (MD) in the SN, with no lateralized differences. Significant group differences in fractional anisotropy (FA) and MD were seen in the AOS, but these differences were restricted to the right side and were not associated with the primary side of motor symptoms amongst PD patients. No associations were observed between lateralized motor impairment and lateralized microstructural changes in AOS. Impaired olfaction and microstructural changes in AOS are useful for early identification of PD but asymmetries in AOS microstructure seem unrelated to the laterality of PD motor symptoms.

Objective There is a growing body of research on the impact of stimulant medication on sleep in children with attention-deficit/hyperactivity disorder (ADHD). Negative sleep side effects are a common reason for nonadherence or for discontinuing a course of treatment. However, there is no published evidence as to whether pretreatment sleep can predict responses to treatment and the emergence of side effects. Method In this study, baseline sleep variables were used to predict therapeutic effect (i.e., reduction of ADHD symptoms) and side effects (both sleep and global side effects) in a sample of newly diagnosed, medication-naive children (n = 50). Results The results of hierarchical regression analysis showed that parent-reported shorter sleep duration before medication treatment significantly predicted better response to treatment, independent of pretreatment ADHD symptoms. Baseline sleep features did not significantly predict global (nonsleep) side effects but did predict increased sleep side effects during treatment. Conclusion These results indicate that baseline sleep variables may be helpful in predicting therapeutic response to medication and sleep disturbance as a side effect of stimulant medication.

This chapter aims to summarize our knowledge of the functions of major neurochemical systems projecting to the suprachiasmatic nuclei (SCN), and of intrinsic SCN neurochemicals in intercellular communication required for the generation of daily rhythms and their synchronization by external events. Neurophysiological studies both in vivo and in vitro have shown that light, optic nerve stimulation, and glutamate application activate most SCN cells in nocturnal rodents, and these effects can be blocked by local applications of glutamate receptor antagonists. The SCN receive a substantial innervation from the median raphe nucleus, bringing high levels of serotonin primarily to the ventral and medial SCN. The SCN receive a modest innervation from neurons in the basal forebrain and brainstem which contain acetylcholine. Circadian rhythms in electrical activity of the SCN have been demonstrated using both single- and multi-unit recordings from hamster and rat SCN neurons in hypothalamic slice preparations, and from the SCN of several species in vivo.

Summary This study sought to: (1) compare actigraphy-derived estimated sleep variables to the same variables based on the gold-standard of sleep assessment, polysomnography; (2) examine whether the correlations between the measures differ between children with attention-deficit/hyperactivity disorder and typically developing children; and (3) determine whether these correlations are altered when children with attention-deficit/hyperactivity disorder are treated with medication. Participants (24 attention-deficit/hyperactivity disorder; 24 typically developing), aged 6–12 years, completed a 1-week baseline assessment of typical sleep and daytime functioning. Following the baseline week, participants in the attention-deficit/hyperactivity disorder group completed a 4-week blinded randomized control trial of methylphenidate hydrochloride, including a 2-week placebo and 2-week methylphenidate hydrochloride treatment period. At the end of each observation (typically developing: baseline; attention-deficit/hyperactivity disorder: baseline, placebo and methylphenidate hydrochloride treatment), all participants were invited to a sleep research laboratory, where overnight polysomnography and actigraphy were recorded concurrently. Findings from intra-class correlations and Bland–Altman plots were consistent. Actigraphy was found to provide good estimates (e.g. intra-class correlations >0.61) of polysomnography results for sleep duration for all groups and conditions, as well as for sleep-onset latency and sleep efficiency for the typically developing group and attention-deficit/hyperactivity disorder group while on medication, but not for the attention-deficit/hyperactivity disorder group during baseline or placebo. Based on the Bland–Altman plots, actigraphy tended to underestimate for sleep duration (8.6–18.5 min), sleep efficiency (5.6–9.3%) and sleep-onset latency, except for attention-deficit/hyperactivity disorder during placebo in which actigraphy overestimated (−2.1 to 6.3 min). The results of the current study highlight the importance of utilizing a multimodal approach to sleep assessment in children with attention-deficit/hyperactivity disorder.

Background Even subtle impairments on cognitive test scores can be associated with future cognitive decline and dementia. We assayed the relationships between test score impairment and adverse outcomes. Methods Secondary analyses were performed on data from non-institutionalized participants, 50+ years of age (N = 30,038),from 12 countries taking part in the Survey of Health, Ageing and Retirement in Europe (SHARE) longitudinal study onaging. At baseline, participants’ cognition was tested using verbal fluency, immediate recall, and delayed recall tasks. Results Greater levels of cognitive impairment at baseline were strongly associated with future poor health outcomes and functional impairment. Controlling for age, sex and education,those with 1 (OR = 1.58, 95% CI = 1.34–1.87) or ≥ 2(OR = 2.59, 95% CI = 2.17–3.09) impaired tests at baseline were more likely to die after an average of 40 months compared to individuals with no impairments. After selecting for participants who reported the absence of dementia initially,those with ≥ 2 cognitive impairments at baseline (OR = 3.34,95% CI = 2.27–4.92) were more likely to report dementia at follow-up compared to those with no impairment. Conclusions People with impaired cognitive test scores at baseline are at greater risk to die or develop dementia within four years than their less impaired or unimpaired counterparts.

Objective To examine the impact of sleep duration on emotional functioning and cognitive performance in children. Methods 32 children (8–12 years) wore actigraphs for 3 weeks. Following a week of typical sleep, each child was randomly assigned to go to bed 1 hr earlier for 4 nights (Long Sleep) or 1 hr later for 4 nights (Short Sleep) relative to their typical bedtime. Each child then completed the opposite condition. After each week, emotional and cognitive functioning were assessed using objective and subjective measures. Results Results revealed impaired functioning in the Short- relative to the Long-Sleep condition on measures of positive affective response, emotion regulation, short-term memory, working memory, and aspects of attention. Conclusions Results suggest that even modest differences in sleep duration over just a few nights can have significant consequences for children’s daytime functioning. These findings demonstrate the important impact of sleep duration on children’s daytime functioning.

Disruption of sleep/wake cycles is common in patients with schizophrenia and correlates with cognitive and affective abnormalities. Mice deficient in stable tubule only polypeptide (STOP) show cognitive, behavioral, and neurobiological deficits that resemble those seen in patients with schizophrenia, but little is known about their sleep phenotype. We characterized baseline sleep/wake patterns and recovery sleep following sleep deprivation in STOP null mice. Polysomnography was conducted in adult male STOP null and wild-type (WT) mice under a 12:12 hours light:dark cycle before, during, and after 6 hours of sleep deprivation during the light phase. At baseline, STOP null mice spent more time awake and less time in non-rapid eye movement sleep (NREMS) over a 24-hour period, with more frequent transitions between wake and NREMS, compared to WT mice, especially during the dark phase. The distributions of wake, NREMS and REMS across the light and the dark phases differed by genotype, and so did features of the electroencephalogram (EEG). Following sleep deprivation, both genotypes showed homeostatic increases in sleep duration, with no significant genotype differences in the initial compensatory increase in sleep intensity (EEG delta power). These results indicate that STOP null mice sleep less overall, and their sleep and wake periods are more fragmented than those of WT mice. These features in STOP null mice are consistent with the sleep patterns observed in patients with schizophrenia.

Objective Age-related abnormalities in caudate volumes have been reported to differ across the periods of childhood and puberty in children with ADHD. This study assessed caudate volumetric abnormalities across two narrow age clusters within the childhood period. Method Three-dimensional manual tracings of the head and body of the caudate nucleus and of the cerebrum were acquired from 26 medication-naive boys with a diagnosis of ADHD (ages 5.9–10.8 years), and 24 age-matched normal controls. Results Boys with ADHD had smaller total caudate volumes relative to controls, F(1,48) = 4.29, p = 0.04. Adjustment of caudate volumes with respect to age demonstrated that this group difference was driven solely by participants in the 5.9–7.3 year range, F(1, 46) = 5.64, p = 0.022, with an effect size of d = 0.69. No Group effect was found in older participants, F(1, 46) = 0.82, p = 0.37. Conclusions These novel findings suggest a different pattern of caudate volume abnormalities across narrow age clusters prior to puberty in boys with ADHD. Anatomical differences in brain structures related to ADHD in prepubertal children should be evaluated with respect to the changing developmental trajectory of brain regions within this period of rapid brain growth.

This study examined sleep in relation to daytime functioning in 32 typically developing children (8–12 y). Participants wore actigraphs for one week and then completed tasks designed to measure emotional functioning, short-term memory, working memory, and attention. Results revealed that children slept approximately 1 h less per night than recommended. Older children had shorter sleep durations, higher sleep efficiencies, and later sleep onset times. Examination of the relationships between sleep and daytime functioning revealed that small variations in sleep were significantly associated with differences in emotional functioning and attention. Results highlight the need to increase awareness about the importance of sleep in children.

Sleep restriction alters hormone patterns and appetite in men, but less is known about effects on women. We assessed effects of overnight sleep restriction on cortisol and leptin levels and on appetite in young women. Participants' baseline sleep duration and eating habits were monitored for a week before the study. Salivary cortisol and leptin were sampled from fifteen healthy women (aged 18-25) during two consecutive days: first after a 10h overnight sleep opportunity (Baseline day) and then after a night including only 3h sleep (Post sleep-restriction day). Participants also completed appetite questionnaires on both days. Sleep restriction significantly reduced morning cortisol levels (p=0.02), elevated morning leptin levels (p=0.04), elevated afternoon/evening cortisol area under the curve values (p=0.008), and slowed the decline in cortisol concentration during the day (p=0.04). Hunger and craving scores did not differ significantly between days. A single night of restricted sleep affected cortisol rhythms and morning leptin levels in young women.

Women recover from sleep deprivation more efficiently than men, but the mechanism for this difference is unknown. Effects of estrogen on sleep suggest that it could play a role, but the brain targets on which estrogen may act to have this effect have not been identified. Sleep deprivation increases levels of the immediate-early gene protein c-Fos in selected brain regions, but it is unknown whether estrogen modulates this response. We investigated the influence of different levels of exogenous estradiol on the c-Fos response to sleep deprivation in ovariectomized female rats. Female rats were treated with low or high levels of estradiol (mimicking diestrous and proestrous levels, respectively) delivered via subcutaneous silastic tubes. Control ovariectomized females and sham-operated males were implanted with tubes filled with cholesterol. One week after surgery, half of the rats underwent a 3 h period of sleep deprivation during the light phase in a motorized Wahmann activity wheel that rotated constantly at a slow speed, while half were confined to fixed wheels. Immediately after sleep deprivation, animals were killed and their brains processed to detect c-Fos using immunohistochemistry. Sleep deprivation increased the number of c-Fos positive cells in a number of brain areas, including the caudate putamen, medial preoptic area, perifornical hypothalamus, and anterior paraventricular thalamic nucleus. Other areas, including the suprachiasmatic nucleus, posterior paraventricular hypothalamic nucleus, posterior paraventricular thalamic nucleus, arcuate nucleus, and central amygdala, did not respond to 3 h sleep deprivation with a significant increase in c-Fos levels. Levels of c-Fos induced in the selected brain regions by sleep deprivation were not modulated by estrogen levels, nor by sex.

To understand how female sex hormones influence homeostatic mechanisms of sleep, we studied the effects of estradiol (E2) replacement on c-Fos immunoreactivity in sleep/wake-regulatory brain areas after sleep deprivation (SD) in ovariectomized rats. Adult rats were ovariectomized and implanted subcutaneously with capsules containing 17β-E2(10.5 μg; to mimic diestrous E2levels) or oil. After 2 wk, animals with E2capsules received a single subcutaneous injection of 17β-E2(10 μg/kg; to achieve proestrous E2levels) or oil; control animals with oil capsules received an oil injection. Twenty-four hours later, animals were either left undisturbed or sleep deprived by “gentle handling” for 6 h during the early light phase, and killed. E2treatment increased serum E2levels and uterus weights dose dependently, while attenuating body weight gain. Regardless of hormonal conditions, SD increased c-Fos immunoreactivity in all four arousal-promoting areas and four limbic and neuroendocrine nuclei studied, whereas it decreased c-Fos labeling in the sleep-promoting ventrolateral preoptic nucleus (VLPO). Low and high E2treatments enhanced the SD-induced c-Fos immunoreactivity in the laterodorsal subnucleus of the bed nucleus of stria terminalis and the tuberomammillary nucleus, and in orexin-containing hypothalamic neurons, with no effect on the basal forebrain and locus coeruleus. The high E2treatment decreased c-Fos labeling in the VLPO under nondeprived conditions. These results indicate that E2replacement modulates SD-induced or spontaneous c-Fos expression in sleep/wake-regulatory and limbic forebrain nuclei. These modulatory effects of E2replacement on neuronal activity may be, in part, responsible for E2's influence on sleep/wake behavior.

Transforming growth factor-alpha (TGF-alpha) has been identified as a potential output signal of the principal circadian pacemaker housed in the mammalian suprachiasmatic nucleus (SCN). The goal of the present study was to characterize the temporal pattern and cellular localization of TGF-alpha immunoreactivity (IR), and to examine its localization relative to astrocytic and neuronal markers in the hamster circadian system. In contrast to previous reports of circadian rhythms in TGF-alpha mRNA levels in the hamster SCN, we did not detect any statistically significant changes in the levels of TGF-alpha protein IR in the hamster SCN across a 14:10 light-dark cycle using densitometric analyses. TGF-alpha was found to be colocalized with glial fibrillary acidic protein (GFAP), but not with the general neuronal marker NeuN, or calbindin-D28K which is present in a subgroup of SCN neurons. GFAP IR showed a small but significant daily variation in the SCN, with higher levels early in the light phase compared to the middle of the dark phase. The thalamic intergeniculate leaflet (IGL), another component of the circadian regulatory system, did not show any TGF-alpha IR or any detectable daily variation in GFAP IR. These results suggest that daily variations of TGF-alpha mRNA levels in the hamster SCN are not accompanied by corresponding rhythms of TGF-alpha protein levels, and confirm that TGF-alpha is present primarily in astrocytes within the SCN.

We assessed whether daily separation of Mongolian gerbils (Meriones unguiculatus) from mothers and siblings during postnatal days 4-20 would produce behavioral and neurochemical changes in adulthood that parallel some features of depression in humans. Neonatal separation altered the behavior of adult females in the open field test but not in the tail suspension test, and did not affect behavior of males. Separated males, but not females, showed a significant decrease in hippocampal brain derived neurotrophic factor (BDNF) relative to controls. Western blot and optical densitometry measurements in the hippocampus did not reveal significant group differences in synaptophysin levels in either sex, but there was a tendency toward decreased levels of synaptophysin in the entire hippocampus as well as the CA1 hippocampal subregion of separated males. Repeated separation of neonates from mothers and siblings led to subtle behavioral and neurochemical changes during adulthood that were expressed differently in male and female gerbils.

Aims The hypothalamic suprachiasmatic nucleus (SCN), which functions as a circadian pacemaker in mammals, is influenced by melatonin and serotonin. Agomelatine, which acts as an antidepressant and can synchronize disturbed circadian rhythms, displays a unique mechanism of action involving both melatonergic agonist and 5-HT 2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT 2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation. Main methods Brain slices containing the SCN were prepared from male Wistar rats and maintained in a recording chamber. Changes in firing rates of SCN neurons were recorded after perfusion of drugs. Key findings SCN firing rates were dose-dependently suppressed by 19.2–80.9% following perfusion of 0.04–0.32 mM agomelatine (p 50 = 0.14 mM). Perfusion with melatonin (0.4–3.2 mM) resulted in 16.6–62.5% dose-dependent reductions in firing rates (at least p 50 = 1.59 mM) and of the duration of suppression. A selective melatonin receptor antagonist (S22153 at 0.32 mM) and a 5-HT 2c receptor agonist (Ro60-0175) reduced the suppressive effects of 0.16 mM agomelatine by 35% and 50.2%, respectively. A 5-HT 2C receptor antagonist (S32006; 0.03–0.12 mM) significantly decreased SCN firing rates (19.6–91.8%; at least p 50 = 0.05 mM). Co-perfusion of S32006 (0.06 mM) with a 5-HT 2C agonist (Ro60-0175; 0.003 mM) reduced suppressions evoked by S32006 alone by ~ 72.1%. Significance These results are consistent with the hypothesis that agomelatine acts directly on the SCN via both agonist effects at melatonergic receptors and antagonist effects at 5-HT 2C receptors, which parallel its mechanisms of action as an antidepressant.

Several observational, cross-sectional, and longitudinal studies as well as a few well-controlled experimental studies have examined the impact of sleep loss on children's daytime functioning. The emerging results indicate that sleep plays a critical role in various aspects of daytime functioning in children, including cognitive and emotional functioning. Furthermore, studies indicate that daytime functioning may be impaired by even small amounts of sleep restriction in children.

Objective Our goal was to model the temporal dynamics of sleep–wake transitions, represented by transitions between rest and activity obtained from actigraphic data, in patients with bipolar disorder using a probabilistic state transition approach. Methods We collected actigraphic data for 14 days from 20 euthymic patients with bipolar disorder, who had been characterized clinically, demographically, and with respect to their circadian preferences (chronotype). We processed each activity record to generate a series of transitions in both directions between the states of rest (R) and activity (A) and plotted the estimated transition probabilities (pRA and pAR). Each 24-hour period was also divided into a rest phase consisting of the eight consecutive least active hours in each day and an active phase consisting of the 16 consecutive most active hours in each day. We then calculated separate transition probabilities for each of these phases for each participant. We subsequently modeled the rest phase data to find the best fit for rest–activity transitions using maximum likelihood estimation. We also examined the association of transition probabilities with clinical and demographic variables. Results The best-fit model for rest–activity transitions during the rest phase was a mixture (bimodal) of exponential functions. Of those patients with rapid cycling, 75% had an evening-type chronotype. Patients with bipolar II disorder taking antidepressants had a lower probability of transitioning back to rest than those not on antidepressants [mean ± SD = 0.050 ± 0.006 versus 0.141 ± 0.058, F(1,15) = 3.40, p < 0.05]. Conclusions The dynamics of transitions between rest and activity in bipolar disorder can be accounted for by a mixture (bimodal) of exponential functions. Patients taking antidepressants had a reduced probability of sustaining and returning to sleep.

STUDY OBJECTIVES: Chronic sleep restriction (CSR) impairs sustained attention in humans, as commonly assessed with the psychomotor vigilance task (PVT). To further investigate the mechanisms underlying performance deficits during CSR, we examined the effect of CSR on performance on a rat version of PVT (rPVT). DESIGN: Adult male rats were trained on a rPVT that required them to press a bar when they detected irregularly presented, brief light stimuli, and were then tested during CSR. CSR consisted of 100 or 148 h of continuous cycles of 3-h sleep deprivation (using slowly rotating wheels) alternating with a 1-h sleep opportunity (3/1 protocol). MEASUREMENTS AND RESULTS: After 28 h of CSR, the latency of correct responses and the percentages of lapses and omissions increased, whereas the percentage of correct responses decreased. Over 52-148 h of CSR, all performance measures showed partial or nearly complete recovery, and were at baseline levels on the first or second day after CSR. There were large interindividual differences in the magnitude of performance impairment during CSR, suggesting differential vulnerability to the effects of sleep loss. Wheel-running controls showed no changes in performance. CONCLUSIONS: A 28-h period of the 3/1 CSR protocol disrupted performance on a sustained attention task in rats, as sleep deprivation does in humans. Performance improved after longer periods of CSR, suggesting allostatic adaptation, contrary to some reports of progressive deterioration in PVT performance during CSR in humans. However, as observed in humans, there were individual differences among rats in the vulnerability of their attention performance to CSR. Language: en

Neurons in the mammalian suprachiasmatic nucleus (SCN), the principal pacemaker of the circadian system, receive direct retinal input. Some SCN neurons respond to retinal illumination or optic nerve stimulation with changes in firing rates. In nocturnal rodents, retinal illumination increases firing rates of a large majority and decreases firing rates of a minority of responsive neurons. In two species of diurnal rodent, these proportions are altered or even reversed. Since retinal input to the SCN has been reported to involve release of the excitatory neurotransmitter glutamate, the mechanism mediating suppressions is unknown. We studied responses of neurons in SCN slices from diurnal degus and nocturnal rats to optic nerve stimulation. To test whether suppressions are mediated indirectly by release of the inhibitory neurotransmitter GABA from SCN neurons that are first activated by glutamate release, we attempted to block suppressions by adding to the bath either APV, an antagonist for excitatory glutamate receptors, or bicuculline, a GABA(A) receptor antagonist. If glutamate is the only neurotransmitter released by optic nerves in the SCN, APV should prevent both activations and suppressions in response to optic nerve stimulation. We found that APV had little effect on suppressions although it effectively blocked activations. Bicuculline blocked most suppressions. These findings are inconsistent with a model in which the retina provides only excitatory glutamate input to the SCN via NMDA receptors. Since some retinal fibers in adult mammals contain GABA, it is possible that the retinal innervation of the SCN includes both glutamate- and GABA-containing axons.

Several immediate-early genes have been shown to be induced in the rodent circadian pacemaker, the suprachiasmatic nucleus, by retinal illumination at night. We compared spontaneous and light-evoked levels of the immediate-early gene protein ZIF268 (NGFI-A) in the Syrian hamster and C57BL/6J mouse suprachiasmatic nucleus. Exposure of both hamsters and mice to light pulses early and late in the subjective night caused increased ZIF268 immunoreactivity in the region of the suprachiasmatic nucleus that receives retinal innervation. In contrast to hamsters, mice also showed spontaneous increases in ZIF268 at both subjective night phases at the lateral edges of the suprachiasmatic nucleus. Light also evoked a significant increase in ZIF268 levels during the subjective day in the lateral suprachiasmatic nucleus, with few labeled cells in the ventral and dorsal suprachiasmatic nucleus. These results demonstrate a novel circadian pattern and regional differentiation of ZIF268 immunoreactivity in the suprachiasmatic nucleus of mice that differ from those in other rodents. There are pronounced species differences in both spontaneous and light-evoked expression of ZIF268 immunoreactivity.

There is extensive evidence that sleep restriction alters endocrine function in healthy young men, increasing afternoon cortisol levels and modifying levels of other hormones that regulate metabolism. Recent studies have confirmed these effects in young women, but have not investigated whether menstrual cycle phase influences these responses. The effects on cortisol levels of limiting sleep to 3h for one night were assessed in two groups of women at different points in their menstrual cycles: mid-follicular and mid-luteal. Eighteen healthy, young women, not taking oral contraceptives (age: 21.8±0.53; BMI: 22.5±0.58 [mean±SEM]), were studied. Baseline sleep durations, eating habits and menstrual cycles were monitored. Salivary samples were collected at six times of day (08:00, 08:30, 11:00, 14:00, 17:00, 20:00) during two consecutive days: first after a 10h overnight sleep opportunity (Baseline) and then after a night with a 3h sleep opportunity (Post-sleep restriction). All were awakened at the same time of day. Women in the follicular phase showed a significant decrease (p=0.004) in their cortisol awakening responses (CAR) after sleep restriction and a sustained elevation in afternoon/evening cortisol levels (p=0.008), as has been reported for men. Women in the luteal phase showed neither a depressed CAR, nor an increase in afternoon/evening cortisol levels. Secondary analyses examined the impact of sleep restriction on self-reported hunger and mood. Menstrual cycle phase dramatically altered the cortisol responses of healthy, young women to a single night of sleep restriction, implicating effects of spontaneous changes in endocrine status on adrenal responses to sleep loss.

The circadian pacemaker housed in the suprachiasmatic nucleus (SCN) synchronizes daily sleep-wake cycles, presumably by modulating the sleep-wake regulatory system, including ventrolateral preoptic area (VLPO) neurons. We used whole-cell patch-clamp recording to study the projections from the SCN to the VLPO in horizontal slices of rat hypothalamus. Single-pulse stimulation of the SCN region elicited postsynaptic currents (PSCs) in 20 of 66 neurons (30%) recorded within the VLPO region as verified by intracellular biocytin labelling. At a holding potential of -60 mV, the evoked PSCs had an amplitude of 17.6 +/- 3.2 pA (SEM) and a latency of 6.3 +/- 0.5 ms (n = 10). There was a trend for simple excitatory postsynaptic currents (EPSCs) to be evoked in the VLPO cluster, simple inhibitory postsynaptic currents (IPSCs) in the extended VLPO, and a combination of EPSCs and IPSCs in both regions. IPSCs were blocked reversibly by bicuculline (10 microm, n = 11). In both the presence and absence of bicuculline, EPSCs had fast and slow components that were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 microm; n = 7), and (+/-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 10 microm, n = 6), respectively. Reversal potentials for the evoked IPSCs and EPSCs were consistent with mediation via GABAA and ionotropic glutamate receptors, respectively. These results suggest that the SCN region provides both inhibitory and excitatory inputs to single VLPO neurons, which are mediated, respectively, by GABAA receptors and by both non-NMDA and NMDA glutamate receptors. These projections may play important roles in conveying circadian input to systems in the preoptic area that regulate sleep and waking.

Pituitary adenylate cyclase activating polypeptide (PACAP38) is a putative neurochemical of the main retinal input to the mammalian circadian pacemaker housed in the suprachiasmatic nucleus (SCN). We assessed the phase-resetting effects of microinjection of PACAP38 into the SCN region on hamster wheel-running rhythms. When administered during the middle of the subjective day, PACAP38 evoked large but transient phase advances ( approximately 60 min), that were followed by small, steady-state phase delays. During the early subjective night, PACAP38 elicited small to moderate phase delays without any detectable concentration-dependence. Late in the subjective night, PACAP38 had no significant effects. Saline microinjection had no effect at any phase tested. These findings show that PACAP38 has small to moderate effects on the phase of the hamster SCN circadian pacemaker, including significant phase delays early in the subjective night.

Dynamic changes in astrocytic processes in the Syrian hamster suprachiasmatic nucleus (SCN) have been reported with maximal process extension in the light phase and maximal process retraction in the dark phase of a daily light:dark cycle. In the present study, we asked whether dynamic changes occur in the distribution of an astrocytic metabolic marker, glycogen phosphorylase (GP), using a histochemical assay to reveal the distribution of both active and total GP, in the hamster SCN. Changes in glial acidic fibrillary protein (GFAP) immunoreactivity also were assessed using a relative optical density measure (ROD). We observed changes in the localization and distribution of GP both in the SCN and in the paraventricular nucleus of the hypothalamus (PVN) as a function of time of day. In the light phase, there were concentrated, large, dot-like deposits of GP throughout the SCN and PVN on an empty background. In the dark phase, diffuse, small, granular particles were seen throughout both nuclei. Selectively, in the dark-phase SCN, these granular particles formed a rim of intense GP reactivity on the lateral, ventral, posterior, and medial borders. Significantly higher levels of GP reactivity were seen in anterior sections of the medial optic chiasm in the light phase. GFAP-immunoreactive astrocytic processes had higher ROD levels in the dark phase. In conclusion, the astrocytic metabolic marker, GP, exhibits a significant daily variation in localization in both the SCN and the PVN that correlates with dynamic changes in the distribution of astrocytic processes in the SCN. Increased GP activity also occurs in astrocytes among optic fibers subjacent to the SCN during light input. J. Comp. Neurol. 435:249–258, 2001. © 2001 Wiley-Liss, Inc.

Extracellular and whole-cell patch-clamp recordings were made from neurons in the ventromedial preoptic area in rat horizontal brain slices. Responses to single-pulse electrical stimulation of the ipsilateral suprachiasmatic nucleus were characterized using peristimulus time histograms or postsynaptic current recordings, and bath application of neurotransmitter receptor antagonists. Extracellular recordings showed that suprachiasmatic nucleus stimulation (50-150 microA) elicited a short-latency suppression in 35 of 64 neurons (55%), with the majority (29/35, 83%) showing a biphasic response consisting of a short-latency suppression followed by a long-duration activation. In addition, 14 cells (22%) showed activation only, while 15 (23%) were unresponsive. The GABA(A) receptor antagonist bicuculline (5-10 microM) reversibly blocked suppressions evoked by suprachiasmatic nucleus stimulation (20/20 cells). In the majority of these neurons (13/20), bicuculline also unmasked an activation in response to stimulation. Activations elicited by suprachiasmatic nucleus stimulation, either in the presence or absence of bicuculline, were blocked by the non-N-methyl-D-aspartate and N-methyl-D-aspartate glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3-dione and (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (10/10 cells). 6,7-Dinitroquinoxaline-2,3-dione (10 microM) selectively and reversibly blocked the initial, short-duration (50 ms) activation, but had no effect on the longer-duration activation. In contrast, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (10 microM) appeared to inhibit the long-duration activation selectively without affecting the initial rapid activation. Combined applications of the two ionotropic glutamate receptor antagonists blocked stimulation-induced activations completely. All the pharmacological effects were concentration dependent. Whole-cell patch-clamp recordings showed that suprachiasmatic nucleus stimulation elicited inhibitory postsynaptic currents or a combination of inhibitory and excitatory postsynaptic currents in 25 of 33 neurons tested. The inhibitory postsynaptic currents had short onset latencies (4.9+/-0.3 ms) and a reversal potential of -56.0+/-3.8 mV (n=5), and were reversibly blocked by bicuculline (5-10 microM, 4/4 cells). In the presence of bicuculline (5-10 microM), excitatory postsynaptic currents had short onset latencies (4.7+/-0.5 ms), and had a fast and a slow component. (+/-) 3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid blocked the slow, but not the fast, component, whereas 6,7-dinitroquinoxaline-2, 3-dione blocked the fast, but not the slow, component (n=7). These results suggest that the projection from the suprachiasmatic nucleus conveys both inhibitory (GABA) and excitatory (glutamate) inputs to the ventromedial preoptic area. GABA(A) receptor and both non-N-methyl-D-aspartate and N-methyl-D-aspartate glutamate receptors mediate these influences. These inputs may be responsible for conveying information related to circadian phase from the suprachiasmatic nucleus to regions of the preoptic area known to be involved in regulation of sleep/waking and other physiological functions.

The hypothalamic suprachiasmatic nucleus (SCN) functions as a circadian pacemaker regulating a variety of physiological and behavioral rhythms in mammals. Retinal illumination evokes expression of several immediate-early genes, including junB, in the ventral SCN early in the subjective night and throughout the SCN later in the subjective night. junB mRNA and protein are also expressed spontaneously around subjective dawn in nocturnal rodents, but only in the dorsal SCN. We examined the biochemical signaling mechanisms underlying both spontaneous and light-evoked expression of junB mRNA in the SCN of Syrian hamsters. Hamsters were injected (i.p.) before subjective dawn with vehicle or with either tyrphostin or genistein, inhibitors of protein tyrosine kinase, and maintained in the dark for 30 min. They were then exposed to a light pulse or kept in darkness for another 30 min. In situ hybridization studies demonstrated that tyrphostin pretreatment (12 or 24 mg/kg) reduced both spontaneous and light-evoked expression of junB mRNA only in the dorsal, and not the ventral, portion of the SCN. Conversely, genistein had little effect on either spontaneous or light-evoked expression of junB mRNA in any part of the SCN. These results indicate that a protein tyrosine kinase sensitive to tyrphostin but not to genistein is involved in the transduction pathways leading to expression of junB mRNA selectively in the dorsal SCN, independently of circadian phase and independently of the involvement of light.

Nocturnal light induces the expression of various immediate-early genes (IEGs) in the suprachiasmatic nucleus (SCN), the primary pacemaker of the circadian system of mammals, and causes phase shifts of behavioral rhythms. In the hamster SCN, some IEGs show both sensitivity to light induction at night and a daily peak of spontaneous expression near dawn in different regions of the nucleus. To investigate whether both patterns of IEG expression are observed in the rat SCN, the authors studied the expression of NGFI-A, junB, c-fos, and fosBnear the time of subjective dawn in rats entrained to a light-dark 12:12 cycle and then maintained in constant total darkness for ~48 h. They found that there were two independent rhythms of expression for junB and c-fos mRNAs in the SCN: (1) a rhythm of photic sensitivity expressed throughout the night and (2) a spontaneous rhythm of expression triggered around dawn and persisting for at least 2 h into the day. By contrast, fosB and NGFI-A transcripts were expressed only after light exposure at night and did not exhibit significant levels of spontaneous expression in the absence of photic input. These observations demonstrate that the circadian clock gates expression of two independent rhythms related to IEG expression in the rat SCN. The rhythm of sensitivity to nocturnal light exposure is expressed more strongly in the ventral SCN and may be related to photic entrainment. The second rhythm is triggered spontaneously in darkness around subjective dawn and is expressed in more dorsal parts of the SCN.

Nocturnal light exposure induces immediate-early gene (IEG) expression in the hypothalamic suprachiasmatic nucleus (SCN) and causes phase shifts of activity rhythms in mammals. Some IEGs also show a circadian rhythm of expression in the SCN. While excitatory amino acids (EAAs) are known to be involved in mediating photic regulation of entrainment and gene expression, their involvement in spontaneous rhythms of gene expression has not been studied. We assessed the role of NMDA receptors in the expression of NGFI-A, junB and fosB mRNAs induced by light pulses of different intensities late in the night (Zeitgeber Time [ZT] 18). We also examined the spontaneous expression of junB mRNA near subjective dawn (ZT 0). Both dim (5 lx) and bright (100 lx) light pulses induced similar levels of expression of NGFI-A and junB in the SCN late in the night. fosB mRNA was strongly induced by bright light but was less sensitive to dim light. At ZT 18, dizocilpine (MK-801) (3 mg/kg, i.p. ), a non-competitive NMDA receptor antagonist, almost completely blocked light-evoked expression of IEG mRNAs in the ventral SCN but not in the dorsolateral region at a mid-caudal level using either light intensity. At ZT 0, MK-801 strongly reduced light-evoked expression of junB mRNA in both SCN subdivisions, but inhibited spontaneous expression significantly only in the dorsal region. NMDA receptors appear to play an important role in mediating photic input regulating IEG expression only in the ventral SCN at night. At dawn, however, NMDA receptors are involved in mediating photic effects in both parts of the SCN, as well as being involved in spontaneous activation of junB expression selectively in the dorsal SCN. These findings support the idea that the effects in the dorsolateral SCN of nocturnal light exposure are mediated by different mechanisms than those in other portions of the nucleus.