Reidun Ursin

The association between sleep duration, body mass index and metabolic measures in the Hordaland Health Study.

Several studies show that short self‐reported sleep duration is associated with elevated body mass index (BMI). Short sleep duration may change appetite hormones, but whether this also influences metabolic measures like cholesterol and triglycerides is less clear. Furthermore, obesity is linked to increases in blood pressure, and recently, short sleep duration has been shown to be an independent risk factor for hypertension. This is a population‐based cross‐sectional study (The Hordaland Health Study). A subgroup of 8860 subjects, aged 40–45 years, answered a sleep questionnaire. Body weight, height and blood pressure were measured, and non‐fasting blood samples were collected and analyzed for total cholesterol, HDL‐cholesterol and triglycerides. Sleep duration was divided into the following subgroups: <5, 5–5.99, 6–6.99, 7–7.99, 8–8.99 and ≥9 h. The results show that short sleep duration was associated with elevated BMI and increased prevalence of obesity. Similar to BMI, levels of cholesterol, triglycerides, systolic and diastolic blood pressure were higher in subjects with short sleep duration. This co‐variation seemed to be attributed to variables like gender, smoking and BMI. In conclusion, our study confirms a clear association between short sleep duration and elevated BMI and obesity. Furthermore, levels of total cholesterol, HDL‐cholesterol, triglycerides and blood pressure were associated with sleep duration.

Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies

Several areas in the brainstem and forebrain are important for the modulation and expression of the sleep/wake cycle. Even if the first observations of biochemical events in relation to sleep were made only 40 years ago, it is now well established that several neurotransmitters, neuropeptides, and neurohormones are involved in the modulation of the sleep/wake cycle. Serotonin has been known for many years to play a role in the modulation of sleep, however, it is still very controversial how and where serotonin may operate this modulation. Early studies suggested that serotonin is necessary to obtain and maintain behavioral sleep (permissive role on sleep). However, more recent microdialysis experiments provide evidence that the level of serotonin during W is higher in most cortical and subcortical areas receiving serotonergic projections. In this view the level of extracellular serotonin would be consistent with the pattern of discharge of the DRN serotonergic neurons which show the highest firing rate during W, followed by a decrease in slow wave sleep and by virtual electrical silence during REM sleep. This suggests that during waking serotonin may complement the action of noradrenaline and acetylcholine in promoting cortical responsiveness and participate to the inhibition of REM-sleep effector neurons in the brainstem (inhibitory role on REM sleep). The apparent inconsistency between an inhibitory and a facilitatory role played by serotonin on sleep has at least two possible explanations. On the one hand serotonergic modulation on the sleep/wake cycle takes place through a multitude of post-synaptic receptors which mediate different or even opposite responses; on the other hand the achievement of a behavioral state depends on the complex interaction between the serotonergic and other neurotransmitter systems. The main aim of this commentary is to review the role of brain serotonin in relation to the sleep/wake cycle. In particular we highlight the importance of microdialysis for on-line monitoring of the level of serotonin in different areas of the brain across the sleep/wake cycle.

Effects of chronic mild stress on sexual behavior, locomotor activity and consumption of sucrose and saccharine solutions

Many symptoms of human depressive disorders are also observed in animals after exposure to unpredictable stressors. The chronic mild stress (CMS) paradigm was developed in order to better model the human situation by using chronic mild stressors over a longer period. It is claimed that the model induces anhedonia in the animals, a core symptom of depression in humans. Despite the fact that the CMS model has a high degree of face validity, there are a number of laboratories in which the establishment of the model is less reliably observed. We have examined behavior (sexual activity and open field activity) together with hedonic measures (sucrose and saccharine intake) after exposure to CMS. CMS decreased male sexual activity (e.g. reduced capability to ejaculate) and increased activity in an open field test. The hedonic measures showed diverging results after CMS in our laboratory. Sucrose consumption was reduced, while saccharine consumption did not show a comparable change. It is concluded that CMS induces comparable alterations to some depression-like symptoms in humans. Saccharine consumption is not a reliable indicator of the hedonic responsiveness to CMS.

On-line detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat

We used in vivo microdialysis coupled with polygraphic recording to monitor 5-hydroxytryptamine levels in the dorsal raphe nucleus and frontal cortex across waking, slow-wave sleep and rapid eye-movement sleep. Male Sprague-Dawley rats were prepared with electroencephalogram and electromyogram electrodes. Microdialysis probes were placed in dorsal raphe nucleus and/or frontal cortex. Dialysate samples were manually collected during polygraphically-defined behavioural states and the level of serotonin was assayed by means of microbore high-performance liquid chromatography separation and electrochemical detection. Samples from microdialysis probes histologically localized to the dorsal raphe nucleus and frontal cortex showed different levels of extracellular 5-hydroxytryptamine in waking, slow-wave sleep and rapid eye-movement sleep. In dorsal raphe nucleus the extracellular level of serotonin was highest in waking, decreased in slow-wave sleep to 69% and in rapid eye-movement sleep to 39% of waking mean level (waking 3.2 +/- 0.9; slow-wave sleep 2.2 +/- 0.8; rapid eye-movement sleep 1.3 +/- 0.4 fmol/sample). Mean extracellular levels of serotonin in frontal cortex displayed a similar pattern (waking 1.7 +/- 0.4; slow-wave sleep 1.0 +/- 0.3; rapid eye-movement 0.5 +/- 0.05 fmol/sample). In frontal cortex, rapid eye-movement sleep samples were only obtained in three animals. Our findings are consistent with previous results in cats, and suggest that in rats also, extracellular 5-hydroxytryptamine levels in dorsal raphe nucleus and frontal cortex across the sleep/wake cycle might reflect serotonergic neuronal activity. The findings stress the importance of controlling for behavioural state when investigating neurochemical correlates of serotonergic function.

Chronic mild stress affects sucrose intake and sleep in rats.

Depression in humans is associated with sleep abnormalities of three types: altered rapid eye movement (REM) sleep, fragmented sleep, and reduced delta sleep. In an animal model of depression, chronic exposure to mild stressors (CMS, e.g. periods of soiled cage, reversed light/dark cycle, grouped housing, food and/or water deprivation) causes behavioral and hormonal changes which, in humans, often are associated with depression. In the CMS model, a reduced sucrose intake has been defined as one of the core symptoms of depression, anhedonia, although this finding is not consistent among various laboratories. In the present study, we investigated if the CMS procedure, in our laboratory, would cause decreased sucrose intake and, also, give sleep changes similar to what is found in depressed patients. Exposure to CMS decreased sucrose intake in our rats. The largest effect was obtained after 2 weeks of the stress protocol. CMS rats spent more time in REM sleep and showed more fragmented sleep compared to their baseline recording, while there were no changes in the control rats. Increased sleep fragmentation in CMS rats was particularly evident by increased number of arousals, and increased REM sleep and slow-wave-sleep-1 (SWS-1) episodes. The duration of sleep stage episodes was decreased. The amount of slow-wave-sleep-2 (SWS-2) was not decreased, however SWS-2 in percent of total SWS was reduced. Correlation analysis showed that animals that had less consumption of sucrose spent more time in REM sleep and had increased number of REM sleep episodes. In this study, CMS appears to be a model of depression.

Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression

One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric acid (GABA). Furthermore, altered GABAergic function is also evident in depressed patients and in animal models of depression. Disturbed sleep is characteristic of patients with mood disorders. The most pronounced changes of the 5-HT firing activity occur during sleep. Hence, the present paper reports a study on simultaneously measurement of hippocampal levels of serotonin and GABA during waking and sleep in the chronic mild stress (CMS) animal model of depression. The neurotransmitter findings are accompanied by depression-like symptoms (e.g. sleep alterations and reduced sucrose intake, a putative indicator of anhedonia in rodents). Our results show that animals exposed to CMS had lower hippocampal GABA levels compared to controls. In addition, after CMS there was a lack of 5-HT stage-dependency. A subgroup (five out of eight animals) showed a consistent increase in 5-HT levels in slow wave sleep and REM sleep. We also observed that this increase occurred in those animals regarded as most anhedonic (lowest intake of sucrose solution). Moreover, REM sleep was positively correlated with anhedonia. No interaction between 5-HT and GABA was found in the hippocampus. The data suggest that both GABAergic and serotonergic systems may be simultaneously but independently involved in depression. The alteration in 5-HT function may represent a link between depression-like behaviour and sleep abnormalities found in depressed patients.

Sleep/waking effects of a selective 5-HT1A receptor agonist given systemically as well as perfused in the dorsal raphe nucleus in rats.

Sleep/waking stages and behavior were studied following the selective 5-HT1A agonist 8-OH-DPAT given subcutaneously (s.c.) (0.010-0.375 mg/kg) as well as perfused continuously (10 microM) for 6 h into the dorsal raphe nucleus (DRN) using microdialysis. Given systemically, 8-OH-DPAT at 0.375 mg/kg s.c. induced 5-HT behavioral syndrome, increased waking to 149% and reduced slow wave sleep (SWS) to 86%, transition to 76% and rapid eye movement (REM) sleep to 73%. The effect on deep SWS (SWS-2) was biphasic, with an increase after 2 h. 8-OH-DPAT at 0.010 mg/kg did not have any vigilance effects. 8-OH-DPAT perfusion in DRN produced a fourfold increase in REM sleep compared to perfusion of artificial cerebrospinal fluid. This is consistent with the hypothesis that reduced 5-HT neurotransmission following 5-HT1A autoreceptor stimulation will disinhibit cholinergic REM-promoting mesopontine neurons and thereby lead to a REM sleep increase. The other sleep/waking stages were not significantly affected by 8-OH-DPAT perfusion in DRN.

The effect of sleep deprivation and recovery sleep on plasma corticosterone in the rat

The effect of 24-h sleep deprivation by forced locomotion on plasma corticosterone was investigated in the rat. Corticosterone was slightly elevated after 21.5 h sleep deprivation, but did not differ from controls after a 2.5-h recovery period. An acute 20-min forced locomotion period caused a marked rise in plasma corticosterone. It is concluded that stress is not a major factor contributing to the massive effects of sleep deprivation on sleep parameters.

Sleep stage relations within the sleep cycles of the cat.

Abstract In two 24 h recordings from each of 11 cats, sleep was divided into light slow wave sleep (LSWS), deep slow wave sleep (DSWS) and REM sleep. Sleep stage alternation, hourly distribution of sleep stages and correlations of the different sleep stages within the sleep cycles were analysed. The main line in stage alternation was from awake to LSWS to DSWS to REM sleep. In 8 of the cats there was a significant positive correlation between the inter-REM content of DSWS and the preceding REM sleep period. Two factors are postulated to account for this interaction of DSWS and REM sleep: a triggering factor, possibly neural, and a duration control factor, possibly humoral.

Platform sleep deprivation affects deep slow wave sleep in addition to REM sleep

Rats were sleep deprived by the platform method to look for differential effects on light and deep slow wave sleep depending on platform size. Diameters of large and small platforms were 15 cm and 5.1 cm respectively. Sleep was recorded during a baseline light period (09.00-19.00 h), continuously during 48 h of sleep deprivation and during the first lights on recovery period (09.00-19.00 h). In both platform conditions REM sleep was virtually abolished during the first light period (hours 0-10 of sleep deprivation), while NREM sleep was reduced to approximately half of control values. During the second light period (hours 22-34 of sleep deprivation) REM sleep recovered somewhat in the large platform group. Light slow wave sleep (SWS-1) was comparable to baseline while deep slow wave sleep (SWS-2) was still significantly reduced. In the small platform group both SWS-2 and REM sleep was considerably reduced on day 2. Over the whole deprivation period there was an effect of platform size on SWS-1 (higher in the small platform group), and on SWS-2 and REM sleep (lower in the small platform group). During the 9 h light-time recovery sleep there was an REM sleep rebound in both groups. SWS-1 was reduced in both groups while SWS-2 was not significantly increased. The ratio SWS-2/SWS-1 was, however, significantly increased only in the small platform group recovery sleep. The results suggest that platform sleep deprivation deprives the animals of deep slow wave sleep in addition to REM sleep. This has implications for conclusions on REM sleep function based upon REM sleep deprivation.