Mayumi Kimura

Wake and sleep EEG provide biomarkers in depression

Both wake and sleep electroencephalogram (EEG) provide biomarkers of depression and antidepressive therapy, respectively. For a long time it is known that EEG activity is altered by drugs. Quantitative EEG analysis helps to delineate effects of antidepressants on brain activity. Cordance is an EEG measure with a superior correlation with regional brain perfusion. Prefrontal quantitative EEG cordance appears to be a predictor of the response to antidepressants. Sleep EEG shows characteristic changes in depression as impaired sleep continuity, desinhibition of REM sleep and changes of nonREM sleep. Elevated REM density (a measure for frequency of rapid eye movements) characterizes an endophenotype in family studies of depression. REM-sleep changes including a more distinct REM rebound after sleep deprivation are found in animal models of depression. Most antidepressants suppress REM sleep in depressed patients, normal controls and laboratory animals. REM suppression appears to be a distinct, but not an absolute requirement for antidepressive effects of a compound. Sleep-EEG variables like REM latency or certain clusters of variables were shown to predict the response to the treatment with a certain antidepressant or even the course of the disorder for several years. Some of these predictive sleep-EEG markers of the longterm course of depression appear to be closely related to hypothalamo-pituitary-adrenocortical system activity.

The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection

Abstract: During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin‐1 (IL‐1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic‐pituitary secretion that characterizes infection. IL‐2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin‐releasing hormone (CRH)‐secreting neurons and releases CRH. IL‐2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL‐1α blocks the NO‐induced release of luteinizing hormone‐releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle‐stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL‐1α and granulocyte macrophage colony‐stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on γ‐aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL‐1α inhibits growth hormone (GH) release by inhibiting GH‐releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL‐1α‐induced stimulation of PRL release is also mediated by intra‐hypothlamic action of NO, which inhibits release of the PRL‐inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase‐liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL‐1β, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep.

Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Background Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called ‘stress reactivity’ (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors. Methodology/Principle Findings In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice. Conclusion/Significance Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD.

Arousal effects of orexin-A correlate with GLU release from the locus coeruleus in rats

Although orexin was found to promote food intake, recent reports proposed its involvement in the regulation of vigilance. To study the mechanism of how orexin affects arousal, we analyzed glutamate (GLU) release from the locus coeruleus (LC) in rats after systemic injection of orexin-A. Baseline levels of orexin-A in the LC were significantly higher during the dark period than the light period. Intravenous administration of orexin-A increased GLU levels as well as orexin in the LC, simultaneously promoting wakefulness. These results suggest that increases in GLU release may reflect the arousal-inducing effects of orexin.

Sleep patterns in cyclic and pseudopregnant rats

In order to clarify the relationship between sleep and reproductive activities, time-course changes in sleep were analyzed in normal female rats. The state of sleep-wakefulness was continuously monitored for 4 weeks including two-consecutive 4-day estrous cycles, a 12-day pseudopregnant period and a subsequent 4-day cycle. Sleep patterns in estrous cycle were characterized by a marked reduction in nocturnal non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) at proestrus. A significant increase in nocturnal NREMS and REMS occurred immediately after the induction of pseudopregnancy by sterile mating, lasting for the whole pseudopregnant period for NREMS and during the early and mid period for REMS. In contrast, diurnal REMS tended to decrease towards the end of pseudopregnancy. The circadian rhythm of brain temperature exhibited no reproductive activity-dependent change. The dynamic changes in sleep may correlate alterations in neuroendocrine activities specific to estrous cycles and pseudopregnancy.

7 - Somnogenic Cytokines: Methods and Overview

Publisher Summary The cytokines, especially interleukin 1 (IL-1), play a key role in the biochemical regulation of sleep. IL-1α or β enhances sleep in rabbits, rats, cats, and humans. The IL-1 receptor antagonist transiently inhibits sleep in rabbits. Substances that induce IL-1 production enhance sleep and substances that inhibit IL-1 production inhibit sleep. Antibodies to IL-1 attenuate sleep rebound that normally occurs after sleep deprivation. Other cytokines, for example, tumor necrosis factor α and β, interleukin 2 and interferon are also implicated in sleep regulation; however, the role of these cytokines in sleep regulation is not as well studied as that of IL-1. Animals that sleep more after challenge have a higher probability of survival. The mechanisms that are responsible for this enhancement involve the microbial product induction of cytokine production. Cytokines are involved in both physiological sleep and in sleep responses during pathology. There are no direct measures of sleep.

Sleep disturbances in highly stress reactive mice: Modeling endophenotypes of major depression

BackgroundNeuronal mechanisms underlying affective disorders such as major depression (MD) are still poorly understood. By selectively breeding mice for high (HR), intermediate (IR), or low (LR) reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis, we recently established a new genetic animal model of extremes in stress reactivity (SR). Studies characterizing this SR mouse model on the behavioral, endocrine, and neurobiological levels revealed several similarities with key endophenotypes observed in MD patients. HR mice were shown to have changes in rhythmicity and sleep measures such as rapid eye movement sleep (REMS) and non-REM sleep (NREMS) as well as in slow wave activity, indicative of reduced sleep efficacy and increased REMS. In the present study we were interested in how far a detailed spectral analysis of several electroencephalogram (EEG) parameters, including relevant frequency bands, could reveal further alterations of sleep architecture in this animal model. Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days.ResultsDifferences in the amount of REMS and wakefulness and in the number of transitions between vigilance states were found in HR mice, when compared with IR and LR animals. Increased frequencies of transitions from NREMS to REMS and from REMS to wakefulness in HR animals were robust across the light-dark cycle. Detailed statistical analyses of spectral EEG parameters showed that especially during NREMS the power of the theta (6-9 Hz), alpha (10-15 Hz) and eta (16-22.75 Hz) bands was significantly different between the three breeding lines. Well defined distributions of significant power differences could be assigned to different times during the light and the dark phase. Especially during NREMS, group differences were robust and could be continuously monitored across the light-dark cycle.ConclusionsThe HR mice, i.e. those animals that have a genetic predisposition to hyper-activating their HPA axis in response to stressors, showed disturbed patterns in sleep architecture, similar to what is known from depressed patients. Significant alterations in several frequency bands of the EEG, which also seem to at least partly mimic clinical observations, suggest the SR mouse lines as a promising animal model for basic research of mechanisms underlying sleep impairments in MD.

Fully automated sleep deprivation in mice as a tool in sleep research

Although total sleep deprivation is frequently used in sleep research, the techniques used such as gentle handling are labor consuming and not standardized (and boring). In order to minimize these limitations, we developed a fully automated setup, which can be used for total sleep deprivation. A shortfall of individually adjustable thresholds of electromyogram (EMG) signals from sleep deprived animals was used online to switch running wheels incorporated into the home cages. Randomized direction of rotations, adaptable rotational speed and automatic deactivation of the running wheels during quiet waking of the animals provided robust and standardized sleep deprivation without increased stress, when compared to gentle handling. The setup can easily be introduced to a variety of home cages and is individually adaptable to each animal to be sleep deprived.

Assessing Behavioural Effects of Chronic HPA Axis Activation Using Conditional CRH-Overexpressing Mice

The corticotropin-releasing hormone (CRH) and its cognate receptors have been implicated in the pathophysiology of stress-related disorders. Hypersecretion of central CRH and elevated glucocorticoid levels, as a consequence of impaired feedback control, have been shown to accompany mood and anxiety disorders. However, a clear discrimination of direct effects of centrally hypersecreted CRH from those resulting from HPA axis activation has been difficult. Applying a conditional strategy, we have generated two conditional CRH-overexpressing mouse lines: CRH-COEDel mice overexpress CRH throughout the body, while CRH-COEAPit mice selectively overexpress CRH in the anterior and intermediate lobe of the pituitary. Both mouse lines show increased basal plasma corticosterone levels and consequently develop signs of Cushing’s syndrome. However, while mice ubiquitously overexpressing CRH exhibited increased anxiety-related behaviour, overexpression of CRH in the pituitary did not produce alterations in emotional behaviour. These results suggest that chronic hypercorticosteroidism alone is not sufficient to alter anxiety-related behaviour but rather that central CRH hyperdrive on its own or in combination with elevated glucocorticoids is responsible for the increase in anxiety-related behaviour. In conclusion, the generated mouse lines represent valuable animal models to study the consequences of chronic CRH overproduction and HPA axis activation.