Peter Meerlo

Restricted and disrupted sleep: Effects on autonomic function, neuroendocrine stress systems and stress responsivity

Frequently disrupted and restricted sleep is a common problem for many people in our modern around-the-clock society. In this context, it is an important question how sleep loss affects the stress systems in our bodies since these systems enable us to deal with everyday challenges. Altered activity and reactivity of these systems following insufficient sleep might have serious repercussions for health and well-being. Studies on both humans and rodents have shown that sleep deprivation and sleep restriction are conditions often associated with mild, temporary increases in the activity of the major neuroendocrine stress systems, i.e., the autonomic sympatho-adrenal system and the hypothalamic-pituitary-adrenal axis. Sleep deprivation may not only have a direct activating effect by itself but, in the long run, it may also affect the reactivity of these systems to other stressors and challenges. Although the first signs of alterations in the way people deal with challenges under conditions of restricted sleep appear to be on the level of emotional perception, chronic sleep restriction may ultimately change the fundamental properties of neuroendocrine stress systems as well. Understandably, few controlled studies in humans have been devoted to this topic. Yet, experimental studies in rodents show that chronic sleep restriction may gradually alter neuroendocrine stress responses as well as the central mechanisms involved in the regulation of these responses. Importantly, the available data from studies in laboratory animals suggest that sleep restriction may gradually change certain brain systems and neuroendocrine systems in a manner that is similar to what is seen in stress-related disorders such as depression (e.g., reduced serotonin receptor sensitivity and altered regulation of the hypothalamic-pituitary-adrenal axis). Such data support the view that insufficient sleep, by acting on stress systems, may sensitize individuals to stress-related disorders. Indeed, epidemiological studies suggest that sleep complaints and sleep restriction may be important risk factors for a variety of diseases that are often linked to stress, including cardiovascular diseases and mood disorders.

Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action

Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to the etiology of depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in antidepressant action.

The temporal dynamics of the stress response.

This paper summarises the available evidence that failure of defense mechanisms in (semi)-natural social groups of animals may lead to serious forms of stress pathology. Hence the study of social stress may provide animal models with a high face validity. However, most of the animal models of human stress-disorders have concentrated on the consequences of chronic exposure to stressors. The present paper considers recent data, indicating that a single experience with a major stressor in the form of social defeat may have long-term consequences ranging from hours to days and weeks. It seems that the experience of a major stressor sensitizes the animal to subsequent stressors. The consequences of these long-term temporal dynamics of the stress response to the development of stress-related disorders and stress-vulnerability are discussed.

Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat.

Social stress in rats is known to induce long-lasting, adverse changes in behaviour and physiology, which seem to resemble certain human psychopathologies, such as depression and anxiety. The present experiment was designed to assess the influence of individual or group housing on the vulnerability of male Wildtype rats to long-term effects of inescapable social defeat. Group-housed rats were individually exposed to an aggressive, unfamiliar male conspecific, resulting in a social defeat. Defeated rats were then either individually housed or returned to their group. The changes in their behaviour and physiology were then studied for 3 weeks. Results showed that individually housed rats developed long-lasting, adverse behavioural and physiological changes after social defeat. Their body growth was significantly retarded (p < .05) between 7 and 14 days after defeat. When individually and group-housed rats were exposed to a mild stressor (sudden silence) 2 days after defeat, both groups became highly immobile. However, when exposure was repeated at day 21, individually housed rats were still highly immobile compared to group-housed rats which regained their normal mobility after only 7 days. In an open field test, also regularly repeated, individually housed rats took significantly longer to leave their home base and were also significantly less mobile than group-housed rats over the entire 3-week test period as well as at specific timepoints. When the rats were placed in an elevated plus-maze 14 days after defeat, those that were individually housed were significantly more anxious than those that were group-housed. When tested at 21 days after defeat in a combined dexamethasone (DEX)/corticotrophin-releasing factor (CRF) test, results showed that the hypothalamic-pituitary-adrenocortical (HPA) activity in individually housed rats was higher. This was evidenced in the latter animals by the fact that DEX was significantly less able to suppress the secretion of ACTH and corticosterone, and by a significantly higher release of ACTH after administration of CRF. Although the weights of the spleen and testes of the two groups did not differ, the adrenals of individually housed rats were larger and the thymus and seminal vesicles were smaller. We conclude that when rats are isolated after defeat, they show long-lasting, adverse behavioural and physiological changes that resemble symptoms of stress-related disorders. In contrast, when familiar rats are housed together these effects of a social defeat are greatly reduced. These findings show that housing conditions importantly influence the probability of long-term adverse behavioural and physiological effects of social defeat in male Wildtype rats.

The Influence of Postnatal Handling on Adult Neuroendocrine and Behavioural Stress Reactivity

Environmental stimuli during early stages of life can influence the development of an organism and may result in permanent changes in adult behaviour and physiology. In the present study we investigated the influence of early postnatal handling on adult neuroendocrine and behavioural stress reactivity in Wistar rats. Pups were subjected to handling from postnatal day 1–21. The young were taken from the nest every day for 15 min and each of the pups was handled separately. Control nests were left undisturbed. When the animals had reached an adult age of 3–4 months they were individually housed and subjected to a series of tests to measure their stress reactivity. In the first experiment we established adult behavioural coping with stressors and anxiety in the following series of tests: open field test, shock prod defensive burying test, elevated plus maze and conditioned fear test. Collectively, the data clearly indicate that handled animals are characterized by a lower stress‐induced anxiety. Yet, handled and control animals do not differ in their general way of coping with stressors. Although the lower anxiety in handled animals is often reflected in a higher activity, they are not more active per se. In a second experiment, animals were provided with a permanent jugular vein canula for repeated blood sampling to determine stress hormones: noradrenaline, adrenaline, prolactin and corticosterone. Animals were subjected to a novelty test and a conditioned fear test. The neuroendocrine response profile is consistent with the conclusion that handled animals are less anxious than controls but are not different in their general strategy of coping with stressors. The handled animals showed an attenuated adrenaline, prolactin and corticosterone response. Yet, in neither of the two tests there was a difference in noradrenaline response, a typical marker for an active coping strategy. Interestingly, the differences in neuroendocrine reactivity already appeared in response to a mild novelty challenge when there were no clear behavioural differences yet. The neuroendocrine measures are in line with the behavioural data but more sensitively reflect the differences between handled and control animals.

New neurons in the adult brain: The role of sleep and consequences of sleep loss

Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.

Changes in daily rhythms of body temperature and activity after a single social defeat in rats

The long-term consequences of social stress on daily rhythms of body temperature and activity in rats were studied by means of radiotelemetry with intraperitoneally implanted transmitters. Rats were subjected to a single social defeat by placing them into the territory of a male conspecific for 1 h. Social defeat caused a sharp subsequent reduction in the amplitude of the daily temperature rhythm, which lasted for at least 4 days. The reduced amplitude was mainly due to higher temperatures during the circadian rest phase, i.e., the light period. Movement activity was less affected, but the decrease in activity during the dark phase after defeat correlated significantly with the temperature increase during the light phase. The stress-induced changes in daily rhythms of body temperature and activity are discussed in terms of their relevance to the role of rhythm-disturbances in the pathogenesis of affective disorders.

Changes in behaviour and body weight following a single or double social defeat in rats.

In a series of experiments, the consequences of a single and double social conflict on various behaviours and body weight in rats were studied. Animals were subjected to social defeat by placing them into the territory of an aggressive male conspecific for one hour, either once, or twice at the same time on two consecutive days. To assess the consequences of social defeat, three experiments were performed with independent groups of rats. In the first experiment, an open field test was performed two days after the last conflict. Locomotor activity was strongly reduced after social defeat. There were no differences between the single and double defeat group. To assess the effects of social defeat on subsequent social behaviour, a second experiment was performed in which experimental animals were confronted with an unfamiliar non-aggressive rat two days after a single or double conflict. Social defeat resulted in a reduction of social contact with the unfamiliar conspecific. There was no difference between the single and double conflict group. In the third experiment, the effects of social conflict on food intake, body weight and saccharine preference were measured. Food intake was not affected after a single conflict, but in the double conflict group food intake was decreased for several days. Body weight gain was decreased after both single and double social defeat. The decrease was stronger in the double conflict group. Water intake and saccharine preference were not significantly affected. This study revealed that social defeat in rats causes pronounced changes in various behaviours and body weight. Different aspects of behaviour are differentially affected by defeat with respect to the magnitude and time course of the changes induced. Moreover, different behavioural parameters are differentially sensitive to repetition of the stressor.

Sleep Restriction Alters the Hypothalamic-Pituitary-Adrenal Response to Stress

Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic‐pituitary‐adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short‐lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8‐day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30‐min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under conditions of long total sleep deprivation but also after repeated sleep curtailment.

Poor sleep as a potential causal factor in aggression and violence

Clinical observations suggest that sleep problems may be a causal factor in the development of reactive aggression and violence. In this review we give an overview of existing literature on the relation between poor sleep and aggression, irritability, and hostility. Correlational studies are supporting such a relationship. Although limited in number, some studies suggest that treatment of sleep disturbances reduces aggressiveness and problematic behavior. In line with this is the finding that sleep deprivation actually increases aggressive behavior in animals and angriness, short-temperedness, and the outward expression of aggressive impulses in humans. In most people poor sleep will not evoke actual physical aggression, but certain individuals, such as forensic psychiatric patients, may be particularly vulnerable to the emotional dysregulating effects of sleep disturbances. The relation between sleep problems and aggression may be mediated by the negative effect of sleep loss on prefrontal cortical functioning. This most likely contributes to loss of control over emotions, including loss of the regulation of aggressive impulses to context-appropriate behavior. Other potential contributing mechanisms connecting sleep problems to aggression and violence are most likely found within the central serotonergic and the hypothalamic-pituitary-adrenal-axis. Individual variation within these neurobiological systems may be responsible for amplified aggressive responses induced by sleep loss in certain individuals. It is of great importance to identify the individuals at risk, since recognition and adequate treatment of their sleep problems may reduce aggressive and violent incidents.