The hypothalamo-pituitary-adrenal (HPA) system is a most important mediator of the organism's response to stress. Secretory activity of this endocrine system displays a specific regulation during normal nocturnal sleep in humans. Pituitary release of adrenocorticotropin (ACTH) as well as adrenocortical release of cortisol decreases to a minimum during early sleep which is simultaneously characterized by maximum release of growth hormone (GH) and a predominance of slow wave sleep (SWS). In contrast, release of ACTH and cortisol reaches a maximum during late sleep which is simultaneously characterized by minimum plasma concentrations of GH and a predominance of rapid eye movement (REM) sleep. The nadir activity of the pituitary-adrenal system during early sleep reflects an active inhibition of this 'stress' system. One of the factors mediating this inhibition presumably is the sleep associated hypothalamic secretion of a release inhibiting factor of ACTH. In addition, limbichippocampal neuronal networks contribute to the inhibitory control over HPA activity during early sleep. Those structures appear to coordinate HPA inhibition and cortical activity (with prevalent SWS) during early sleep, thereby facilitating the formation of memories in sleep. As indicated by studies testing the effects of elevated plasma glucocorticoid levels, the inhibition of HPA activity during early sleep is an essential prerequisite for the memory function of sleep. Possibly, immunological memory formation likewise benefits from this inhibition. The suppression of pituitary-adrenal secretory activity during early sleep can be significantly weakened after profound acute stress as well as in states of chronic stress (including normal aging) which thereby disturb regular memory formation in sleep.
Keywords: hypothalamo-pituitary-adrenal system, sleep, memory, stress
|How to cite this article:|
Born J, Fehm HL. The neuroendocrine recovery function of sleep. Noise Health 2000;2:25-37
| Introduction|| |
Since the work of Selye (1956), enhanced secretory activity within the HPA system is known to be a primary stress response of the organism. The pituitary-adrenal response can be elicited by a great variety of aversive events including noise load, although in humans responses to noise strongly differ from individual to individual (e.g., Fruhstorfer et al. 1988, Borg 1981). Chronically enhanced release of pituitary-adrenal hormones has been considered to be an essential mediating factor in the pathogenesis of various psychosomatic diseases (Mason 1970, Munck et al. 1984). Sleep is generally assumed to be important for recovery from the stress of the wake phase, and this view derives its main support from everyday experience. If this is true, pituitary-adrenal activity should be shut off during sleep.
This short review will cover a series of experiments from our laboratory which aimed to clarify the regulation of the pituitary-adrenal system during human sleep, its underlying mechanisms, its sensitivity to stressful events and its functions. The study results indicate in fact an inhibition of pituitary-adrenal activity restricted to the first hours of nightly sleep. It is proposed that it serves primarily to support the formation of long-term memory during sleep, and thereby improves long-term adaptation of the organism to psychological and perhaps also to immunological stressors.
Pituitary-adrenal activity in human sleep
The release of ACTH and cortisol is subject to a pronounced circadian rhythm which is preserved also during a continuous 24-hour wakefulness (Weitzmann et al. 1971, Born et al. 1997a). In addition, under normal physiological conditions pituitary-adrenal activity is synchronized to the sleep-wake cycle. This implies that sleep per se influences the phase of the circadian oscillation in pituitary-adrenal activity. Typically, ACTH/cortisol concentrations in plasma reach a minimum during the early hours of night-time sleep ('cortisol nadir'). But concentrations increase during the second half of the night to reach a maximum at about the time of morning awakening (Spath-Schwalbe et al. 1992; Born et al. 1986, 1998). At the central nervous system level, cortisol nadir concentrations during early sleep coincide with a prevalence of SWS. During the second half of sleep, SWS decreases to a minimum whereas REM sleep becomes prominent. The extended epochs of SWS during the early night are not only associated with minimum cortisol release, but simultaneously they coincide with peak secretion of growth hormone (GH, Takahashi et al. 1968). Thus, a pattern of endocrine activity is established during early sleep which, in fact, is unique to the state of sleep. Stressors during the wake phase can induce joint activation of cortisol and GH secretion. There are also instances (like meal intake) invoking sole activation of pituitaryadrenal secretion. However, minimum activity of ACTH/cortisol release in the presence of maximum GH release forms a pattern apparent only during the early hours of regular nocturnal sleep [Figure - 1]. Moreover, in light of the almost complete suppression of ACTH/cortisol release, early sleep from a psychoendocrinological perspective can be regarded as the only period during the day which is virtually free of any stress.
Sensitivity to stress
An important characteristic of the neuroendocrine regulation during early sleep described above, is its sensitivity to stressful events during the wake phase. This has been shown for acute (physical and psychological) stressors but, there are also data suggestive for a detrimental influence of chronic states of stress on the neuroendocrine architecture of nocturnal sleep.
[Figure - 2] summarises results from a study examining the effects of daytime physical exercise on subsequent sleep (Kern et al. 1995). Sleep recordings and parallel measurements of plasma concentrations of cortisol and GH were obtained in nonprofessional male tri-athletes (i) after a day of intense exercise (120-150 km of biking, between 1600 and 2030 h), (ii) after moderate exercise (40 km of biking, 18002030h) and (iii) after a day without exercise. The intense exercise was experienced as unusually overwhelming distress, and was followed by a significant decrease in time spent in REM sleep. Also, SWS was reduced although this effect failed to reach significance. However, most pronounced changes were revealed for hormonal concentrations. The physical distress completely destroyed the typical neuroendocrine pattern during early sleep by enhancing cortisol nadir concentrations by more than 80 % on average. Simultaneously, GH concentrations were distinctly reduced. In the second part of the night, the pattern was reversed with significantly reduced cortisol concentrations and significantly enhanced GH concentrations after physical distress as compared to nights preceded by moderate or no exercise. There are preliminary data indicating that similar increases in cortisol concentration during early sleep can occur also after acute psychological stressors such as public speaking (Pietrowsky et al. 1998).
Increased cortisol nadir concentrations appear to be also an essential marker of some states of chronic stress. Thus, an elevation of plasma cortisol concentrations observed in depressed patients was found to be most pronounced during early sleep (Deuschle et al. 1997). In addition, depressed patients suffer from sleep disturbances including a considerable decrease in time spent in SWS and in concordant secretion of GH (Jarett et al. 1990; Steiger et al. 1993).
Normal aging has been also proposed as a model of chronic stress (Sapolsky et al. 1986). During the wake phase, elderly people suffer from an overreactivity of the pituitary-adrenal system to stressors (Gotthardt et al. 1995, Born et al. 1995a). During sleep they show a neuroendocrine pattern as if they were acutely stressed. As depicted in [Figure - 3], aging is associated with a distinct and progressive elevation of cortisol nadir concentrations during early sleep and with a simultaneous decline in the secretion of GH (Kern et al. 1996). These changes are accompanied by a profound decrease in SWS during early sleep, and although somewhat less distinct, also by a decrease in REM sleep.
Together the data indicate that an enhanced cortisol nadir during early sleep in conjunction with reduced GH secretion and SWS represents a neuroendocrine pattern which indicates sensitively the effects of acute as well as chronic stress. The results lend themselves to speculate that in particular the minimum cortisol concentration reached during early sleep could be a useful marker as to the efficiency of coping with stress during the active phase.
Mechanisms of pituitary-adrenal inhibition during early sleep
Considering the potentially damaging sequelae of pituitary-adrenal hypersecretion, the mechanisms mediating the down-regulation of this system during the early night are of utmost interest to psychosomatic research. In fact, aside from contributions of circadian oscillators, nadir secretory activity of this endocrine stress system during the first hours of night-time sleep reflects a direct suppressive influence by central nervous sleep processes. This conclusion has been confirmed by studies in which sleep schedules were shifted as well as by studies probing the responsiveness of this endocrine system during different periods of the sleep/wake cycle.
Imposing an artificial 3-hour sleep-wake cycle upon their subjects, Weitzmann et al. (1974) observed reduced plasma cortisol concentrations during sleep, and in particular during SWS. Also, shifting sleep time by about 3 hours (i.e., permitting sleep either 23.00 h or after 2.00 h) led to a parallel shift of the interval of nadir cortisol concentrations during the early night. The first morning rise in cortisol concentrations in this condition was delayed by about 90 min (Born et al. 1988a). However, an early sleep suppression of cortisol release was not consistently observed when the sleep phase was shifted to daytime (VanCauter et al. 1991, Pietrowsky et al. 1994; Weibel et al. 1995). This pattern points to an interaction of the effects of sleep with the circadian rhythm. The pituitaryadrenal suppression during sleep is obtained only within a limited range of phase shifts, i.e., after a phase shift of 3-hours but not after 12-hour phase shifts of sleep.
An inhibitory influence of early nocturnal sleep on pituitary-adrenal activity was revealed also in studies examining the secretory response of the stress system by exogenous administration of ACTH secretagogues. Spath-Schwalbe et al (1993) compared ACTH and cortisol increases following intravenously administered corticotropin releasing hormone (CRH) either during the first hours of sleep when SWS was present, or during a period of stage 2 sleep within the later part of sleep. To control for circadian influences, in an additional control condition, CRH was administered at identical points in time during the night but, this time the subject was kept awake. ACTH/cortisol secretory responses invoked during SWS in the early part of sleep were distinctly suppressed as compared to responses obtained during late sleep or during wakefulness. Corresponding results were obtained also following the administration of vasopressin which is the second major secretagogue of ACTH in humans (SpathSchwalbe et al. 1987) as well as following the combined administration of CRH and vasopressin (Bierwolf et al. 1997). Also, in subjects infused continuously with CRH, sleep onset and, in particular, the subsequent occurrence of SWS episodes were associated with distinct decreases in plasma cortisol levels (Bierwolf et al. 1997). Overall, these data demonstrate an inhibitory influence of early sleep and primarily of SWS on pituitary-adrenal responsiveness. It is tempting to speculate that this inhibition is due to the hypothalamic secretion of a release inhibiting factor of ACTH during the first hours of sleep whose structure remains to be identified. The influence of this factor appears to add to the action of circadian oscillators also lowering pituitary-adrenal activity during the evening hours.
While animal experiments revealed several candidate hormones attenuating or even completely inhibiting activity of the pituitaryadrenal system, the factor mediating the early sleep inhibition of this system in humans is entirely unclear. Several studies have provided evidence for a lowered ACTH/cortisol response to CRH during concurrent infusion of atrial natriuretic peptide (ANP). This effect appeared to be more pronounced in the evening than during the morning hours (Kellner et al. 1992, 1995, Bierwolf et al. 1998). However, these findings are not proof that a similar role is played by endogenous ANP during early sleep. This would require measurement of the actual hormone concentration in portal blood.
Also, growth hormone releasing hormone (GHRH) has been suggested to suppress pituitary-adrenal activity during early sleep (Steiger et al. 1992). Confirmatory evidence for this view derives from a recent study where intranasal administration of GHRH prior to nocturnal sleep distinctly reduced cortisol nadir concentrations in aged as well as young subjects (Perras et al. 1998). Most remarkable was that intranasal GHRH administration in this study was accompanied by reduced rather than increased release of GH suggesting that the peptide via the nasal pathway acted primarily on central nervous hypothalamic sites to inhibit release of the secretagogues of GH. A similar action on hypothalamic sites may also account for the inhibiting action of GHRH on cortisol release.
Aside from hypothalamic factors, inhibitory control of the HPA system may also derive from hippocampal mechanisms. Conclusive evidence stems from animal studies that the hippocampus essentially contributes to the circadian regulation of HPA activity (e.g., Dallmann et al. 1989, DeKloet et al. 1998). Hippocampal neuronal networks involved in this control receive feedback information about HPA activity via corticosteroid receptors of two different types: type I mineralocorticoid receptors (MR) and type II glucocorticoid receptors (GR) (DeKloet et al.1998). GRs are widely distributed all over the brain. MRs are, however, concentrated in a very high density in the hippocampus and some related structures. GRs bind cortisol with less affinity than MRs and become activated only with higher glucocorticoid levels as present during acute stress. Under this condition, they appear to mediate a fast negative feedback. In contrast, MRs are typically occupied persistently by more than 80% endogenous glucocorticoids. They appear to transfer circadian control over HPA activity via a tonic inhibitory influence on this system. In fact, in humans administration of canrenoate which is a selective blocker of MRs, was found to significantly increase cortisol concentrations around the time of nadir activity (Dodt et al. 1993). Also, pretreatment with canrenoate compensated for the early sleep decrease in pituitary-adrenal responsiveness to CRH (Born et al. 1997b). The disinhibiting influence of canrenoate on pituitary-adrenal activity was found to be accompanied by a profound reduction in SWS by more than 50 % during the early hours of sleep (Born et al. 1991). Together, these changes after pretreatment with canrenoate support the view that hippocampal neuron assemblies containing MRs play a coordinating role during early sleep by linking the inhibition of pituitary-adrenal activity with the emergence of SWS.
The memory function of early sleep
Data discussed in the preceding paragraphs suggest that the inhibition of ACTH and cortisol release during the early night could be established by a concerted action of different factors acting on the pituitary, hypothalamic and also limbic-hippocampal stages of this system. Moreover, based on concurrent changes in SWS and cortisol concentrations after limbic hippocampal MR blockade with canrenoate, it was proposed that the higher order control over the HPA system by hippocampal neuron networks serves to link pituitary-adrenal inhibition with epochs of SWS. The question arises what the function of this linkage could be. A clue to this issue derived from studies investigating memory formation during sleep.
It is well established that a primary function of sleep is the formation of long-term memory (Jenkins and Dallenbach 1924; Cippoli 1995). Traditionally, REM sleep was considered to be more important in this process than SWS. However, this view was based mainly on effects of REM sleep deprivation which is a questionable manipulation in this context. For REM sleep deprivation invokes emotional disturbances which per se exert non-specific impairing influences on memory recall. In fact, in studies which did not rely on selective sleep deprivation techniques, overall memory appeared to benefit more from SWS than from REM sleep (Barret and Ekstrand 1972, Ekstrand et al. 1977, Yaroush et al. 1971, Fowler et al. 1972). Notably, in those experiments recall of learned materials was compared after undisturbed periods of early sleep and of late sleep. These are known to differ strikingly in the distribution of SWS and REM sleep and also in plasma concentrations of cortisol. If learning was followed by a 4-h retention interval placed in the early period of nocturnal sleep with prevailing SWS, recall of word pairs was significantly superior to recall after a 4-h retention interval placed in the late part of nocturnal sleep when REM sleep was predominant.
We have recently confirmed and extended these results of Ekstrand's group (Plihal and Born 1997). In this study effects of early and late sleep were examined using memory tasks differentiating between the two principle types of memory, i.e., declarative memory and procedural memory. Declarative memory refers to the acquisition of new facts and events (e.g., the date of a birthday party) while procedural memory is considered to be formed by repeatedly practicing on perceptuo-motor skill learning tasks (such as skiing and type-writing). Most important, animal experiments and studies in brain lesioned patients coherently demonstrated that the declarative memory system is essentially based on functions of the hippocampus and adjacent temporal lobe structures. In contrast, hippocampus lesioned animals and humans are not substantially impaired in forming procedural memories (Squire 1992, Squire and Zola-Morgan, 1991). In the Plihal and Born (1997) experiments, before retention sleep, healthy men learned word pairs until a criterion of 60 % correct recall responses. Such a paired associate learning task represents a classical task of declarative memory. They were also trained in a mirror tracing task (i.e., to trace a figure with a stylus while visual feedback is given only through a mirror). This is a typical task of procedural memory. The 3-h period of retention sleep between learning and recall was defined either by the early part or the late part of nocturnal sleep. Under a further control condition subjects remained awake during the respective retention periods. Early sleep which as expected was dominated by extended epochs of SWS, selectively improved recall of declarative memories (of word pairs), as compared to late retention sleep and to retention intervals filled with wakefulness. Procedural memory did not benefit from early sleep. The view that SWS during the early night selectively facilitates the consolidation of hippocampus mediated declarative memory materials has been further substantiated by experiments in rats indicating that a 'replay' of previously acquired declarative materials take place within hippocampal neuron assemblies during the SWS epochs immediately following the period of learning (Wilson and McNaugthon 1994; Skaggs and McNaughton 1996). This replay is supposed to serve to engrave the information gathered during learning for long-term storage into neocortical cell assemblies.
In recent experiments we showed that the storage of declarative memory materials during sleep is severely disrupted by elevated glucocorticoid concentrations during early sleep (Plihal et al. 1998; Plihal and Born 1998). In one of these experiments which were designed similar to those reported above (Plihal and Born 1997), subjects were infused with cortisol during the period of early retention sleep. While in a corresponding placebo condition cortisol concentrations were minimal during retention sleep (averaging 1.9 µg/dl), cortisol infusion enhanced plasma glucocorticoid concentrations to 15.2 µg/dl on average which is a level achieved also during mild stresses. Elevated cortisol levels during retention sleep distinctly impaired subsequent recall performance on the declarative memory test of paired word associates. But, they did not affect recall of mirror tracing skills [Figure - 4]. Since cortisol concentrations during learning and during the phase of recall testing were comparable between the cortisol and placebo conditions, these results suggest a selective effect of cortisol on the consolidating of declarative memories taking place in early SWS. Notably, SWS per se was not changed by cortisol infusion. A comparable impairment of declarative memory consolidation during early sleep was found also after administration of the synthetic glucocorticoid dexamethasone (Plihal et al. 1998). Since dexamethasone is a selective agonist of GRs and does bind substantially to MRs, this finding points to an essential contribution of GRs in mediating the memory impairment by cortisol, although after the oral administration only small amounts of the synthetic glucocorticoid may have reached brain target receptor sites. A greater contribution from GRs than MRs regarding the impairment of sleep associated memory after cortisol infusion was also suggested by experiments examining effects of the MR blocker canrenoate which left declarative memory consolidation during early sleep unchanged (Plihal and Born 1998). Regardless of the issue of receptor mediation, the data coherently support the view that by inhibiting adrenal release of glucocorticoids during early sleep, hippocampal activity induces a neuroendocrine milieu optimal for the transfer of declarative memory into long-term storage.
Immune function and sleep
It should be mentioned here that the supportive effect of sleep on memory may not only concern psychological events but also the response to immunological challenges. Upon immune challenge antigen presenting macrophages and monocytes release various proinflammatory cyctokines including interleukin-1 (IL-1) and tumor-necrosis-factor-cc(TNF-(c) which exert an activating influence on T cells. Upon activation, T cells by stimulating the proliferation of B and T cells, induce the formation of a specific immune response including synthesis of antigenspecific antibodies as well as the differentiation of memory cells. A principal factor controlling these processes is the T cell cytokine IL-2.
Several studies have aimed to discriminate the effects of sleep versus sleep deprivation on this chain of cytokine responses by monocytes/makrophages and T cells. Contrary to expectations, production of IL-1 and TNF-cc (after in-vitro mitogen stimulation) was found to be significantly higher in blood samples collected during a night of total sleep deprivation than during regular nocturnal sleep (Uthgenannt et al. 1995; Born et al. 1997a). However, analysis of blood cell counts indicated that this effect reflects primarily an influence of sleep versus sleep deprivation on the number of monocytes circulating in peripheral blood. Monocytes are the main source of these cytokines and their number was significantly enhanced during sleep deprivation. On the other hand, compared with continuous nocturnal wakefulness, regular sleep induced a pronounced increase in the production of IL-2 by T cells. This effect could not be explained by a redistribution of T cells (i.e., a changing number of T cells in blood). Considering IL-2's key function in the regulation of T and B cell differentiation this effect represents a first hint of a possible supportive influence of sleep also on processes resulting in the formation of immunological memories. Yet further studies of parameters more specifically reflecting different aspects of the memory process need to be done to substantiate this view.
Notably, aged people with chronically poor sleep display changes in cytokine production reminiscent of those due to the acute stress of sleep deprivation. They show increased production of IL-1 and TNF-α during sleep while production of IL-2 appears to be reduced (Born et al. 1995b, Rabinowitch et al. 1985). Also, both sleep in the aged as well as acute sleep deprivation are characterised by increased cortisol nadir concentrations during the early hours of the night, suggesting an insufficient inhibitory control over HPA activity in these states. A disinhibited HPA activity associated with chronically poor sleep and acute sleep deprivation could well be one of the factors causing immunological dysregulation and reduced production of IL-2 under these conditions. Hence, an important issue to be solved in future studies is whether and to what extent the sleep associated increase in IL-2 production can be abolished by experimentally elevating early sleep cortisol levels.
In humans, pituitary-adrenal secretion is reduced to a minimum during the early hours of regular nocturnal sleep. An inhibitory control is established during this time encompassing presumably an integrated action at the pituitary, hypothalamic and limbic-hippocampal level of this neuroendocrine stress system. Evidence has been provided that the suppression of cortisol release during the early period of sleep facilitates the sleep associated consolidation of declarative memories. Formation of immunological memories could likewise benefit from this suppression, although this needs to be further substantiated. The memory experiments, however, point to potentially adverse consequences of a deranged neuroendocrine architecture of early sleep. Acute and chronic stress during the wake phase which prevents the recovery of regular nadir glucocorticoid concentrations during early sleep, are to be expected to impair sleep associated declarative memory formation which eventually hampers the effective cognitive adaptation of an individual. In fact, due to a diminished formation of novel long-term memories, on the long run changes in consciousness and cognitive control of behaviour would be expected reminiscent of some of those observed in aged persons who display distinctly increased cortisol nadir concentrations during sleep. Also, in aged people, capabilities to form antibodies upon primary immunization has been found to be diminished (e.g., Fagioli et al. 1997, Wick and Grubeck-Loebenstein 1997).
There is good reason, to consider aging as an acceptable model of chronic stress. But, conclusions drawn here with regard to the role of neuroendocrine regulation of early sleep in the coping with stress cannot be a priori generalized to other perhaps more annoying types of chronic stress including that resulting from chronic noise load. Experiments examining endocrine activity during sleep after noise load during the wake phase yielded, if at all only marginal changes in pituitary-adrenal secretion during sleep, although some individuals may show quite strong reactions (e.g., Fruhstorfer et al. 1988). Data on neuroendocrine effects of noise presented during night-time sleep are scarce. Arousals and short awakenings provoked by auditory stimulation during early sleep may under certain conditions induce transient increases in ACTH and cortisol plasma concentrations indicating that the sleep associated inhibitory control over HPA activity, if at all, can only temporarily be removed after such manoeuvers (Spath-Schwalbe et al. 1991, Born et al. 1988b). In a study by Maschke et al. (2000) experimental exposure to aircraft noise during the night was found to increase urinary cortisol excretion during the first days of a 40 day experimental period. Later on, in some individuals the response habituated while in some others it tended to increase. Moreover, there are hints that aircraft noise could disrupt the formation of long term memories (Hygge 1998). Together, these data suggest that chronic noise exposure in some persons enhances glucocorticoid release and impairs memory formation. However, those studies did not focus on the neuroendocrine regulation during early sleep. Here we propose that the inhibition of ACTH/cortisol release during early sleep is of special importance for the recovery from stress and associated processes of declarative memory formation during sleep. On this background, there is a strong need to answer the question to what extent such chronic stresses have a particular impact on the neuroendocrine activity during this early period of sleep. If so, it would be also intriguing to examine whether this influence disturbs or delays the process of memory formation as it develops across several nocturnal sleep phases.
| Acknowledgement|| |
We thank A. Otterbein for valuable help in preparing the manuscript.
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Klinische Forschergruppe, Medizinische Universität Lübeck, Ratzeburger Allee 160, Haus 23a, D-23562 Lübeck
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]