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SLEEP AFTER IMMOBILIZATION STRESS AND SLEEP DEPRIVATION:
COMMON FEATURES AND THEORETICAL INTEGRATION

Vadim S. Rotenberg   vadir@post.tau.ac.il
Abarbanel Mental Health Center, Tel-Aviv University, Israel

CRITICAL REVIEWS IN NEUROBIOLOGY, 14(3&4): 225-231. 2000.

ABSTRACT: The goal of the present paper is to elucidate and to resolve contradictions in the relationships among different forms of stress, sleep deprivation, and paradoxical sleep (PS) functions. Acute immobilization stress and the stress of learned helplessness are accompanied by an increase of PS, whereas the stress of defense behavior and the stress of self-stimulation cause PS reduction. Recovery sleep after total sleep deprivation performed on the rotating platform is marked by a dramatic rebound of PS although NREM (non-rapid eye movement) sleep deprivation is more prominent than PS deprivation. This PS rebound leads to a quick reversal of the pathology caused by prolonged sleep deprivation. The search activity (SA) concept presents an explanation for these contradictions. SA increases body resistance to stress and diseases, whereas renunciation of search (giving up, helplessness) decreases body resistance. PS and dreams contain covert SA, which compensates for the lack of the overt SA in the preceding period of wakefulness. The requirement for PS increases after giving up and decreases after active defense behavior and self-stimulation. Immobilization stress prevents SA in waking behavior and increases the need in PS. Sleep deprivation on the rotating platform, like immobilization stress, prevents SA, produces conditions for learned helplessness and, suppresses PS. Such a combination increases PS pressure and decreases body resistance.

KEYWORDS: search activity, sleep deprivation, stress

I. INTRODUCTION: STRESS, BEHAVIOR, AND SLEEP

In this article, the author discusses the relationship between sleep studies and stress. Using the concept of search activity, it is possible to show how the variable reactions of REM sleep architecture to different types of stress can help us understand more fully the profound effects of sleep deprivation as reported by Rechtschaffen et al.1

Sleep deprivation and the evaluation of sleep structure after stress are two productive approaches to the investigation of sleep functions. Recent investigations demonstrated that an acute immobilization stress for 12 hours was accompanied by an increase in sleep duration, partly resulting from an increase of slow wave sleep (SWS), but mostly caused by an increase of the number of paradoxical sleep (PS) episodes.2-4 On the other hand, fighting and active avoidance during stress is not accompanied by an increase of PS, in comparison to the control baseline state.5 Moreover, these types of acute stress are often followed by a decrease of PS without a subsequent rebound. PS is also reduced after self-stimulation of the positive brain zones.6 Self-stimulation corresponds to Selye's7 concept of eustress in contrast to the distress produced by fighting and footshock. At the-same time, footshock causes different outcomes on sleep structure in different periods.8 The initial presentation of inescapable shocks during 1 hour was accompanied by the increase of PS latency and PS reduction. The subsequent session of foot-shocks caused the increase of PS, which correlated with the level of learned helplessness. However, this increase in PS was only transient, limited in time and space, and disappeared in the following sessions of footshocks. In the state of maladaptive anxiety caused by meaningful failures, REM sleep also has a tendency to increase.9,10 Thus, a theory that attempts to explain the influence of stress on sleep must integrate these opposite alterations of sleep structure after different types of acute and chronic stress.

The search activity concept provides such an integrative theory.11-15 Search activity is defined as activity designed to change a situation or the subject's attitude to it in the absence of a definite promise of positive results from such activity (i.e., in the case of pragmatic indefiniteness), but with constant monitoring of the results at all stages of activity. This definition makes it clear that certain behavioral categories such as stereotyped or panicky behavior cannot be classified as search behavior. Stereotyped behavior, by definition, has a quite definite outcome with no room for a search for new solutions. Panicky behavior may, at first glance, seem to imitate search behavior, but differs from it by the disturbance of the feedback between the activity and its regulation. In effect, during a panic, the results of the activity are not considered at any stage and cannot be used for the correction of behavior. No line of activity can be traced to its conclusion and panicky behavior easily becomes imitative, approaching stereotyped behavior. Finally, the antipode of search behavior is the state of renunciation of search that, in animals, may assume the form of freezing or learned helplessness and, in humans, corresponds to depression and maladaptive (neurotic) anxiety.10

One of the best indications of search activity in animals is a high-amplitude and well-organized hippocampal theta rhythm.10,13

We propose to distinguish freezing, as a reaction of surrender, from the defensive and adaptive motionless behavior that displays itself in passive avoidance or startle reaction.10,16 Freezing is nonflexible behavior and is not accompanied by hippocampal theta rhythm. On the other hand, passive avoidance reflects the temporary blocking of overt behavior while facing an unexpected and dangerous situation. It does not represent renunciation of search and can be changed immediately to active behavior in cases of changing conditions. Startle reaction is a state of intense reappraisal of the situation, in which search activity is not expressed in overt behavior.10,11 On the contrary, freezing as a surrender reaction is a form of learned helplessness and does not change until some kind of adaptive mechanism is included.17

Search activity is a component of many different forms of behavior: self-stimulation in animals, creative behavior in humans, as well as exploratory and active defense (fight/flight) behavior in all species. In all these forms of activity the outcome is indefinite, but there is a feedback between the behavior and its outcome enabling subjects to correct their behavior in accordance with the outcome. The value of a new classification of behavior based on the presence or absence of search activity is supported by its important biological correlates. In research conducted with V. Arshavsky,11,14,16 we found that all forms of behavior that include search activity increase body resistance to different forms of artificial pathology (artificial cobalt epilepsy, artificial extrapyramidal disturbances caused by neuroleptics, anaphylactoid edema, and artificial arrhythmia of cardiac contractions), whereas renunciation of search decreases body resistance, suppresses immune functions, and predisposes subjects to somatic disorders. We concluded that the presence of search activity, whether or not it is successful in finding a solution, protects the subject from somatic disorders.

It is important to emphasize that the positive outcome of search activity on body resistance and adaptation is determined mainly by the process of searching, and not by its result which is the benefit of successful search behavior. It is a crucial point of the very concept of search activity, as opposed to the concept of coping behavior, which must be successful in any case. Search activity may be unsuccessful from the pragmatic point of view and may not help to overcome obstacles, but, nevertheless, its continuation has a positive outcome on body resistance. This statement was confirmed in experiments: If an animal remains active even in the case of inescapable stressors, its resistance to the fatal disease (sarcoma) is higher than in the case of passive behavioreven in an objectively controllable situation.18,11

If search activity is so important for survival and if renunciation of search is so destructive and harmful, it would be reasonable to assume a special brain mechanism able to restore search activity after temporary and occasional renunciation of search. According to the search activity concept, this function is fulfilled by PS. Covert search activity in PS during dreams compensates for the lack of search activity in the preceding period wakefulness and ensures the resumption of search activity in the wakefulness that follows. This claim is based on the findings that:

1. Renunciation of search evoked by the direct stimulation of the ventromedial hypothalamus causes an increase of PS in subsequent sleep, while search behavior evoked by brain stimulation decreases PS in subsequent sleep.19

2. Depression in humans and learned helplessness in animals are accompanied by an increased PS requirement (decreased PS latency and increase of PS in the first sleep cycle). A correlation is detected between learned helplessness and PS percentage.8

3. Both PS and search activity in wakefulness are characterized by regular and synchronized hippocampal theta rhythm. Moreover, the more pronounced the theta rhythm in wakefulness, the less pronounced it is in the subsequent PS.19 PS in animals regularly contains pontogeniculooccipital (PGO) waves, which in wakefulness correspond to orienting activity.20

4. If the particular part of nucleus coeruleus (nucleus coeruleus aleph) in the brain stem is artificially destroyed and, as a result, muscle tone does not drop during PS, animals demonstrate complicated behavior that can be generally described as orienting activity or search behavior.21 If behavior in a stressful situation contains search activity (aggression or active avoidance), PS decreases without subsequent rebound because such behavior in wakefulness does not require the restoration of search activity in PS.5

Search activity concept is a basis for a practical discrimination between generalized learned helplessness that represent a true renunciation of search, and a conditioned learned helplessness tied only to specific conditions. In the latter state subject remains active in all situations except of those which create helplessness22 while renunciation of search corresponds to the global learned helplessness which covered different situations.23 The conditioned learned helplessness does not require an increase of PS for its compensation. This approach may be useful for understanding different outcomes of chronic stress. It was shown that the activity of the hypothalamus-pituitary-adrenal axis may drop in conditions of repeated or chronic stress.24 It may have been caused by one of two opposing events: exhaustion of this system in the state of global learned helplessness (renunciation of search), or adaptation of this system to the restricted, conditioned learned helplessness. In rats, daily administration of stressors (forced swimming, noise, immobilization, cold) sometimes led to the gradual attenuation of the hormonal stress response. In such cases of conditioned helplessness, the superimposition of a novel, acute stressor can increase the attenuated ACTH level (and brain norepinephrine release and synthesis) because search activity is not inhibited.25 In other cases, the adrenocortical response persisted and lead to numerous somatic disorders if the restoration of search activity in PS does not take place. According to the above-mentioned data and theoretical assumptions, it is possible to suggest that the PS increase after immobilization for 12 hours reflects an attempt of the brain to compensate for the lack of search activity. This lack of search activity in immobilized animals is accompanied by strong distress that plays an important role in the increase of PS requirement: In adrenalectomized rats distress is abolished and immobilization causes a delayed and less prominent PS rebound in comparison to the intact animals.2

It is worth stressing that PS compensates for the lack of search activity only until PS by itself is functionally sufficient and search activity in PS is available. A prenatal stress followed by immobilization3 or a long lasting immobilization stress for more than 4 hours26 may cause an overwhelming distress with general sleep disorders and functional insufficiency of PS. In this condition PS rebound does not appear.

Depression is characterized by the functionally insufficient REM sleep which is worsening the depressive state and that is why REM deprivation may have a positive outcome in depression.27

II. SLEEP/PS DEPRIVATION

The above-mentioned approach can also explain the data derived from experimental awakenings of animals on every PS onset during sleep.19,28 When awakenings involved just short fragments (2-3 sec) of non-emotional wakefulness, typical effects of PS deprivation appeared: PS onset frequency increased in comparison to the baseline level, and a PS rebound in the post-deprivation period occurred. However, if after momentary awakening, animals were maintained in a condition of active and emotional wakefulness equal in length to the PS mean duration, neither the accumulation of PS need nor the post-deprivation PS rebound appeared. The authors28 stressed that fragments of active wakefulness are able to satisfy the accumulated PS need, and from our point of view this effect can be explained by the domination of search activity in the evoked wakefulness. Short total sleep deprivation (4-12 h), performed by awakenings, decreases sleep latency and increases SWS (slow wave sleep) and delta power in subsequent sleep. However, PS is not increased after such deprivation.29 In contrast, immobilization stress makes the manifestation of search behavior in wakefulness unavailable and, as a result, the need for subsequent compensatory PS increases.

Similar conditions are created during total sleep deprivation on the rotating platform surrounded by water.1,30 Although this is not an immobilization, animals' free behavior in this condition is restricted and search activity is almost completely blocked. Of course, rats in this procedure continued to walk the disk to avoid water exposure, however it is a stereotyped behavior with a predicted outcome that cannot replace search activity.

The physiological outcomes of this sleep deprivation are very complicated. During 3 weeks of SD, the energy expenditure in animals increased progressively and body weight was lost in spite of a dramatic increase in food intake. Rats displayed a progressive decline in circulating thyroid hormones due to altered central regulation; sympathetic activation without over-activation of the hypothalamic-pituitary-adrenal axis (stressor system); development of erythematous papules on the skin, and so forth. This state is characterized also by a regional decrease of glucose utilization (reduction of metabolic activity) in the hypothalamus, thalamus, and limbic system. At the same time, after the first period of SD, no changes in brain monoamine concentration or turnover have been found.30 Sleep-deprived rats die after approximately 3 weeks, but the real reason for death is still unknown.31

In control (yoked) rats, housed on another part of the same rotating platform, total sleep time and high-amplitude sleep were reduced approximately 25% and PS was reduced approximately 47% of baseline amounts; their search activity was also blocked. Control rats demonstrated a constellation of physiological functions similar to that of the experimental rats. However, these alterations of physiological functions were much less prominent and they did not die.

Thus, although sleep deprivation on the rotating platform is not accompanied by acute distress, it has a negative outcome on body resistance. Being on this platform means to have no opportunity for search, and a long-lasting reduction of search behavior not compensated in PS (due to sleep deprivation) decreases the activity of the nonspecific protective stressor system.13 It is important to note that in experimental rats, brain energy metabolism is decreased only in the hypothalamus and limbic systemthe brain areas responsible for the regulation of search activity.14

Because of the relatively comfortable conditions on the platform during wakefulness and a gentle way of sleep deprivation, lack of search activity in the first 2 weeks does not cause either a substantial alteration of the brain monoaminergic systems nor the development of overt prominent somatic disorders. The suppression of the immune system in this period is also only moderate. It is possible to suggest that in the initial period of sleep, rats' active avoidance of water partly displayed search behavior. Later, this avoidance became stereotypical behavior.

In addition to the lack of search activity, experimental animals are regularly frustrated in their attempts to satisfy their natural need for sleep and for REM sleep that would restore search activity. Regular awakenings, being accumulated in the process of sleep deprivation, serves as an unavoidable punishment. A control animal does not develop the experience of the inexorability of punishment at every attempt to satisfy its sleep requirement, whereas an experimental animal has exactly such an experience, which may finally lead to learned helplessness as a manifestation of renunciation of search.23 As a result, the need for PS increases, but PS is suppressed together with the total sleep.

Such a combination of the increased requirement for search activity with PS deprivation can help explain the main outcomes of total sleep deprivation. Everson30 found that, for those animals that survived the prolonged platform, sleep deprivation-recovery sleep was marked by a dramatic rebound of PS. NREM-sleep rebound was not observed although most of the lost sleep was of the NREM-sleep type. This means that the requirement for PS caused by the combination of sleep deprivation and the frustration of behavioral search activity is more important for the organism than the requirement for NREM sleep. Moreover, after the PS rebound, the symptomatology of prolonged sleep deprivation is quickly reversed and health is restored.

Also, among the control animals, the rats that showed the shortest REM sleep were in the gravest functional state. This finding strongly suggests that the symptomatology is related to the lack of renewal of search activity by PS during deprivation. Everson30 suggests that the real reason for the deaths of the sleep-deprived animals is the decreased body resistance to infections caused by decreased host defense.

The investigations performed by Bergmann et al.31 have not confirmed this suggestion. Antibiotic administration to the experimental rats was effective in preventing the development of bacteremia however it was unable to prevent skin lesions, weight loss, energy expenditure and death.

The authors conclude that host-defense failure may be secondary to the multiple-organ-failure syndrome. However, it is possible that both syndromes (host-defense failure and multiple-organ failure) represent outcomes of the chronic frustration of search activity during sleep deprivation. Decreased body resistance to all kinds of deteriorative factors, including infection, is the most important outcome of the lack of search activity (renunciation of search).11,14,16

Multiple-organ failure syndrome can be considered an outcome of the decreased-body resistance. In sleep deprivation on the platform, this lack of search activity during wakefulness could not be compensated for by the increased search activity normally provided by PS (in contrast to what happens in sleep after immobilization stress). It is worth stressing that yoked rats, placed on the same platform, but only partly sleep-deprived, displayed alterations of host defense similar to the experimental rats, but much less pronounced. This means that sleep, and especially preserved PS, protected these rats from the critical dysfunction of the immune system.

From the perspective of the search activity theory, it is not a sustained wakefulness by itself (as Everson suggested) that explains the decreased body resistance and host defense. First of all, sustained wakefulness in other conditions is not accompanied by an initial PS rebound. Second, sleep deprivation and sustained wakefulness produced by the gentle handling of mice or by cage tapping, which elicited orienting (search) activity, actually had a beneficial effect on immune functions and host defense.32

An increase in whole body catabolism and a nonlimited energy expenditure in experimental rats may be the price an organism is paying for maintaining chronic wakefulness not accompanied by search activity.

As we have proposed,27 in the state of search activity in wakefulness, brain catecholamine synthesis is stimulated by its catabolism and such a feedback leads to restoration of the brain catecholamines (CA), which has been expended in the process of search behavior. A state of renunciation of search upsets this feedback system, and, as a result, the expenditure of brain catecholamines during stress is not recovered. A very similar mechanism may well be responsible for the progressive energy expenditure in the state of renunciation of search caused by sleep deprivation on the platform. Everson30 stressed that this energy expenditure is far in excess of that required by waking activity, thus there is no physiological explanation for this expenditure. This means that it is the particular state caused by sleep deprivation responsible for this energy expenditure. Increased food intake may represent an unsuccessful effort to compensate for this energy expenditure. At the same time, because of this dramatic increase in food intake, the hemorrhagic stomach ulcerations that are typical for starved and distressed rats do not occur in sleep deprivation. Thus, the symptomatology resulting from the total sleep deprivation caused by the platform method might be best explained as the result of the combination of abolished waking search activity and PS deprivation. Furthermore, the search activity concept, which predicted the increase of REM sleep caused by immobilization stress, suggests that the common feature shared by immobilization stress and sleep/PS deprivation on the platform is the lack of search behavior that increases the REM sleep requirement. This approach, therefore, provides an explanation for the paradoxical findings found with different types of sleep/PS deprivation.

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