Oswald Is Sleep Related to Synthetic Purpose? 225, Exercises of Biochemistry

Download Oswald Is Sleep Related to Synthetic Purpose? 225 and more Exercises Biochemistry in PDF only on Docsity! OSWALD Is Sleep Related to Synthetic Purpose? 225 of the central monoamine neurons in the rat. Recently the ontogenesis of these systems has been described also in man [OLSON et al., 1973]. In the rat, the development of the monoamine cell and their outgrowing axons was found to be very early. Thus, the cellular identity of the 5-HT, dopamine (DA) and NA cell bodies could be established at a crown-rump length of 8, 9 and 1 mm, respectively, corresponding to a gestational age of 12-14 days. The monoamine axons sprout into the various areas of the brain as they are being formed, which may suggest an organizing influence by these axons on the areas reached [OLSON and SEIGER, 1972]. The genesis of mono­ amine synapses occurs at a later stage and is mainly a post-natal event [COYLE and AXELROD, 1971; LOIZOU, 1972; OLSON et al., 1972]. The early development of the NA and 5-HT cell bodies and their axons may thus have at least two functions in the fetal brain. Firstly, the outgrowth ofaxons into the pons and the medulla oblongata, especially the reticular formation, might be necessary for the development of PS in the prenatal brain. The stage of PS in turn may provide the proper electrical environment for the formation of the neuropil in several areas of the brain and, later on, also for the facilitation of activity in certain brain circuits involved in func­ tions necessary for the survival of the animals [JouvET, 1972]. Secondly, the outgrowth of the monoamine axons themselves into various areas could have a general stimulating and organizing action on the neuronal network formed [OLSON and SEIGER, 1972]. Sleep: Physiology, Biochemistry, Psychology, Pharmacology, Clinical Implications. 1st Europ. Congr. Sleep Res., Basel 1972, pp. 225-228 (Karger, Basel 1973) Is Sleep Related to Synthetic Purpose? I. OSWALD Edinburgh Any organism is a system in equilibrium. All systems in equilibrium are liable to oscillations and even the simplest living organisms show oscil­ lations or rhythms of activity - motor activity and motor inactivity. Humans have wakefulness and sleep. The simple, unicellular organism has both external and internal require­ ments. It pushes out its pseudopodia, spending energy on motor activity Symposia: E. The Physiological Role of Sleep 226 and things external. But it also spends energy on internal needs. It repairs its cell wall after damage, its structural constituents must be renewed through normal turnover, and it must spend energy on synthesis for cellular division. Here, then, are internal energy expenditures for synthesis - ana­ bolic rather than catabolic processes. Energy expenditure relies on enzyme systems, and Nature is economical. The biochemists tell us that the same enzyme can serve more than one func­ tion. Under one condition it will promote one process, but if the conditions are changed slightly, it will promote another. At one time, for example, it may promote a catabolic process, and at another time an anabolic process. These basic principles of economy in enzyme systems are no less true of vertebrates, such as ourselves. We also have periods when we must ex­ pend energy chiefly to cope with the external world. It is my theme to suggest that we have other periods, namely sleep, when energy expenditure is more predominantly internally directed, for synthesis of molecules required for growth and repair. Cell Division I spoke of cell division as an internal energy expenditure. What of cell division in vertebrates? Peaks of mitotic activity occur in human bone marrow, and probably in human skin, soon after the usual sleep onset time [COOPER, 1939; KILLMAN et al., 1962; MAUER, 1965]. How appropriate that at this time, as the cells divide, there should be a flood of growth hormone to help the dividing cells to grow. In rats and mice, cellular division in epi­ dermis [HALBERG et al., 1965], bone marrow [CLARK and KORST, 1969], pineal gland [RENZONI and QUAY, 1964], liver parenchyma [HALBERG and BARNUM, 1961], blood reticulocytes [CLARK and KORST, 1969] and eosino­ phils [HALBERG, 1960] show circadian rhythms with maxima during the hours when the animals are predominantly asleep. Cellular and tissue synthesis are most active in the young organism that spends so much time asleep and growing, namely on internal energy demands, and less time directing energy to external demands. Anabolism and Sleep What further evidence can support the idea that sleep alternates with wakefulness and permits economy in metabolic systems, with catabolic pro- General Discussion 229 If I am not wrong, it appears that two main ways of considering the physiological role of sleep have been indicated by our speakers. The first one - which seems to be shared by the large majority of you - is that the main functional role of sleep is that of ' restoring' some brain loss occurring during wakefulness. In particular, this is the view of KOELLA and OSWALD. Quite close to this position is that of V ALATX and FUXE, who suggest that - in addition to facilitating' restora­ tion ' - sleep, in the newborn organism, might as well facilitate 'maturation '. It appears that there is also some agreement on the view that brain ' restoration ' and ' maturation ' take place particularly during paradoxical sleep. What happens during slow-wave sleep would be - in a way - preparatory to the paradoxical sleep events. Actually, this way of considering the physiological role of sleep seems to be the most popular not only here, but also in the sleep literature. It might perhaps interest you to know the various terms used to describe this role of sleep. Going through the literature, I could find the following terms: sleep' restores " 'restitutes', 'repairs', 'reorganizes', 'renews', 'recovers', 'protects' and, finally, 'detires '. The second way of considering the physiological role of sleep is that indicated by P ARMEGGIANI: sleep, he says, might be regarded as a sequence of processes leading to a consummatory act, identified with the desynchronized sleep episode. The possible utility of approaching the problem of the functional role of sleep from an ethological point of view - i.e., to regard sleep as an instinctive behavior - was stressed by MORUZZI a few years ago [1969]. MORUZZI suggested that' sleep may be regarded as a chain of consumma­ tory acts, represented by the alternation of synchronized and desynchronized episodes; it is preceded by an appetitive phase, whose subjective correlate is drowsiness' [MORUZZI, 1969, p. 212]. PARMEGGIANI'S hypothesis is somewhat different. In fact, for him the consummatory act is not sleep per se, but only its desynchronized phase. If you accept this schematic attempt of synthesis we might now discuss the two main hypotheses: sleep has the function of allowing restoration and maturation, and sleep is an instinctive behavior. Both hypotheses are open to discussion. I would appreciate that the discussion be started by two well-known experts of sleep who are present here: Prof. MONNIER and Prof. JUNG. MONNIER: I would like to emphasize the concept of sleep as ' protector' of waking functions. Wakefulness is a function to be considered as primary, sleep as a control organi­ zation with inhibitory mechanisms. I think it is impossible to speak of sleep without considering wakefulness, just as it is impossible to speak of heat loss without considering heat production. I was always very impressed during my research on neural as well as on humoral organization of sleep, by the duality of both states. This duality, for instance. seems apparent at thalamic level. The so-called intralaminary hypnogenic area is concerned mainly with modulation of cortical activity, modulation of attention, modulation of per­ ceptions. This area can exert both an activating and an inhibiting action on the cortex. In other waking areas - viz., the hippocampus and hypothalamus - we have control systems antagonizing chiefly the emotional aspects of wakefulness and the instinctive aspects of wakefulness. In the original work of the school of Pisa, it was proposed that there are modulators which are concerned partly with body sleep and so on. Now the problem which puzzles me most is ' What are the requirements for the phase reversal; what happens in the moment of phase reversal from sleep to wakefulness? • Symposia: E. The Physiological Role of Sleep 230 This is a very important question. The neural and humoral organization of the brain must allow a rapid shift from sleep to wakefulness. This is a very important biochemical and pharmacological problem to solve. When we started our experiments on serotonin (around 1957), we were for the first time confronted with the two aspects of serotonin and we described the pattern of arousal, mixed arousal and relaxation: serotonin was found to have an ambivalent function. As we well know, thalamic stimulation with high frequency produces cortical activation; thalamic stimulation with low frequency induces synchro­ nized sleep. When we studied some of the properties of the factor extracted from the blood while stimulating the thalamus, and thus inducing synchronized sleep, we found it most difficult to produce this synchronized sleep factor without contamination by the waking factor; we had to establish conditions which did not allow contamination of the substance to be extracted by the waking factor. This synchronized sleep factor was found to be labile and very sensitive; it is sensitive to all kinds of physicochemical factors and must be puri­ fied very well in order to get reliable stability, but even this stability may fade after some weeks. This substance probably has something to do, or some properties in common, with those of the releasing factors of the hypothalamus. In my opinion, this sleep factor may allow a shifting from deep sleep state to arousal. But serotonin is not like that. Serotonin acts for a long time, it is a long-acting substance; serotonin, in my opinion, has some effectory function, it is closer to the effector level than this factor produced by stimulating the thalamic region. We may call it a modulator of sleep activity. JUNG: I am afraid I have not much to say but to give some comments to the inte­ resting things we have heard this morning. I think that in spite of the many publications on sleep in these last 10 years, we still need basic concepts. As Prof. ROSSI has said, we know very little about the restoration processes; everybody agrees that we are restored in sleep, but how we are restored we don't know. One interesting aspect is mitosis in slow-wave sleep, but probably it has nothing to do with the brain: the brain has no mitosis. So slow­ wave sleep may be more for the body, as I understood from OSWALD. But what happens to the brain? Is only paradoxical sleep necessary for the brain? P ARMEGGIANI suggested this for the instinct. I think that only 20 % of sleep for brain restoration would be too little, and I suspected that the other 80 % should have also some importance for the brain. We do not know very much about this. I think that it was from biochemistry that the main advances came in the last years. For instance, the stimulating work of JOUVET on the monoamines, which is an important key for understanding some of the things which happen in the brain stem and the brain stem-cortical relations. When we look back, I think that the concepts of HESS still stand. Although, of course, we know today many more details, the general concepts are still sound and I was very happy to hear the comment on this made by Prof. KOELLA. It appears that some people do not know very much about HESS' work; as we heard in the discussion, it was thought that stimulation of the hypo­ thalamus causes sleep; HESS stressed the midline thalamus. Well, I hope that the biochemist joins forces with the physiologist, and the clinician. I think one of the main intriguing problems is emotion and sleep. This was stressed by HARTMANN in his work on long sleepers and short sleepers. I would not be surprised if most of these short sleepers were more asthenic and the long sleepers more athletic. I don't know if Dr. HARTMANN has looked for these constitutional correlations. This brings me to psychiatry. I think that the manic-depressive syndrome is still the key for this con- General Discussion 231 nection between emotion and sleep, and if we could know more about the biochemical changes in the manic-depressive phases, perhaps we might find answers to this problem. ROSSi: I think that most, if not all of us, agree that biochemistry or - to our pur­ poses - neurochemistry appears one of the most promising tools to approach the problem of sleep. Now, if we want to continue to discuss that sleep facilitates or permits' restorat­ tion " I think we should take into consideration a particular aspect of these hypothetical restorative processes, namely the time required for these processes to take place. As every­ body knows, the time spent in sleep is different in the different animal species. These differ­ ences can be quite impressive. Does this fact contrast with the' restorative' hypothesis of the function of sleep? Or is it possible that restorative processes - even if they should be basically similar in the different species - require different times in the different ani­ mals? I should like to invite you to discuss this point. I might start by asking our expert in neurochemistry, Dr. FuxE, whether the difference in the temporal organization of sleep shown by different animals is compatible with a neurochemical interpretation of restoration or not. FuxE: I certainly think it would be compatible. It is a matter of turnover of the molecules involved, and I guess it may differ from species to species. As far as I can see, there are in wakefulness continuous changes in the synapses, particularly in the cortex cerebri as the signals are coming in from the environment. This continuous activity may in some way cause changes in proteins in the synaptic membranes to leave memory traces. These processes must be very rapid. You just read a newspaper, for instance, you start to learn a lot of new things at an extremely rapid rate. I think this very rapid rate of learning must be reflected in continuous changes in the molecules in the synapses in the cortex cere­ bri so as to leave trends enabling some sort of a memory. Due to the high demands of the environment you have to have periods of slow-wave sleep in order to restore new energy­ rich compounds which will again enable very rapid energy transfer in these synapses. I think the variations in amount of sleep from species to species may then be dependent on the type of energy-rich molecules involved and also on the extent of the learning pro­ cesses. WEBB: The point raised by Dr. ROSSI on the differences in the amount of sleep in different animals was at the basis of a particular theory of the function of sleep which I formulated some 2 or 3 years ago. According to this theory, sleep is not restorative or concerned with restoration. Rather, sleep would be a behavioral control system protecting the animal from excessive or dangerous energy expenditure. According to this hypothesis the animals are sleeping to protect themselves and to be able to collect their energy resources most efficiently. The theory that I have been exposing is non' restorative '. I think that I can marshal together a considerable amount of evidence to suggest that, for example, ungulate animals which sleep only 1 or 2 h every 24 h are animals which must sleep only 1 or 2 h; they have no natural hiding place, they are not ferocious, they are usually quite slow and, therefore, they must stay awake to survive. Their metabolism requires an almost continuous wakefulness. On the other hand, you will find other animals which would sleep 12-14 h/day. The nature of the length of sleep, in short, seems better explored on an ecological rather than on a neurophysiological basis. FuxE: How do you know that the animal is not asleep during very brief periods? Symposia: E. The Physiological Role of Sleep 234 appropriate elaboration of the assumption of sleep as an expression of an instinctual need of repair could reveal the distorted or transformed routes along which repair finds its instinctual gratification once blocked at its proper site. PARMEGGIANI: Thank you for your stimulating question which gives me the oppor­ tunity to clarify that my position with regard to sleep as an instinct is not exactly the same as Prof. MORUZZI'S. In fact, I approached the problem of sleep from the behavioral point of view because I think that behavior is a kind of language of the organism that we can understand directly. On the other hand, at the present time we still have great difficulties to decode the patterns of neuronal discharge. Thus, the behavioral approach to sleep is justified also by methodological reasons. This does not mean, however, that I have attained an explanation for sleep, I am only compelled by experimental results to use this method in order to define the nature of sleep. In brief, my aim is to put the problem into a logical frame. So, following this line of thinking, I have concluded that the consummatory act should be paradoxical sleep. Concerning a question of Prof. JUNG, the consummatory act of sleep would be remarkably long if it were not distributed into short episodes. The reason for this may be that without this fractionation the organism would be endangered. The results I have pre­ sented today suggest that this danger may consist in the fact that the regulation of homeo­ stasis is altered during the consummatory act of sleep. ROSSI: I am sorry that we cannot go on with this discussion; our time is over. As I said at the beginning, it was unlikely that we would reach in this symposium a satis­ factory definition of the ' physiological role of sleep , and, indeed, an agreement on the physiological role of sleep acceptable for everybody has not yet been obtained. I do not think that we should feel ashamed of that. Let us hope that the next time we meet again to discuss this intriguing subject, some more data which might facilitate our discussion will be available. I thank all of you for your participation. 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