Table Of ContentStudies of Brain Function, Vol. 3
Coordinating Editor
V. Braitenberg, Tiibingen
Editors
H. B. Barlow, Cambridge
E. Bizzi, Cambridge, USA
E. Florey, Konstanz
O.-J. Grosser, Berlin-West
H. van der Loos, Lausanne
J. T. Enright
The Timing of
Sleep and Wakefulness
On the Substructure and Dynamics of the Circadian
Pacemakers Underlying the Wake-Sleep Cycle
With a Foreword by E. Florey
and an Appendix by J. Thorson
With 103 Figures
Springer-Verlag
Berlin Heidelberg New York 1980
Professor JAMES T. ENRIGHT
University of California
Scripps Institution of Oceanography
La Jolla. CA 92093, USA
ISBN-13: 978-3-540-09667-2 e-ISBN-13: 978-3-642-81387-0
DOl: 10.1007/978-3-642-81387-0
Library of Congress Cataloging in Publication Data. Enright, James Thomas,
1932- The timing oC sleep and wakefulness. (Studies of brain function ;
Bibliography: p. Includes index. 1. Sleep-Physiological aspects. 2. Circadian
rhythms-Mathematical models. 3. Circadian rhythms-Data processing.
4. Action potentials (Electrophysiology) I. Title. II. Series. QP425.E57
612'.821'018479-22480
This work is subject to copyright. All rights are reserved, whether the whole
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printing, re-use of illustrations, broadcasting, reproduction by photocopying
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a fee is payable to the publisher, the amount of the fee to be determined
by agreement with the publisher.
© by Springer-Verlag Berlin Heidelberg 1980.
The use of registered names, trademarks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore
free for general use.
2131/3130-543210
Dedicated to Professor Jiirgen Aschoff
with warm affection and deep respect
Foreword
The brain functions like a computer composed of subsystems which in
teract in a hierarchical manner. But it is not a single hierarchy, but a com
plex system of hierarchies each of which has its very own and unique fea
ture. One of these concerns the cyclic or rhythmic control of neuronal ac
tivities which, among others, give rise to alternating states of wakefulness
and sleep.
The phenomenon of sleep still remains a mystery. The present monograph
does not give us any new insights into its meaning and significance. Yet
sleep research may not be the same after the appearance of this book be
cause it gives us a comprehensive mathematical theory which opens our eyes
to new insights into the mechanism of the rhythm generation that under
lies the "wake-sleep" cycle.
No one who has worked his way through this book can again look at ex
perimental data without recognizing features which the "models" developed
in its various chapters so strikingly reveal.
The importance of this new vista lies not only in the possibilities it gen
erates for computer simulation of the effects 'of timed stimuli on parameters
of diurnal rhythms; the new ideas presented here also indicate novel experi
ments - and, more important even, they force the physiologist to have a
new look at the nervous system. Physiologists and behaviorists too often
have tacitly assumed that the rhythm generator, the "clock", is a singular
locus, possibly a single cell - the mysterious "oscillator" - which keeps
time and controls the timing of rhythmic behavior.
Enright's interactionist view which envisions the participation of hun
dreds, thousands, possibly millions of neurons in rhythm generation may
not be fully applicable to invertebrates with small-number nervous systems
like those of gastropod molluscs. His concept cannot be overlooked, how
ever, and has important implications even for the interpretations of rhyth
mic behavior of invertebrate species.
And who knows: these numerous elements (Enright's "pacers") that in
teract to produce precise pacemaker activity might not always be whole
neurons but elementary SUbsystems within neurons - particularly if these
are large. And if this were so, Enright's "ensemble" might well tum out to
be present within a single cell after all.
VIII Foreword
While up to now there developed a growing confidence, that a "biological
clock" can actually be found, Enright now shows us how it might work, -
in fact the success of his approach, so clearly made evident in this book,
suggests that his theory demonstrates how this clock ought to work.
Konstanz, April 1979 Ernst Florey
Preface
Twenty years ago, the daily rhythmicity of plants and animals was re
garded by most biologists as an abstruse and purely descriptive area of re
search, important perhaps to ecologists but with little relevance to the
broader concerns of modern experimental science. Today, however, the
situation is very different. The attempts to understand these rhythms in
terms of their physiological origins and consequences constitute one of the
most rapidly expanding branches of biology. An extensive literature, based
on a huge body of data, has been published. The basic phenomena have
been rechristened, and are now known as "circadian" (= about a day)
rhythms. The experimental methods employed range from simple mani
pulation of external stimuli to microsurgical intervention, from the tech
niques of genetics and biochemistry to those of the neurophysiologist. To
day even the educated layman can speak knowingly of some of the conse
quences of his "biological clock".
In humans, and in other higher vertebrates as well, a daily interval of
sleep is the most conspicuous manifestation of this clock. It is now general-
ly recognized that the regular alternation between the waking and sleeping
states is an overt expression of an endogenous circadian rhythm, and the
general objective of this book is to explore certain hypotheses about the
physiological mechanisms which underlie the wake-sleep rhythm. The quan
titative consequences of these hypotheses will be examined by means of
formal models, in which postulated physiological variables will be represented
by mathematical symbols, and computer simulation of the behavior of the
models is a central component of the research method described here.
The treatment of the subject matter, however, is not aimed solely nor
even primarily at specialists in circadian rhythms, at advanced researchers
in the study of sleep, or at those well versed in the use of mathematical
models. Instead, the presentation is intended for a broader audience, in the
belief that this case study has heuristic value for beginning graduate students
in the neurosciences, experimental psychology and related disciplines. No
prior background in the literature of circadian rhythms is presumed, no
extensive mathematical preparation, no familiarity with the strategy of
modeling or computer simulation. The reader with such specialized back
ground should be prepared, therefore, to skip through familiar materials,
concepts and caveats, which are included here for the outsider. There is, I
x Preface
think, substance here for the specialist as well, but a variety of issues of
less general interest have been relegated to appendixes which the general
reader is, then, encouraged to bypass.
The interpretation proposed here for the wake-sleep cycle has as its foun
dation the assumption that single nerve cells, acting independently, can in
ternally generate oscillations with more or less circadian frequency. This
assumption is simply an extrapolation of the experimental observation that
many kinds of unicellular organisms are able to show circadian variation in
their properties; but in taking that experimental fact as a point of depar
ture, I have sidestepped one of the primary questions which arises from
circadian research: how is it possible that a single cell can generate such
long-period oscillations? The biochemical and biophysical origins of cir
cadian periodicity constitute the focus of research in many laboratories
today, and the whole armamentarium of molecular biology has been un
sheathed in that research.
Eventually, such studies will lead to an understanding of the mechanistic
details of single-cell circadian rhythms; but there is a large conceptual gap
between elucidation of rhythms at that level, and the full understanding of
the circadian performance of multicellular animals. There are many complex
phenomena which are characteristic of the rhythms of higher vertebrates,
and which are unlikely to be explainable as self-evident consequences of
single-cell rhythms. For example, the whole-animal rhythm is often extreme
ly precise in its timing; the rhythm can be "molded" in frequency by past
experience; it shows complex responses to synchronizing stimuli, to phasic
as well as to tonic sensory input; and it controls response systems such as
the sleep-wake cycle which have no counterpart in the single cell. In order
to account fully for these whole-animal responses, an intervening level of
explanation will be required, which deals with the principles by which
single-cell oscillations and their output are organized into a unified whole:
how the cellular oscillations are affected by sensory input, how they inter
act with each other, and how they determine the behavior of the whole
animal. These issues represent the level of explanation with which the pre
sent treatise deals.
More explicitly, the question to be examined here is how nerve cells -
which are presumed to have an intrinsic circadian capacity - might be inter
connected and might interact to produce a unitary oscillatory output such
as that seen in the wake-sleep cycle. The consideration of this issue leads
to the formulation of an explicit model to describe the behavior of a par
ticular sort of simple neuronal network, in which random (stochastic) events
playa major role. While detailed information about the biochemical and
ionic events which underlie the circadian rhythms of the single cells is not
necessary for the models, a formal characterization of the processes is re
quired. For that purpose, I invoke data from nerve cells which show "tonic
Preface XI
activity" in the high-frequency domain: a more or less rhythmic, steady
state discharge pattern in the absence of phasic stimulation. From the study
of these endogenous oscillations, which have periods of a few milliseconds
to a few minutes, and which can be accelerated or slowed by the intensity
of tonic stimuli, a number of researchers have all been led to the same gen
eral sort of formal model, which can satisfactorily account for the observed
discharge patterns. I propose to extrapolate these models for high-frequency
neuronal rhythms to the circadian time domain by using an equivalent for
malism to describe the hypothesized circadian oscillations in single nerve
cells.
The initial motivation for this study was to find a simple plausible ex
planation for-the remarkable temporal precision of the circadian wake-sleep
rhythms of higher vertebrates: how can biological clocks be so precise? As
an emergent, and, in many ways, unanticipated consequence of the pro
posed mode of coupling within an ensemble of neuronal oscillators, models
of this sort can also account naturally for a large body of experimental data
on other properties of the circadian wake-sleep rhythm, and on the influ
ences of light on the overt cycle. In its narrowest context, then, this book
describes an attempt to bridge the gap which presently separates neuro
physiology from the experimental study of the circadian rhythms of higher
vertebrates. In a broader context, however, it represents an example of a
general line of investigation which I think will be of considerable impor
tance in the future of neurophysiology and the study of behavior: the com
puter-assisted study of significant behavioral phenomena by means of sim
ulation models which are based upon known or reasonably inferred proper
ties of the nervous system.
The need for approaches of this sort arises because of serious practical
limitations on what a neurophysiologist can, at present, measure directly.
A variety of data are now available about possible consequences of single
neuronal connections, and these data can be used to synthesize plausible
explanations for elementary kinds of behavior, in terms of a small circuit
diagram, provided that the behavioral event of interest is not far removed
in complexity from a simple reflex. In the vertebrate brain, however, there
are huge arrays of cells which are similar to each other in both morphology
and behavior, ensembles of units which are by no means redundant, but
which instead constitute an interconnected and interacting whole. Such ar
rays of cells are probably responsible for many interesting kinds of complex
behavior, ranging from finely controlled muscle movements to decision
making, from sleeping to learning. What are the likely consequences of ele
mentary kinds of interconnections and interactions among these arrays of
neurons which constitute the central nervous system? To what extent can
such interconnections, now understood at an elementary level, also account
for details of the behavior of the whole organisms?
XII Preface
Direct simultaneous and independent measurements from large arrays
of neurons are not yet available, and probably will not be feasible for some
time to come. Intuition cannot be relied upon as a guide to answers to the
questions of interest - as I have often found to my dismay in the studies
described here. Computer simulation offers an alternative means - and per
haps the only one possible now - for exploring some of the consequences
of interactions within such large networks, in the search for answers to
questions which otherwise may seem completely intractable. The nonspe
cialist reader will, I hope, find this book a useful introduction to some of
the methods, the limitations and the possible accomplishments of computer
simulation models as a means of research in the behavioral sciences.
The final chapter of this book represents a summary which is intended
to be comprehensible without reliance on detailed concepts developed in
the text. For the reader who seeks a brief account of the substance of the
treatise, therefore, that chapter can be read first, or perhaps better, after
completion of Chap. I, which is intended to set the stage for the more com
plex treatment which follows.
Acknowledgements
The ideas underlying this treatise can be clearly traced back to my long,
pleasant and fruitful associations in the laboratories of Professor Jiirgen
Aschoff, of the Max-Planck-Institut fUr Verhaltensphysiologie. My colleagues
there, particularly Drs. Aschoff, Hoffmann and Wever, and also Drs. Daan,
Gwinner, Pohl and others, have contributed importantly not only to my
thoughts about biological clocks, but also to my entire view of the business
of science. The development of the computer models, as well as the collec
tion of some of the data presented here, have been supported by a series of
grants from the National Science Foundation and the National Institutes of
Health. Dr. T.H. Bullock has played a major role in this undertaking by his
interest and encouragement. Many others of my colleagues and acquaintances
have helped shape my ideas by the kinds of experimental data they have col
lected and the interpretations they have proposed. Preliminary versions of
the manuscript were subjected, several years ago, to the penetrating critiques
of Drs. Klaus Hoffmann and John Thorson. Later versions have benefitted
greatly from comments of Mr. Curtis Baker, and Drs. G.D. Lange, S. Daan
and J. Aschoff. Dr. E. Gwinner offered valuable advice on Chapter 15. The
contributions of Drs. John and Ann Thorson to the final revision of the
text, both in form of substance, have been more valuable to me than any
few words here can describe. That revision was undertaken during a Ful-
