Chapter 6

UCLA (1961 1968, 1972), Close, Detailed Monitoring of Animal Behavior, Wheel-Running Preferences, Twilight and Darkness Influences, Program Clocks, Konrad Lorenz

Overview
This chapter deals entirely with animal behavior research on WF (white-footed) mice. It is opened by what are primarily 'methods' papers on two of the many advances that made possible our detailed, largely unprecedented, studies. These concerned identification of small mammals by proximity sensors and monitoring of drinking.

The next paper was titled, "Behavior: confinement, adaptation and compulsory regime in laboratory studies." It was suggested by Editor P. A. Abelson of Science in lieu of a submitted letter. This 1 page Report was very timely, as it produced a 'firestorm' of comments and reprint requests, including comments such as:

....extremely important....elegant....tremendously impressed....very provocative....exciting.

Additionally, it was reprinted in two books. Next I treat studies in new mazes that were vastly more complex than those employed by others with domesticates. We showed that WF mice explored and learned these mazes, forward and backward without external reward, findings that cast some doubt on existing postulates that wide-ranging movements in the wild are motivated primarily by the reduction of hunger, thirst, and sex drives.

Preliminary studies of wheel-running follow, indicating that mice tend to prefer forms of exercise that require quick reflex actions and split-second timing and coordination of movements, over those forms in which vigorous muscular activity is the main benefit.

In another surprise, Abelson invited me to contribute a review article to Science, titled, "Behavior of Captive white-footed Mice." This 17-page, copiously illustrated 1967 paper (with 19 figures), even more than my preceding Report, produced a large, greatly favorable response, including comments from reviewers and readers, such as:

 "extremely sophisticated....extremely high level of technical competence....very highly impressed....an invigorating breeze....remarkable work....most refreshing general outlook....a superb piece of work....brilliant research....fascinating and thought provoking....extraordinary research program....splendid article....exhaustive and highly impressive....most important....engrossing and new ecological subject....best paper I have read in a long, long time....really tremendous....most enlightening."

Two topics from this review were selected for illustration. In one I compared activity profiles of an individual on three regimes: water, followed by 25% ethanol, and a return to water. The observed behavioral changes in activity, nesting, sleep, liquid consumption, fastidiousness, etc., and return to 'normal,' afterward, were reminiscent of ethanol's similar influences on man. The same 'assay' procedure, though even today (2008) barely exploited, could assess effects of other drugs, altered schedules, dietary changes, etc.

The other selected topic concerned light-level preferences of mice on a regime allowing them complete control of ambient illumination. The levels preferred during activity were in the same range as those encountered at night in the wild, with dimmer levels (or dark) preferred during sleep, just as in the nest or burrow. Minor individual differences also were revealed. The ability, itself, to control ambient light was rewarding. This was revealed by the very high level of alterations of the light level during running (as opposed to their simply leaving it at preferred levels all the time).

Social interactions were studied with two female mice, in an  enclosure that allowed identification as each passed through a passageway between compartments. When living together the activities of each changed markedly. Both settled into a regular routine in which each tended to draw nearer to the behavior pattern of the other, with marked tendencies also to remain in each other's company. When separated again, they returned essentially to their prior habits.

In further studies of wheel-running the prior conclusion concerning preference was confirmed by employing a wheel with hurdles, which was preferred to plain round wheels and a square 'wheel.' I carried on a correspondence with Konrad Lorenz, the great German ethologist, at that time, and have included a sketch of his observations of a house mouse running a wheel, as well as some of his letters. Also included is a diagram of running 'wheels' from Walter Sullivan's 1966 New York Times article, Why do mice run?. Numerous newspapers appropriated and featured material from Sullivan's article.

In a most fascinating discovery, we found that some mice possess the endogenous equivalent of a program clock. This enables them to reproduce the same wheel-running pattern (same speeds of running, times of changing direction, lengths of running bouts, and ceasing running), sometimes within seconds of the starting time, on successive nights. This occurred in identical external conditions from night-to-night. That this ability is not restricted to WF mice is illustrated in chapter 9. Larger mammals, even sub-human primates, also have, and sometimes employ, the same capability.

Lastly, I treat studies from an 7-1/2 page paper in Nature with 13 figures and 21 running records, titled, "Activity and Orientational Responses of white-footed Mice to Light." These records demonstrate that the animals have a strong tendency to orient their running direction with respect both to the position of the artificial moon and sun, and to enclosure landmarks. In constant light they typically warm-up to top speed, just as an athlete does. During changing twilight light, they engage in characteristic, marked changes in running speed, quitting abruptly during a certain phase of dawn. If the position of the 'moon' is altered periodically, they correspondingly alter their direction of running.

If 'unexpected' changes in ambient lighting (or other conditions) occur, the animals may respond by also abruptly changing their characteristic routine. When the animals have no choice but to run in darkness, the former, and still (2007), state of the art employed by other experimentalists for nighttime lighting, all aspects of their running deteriorate. When they have a choice between darkness and dim-light, they run in the dim-light and sleep in the dark. Under conditions in which running cannot be influenced by the location of the light source, the mice will 'work hard' to run in their 'preferred' direction; using enclosure landmarks for orientation.

Findings from the Nature paper indicate that WF mice have a highly developed sense of direction and maintain a constant 'awareness' of their immediate surroundings and directions of movements. The strong tendencies to orient to light sources and enclosure features suggest that the moon, the sun, and near and distant landmarks are used as navigational aids in the wild. Findings with other small mammals, medium-sized mammals, even relatively large mammals (e.g., a red wolf, bobcat, and coyotes), and a roadrunner, did not contradict those discussed above. Accordingly, these findings may apply to all.
End Overview

Identification of Small Animals by Proximity Sensing
Inasmuch as I received many requests in the early 1960s for details of my monitoring, interfacing, and recording techniques, I treat two papers in this domain in the following. Detection of animals typically occurred by means of their weight at certain locations, their interrupting the beam of an infrared electric eye, or their mere proximity to a detecting device. The latter might be an infrared reflective electric eye (beam reflected by the animal, back to the source, and detected by a sensor there). Alternatively, and with much more adaptability, it might be a proximity switch of the magnetic, capacitative (see Chap. 2 & Fig. 2-10), or conductive type. Proximity switches are activated either by the animal's mere physical presence (capacitative and infra-red reflective), or by small, unobtrusive collars worn by the animals (magnetic and conductive). Using the collar sensing types, four different individuals can be identified readily.

In one proximity switch conformation, in the above-titled paper in Science (1961;134:1694-1696), a conductive type switch (Fig. 6-1, l) is placed just beneath an aperture through which an animal must pass to gain access to another part of an enclosure. A magnetic type (Figs. 6-1d & 6-8a,b) is placed just to the left of the aperture. At first, the magnetic switch is not armed, so that no magnetic field is experienced when an animal with a ferromagnetic collar is in its near vicinity. As soon as an animal with such a collar passes through the aperture, brushing aside the shutter in the process, the switch is armed by the microswitch lever closing a circuit. Within a millisecond or two, the collar is addressed in both high and low sensitivity modes, after which the switch automatically disarms.

With a small plastic collar, animal #1 is identified by only the microswitch closing. With a small conductive collar, animal #2 is identified by both the microswitch closure and triggering of the conductive proximity switch. Animal #3, with the heavy ferromagnetic collar, is identified by closing of both the low sensitivity and high sensitivity channels of a magnetic switch at the side. Animal #4 (with the light ferromagnetic collar) is identified, as for #3, but with only the high sensitivity ferromagnetic channel closing (the collar is too light to trigger the low sensitivity channel). The need to detect a fourth animal, however, never arose in my studies.

In the Science paper, the tendency of two mature female deer mice (copper versus iron collars) to follow one another to and from the nest compartment into the other compartment, (food, water, running wheel) through the passageway was determined. As an example, the great majority of followings occurred within 3 min. On only 11 of a total of 81 occasions when one animal followed the other did it wait longer than 10 min. before following. Since failure of animal X to follow is defined by the return of animal Y to the original location while animal X is still present, many failures to follow may simply reflect prompt returns.

Precise Monitoring of Drinking Behavior in Small Mammals
In 1962, a paper of mine appeared in J. Mammalogy (43:345-351) with the above title. By means of rotary and linear solenoids and a microswitch, a lever arm ("shutter") occluding the spout of a water bottle could be locked and unlocked, either preventing or allowing an animal to brush the shutter aside, exposing its spout and allowing it to drink (Figs. 6-2 & 6-8a,b).

By this means, and appropriate recording equipment, one could monitor water consumption, say on an hourly basis, and correlate it with running activity (wheel revolutions), time out of nest (minutes), and food consumption (grams of pellets obtained from a dispenser) (Fig. 6-3, upper two graphs). One also could obtain, and correlate with the above, the number of drinks and their average length (Fig. 6-3, lower two graphs). Additionally, one could readily plot distributions of the lengths of individual drinks (avg. no. of sec the shutter was held open each time) and the times between drinks (Fig. 6-4), assuming only that the animal drank at a uniform rate (1.42 ml/min) while holding the shutter open.

Representative data for a mature female deer mouse showed that drinking behavior followed a specific pattern correlated with the time of day and other ongoing activities (Fig. 6-3). The findings, however, are not necessarily representative of the behavior of the species in captive conditions. In the highly structured enclosures used, individual differences are afforded opportunity for a relatively great degree of expression.

The requirement to unlock and brush aside a shutter to drink appears to have no significant effect on drinking habits, not differing greatly from manipulating vegetation to lick dew. The requirement for instrumental acts to engage in a number of activities increases the goal directedness of the activities and establishes more firmly bases for interpreting them.

As to the specific findings, all of the 'daylight' (2 ft-c illuminance level = 20 lux) hours were spent in the nest, except for occasional excursions for eating, drinking, or eliminating. 'Dark' (0.0004 ft-c = 1/3 clear moonless night) hours were spent largely running the wheel. The hourly consumption of water increased throughout the running period, and was appreciable after running ceased, whereas food consumption peaked at both the beginning and end of the running period (Fig. 6-3). Most drinks lasted from 3 to 6 sec with very few greater than 15 sec. Drinks tended to occur at 10-40 min intervals, occasionally more closely or distantly spaced (Fig. 6-4).

Behavior: Confinement, Adaptation and Compulsory Regime in Laboratory Studies
In 1963, there appeared in Science (1963;142:1087-1088) a Report by Hundt and Premack titled, "Running as both a positive and negative reinforcer." Thc findings of this article were at odds with those of my own studies, which prompted me to write a Letter to the Editor to the same journal. Unexpectedly, I received the following excerpted reply on Dec. 13 from Editor Philip A. Abelson.

I should like very much to publish your comments on the paper by Hundt and Premack. However, the comments seem to me to be of rather general interest, and I do not believe it is necessary to tie them quite so specifically to Hundt and Premack's paper.

The only change required would be reorientation: Your paper would be a report, rather than a letter. The first paragraph, if shortened to the following, would be a good abstract:

A few generalizations emerging from ethologically oriented work with wild rodents have important bearings on the rationale and design of experiments on reinforcement.

A further three paragraphs followed the above, and the Letter I had submitted was returned. Following Abelson's suggestions, I converted the Letter into a Report with the above title, published shortly thereafter (Science 1964;143:490). I made a number of proposals and drew several conclusions, summarized as below (but omitting references, all to my previous studies). The material below followed Abelson's suggested introductory sentence.

Depriving animals of natural outlets for activity by confining them in small and barren enclosures greatly influences their behavior. Thus, when given the means to modify their environment in ways that do not subject them to great stress, captive rodents exercise this control repeatedly. These animals find it rewarding to attain and to exercise to a high degree of control over their environment, perhaps in partial substitution for the freedom of action enjoyed in the wild but denied in confinement. Accordingly rodents repeatedly turn on and off (or otherwise modify) any suitable variable placed under their control, whether it is intracranial stimulation, a motor-driven activity wheel, lights or sound, or whether it is merely the ability to visit a nest, run a wheel, jump on and off a platform, patrol an enclosure, traverse mazes, or gnaw wood into fine fibers.

The initial responses of rodents in laboratory enclosures do not reflect the preferences or behavior of animals adapted to the experimental situation, but rather those of animals forced to endure unnatural and completely arbitrary conditions and schedules of confinement and experimentation. The time required for animals to adapt to the "insults" of laboratory experimentation is measured not in minutes or hours but in days or weeks. Thus, even in experiments in which the design and analysis do not penetrate beyond regarding the animal as a convenient experimental machine or black box, the responses to daily short experimental sessions generally give information only about the initial, and often rebellious, reactions of the "machine" to abnormal and enforced working conditions. Only studies over long periods permit the delineation of adaptational from adapted behavior.

Thus, taken alone, the nature of a specific stimulus (or activity) is an unreliable guide for interpreting the behavior of small mammals given control over its initiation or cessation, or both, or forced exposure to it. Stimuli which are rewarding or punishing in certain circumstances have the opposite effect under other conditions.

Using such atypical species representatives as domestic rats and mice for laboratory studies of behavior narrows the animal response spectrum to a point where its significance for adaptation, survival, and evolution becomes highly questionable. These selectively inbred animals are hundreds of generations removed from the wild. Their bland behavior tells us mainly how animals react to experimental regimes after many of the characteristic adaptive responses of the species have been largely or completely lost. Domestic animals remain convenient vegetalized strains for physiological studies but only wild animals provide the full range and vigor ofüresponses upon which solutions to the central problems of behavior must be based.

Important advantages to the use of wild rodents stem from their extraordinary capacity to learn complex contingencies and to gain detailed familiarity with a vast laboratory "habitat." Mice of the genus Peromyscus have mastered programs in which seven different manipulanda [levers and shutters] involving four different functions were in use concurrently. These animals also learn their way through burrow simulating mazes of unprecedented complexity--containing hundreds of blind alleys--without extrinsic reward. There is no reason to believe that these remarkable feats even approach the limits of the learning capacity of the wild animal, although they far exceed the performances of domestic rodents. The animals readily learn to distinguish the functions of even identical manipulanda. Accordingly, identical levers can be used to both initiate and terminate environmental and activity changes, and they can be located at many positions and their functions interchanged and rotated, bringing this variable under close experimental control [I mention, in passing, that my subsequent studies with small parrots, largely unpublished, showed no lesser potentials and abilities in all respects].

This paper was very timely, as it produced a virtual 'firestorm' of comments and reprint requests, including the following.

from psychologists:

I would like to congratulate you on your fine paper....I consider your work extremely important, and hope it will become known to many psychologists.

....your comments were so timely that I read them in their entirety to my class in Experimental Psychology....As a psychologist, I have been waging a long battle with my colleagues over precisely the same points.

This was an elegant article!

....My opinion is that you have hit the confused animal mystics in learning and motivation psychology in a sensitive spot. It is certain that these people....have no real appreciation of the artificialities of their animal strains or of the experimental condition which they have gradually evolved to motivate their animals.

....upon reading your interesting paper....my comment in the vernacular was "It's about time!" For in the course of experimentation in years gone by I found myself frequently pondering the kinds of questions you have apparently been considering--and giving truly scientific attention.

It strikes me that your work is furnishing broader background and complementary approach to the recently so popular experimental inquiries into "sensory deprivation"....

....this very provocative line of research

....your article.... is exciting and parallels some of my own thinking

I am glad to see this article in a journal of wide circulation, since I believe psychologists have wasted untold research time, for lack of familiarity with the ideas you expressed so well.

....you made a lot of good points!

I have just read with great interest your article....Since all of my work has been with the domesticated rat I am very interested in the perspective which your article represents.

I'm in the enviable position to proselytize on the topic of non-representative populations and I fully concur with your views.

From Prof. D. Premack:

Hundt is reeling from the impact of your reprint; it seems that you have done essentially everything which he is in the course of doing for his doctoral thesis. He is reeling, not only from the unlikely fact that someone has employed "his" technique first, but from your definitive handling of the matter. If you had been a little sloppy, offering him grounds for carping, he would doubtless feel better. As it is, I've tried to encourage him to seek recompense in the object lesson of simultaneous independent discovery--I talk to him about the light bulb from time to time--and in the fact that he now has someone to talk with. He will finish his thesis in any case and, along with a few fillips of his own, there will be an opportunity to compare the two species [species of Peromyscus vs. domestic rats]. [I have not seen the thesis publication by Hundt. He has published jointly in at least 20 papers through 2001. Nor have we been in correspondence. JLK]

from zoologists:

....remarkable studies....

I believe you are really on the right track. My own experience with three species of Peromyscus has convinced me that the laboratory mouse is practically a rodent moron and I am glad to see someone being quantitative on the subject.

....until these factors [effects of shock on learning and avoidance] are controlled we can learn very little, and even that probably misleading, from animal experimentation. You have undoubtedly set the necessary stage for any additional work having validity.

Some of the points made by you seem fairly obvious to anyone who knows anything about animals....I am glad to see white rats and mice reduced to just what they are--spiritless, vacuous vestiges of their original wild forebears--with all their real vigor leached out by countless generations of domestication and in breeding. Experiments with these damn things are so far removed from the real world that a new discipline is virtually involved--the laboratory biology and responses of white rats and mice

I find myself very much in agreement with your observations, though my work has been mostly on animals in the field in uncontrolled situations....In particular, I have felt that much of the persecution of the coyote that goes on produces a kind of backlash such as you describe in your article for mice when their environment or routine is suddenly arbitrarily changed....

I would very much like to know if you have observations along this line, i.e., the effect of suddenly intruding on an animal's territory or home range....

Your article in Science has certainly served the function of bringing to the awareness of many persons an issue which they did not even realize existed. What is hoped for from such discussions is that it will not degrade itself into a controversy between two irreconcilable camps, but rather that efforts will materialize which can seek for the most effective uses of both wild and domesticated forms.

In response to one zoologist's request, a student elsewhere, Edward Berger, my secretary included my reprint request record book. Fortunately he returned it. Ed later came to UCLA and obtained his doctorate under Prof. Sjöstrand, whose facility adjoined my office.

from a neurosurgeon:

I have just read, and enjoyed, your article....It brings out some issues that have occurred repeatedly to me, and expresses some views I have held concerning my own work, as well as that of others.

from a psychologist sociologist: .

I am tremendously impressed by this report....I have never understood what it is about the usual learning theorist's views that has given this position such tremendous hold over the mind of the academic psychologist over the past several decades....I  hope that your work will help to irrigate the arid waste land in which learning theory has been floundering for fifty years.

from a medical psychologist:  .

The ideas which you expressed concerning the behavior and artificially confined animals are very much in agreement with some feelings I have been formulating. In fact, I wonder if the whole block of studies done on primates severely constrained in experimental chairs may not represent highly questionable data with reference to their relevance to normal behavior.

from a neuropsychiatrist: .

I just read your exciting paper....The implications of your work both thrill and frighten me.

[Among others (the complete file was lost), the above surviving comments were from: J. B. Calhoun, NIMH; A. G. Etter, zoologist; A. Rabe, N. J. Neuropsychiatric Inst.; K. U. Smith, U. Wisconsin; W. H. Thorpe, Cambridge Univ....]

From the Associate Director for Conservation at the National Zoological Park: Years later on July 11, 1991 I received a letter from Chris Wemmer, Ph.D., as follows.

Since I was a beginning student I have followed your work on compulsory regime and have found it relevant to the management of wild animals in captivity. Having now worked in zoos for over twenty years, I've also been disappointed by the limited biological knowledge of many of our curators. Most of them are not aware of your work or other research on related topics significant for the improvement of zoos. In response to all this I am writing a book on zoo biology; it will actually be a synthesis of the pertinent literature in ethology, comparative psychology and behavioral ecology. Naturally your own work on compulsory regime will be included.

In this connection, I'd like very much to get some photographs of your research to use in lectures - in particular a photograph of you at work in your "mouse universe," and also a picture or two of the creatures controlling their environment.....

I realize this is a rather odd request, and that you are busy, but I'd be grateful for any help you can provide.....With kind regards, sincerely,

I put together a package for Chris but, as yet, his projected volume has not appeared, Chris did, however, edit a book in 1995, "The Ark Evolving: Zoos and Aquariums in Transition," but his contribution dealt solely with "A short history of research in zoological gardens." [For material and figures relating to the influences of my studies on zoo practices, see Chap. 7.]

reprinting:
The Behavior: Confinement....paper was reprinted as Chapter 21 in a volume of the Century Psychology Series, The Science of Psychology: Critical Reflections, edited by Duane P. Schultz, 1970, Appleton Century Crofts, New York. Likewise, it was reprinted in The Competent Infant, Research and Commentary, by L. J. Stone, H. T. Smith, and L. B. Murphy, Eds., Basic Books, Inc., New York, 1973, as contribution No. 148.

Unrewarded Exploration, Learning, and Movement Patterns in Complex Mazes
In 1964, a former classmate, Prof. Dan Brant, from my graduate studies at Berkeley, came to UCLA from Humboldt State College on sabbatical leave. We collaborated initially on studies of maze exploration by white-footed (WF) mice. One of our papers was titled, "Unrewarded exploration and learning of complex mazes by wild and domestic mice (Nature 1964;204:267 269). From it and a following paper on the same topics, Exploration and movement patterns of the canyon mouse Peromyscus crinitus in an extensive laboratory enclosure (Fig. 6-5) (Ecology 1965;46:452-461), we concluded that previous studies had tended to over-emphasize the role ofürewards in general theories of learning. Our studies showed that wild and domestic mice, having food and water freely available at all times, would learn highly complex mazes, with hundreds of feet of linear runways--many vertical--and hundreds of turns and blind alleys, without any external reward.

The most extensive complex enclosure (Fig. 6-5) used in our studies contained 427 meters of linear runways, The shortest one way path through its vertical maze system was 96 m long, had 1,205 90° turns, 48 m of vertical passageways, and opened into 445 blind alleys, the latter occupying 53% of the total space. WF mice explored and learned to traverse this complex maze system in as few as 2 or 3 days without reward or prior deprivation of food or water. Unlike a comparable activity of piano playing by humans, the mazes must be learned both forward and backward, since there is only one entrance and exit.

The amount of exploration, learning, running and climbing that occurred in our laboratory enclosures and mazes probably would bring a mouse in the wild into contact with all its needs (food, water, mates, etc.). Since our captive mice persisted in these activities even though 'unrewarded,' the activities, themselves, would appear to be self-rewarding, that is, the expression of inherited tendencies to engage in these activities.

This finding casts some doubt on the postulate that wide-ranging movements in the wild are motivated by the reduction of hunger, thirst, and sex drives. We also found that when an activity wheel was available, their exploration of new regions ceased and their traversal of familiar regions declined. These results suggested that a dynamic balance exists between exploration and general activity.

wheel-running Preferences of Peromyscus
In another study with the above title (Nature 1965;208:597,598), Dan Brant and I investigated whether exercise, alone, was the motivation for running in wheels, even in motor-driven wheels that they start and stop by pressing levers. To that end, we made available two large wheels (10-inches in diameter), one with a smooth surface and one with hardware cloth, a small round wheel (6" with hardware cloth) and a small square wheel (7" with hardware cloth) (see Fig. 6-6). I had previously shown (unpublished) that deer mice will run activity 'wheels' of all manner of shapes, even when round wheels also are available. First we adapted our experimental animals to be familiar with, and have experience in, all the 'wheels.' Otherwise, since white-footed mice are highly conservative, they might run only the first wheel used, and ignore the others.

The results were that experienced animals had a slight to marked preference for the square wheel. The implication is that wild rodents tend to select forms of exercise that require quick reflex actions and split-second timing and coordination of movements, in preference to forms in which vigorous muscular activity is the main requirement. We concluded this because running in the square wheel required jumping at the corners at rates up to fifteen times per second. This finding also suggests that round activity 'wheels' are not the most suitable type for studies of confined wild rodents.

The papers on unrewarded exploration and wheel-running preferences were the topics of a great deal of 'newspaper ink,' particularly the latter paper, as suggested by the following newspaper article titles.

wheel-running preferences:

"Lab mice take advantage of any sort of exercise afforded"
"A mouse runs faster if confronted with a challenge"
"Wild mice prefer square wheels to round ones"
"Mice dig square wheels"
"Because it's there"
"Of mice and men"
"Wheel tests reveal mice like to jump"
"Why do mice run?"

Unrewarded exploration:

"Mice which climb skyscrapers for fun, suggest challenging problems for humans"
"Skyscraper climbing mice may key human actions"
"Mice ignore sex, prefer climbing"
"Mice tests hint man isn't altogether tame"

Behavior of Captive white-footed Mice
On Oct. 28, 1965, I received another unsolicited letter from P. H. Abelson, editor of , Science, inviting me to contribute a review article on "the general topic of Behavior of Field Mice." He goes on to say, "[t]his subject is.... of interest to the wide audience of Science...." In response to this invitation, I submitted a paper that was subsequently revised in accordance with the following reviewer comments.

from reviewer 1 (one page): The first seven pages of this paper contain a point of view, based on extremely sophisticated experimentation, which should be made available to the wide, interdisciplinary audience which reads Science. However, the subsequent 37 pages of text and 28 figures are simply out of the question for Science; Kavanau has ignored your space limitations. Do not reject the ms for this reason; its message is too valuable. I suggest Kavanau be requested to condense the first seven pages slightly, then select from the remaining material 2 or 3 figures, and 10-18 pages of text which serve as examples to illustrate his remarks on pages 3-7.

My feeling is that Kavanau's work represents an extremely high level of technical competence relative to other research in the same field, in part because of his skill with and interest in automation of the experimental setup.

from reviewer 2(13 pages): I am very highly impressed with the approach taken by Dr. Kavanau. It is a prominent factor in the new perspective developing in the behavioral sciences both regard to his instrumental techniques and the broad perspective he takes of the capacities of animals and the complexities of variables which can affect an individual over the course of its life. This first comment is made after a first initial two and a half day reading of the manuscript....A marked reduction in the number of figures and in their simplification will greatly assist the reader and will greatly enhance his appreciation of the approach being developed by Dr. Kavanau. He is missing an important opportunity for salesmanship.

Excerpts or very brief quotes from reviewer 2's following 12 pages of constructive comments are as follows:

Comments on figures.... reduce section length....why two particular species selected?....clarify types ofüresponses, rewards, and control....make problem of strategy clear....show how hypotheses are generated from this procedural approach and how one goes about developing insight to these procedures....concerning explanation of "false ons" and "false offs"....meaning of word "experienced," and roles of initial preferences and conservatism, with respect to choice of different types of wheels....adaptive as opposed to adapted....desirability of adding a section to his paper where he makes very clear his position as to the meaning of volition, selectivity, and compulsion....

We are already in an era ofüradical change, where man is more and more taking control of his own evolution, and where his survival demands education for diversity and variability. It is with regard to such new perspectives of human life that Kavanau's research introduces such an invigorating breeze....

The revised 17-page article, with 19 figures, "Behavior of Captive white-footed Mice," appeared as the lead article of Science in the March 31, 1967 issue (155:1623-1639), the longest article, with the most figures, ever to appear in that publication, and one of the four most widely requested reprints of my behavior papers. Two others of these also appeared in Science (the "Behavior: Confinement...." paper treated above, and "Program Clocks in Small Mammals" (1968;161:1256-1259, treated below), the fourth, "Influences of Light on Activity of Small Mammals," appeared in Ecology (1969;50:548-557), treated in Chap. 7. As I re examine this Science review today, 40-years later, it certainly contained much more detail than any reader of Science would have wanted, and would have benefited from further shortening. Probably my revision was not sent out for additional reviews by Abelson, since the paper had been invited, in any event, and was on topics he favored. This was my most highly cited paper as a single author, being cited 141 times in subsequent journal articles and books.

Since the "Behavior: Confinement...." paper was only one page long, it was easily copied and most correspondence concerning it had to do with its new contents, whereas the present review paper, being 17-pages long, most correspondence (50% more in numbers) consisted ofüreprint requests and requests for assistance with equipment, etc.

from psychologists:

Thank you for the privilege ofüreading in Science about your remarkable work with mice. To me this represents a real challenge to conventional experimental method and theory.

I enjoyed your recent Science paper very much....it provides very valuable information (not to mention a most refreshing general outlook) on this topic.

I am in wholehearted agreement with many of your general comments, more especially your statement that "failure to take into account the intrinsic tendencies of captive animals to modify environmental variables (almost independently of the nature of the variable) and to avoid or counteract unexpected and non-volitional changes may be responsible for many conflicting findings..."

....I am bringing some of these animals into a small 'starting' laboratory and hope to expand the effort over the next few years....to follow out some of the provocative ideas summarized in your excellent Science article.

I would like to congratulate you on your paper on the Behavior of Captive white-footed mice....

Your article on Behavior of Captive white-footed mice is surely a superb piece of work.

from biologists and zoologists:

I think this is an excellent paper and a review of important work. In general, my congratulations on brilliant research. I'm really astounded at how intelligent and adaptable these mice seem to be.

Permit me to compliment you on a fascinating and thought provoking lead article in the current Science. As a life long student of mammals, I have long realized the deficiencies in laboratory studies of them and you have documented the case beautifully. I do envy you the abundant instrumentation of which you have made such good use.

Our research on the monitoring of a wild population of Peromyscus leucopus under natural conditions has brought your extraordinary research program to our attention.

I would be most grateful to you for a reprint of your splendid article as published in Science.

....You make good points about great individual differences in wild mice and the weakness of simplified "psychological" experiments....

I was very much interested in your article in Science. It was a most thorough work and one which has prompted me to write for your assistance in a similar area.

Congratulations on that exhaustive and highly impressive review on your behavior studies in Science.

I have just read your most interesting article on "Behavior of captive white-footed mice" in Science. While my interests in small animals are primarily field oriented, it is clear that many problems can best be elucidated by careful lab work, of which yours is a fine example.

I finally appreciate the beauty of this work. Can you send me other reprints as well? (from a Ph.D. graduate of UCLA, not one of my students)

A most important paper and one that will start much thinking and alter the tone of innumerable others. Congratulations.

....an engrossing new ecological subject.

from medical and dental doctors:

....your paper would facilitate our teaching in experimental medicine. I am impressed that wild animals may be so much more intelligent and different from domesticates.

That article is really tremendous. Indeed it should be required reading for all experimental courses....I have serious doubts concerning the generality of lab animals' behavior, and I think that your work is a significant improvement in this regard. My purpose in writing is simply to tell you that.

It's the best paper I've read in a long, long time. The implications of your research are intriguing, and I for one will be unable to resist the urge to overgeneralize and anthropomorphize.

I read with great interest your most enlightening article on captive white-footed mice....my interest, of course, is the cranial and dento facial characteristics in mice and the effect of disease and environment of the periodontal structures.

Do you think it would be possible to have some of the heads of your experimental white-footed mice in both the wild state and in those that you have bred for several generations?

Again, congratulations on your most impressive research. [I was unable to comply with this request. JLK]

[Correspondents in the above include: R.W. Alrutz, Biology; M.M. Cohen, Oral Pathology; R. Cowles, Zoology; P.G. Driver, Psychology; E. Friel, Psychology; K.A. Gelpke, Biology; A. Grinnell, Zoology; J.J. Hatch, Zoology; R.T. Hatt, Biology; R.F. Johnston, Zoology; S.M. Lavelle, Psychology; S.M. Levin, Experimental Medicine; W.E. Morris, Neurology; D.G. Nichols, Psychology; R.W. Olsen, Zoology; J. Palka, Biology; M.E.P. Seligman, Psychology; C. Szego, Zoology; N.A. Weber, Biology; R. Wolff, Mental Health ]

from an engineer: Many years later, on June 19, 2003, to my great surprise, I received the following communication:

Some years back I read an article entitled "Behavior of Captive White-footed Mice" in the journal Science. I want to say that it had to be in the late 1970's or early '80's [actually it was in 1967 - JLK]. I was much impressed by that article, and carried around a copy of it for years and through several career changes, telling students and anybody else who would listen about it, whenever the connection was even remotely appropriate.

My memory is untrustworthy in many ways, but it tells me that you were the author. Is that true?

I am working on a presentation to a mathematics meeting on the subject of living with variation (without yielding to it), and I would like to cite this paper (yet again!), but I want to do it correctly.

While we are at it, if this is yours, do you have any second thoughts about anything it said? Just curious. [I had none] My life seems sometimes to be little else but second thoughts, especially about the work I did in my "serious academic days," and I was just wondering.

Thank you.
R. Kent TeVault,
Corporate Quality Engineer,
Panduit Corporation

This review paper provided my first opportunity to present some general details about white-footed mice. I hold my repetition of studies already discussed to a minimum, but some repetition is necessary. Save for some simplifications, most of the contents below are direct quotes from the paper (but with references omitted),

white-footed (WF) mice, genus, Peromyscus,are one of the most widespread, geographically variable, groups of North American rodents. Over 55 species are recognized, more than in an other North American mammalian genus. Species occur from extreme northern Colombia northward to Alaska and Labrador. The animals are found in almost every habitat within their range and often are the most abundant mammals. Some species are found in low arid deserts, others in high tropical cloud forests. A few even inhabit barren arctic and alpine tundras.

Distinguishing characters are long bicolored tails, large ears and eyes, and conspicuously darker and more richly colored fur on the upper parts of the body. When excited, many species thump rapidly with the forefeet, producing a drumming sound. WF mice are active at night throughout the year. "Subzero temperatures do not keep these graceful little creatures at home, and the snow-covered ground is covered with their dainty tracks during the coldest periods of mid-winter. They spend the day in concealed nests of dry, unsoiled vegetation lined with plant down or shredded materials.

WF mice occasionally live in true pairs - a relatively rare occurrence among small mammals. Their home ranges usually encompass 0.1 to 0.6 acre, and the ranges of individuals differing in sex, age, and species may overlap considerably. There is evidence of pronounced homing ability. In the wild, most individuals probably live less than one year. The diet is varied, including berries, fruit, greens, snails, beetles, crickets, and carrion. Large quantities of nuts, seeds, and pits are harvested for winter use. In turn, the mice are one of the main prey groups of many valuable game and fur bearing animals.

Additional introductory material was the following:

The automatic non-disturbing detection and recording of activities of captive animals in my laboratory depend heavily on small,, sensitive electromechanical components, such as linear and rotary microswitches and solenoids, rotatable shutters, clutches, generators, and pressure transducers. Ferromagnetic, conductance, capacitance, and reflective infrared sensors are employed for non-contact proximity sensing, and infrared and ultrasonic beams are used for line-of-sight sensing. Computer type panels and standard hardware are used for programming and systems controls. The programming system also functions as a real time digital computer from which, by appropriate connections to digital printing timers and counters, all desired information is obtained. Single and multi-point analogue and event strip-chart recorders complete the recording ensemble.

The responses of small captive animals cannot be interpreted at face value because of severe distortions of behavior that are caused by depriving the animal of natural outlets for activity. Confined animals are likely to seize upon and exercise virtually any opportunities to modify (and alter relationships with) their surroundings. Two examples are illustrative, as follows. Caged animals in my vivarium are given a small cardboard carton with an entrance hole and sand and a cotton wad inside. In addition to providing a dark secluded nest, the carton furnishes a new channel for interaction with the environment. Although some animals nest in the cartons without ever gnawing on them, others typically gnaw them into shreds and construct a nest. But nest construction apparently is only a secondary basis for this behavior. Modifying the environment seems to be the primary basis, because some animals continue to gnaw into shreds each new nest carton, in turn, until the cage is full of shredded material.

A second example is provided by the activities of several mice in an enclosure containing a plastic wood nest and a wad of cotton. At the rear of the nest is a small crack through which the cotton can be grasped from outside. The mice spend hours reeling the cotton out through this crack, compacting the fluffy strung out mass with their forelegs and teeth, and stuffing the wad back into the entrance to the nest, and then repeating the entire sequence hundreds of times day after day.

WF mice learn complex experimental regimes with such facility that their learning capacity may have to be probed at the high levels used with non-human primates. The 2-factor program of this study probably is the most complex experimental regime mastered by a non-primate. To obtain a food pellet, the mice had to press two levers in correct sequence within 5 seconds. To obtain water, a 3rd lever had to be pressed, unlocking a shutter which had to be brushed aside within 3 seconds. To leave the nest, a 4th lever had to be pressed, unlocking the nest shutter for 3 seconds, so the animal could brushed it aside and go out; to run an activity wheel, a 5th lever had to be pressed, which unlocked the wheel for 5 min. This regime was learned rapidly with the aid of programmed auditory cues, its complexity having been increased in single nightly steps.

Correlations between eating, drinking, and eliminating were measured in one of the instrumented enclosures. In one experimental run, eating and drinking tended to precede or follow eliminating by less than 1 minute. Except for periods between daytime excursions, only infrequently did a period of greater than 15 minutes intervene between eating and the next drink; 69% of all instances occurred within 10 minutes.

Such activity profiles and correlations (see Figs. 1-8, 6-7, bars) are useful for studying individual and species differences. They also pinpoint performances under precisely specified conditions, providing controls for studies of the effects of diet, drugs, diseased states, surgical intervention, and environmental changes. By way of illustration, results are given for one week of study of a male deer mouse provided with 100% water, followed by one week with the water replaced by 15% ethanol and a subsequent 3 days on 25% ethanol, followed by another week with a return to 100% water. 'Daylight' was at a level of 4 ft-c, and 'nightlight' at 0.0008 ft-c, with transitions between them being abrupt (indicated by the arrows in Fig. 6-7, left and right). Results therefrom, of course, are of particular interest involving, as they do, the use of one of man's favorite drugs. The mouse was on the 2-factor program described above. A representative 20-channel event record for the mouse on this regime in a complex running wheel enclosure (Figs. 2-10 & 2-11) is given in Fig. 1-7.

In Fig. 6-7, the first bar in all the plots is for the first week, on 100% water, the second bar for the final week on 100% water. The open blocks are for the 3 days on 25% ethanol (expressed as 7 days to allow direct comparisons. Results for the first and last weeks on 100% water were unremarkable and are elucidated in the following comparisons and Fig.6-7. Behavior patterns were altered markedly on 15% ethanol and more so on 25% ethanol. After return to water, the patterns (except for sleeping in the wheel) gradually returned to normal. In general, ethanol produced an increasing lethargy and 'attachment' to the nest.

On 25% ethanol, the mouse spent 23% less time out of the nest at night (Fig. 6-7, blocks in plot at top left) than on the 100% water regimes, and made brief visits to the nest 120% more frequently (not shown). About 30-min per night was spent resting in the wheel, a habit that developed on 15% ethanol (also not shown). Running declined 33%, recorded eliminations (both urination and defecation) 45%, and food consumption 37% (as labeled in plots in Fig. 6-7, left). While total liquid consumption increased 40%, water consumption was up only 5.5% (Fig 6-7, blocks in left middle plot).

Although the number of drinks declined 21% (Fig. 6-7, blocks in right middle plot), their average length doubled (Fig. 6-7, blocks in right upper plot). Much time was spent in the nest between 7 p.m. and midnight (lesser heights of blocks for those hours in Fig. 6-7 left, at top), a habit reflected in the profiles for other activities between those hours (e.g., lesser revolution run, lesser water and food consumption, etc). Part of the decrease in recorded eliminations resulted because the animal began to foul the nest, in sharp contrast to its normal habits. One can see in these influences of ethanol on mice parallels to those on man. Among other advantages of studies of this design, each animal serves as its own control, eliminating the need for independent control groups.

The Study of Social Interactions Between Small Animals
Social interactions were illustrated by studies of two mature female deer mice in a social enclosure (Fig. 6-8), employing a ferromagnetic proximity sensor (see above) that permitted identification of individuals. In a study titled as above (Animal Behaviour 1963;11:263-273), the use of such a sensor in a key location, permitted the assignment of a large fraction of the combined activity of two mice in consort to one individual or the other.

The two mice were well adapted to one another, having been previously housed together for 6 weeks. When subsequently housed alone in the experimental enclosure, each animal displayed a distinctive behavior pattern. When placed in this enclosure in consort, the activities of both changed markedly, particularly during the first few days. An illustrative activity record of both animals in consort is given in Fig. 6-9. Both animals eventually settled into a regular routine in which each tended to draw nearer to the behavior pattern of the other. Thus, animal No. 13, very active when alone, in terms of time out of the nest, became less active in consort, but resumed greater activity when alone again (Fig. 6-10, bottom graph). No, 8, on the other hand, was relatively inactive when living alone, became somewhat more active in consort (Fig. 6-10, second from bottom). The mice had a strong tendency to remain in each other's company, spending only a small fraction of the time alone in or out of the nest (Fig. 6-10, top and second from top). Mouse 8 followed mouse 13 to and from the nest and through a passageway between compartments on 52% of all possible occasions 31% of the time within 1 min and 70% within 5 min (Fig. 6-9). When returned to a solitary existence each animal resumed its previous pattern of behavior.

With regard to other influences of being in consort, total revolutions run decreased markedly, total ambulatory movements increased markedly, far fewer food pellets were consumed, water consumption increased somewhat, with altered distribution, number of drinks increased considerably, and average lengths of drinks was about the same but differently distributed (Fig. 6-11 from top to bottom, respectively; quantitative figures are given in the original paper). For all the above cited results the mice were on a 2-factor program, that is, two levers had to be pressed in proper sequence within 5 sec to obtain a food pellet; and the passage shutter between compartments had to be unlocked for 3 sec by pressing a lever (see, also, legends to Figs. 4-2 & 4-3)

Publishing this paper was not a routine matter. Some referees believed it was more important to study a sufficient number of individuals using routine techniques, and obtaining pedestrian results, than to break new ground with lesser numbers of individuals, sometimes even only one. Thus, Behaviour rejected the paper:

because the Editors are of the opinion that there is a considerable disproportion between the weight of the technical details and the value of the scientific results, the latter are in this stage still based on a very few animals.

Although Animal Behaviour subsequently accepted the paper, one referee recommended that it be rejected because:

the sample size is simply too small to draw many conclusions....while this is an interesting new use of the equipment, I do not believe it warrants such extensive treatment unless combined with a more meaningful set of data [meaning the use of more animals, but the purpose of the paper was not to draw firm conclusions but to introduce a new experimental procedure. - JLK].

 The other referee saved the day, saying:

the major contribution of the manuscript....appears to be the presentation of information about the manner and degree to which the behavior of 2 female deermice was modified by social interaction. This information is valuable and should be published. Animal Behaviour is an appropriate journal for such publication....description of the apparatus and of the procedures....is useful and should not be unduly condensed.

Titles of newspaper reports:

in Mirror of your mind (New York): "Is conformity a natural tendency?"
in Mirror of your mind (Detroit): "Different beings move toward common behavior when thrown together"
"Conformity found to be natural tendency"

Further studies of 'wheel'-running preferences of mice

In previous studies referred to above, it was found that WF mice prefer a 7"-square hardware cloth 'wheel,' to a choice of three round ones, one 6" in diameter, and two 10" in diameter, one of the latter with a smooth acetate lining. Running in the square wheel required jumping at the corners at rates up to 15/sec (roughly four revolutions per second). This suggested that exercise in which quick reflex actions and split-second timing and coordination of movements play a large role is preferred to exercise in which vigorous muscular activity is the primary requirement.

To test this hypothesis, additional studies employing a 10"-round wheel with 4 equally spaced 1.9-cm high hurdles, in place of the acetate lining, were carried out with 6 deer mice and 8 house mice, 4 of them wild and the other 4 domesticated. The other 3 wheels were the same as mentioned above (Fig. 6-6). I reasoned that if the above hypothesis is correct, a round wheel with hurdles probably would be even more suitable than a square wheel, for a mouse actually must jump upward to clear the hurdles, whereas an animal running with the proper rhythm in a square wheel merely has to jump across to the approaching sides as the corners pass beneath.

Running a wheel provides a means of sustained vigorous exercise otherwise difficult to achieve for confined animals. Since vigorous activity keeps muscles in condition, this aspect of wheel-running can be regarded as adaptive. But the opportunity for vigorous exercise can explain the appeal only partly, because in enclosures that provide ample space for sustained vigorous running and jumping, mice frequently spend much time running a wheel. Furthermore, rodents that have escaped or been released enter and run accessible activity wheels.

The results were published in 1966 in the Zeitschrift fur Tierphysiologie (23:858-866), under the title, Wheel-Running Preferences of Mice. After having been adapted to all 4 wheels, of the 14 mice studied, 4 deer mice preferred the wheel with hurdles (tending to confirm my expectation), while the other 2 preferred the square wheel. Of the domestic house mice, 3 preferred the small round wheel, and one the hurdle wheel. Of the wild house mice, 2 preferred the small round wheel, one the large round wheel. The other divided its time between the two large round wheels.

As in other instances, this finding indicates that laboratory studies with domestic mice may be unreliable guides to the behavior of small wild rodents. The different preferences of the wild and domestic house mice from those of deer mice could depend on several factors stemming from their highly atypical evolution in close association with man. In fact, a case could be made for the thesis that sustained vigorous activity of any kind by wild house mice is non-adaptive, because of their generally close association with man. In this connection, maximum rpm's were from 38 to 200% greater for the deer mice than for the house mice.

Years later, in 2004, I received an E-mail from Prof. Raymond Huey of the Dept. of Biology, U. of Washington, for a reprint of this paper, for an acquaintance who wanted to do a project on mouse behavior, as follows.

I read this paper almost 40-years ago as an undergrad at Berkeley in the mid-60s. I was really a pre-med at the time, but I well remember the impact your paper had on me....I found the behavior of the mice non-intuitive, unless one recognized (as you recall, noted in the paper) that the normal environment of wild Peromyscus would be topographically complex.

Anyway, I was struck by your study. it was probably the first time that I'd seen a surprising scientific result (though perhaps not surprising when viewed from the perspective of natural history), and that was just exciting....And looking back after all these years, I'm certain that reading your paper was one of the key experiences that encouraged me to pursue a career in biology. Thanks!

An aside on Konrad Lorenz

In the 20 Feb., 2004 issue of Science there appeared a review of the book Niko's Nature: A Life of Niko Tinbergen and His Science of Animal Behaviour, by Johan J.Bolhuis of Utrecht University. A statement therein reminded me of my interactions with Lorenz. The statement was as follows.

Tinbergen also was enormously influences by Konrad Lorenz, although the two men could not have been more different. Proud, authoritarian, vain, and more of a philosopher, Lorenz was not very keen on fieldwork.

My impressions of Lorenz, in my interactions with him were quite different, though they do not prove the above to be erroneous. On a visit to UCLA, roughly in the period 1962-1963, Lorenz visited my lab and I conducted a tour for him. At one point I showed him one of my instrumented enclosures and described how the mice controlled their environment and almost all activities by pressing numerous switches in appropriate order to obtain food, water, nest entrance and egress, travel through passageways, light level, etc. His verbatim comment was. "und zey really learn to do zis."

In other interactions with Lorenz, a correspondence began on Feb. 21, 1966, when I wrote him as follows. Several years ago when you visited UCLA you told me about escaped mice in your laboratory sometimes entering and running unused activity wheels. I am now writing a review of my work for Science and would like to ask your permission to cite the above information as a personal communication in connection with my discussion of wheel-running. On March 9, he replied (hand written) as follows.

Of course you are welcome to quote our observations in escaped mice indulging in voluntary wheel-running. One observation concerns wild mice which another medical man and myself kept between the windows of our quarters when we were prisoners of war in Russia. The mice soon escaped by gnawing holes through the walls of the old building, but returned every night not only to take food but also to run diligently and for long times in the activity wheel we had built for them.

The other case concerns a golden hamster which I liberated on purpose in my working room in my house in Altenberg in 1948. In one corner of the next room some old hamster cages were stacked. One evening my attention was caught by a regular creaking and my hamster was found assiduously running in the activity wheel of one of these empty cages. The animal continued to do this every evening for a long time.

The interesting question is wherein the reinforcement is lying which causes the animal to run in the wheel instead of assuaging its locomotory drive by simply running about. I have one hypothetical explanation: the torsional moment of the wheel is less than the inertia of the animal's body weight and it enjoys the feeling, or to be objective, the reafference, of a quicker acceleration than it could achieve by real running. This is all I know about this question. Very sincerely yours,

I replied on March 23, thanking him and enclosing some additional material on wheel-running from the Science review, and mentioned some other studies of wheel-running. In the review, I noted, "[F]urthermore, rodents that have escaped or been released enter and run accessible activity wheels." I referenced this as personal communications from J. Aschoff, J.A. King, and K. Lorenz. I also asked Lorenz whether he would like to see the entire review, and said that I would be delighted to have his comments. On June 23, he replied (typed) as follows.

I have read with the greatest interest the pages from your manuscript which I am sending back, assuming you can use them. I am interested to hear that some workers have had the same ideas concerning the reinforcing factors supplied by the wheel, though actually disproving my assumptions. Maybe the real explanation is that mice just enjoy their own skill in exactly the same manner as H. Harlow's monkeys do. One of my common mice, Mus musculus, which I kept as a prisoner of war in Russia, taught itself to use a wheel with four spokes in the manner described in the enclosed sketch [Fig. 6-12]. Stopping and accelerating in exactly the right phases to keep the wheel-running as fast as possible, for instance climbing rapidly and steeply upward along the spoke between phases 3 and 4 in order not to decelerate the wheel and doing the same between phases 4 and 5 so as to get a maximum acceleration of the wheel between phases 6 and 1. The mouse was named Balthasar and was half grown, and none of the other mice sharing the enclosure between the two windows of the Russian blockhouse ever invented the same clever trick nor imitated it when they saw it. Balthasar never used the wheel in the conventional way, he obviously enjoyed the complication of the self-taught behaviour pattern. It should be possible to teach mice to do similar things by offering them eccentric wheels increasing the eccentricity gradually. If the reinforcement really is the complication of the motor pattern, in other words the difficulty which is to overcome, then these mice ought to prefer, in a choice experiment, a wheel of the maximum eccentricity which they are just able to master.

I should be very grateful indeed to receive a copy of your entire review. Very sincerely yours,

In my reply to Lorenz on June 30, I mentioned that I once constructed a Ferris wheel-running wheel in which one or two mice would run while others rode in the baskets. I also submitted my Ms., "Wheel-Running Preferences of Mice," mentioned earlier, for the Zeitschrift für Tierpsychologie, of which Lorenz was Editor. By coincidence, its topics were close to those of Lorenz's previous letter. I also included a copy of my review for Science, also mentioned earlier. On July 19, he replied (typed) as follows.

Thank you very much for your letter of June 30th and for the Science Review of your work. Your manuscript for the Zeitschrift für Tierpsychologie has been sent off to Prof. Koehler, as you already know; it is very appropriate for this journal.

The thing that interested me particularly is the reaction of the mice to the non-volitional start of the motor-driven wheel. I think that this contrariness of many animals (and children!) to any attempt at inducing  a behaviour pattern, though it may on principle be quite popular with them, is very widely spread. As it happens, I demonstrated to my assistant Dr. Bischof only a few days ago that a goose whom you push into the water from the edge of the pond will predictably get out again immediately, though it gets in again and take a swim a moment later. The principle "I won't be pushed" is well known to anybody who knows children.

I don't think that what you term "anthropomorphic interpretation" is really anthropomorphic. That volitional behaviour patterns are self-rewarding, the more so, the more complicated they are, in other words the nearer they are to the limits of the animal's volitional capacity, is indubitably a proven fact. The phenomenon is anthropomorphic only in the sense that it is most marked in Man Himself, for the simple reason that he is the creature with the greatest endowment of volitional movements. Thanking you again very much, Yours very sincerely.

I don't recall, but I must have been somewhat disappointed that the trivial matter of anthropomorphisms was the one that most impressed Lorenz in the review of my work. Aside from my letter of acknowledgement and thanks on July 26, that was the last of my correspondence with the great man. I submitted another paper to the Zeitschrift, but by then he no longer was Editor.

Notices in the press

During the period of our animal behavior studies, Al Hicks, UCLA publicity or informational agent, issued timely news releases about our behavior findings. Since most of them were either unprecedented or, at least, of compelling interest, these releases were picked up by both press and radio - some TV - and widely circulated. Some specific instances of titles of press reports have been cited above. Below is some detailed information.

The results obtained in the paper referred to above that Konrad Lorenz accepted for the Zeitschrift in early July 1966 generated the most attention. Before its publication. I received a phone call from Walter Sullivan, the Dean of American Science Editors, with the New York Times, in mid December, 1965. He wanted to write an article on wheel-running preferences of mice. Having seen the Nature article, he requested pictures of the enclosure and bar graphs. I sent him the requested materials, including, also, a photo of the wheel with hurdles (Fig. 6-6) and some results therefrom. Sullivan's article appeared on January 30, 1966, together with figures, including one with cross sections of 4 wheels--large round, small round, square, and large round with hurdles (Fig. 6-13), His figure was titled, "A Mouse Runs Faster If Confronted with a Challenge."

There was considerable 'fallout' from this article. Early on I received a letter from Scott, Foresman and Company as follows.

While preparing the seventh edition of Dr. Floyd Ruch's Psychology and Life, we came across the article "Why Do Mice Run?" in the New York Times. January 30, 1966. The article states the findings have been reported in recent publications. We would appreciate it if you could give us the names of these publications or more information on the series of experiments. We are especially interested in experimental controls. Sincerely yours, Christine Szalony, College Editorial Dept.

Consulting Ruch's 1967 edition revealed no follow up from this request. Instead, the following earlier material was continued.

Another pair of investigators have made use of wild mice in complex maze systems intermediate between the ordinary simple laboratory maze and their natural habitat. Here again the animals explore and learn exceedingly complex mazes without the use of food and water as an incentive. Very little exploration occurs, however, when the mice have access to activity wheels, These results indicate that while exploration is self-rewarding, mice also seek activity for its own sake (Brant and Kavanau, 1964).

On February 7, 1966, the Wall Street Journal in their Review and Outlook section picked up the article from the NY Times, titling it "Of Mice and Men," highlighting the preference for the most difficult wheels to run. In July, 1966, the Readers Digest picked up an article from the Ames Iowa Tribune, also titled, "of Mice and Men," also from the NY Times, referring to a preference for round wheels with hurdles and square wheels. An article from the Science section of the 1966 San Francisco Chronicle pointed out that when given a choice, the mice run the more challenging wheels, namely a square wheel and a wheel with hurdles.

Control of Ambient Illumination
Studies of voluntary control of ambient illumination by captive wild mice were described in the 1967 Science review (155:1623-1639). At least three factors influence responses in such studies: the conservative tendency to counteract promptly any non-volitional and "unexpected" change in light level (response to compulsion); the tendency to alter the level of illumination (control of environment); and the tendency to spend more time at certain levels than others (selectivity). Each factor may vary with the phase of the activity cycle, the animal's previous experiences, and its degree of adaptation to the regime. For these reasons, the interpretation ofüresponses to changes in light level are far more difficult to interpret than those for nest occupancy and wheel-running. However, experiments on control of illumination give greater insight into the interaction of behavioral variables, have greater ecological significance, and allow greater scope for the expression of individual and species differences.

Here, I give some results only for studies in which four wild-caught deer mice (2 males and 2 females) had 'complete' control over ambient illumination. This was achieved in a wheel-running enclosure with two sets of switches (Figs. 2-10-11). Two switches on one side of the wheel stepped the light to higher levels, one level with each step; likewise, the two on the other side stepped them to lower levels. There were ten steps in all. The following results are for the final phase of a study lasting 15 to 20 weeks, of which phases 1 and 2 occurred in the first weeks (In phase 1, the lights automatically were turned fully on every 30-min or hour. Each press on any lever stepped the lights one level lower, until off. Phase 2 was the same, except the lights were turned off automatically, and each press stepped the lights one level higher, until fully on. For results obtained in these early phases see the Science review).

Although no external time cues were given, the mice with complete control (not being influenced by artificial twilights) maintained 23-25 h rhythms and established characteristic patterns of controlling the illumination (Fig. 6-14, left). The light levels they preferred (open blocks in the figure) during activity were roughly the same as they would have been exposed to during the corresponding phase of activity in the wild. During rest and sleep, the level selected was lower than that preferred during activity. The mice exercised a high level of control over the level during activity, frequently crossing from side to side, stepping it up and down. Exposure to the highest level (4 ft-c) was infrequent and typically was very brief. Periods in darkness also were infrequent but lasted longer and seldom occurred during activity.

Three of the mice spent 77% of their time in the range of starlight to full moon, 8% in darkness, and only 5% in bright light. The fourth mouse, however, spent 53% of its time in darkness, for it developed the habit of turning the lights off just before it became inactive (Fig. 6-14, upper left). These results on 'complete' control are the simplest to interpret because the mice were fully adapted to controlling the illumination and no compulsion was involved. The findings provided controls and baselines for phases 1 and 2 of the same study which, as mentioned, had occurred earlier, in the first weeks.

First, they show which intensity ranges are preferred during different phases of activity; second they show that even fully adapted animals continue to alter the intensity of illumination frequently, long after the novelty has worn off; and third, they give values for the frequencies of these alterations by fully adapted animals exhibiting a high degree of selectivity. At the right, the total time subdivided into time spent running (bars) and not running (open blocks) at the various illuminance levels for deer mouse #3 male (left) and #4 female (right) on the same light regime as at the left.

reprinting of the Science review

The invited paper, Behavior of Captive white-footed Mice, also was reprinted in its entirety, save for some figures, in Readings in Comparative Studies of Animal Behavior, by Charles L. Kutscher, 1971, Xerox College Publishing, Waltham, MA. The paper also led to an invitation (which I did not accept) from John E. Naugle of NASA to propose a flight experiment for the Biosatellite program.

Program Clocks in Small Mammals

In the period 1966-1968, my doctoral student, Carl Rischer, and I were studying wheel-running by old-field mice, Peromyscus polionotus, when we made an almost unbelievable discovery, published with the above title in Science (1968;161:1256-1259). We were studying the influences of both artificial dusks and natural dawns (astronomical dawn = sun 18° below the horizon) on activity in one of our indoor enclosures. One side of the enclosure was open to a window pane with an eastern exposure to capture the natural dawn.

Time, speed, and direction of running were being recorded on a strip-chart recorder, with its paper advancing at one foot per hour. These studies already had shown that natural dawns have the same influence as artificial ones, in stimulating mice to run at increasingly high speed before retiring (see Figs. 4-6,6-19 & 6-22). When we examined wheel-running records for the period Nov. 14 Nov. 19 (Fig. 6-15), all bore many striking similarities, but we discovered that records for Nov. 15 and 16 were almost indistinguishable until about 30-min before natural dawn began. Not only did the records for 6 successive nights show that the running patterns may remain similar for several days, they also illustrated how the patterns 'evolved.'

We have noted earlier that there is a strong tendency of mice to run in a single direction all night, with the source of light having a strong influence. Most mice run in the direction of the light source, but some run away from it. We shall see below that, if the direction of the light source is changed periodically, the mice also change direction correspondingly, with great consistency, so as always to maintain the same orientation with respect to the light.

However, this orientational tendency sometimes does not develop until after several days, or even weeks, of adaptation to the experimental situation, including learning to run the wheel. Changes of running direction usually occur frequently in the first few days but gradually become less frequent. During this early period, it is not uncommon for the reversal of running patterns to show similarities on successive nights. Pattern similarities are most marked for a few animals whose directional habits remain variable. This was one of those cases.

In our paper on program clocks, Rischer and I reported that complex patterns of time, direction, and speed of running by small nocturnal mammals in activity wheels sometimes are duplicated almost exactly from night-to-night. For example, on the successive nights, Nov. 15 and 16 (Fig. 6-15, in which 6 successive nights are shown for purposes of comparison), the first reversal of running direction (from eastward to westward) of an old-field mouse (Peromyscus polionotus) occurred within just a few sec of 54 min after the starting time on both days, the next within a few sec of 150 min, the 3rd within a few sec of 179.5 min, and the 4th within 120 sec of 248 min. Moreover, running ceased within 2 min of 6 h after starting time. The total amount of time spent running was within a few sec of 240.2 min. In terms of the cited time intervals and total, alone, the repetition from night-to-night is truly remarkable. A major difference between the two running records was that the fifth major running session (after the fourth reversal on Nov. 15 was divided into two sessions by another reversal (at about 276 min) on Nov. 16, with the second half being westward.

These truly astonishing activity pattern repetitions disclose that: (1) biological clocks have previously unknown capabilities to act as 'sequence programmers' for behavior; (2) animals can retain a record of the sequence and timing of their activities covering an entire night; and (3) the activities of one night can bias an animal toward similar behavior on subsequent nights. In other words, small mammals not only tend to be highly conservative or stereotypical in their behavior during activity periods, but also from one period to the next.

It should be noted, that running in a new direction involves memory of the most recent direction reversal, because the animals maintain the new direction all through a bout, even though they start and stop running many times during the unidirectional bout. Moreover, the actions of the animals during the 'replaying' of a pattern show that the directional performance is subject to 'continual review and correction.' This is because after a pause in a unidirectional bout, the animals sometimes begin to run in the 'wrong' direction. But they usually 'correct' themselves promptly and revert to the 'scheduled' direction.

We obtained similar results in purely artificial light. The same old-field mouse gave several other noteworthy pattern repetitions. In subsequent studies pattern repetitions were found for a male least weasel (Mustela rixosa), caught in the wild, a female mouse opossum (Marmosa mitis), caught in the wild, and a canyon mouse (Peromyscus crinitus), born in captivity. The mouse opossum also repeated patterns on non-successive nights that were separated by nights with a different light program and patterns. Another wild female old-field mouse repeated a directionally complex pattern three nights in succession. Similar results were obtained with small nocturnal primates. These further studies are treated in Chap. 7.

This paper on program clocks also generated considerable media  attention, of which I have retained only four examples. A 1968 article by George Getze, in the Los Angeles Times was titled, 'Automatic Pilot' Guides Some Nocturnal Animals," with subtitle, "Possibly Key to Survival." Of the 'clock,' it stated, "it is a refined time and space tracking mechanism, a computer-like programmer of sequences that gives them accurately timed signals at set intervals." In the same year in Dateline in Science appeared the article "Biological Clock Guides Mice in Complex Actions," with some precisely quoted data from the paper. Also in 1968, in the Scholastic Teacher Edition of Science World there appeared an article, "The Clock in Our Brain," by John Speicher, with the subtitle, "Many Living Things Seem to Have Built In Alarm Systems that Trigger Patterns of Behavior." In an unknown source, dated August 30, 1968 appeared an article titled, 'Computer' May Chart Activities of Mice, with the first paragraph...."Small nocturnal mammals appear to be endowed with a sophisticated navigational system to plot their nightly routines with almost computer-like precision."

Notice in the Congressional Record

In the Congressional Record for the 92nd Congress in the Senate on February 14, 1972, there appeared the following, under the heading, Environmental Diversity--A Necessary Quality for Survival. The material was derived from an article by Prof. K. E. Watt on diversity, from Natural History, for February, 1972.

"....more carefully designed and measured research leads to the same conclusion. For some years. Prof. J. Lee Kavanau of UCLA has been conducting experiments on small mammal behavior in heavily instrumented cages. These changes are wired, enabling the animal  to change its environment and recording every move the animal makes and every detail of the conditions in the cage. The animals learn to control their environment by pressing levers. Kavanau has discovered that animals will press levers to select other than optimal conditions. In other words, confronted with a choice of living constantly in an optimal world but being bored, or of living in a world that is only optimal part of the time and experiencing variety, even a small rodent will opt for variety. It is reasonable to assume that humans would opt even more strongly for variety rather than constant optimality. Perhaps diversity is not merely a luxury for us. It may be something we need.

Activity and Orientational Responses of WF Mice to Light

In 1968, in Nature (218:245-252), there appeared my article (as opposed to a Letter) under the above title. This 7-1/2 page article presents 13 detailed running records and graphs, some composite, that illustrate its findings in convincing fashion. Many of these are treated below in some detail. The paper was introduced by an editor's summation, as follows:

The behaviour of white-footed mice in response to changes in illumination suggests that nocturnal mice in the wild use the Moon, twilight Sun, and landmarks as navigational aids, and also "keep close track" of their absolute position and distance from the nest and other points of retreat. This implies that the mice immediately flee for known cover when threatened by a predator, without the need to "get their bearings" first a behaviour of obvious adaptive significance.

In the introductory remarks I recalled that, though several features of a captive animal's surroundings can influence running direction, the position of the light source has the greatest influence. When the light was aligned with the wheel, 10 of 21 WF mice ran facing it, 4 ran facing away from it, 5 oriented primarily with respect to other objects in the enclosure, and 2 oriented variably. 'A warm-up typically occurred in unchanging light. Orientation of the mice relative to the light was confirmed by switching its position repeatedly, whereupon the animals also switched running direction, usually maintaining a very high consistency of running direction relative to it.

wheel-running toward 'moon' with warm-up

Unidirectional running with a warm-up is exemplified by the record for a canyon mouse (Peromyscus crinitus) from the Nature paper (Fig.6-16), in which running was 97% toward the artificial moon on a bright-dim-light cycle (lights abruptly dimmed and brightened at the beginning and end of the night phase, respectively). Recall that highly directional running with a warm-up also was exhibited by a deer mouse (Peromyscus maniculatus), even when the light was overhead, and the mouse could only run the wheel for 5 min at a time, before having to press a lever to unlock the wheel for another 5 min (Fig. 4-3b).

high-speed twilight running, and running  toward the 180° alternating 'moon'

Even if the directional location of the artificial moon is changed periodically, the orientational preference toward it is maintained. Fig. 6-17 from the 1967 Science review illustrates this behavior when the directional location of the moon was changed every hour, with the employment of 1-h artificial twilights. The canyon mouse exposed to these conditions ran 97% toward the moon and the setting sun, also engaging in the characteristic high-speed running (rather than warming up) at the beginning of dusk (see, also, Fig. 4-6 for twilight running by a deer mouse).

Also, orientational habits are not immutable. They may change spontaneously as the animals adapt, etc., while a temporary reversal follows any brief disturbance or unexpected environmental change, such as an alarming noise. These temporary reversals apparently can be compared to escape behavior in the wild, which usually involves a temporary change in the pattern and direction of movement. Similarly, a reversal that occurs after water access is withdrawn from a mouse may be an adaptive response, akin to looking for water elsewhere after the customary source has been depleted.

high-speed wheel-running reversal toward altered twilight 'sun'

Illustrating this phenomenon, a cactus mouse (Peromyscus eremicus) that typically ran away from the 'moon' and artificial twilight sun, temporarily (on the first night) ran toward the twilight sun. This occurred when the sun appeared in an unchanging (rather than variable) color temperature, and was more distant. However, the mouse continued to run very consistently away from the 'moon.' On subsequent nights it gradually resumed running away from the same twilight sun. Fig. 6-18 shows the mouse's high-speed twilight running toward the sun during dusk and dawn on the first night of change, with continuation of running away (almost 100%) from the 'moon.'

Characteristic changes in running speed during certain phases of twilights

The middle-to-late phase of artificial dusk and the early phase of artificial dawn have a great activity stimulating effect on WF mice, whereas the brighter middle-to-late phase of dawn has a strong inhibitory effect. The high-speed running and gradual slowing down during dusk (as opposed to warming up in dim-light), as the light level gradually decreases, and the responses during dawn do not occur only during twilights. As we shall see, they are characteristic responses that usually occur whenever the same changing light levels are encountered. We have already seen a detailed running record of a deer mouse with clear-cut, high-speed dawn and dusk responses (Fig. 4-6). Cactus mice also respond characteristically during twilights. These twilight responses are illustrated in Fig. 6-19, where the tips of the arrows on the left mark 25 min into the twilight. The animal's running record, with warm-up, during 2 h of abruptly presented dim-light on the first night of the study (Feb. 20) is given at the bottom for comparison.. This is followed by its dusk plus 1-h post-dusk (in dim-light) running record during the next 6 nights (Feb. 21-26),.

The repeatability of the performance is evident. During each dusk, the mouse began to run at high-speed about 25 min after the bright light began to dim, that is, at about 0.004-0.07-ft-c. It then gradually slowed down over a period ofüroughly 8-10 min, after which it ran at a lesser, but sometimes increasing, speed for the next 95 min. Running by cactus mice during dawn is not as intense as for deer mice, but when it does occur (shown for third and fourth dawns at top, Feb. 23 and 24), it also is characteristic. Note, for example, the high-speed running and its abrupt cessation as the light reaches a sufficiently high level during dawn.

These stereotyped twilight responses show clearly that, if approximately natural stimuli are presented to captive mice (even on a thoroughly unnatural time schedule), the animals can be 'forced,' almost like clockwork, to respond in an approximately natural way, almost at the will of the experimentalist. Results such as these also were obtained, but are as yet unpublished, for small parrots running in activity wheels and studied in parallel fashion, even in studies with cycle lengths (dawn-day-dusk-night) as short as 3 h.

wheel-running slows with each stepwise dimming of light

These results not only illustrate the powerful influences on wild mice of changing light level, within certain ranges, regardless of the absolute time during the natural 24-h cycle in which they occur, they indicate that the influence is level specific. This is shown with another canyon mouse in Fig. 6-20. During three successive 'nights' the intensity of the moon was altered every 30 min from dim to dimmer to dimmest, and sometimes to dark (in second and fourth presentations). Sample periods from each night are represented. The mouse, which ran away from the moon, responded by slowing down each time the moonlight dimmed. It ceased to run in the two dark periods. This emphasizes, again, the great unsuitability of darkness as an ambient condition for activity of nocturnal rodents.

All running parameters deteriorate with each step of stepwise dimming

The above performances are represented quantitatively for the entire nights in Fig. 6-21. Percentage of total time running, revolutions/30-min, and average rpm/30-min are plotted for each 30-min period throughout the 'night.' Illustrating that all wheel-running parameters are affected, not only time, revolutions, and speed, the overall average session lengths and orientational consistency (99.7% at the dim level) also are shown.

Nest occupancy and running in relation to twilight phases

Further highly illustrative examples of the compelling influences of light-level changes during artificial twilights, are the running and nesting responses obtained when simulated dusks and dawns were presented several times in succession to a cactus mouse (Fig. 6-22). During the first dusk the mouse left the nest and commenced running at high speed. Speed declined steadily until the light level began to increase during the immediately following dawn, when speed increased again and running ceased abruptly at high speed. A few min later, after engaging in 'housekeeping' activities, the mouse retired to its nest and slept until midway through the next dusk, when it began running again at high speed.

Running continued, as in the first cycle, whereupon the animal again ceased running abruptly at high speed during dawn. A few min later it again entered the nest. This time, however, it slept almost entirely through the (third) dusk. When it began running at very dim levels near the end of the dusk, it was not at high speed, because the light was very dim. Instead the animal warmed up. Running gradually speeded up again during the third dawn until, again, running ceased abruptly at high speed. A few minutes later the animal entered the nest again. This time it slept entirely through the fourth dusk and did not begin running until the following 'night' phase, when it, as could be predicted, engaged in a typical warm-up. It ceased running before the fourth dawn, and spent considerable time outside the nest before retiring.

Direction is haphazard and running parameters deteriorate in darkness

Since active WF (white-footed) mice avoid total darkness and usually orient strongly to dim-light, it was desirable to study further the effects of darkness on wheel-running. The studies showed that withdrawal of the visual sense usually has some very deleterious effects. Animals that learn to run in darkness usually take longer to learn, running speed is lower, sessions are shorter, time spent running is less, and direction of running is haphazard and unsustained. Furthermore, activity is not confined to the night period, usually does not cease when the bright lights come on, and night-to-night consistency is lower. In short, and not surprisingly, total darkness is very a poor condition for activity of sighted vertebrates.

Notwithstanding this circumstance, all prior studies of mice and rats using wheel-running as a criterion, that is, those of which I am aware, simply used on-off  light regimes. Bright light was used during the 'day' phase, and the lights were turned off, yielding total darkness, as the night 'phase.' The animals ran during darkness and slept during the bright light exposure which, incidentally, tends to destroy the visual cells of rats. This, of course, is convenient for experimentalists but thoroughly unnatural for nocturnal animals. The latter usually are sleeping in the nest or den in darkness during the day (not exposed to bright light) and are in dim-light during the night (not darkness).

Being highly adaptable, however, most nocturnal animals eventually will become active in total darkness, it being the lesser of the two 'evils.' In time, some WF mice even will run unidirectionally in the dark, using the sense of touch. Other running parameters in darkness also may approach the dim-light levels. In fact, WF mice have been found to adapt to almost any unfavorable, non-lethal condition. My experiments showed that these unnatural bright-dark regimes succeeded only because active nocturnal animals avoid bright light much more than darkness. If, instead, the animals are put on an abrupt dim-dark regime, they show the opposite preference. They ran during the dim-light phase and slept in dimmer light or darkness. In the above-described studies, I used total darkness only for two 30-min periods (Fig. 6-20, Jan. 19), whereupon the animal's running performance deteriorated. This is typical of WF mice. Similarly, when controlling the light regime, themselves, they prefer dim-light for activity, sleep in dimmer light, and become inactive on becoming exposed intentionally or accidentally to darkness (see below).

In view of the above it was of interest to study wheel-running orientation of WF mice on a bright-dark regime, the state of the art before I commenced my studies. The running record of Fig. 6-23 is for an adapted Florida mouse (Peromyscus floridanus) on the ninth night of such a regime. With no light as a guide, or to facilitate orienting with respect to landmarks in the enclosure, running direction was haphazard, about the same amount in both directions. As would be expected, the animal did, however, characteristically warm-up, and engaged in haphazard bursts of high-speed running when bright light came on.

Continued use of obsolete, abrupt light-dark illuminance regimes in small, nocturnal mammal, wheel-running, rhythmicity studies

Today (2006-2007), almost 40-years after publication of these results in Nature  (1968;218:245-252), I am unaware of any other laboratory study of animal behavior rhythmicity in which regimes other than the convenient on-off switching to achieve bright light or darkness have been employed. I take as examples two recent studies. The first, by DeBruyne et al. titled, "A Clock Shock: Mouse CLOCK Is Not Required for Circadian Oscillator Function" (Neuron 2006;50:465-477). For this study the influences of bright light or lack thereof on wheel-running activity were paramount.

Although great effort was required by six coworkers in research units in the U.S.A. and U.K. to produce the whole mice knockouts of the CLOCK transcription factor, as test conditions these workers utilized the most primitive 24-hr cycles of bright light and darkness, followed by weeks in total darkness (red light of wave length > 600 nm, beyond the range of the animal's vision, was present continuously).

All the above lighting conditions are 'unnatural' and decidedly undesirable for small nocturnal mammals in investigating the influences of darkness on the prior locomotor activity rhythm of their knockout mice. Understandably their findings, while they were regarded as sufficiently indicative, were far from clear-cut. Needless to say, a repeat of this experiment in appropriate conditions of lighting would be of great interest.

The experimental lighting conditions were virtually identical for the later, also highly sophisticated,  study by McDearman and ten coauthors reported in Science (2006;314:1304-1308) titled, "Dissecting the Functions of the Mammalian Clock Protein BMAL1 by Tissue Specific Rescue in Mice," which also used wheel-running as the measure of locomotor activity. A repeat of this experiment in appropriate conditions of lighting also would be of great interest.

I wrote two 'letters to the editor' to Science, in which there also appeared a News of the week piece, Despite Mutated Gene, Mouse Circadian Clock Keeps on Ticking" (2006;312:673), and one letter to Neuron, in which the research was published. In all three letters, I called to attention the shortcomings of the 40-year obsolescent light regime employed. The editors of both Journals replied, apparently recognizing the validity of the critique, but declined to publish a Letter. It would appear that they felt their obligation was greater to their authors than to their readers. Their replies follow. It should be noted, in connection with the reply from Neuron, that they solicit 'letters to the editor' on their web site, and had published five such letters in their Dec. 8, 2005 issue.

From Science

The replies to both letters to the editor were essentially the same, namely, thank you for sending a Letter-to-the-Editor to Science. We have read over your contribution, but will not be able to publish it in the magazine. We are letting you know as a courtesy in case you wanted to seek another outlet for your letter.    Sincerely, the Editors

From Neuron

We have received your on-line submission as well as emails regarding your "Letter to the Editor" submission "Rodent rhythmicity studies: use of unfavorable light responses. We have read your Letter with interest, but unfortunately will not be able to offer publication in Neuron. As you many know, we do not have a Letters section [see above] and only on very rare occasions do we publish formal correspondence. Therefore, while I can appreciate the points you raise and am grateful for the feedback, there is not currently an appropriate forum in the journal for this publication. You may consider sending this feedback to the authors directly, as I expect that they would find this information useful.

I am sorry that I cannot be more positive at this time. However, I hope that you will continue to consider Neuron for future manuscript submissions as appropriate. With best wishes, The Editor.

In view of these failures I submitted a Note calling attention to the inappropriateness of the light regimes being employed in the rhythmicity studies of small animals to editor Charlton of Medical Hypotheses. The Note, titled "Rodent rhythmicity studies: use of unfavorable light regimes," appeared in 2007 (68:455-456). I also sent reprints of the Note to the 18 authors of the original papers in Neuron and Science. None of them responded.

By coincidence this article, "Rodent Rhythmicity Studies: Use of Unfavorable Light Regimes" was selected for inclusion in the UC System eScholarship Repository. On Oct. 15, 2008, for example, I received the following email from that activity:

Dear Author,
As a service to authors, we are pleased to provide you with a monthly report tracking readership for any content you have posted within the eScholarship Repository:

"Biological time-keeping mechanisms: A need for broader perspectives?"
3 full-text downloads between 2008-09-15 and 2008-10-15
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Sufficiently experienced animals can orient to a high degree in darkness

Significantly, some animals with prior experience in dim light can orient to a high degree in darkness, the best performance having been at a 99.7% level. This shows that the strong orientations in dim light are not necessarily accomplished through vision, alone. Orientation to the enclosure, partly dependent on other senses, must play some role, and probably is largely through the sense of touch in darkness. In all but one of the animals that oriented strongly to light, the running direction in darkness was toward the last light seen. The consistency of orientation achievable in total darkness is an even more impressive indication of a highly developed sense, and continually maintained 'awareness' of direction and immediate surroundings, than the orientation in dim light.

Individual differences in degrees of nocturnal activity

Whether or not a mouse runs all night seems to be primarily dependent on the species. For example, canyon mice (Peromyscus crinitus) typically cease sustained running from 30 min to 2 hours before dawn, and run sporadically with haphazard direction afterwards. But if dawn is started early, while the mice are still running steadily, the typical twilight responses are given (high-speed running during early dawn, with abrupt cessation during middle dawn). More than that, an early dawn resets the internal biological clock, because the mice tend to cease running even earlier on the following night. On the other hand, deer mice run sustainedly until the middle of dawn, before quitting abruptly. Florida mice resemble deer mice in this regard, whereas cactus mice (Peromyscus eremicus) more closely resemble canyon mice.

A high degree of adaptedness to nocturnality and natural light regimes

Similar responses of both captive-born and wild-caught animals to both artificial and natural twilights indicate a high degree of adaptedness to natural light conditions and, of course, for a nocturnal existence. In the above described studies, at least six properties were found to be directly proportional to light level: time spent running; average rpm; maximum speed; orientational consistency; and average and maximum session lengths. At optimum light levels the animals spent most of the time running. They ran at highest speeds, in longest sessions, and with highest orientational consistency. In very dim light or darkness, on the other hand, they ran much less, at low speed, in short, haphazard sessions, and with relatively poor, or even no, orientational consistency.

Wheel-running orientation when light can play no role

It also is interesting to consider the running orientation in circumstances where light can play no role in determining orientation. In these tests, there was no light until an animal started to run, whereupon the light came on in the direction of running and stayed on in that direction for as long as running continued. In other words, running direction determined light direction, rather than vice versa. If an animal that customarily ran toward the light was not influenced by other factors, haphazard orientation would be expected under these conditions, because the light would come on no matter the direction of running. But, somewhat surprisingly, this was not the case. In these conditions, two tested canyon mice oriented strongly toward the enclosure always running unidirectionally.

This finding supports an earlier conclusion that WF mice whose running orientation is strongly influenced by light probably also are influenced, to some degree, by features of the enclosure. This includes the possibility that the direction of the immediately prior session of wheel-running influences the direction of any subsequent session. This follows because the only directional clues in the dark are the landmarks of the enclosure. The results also tend to indicate that the tendency to run for long periods in one direction is primarily the expression of a high degree of conservatism of movement pattern. This tends to tie in with the conclusion that the mice maintain a continual 'awareness' of their immediate surroundings and directions of movements.

Extrapolating to conditions in the wild, the latter finding implies, as noted in the summation heading, that mice "keep close track of their location with respect to the nest and other points of retreat" in the course of nightly activity. This might be expected of animals that have such small home ranges as a fraction of an acre. The more regular the patterns of movement, the more readily this could be done. In line with these interpretations is the finding from 'program clock' studies, that even when running is not unidirectional throughout the night, closely similar patterns are often maintained from night-to-night. This also was true of several other  non-primate mammals and small nocturnal primates, as will emerge in Chap. 7.

Finally, it was of interest to find out whether WF mice would run wheels on a varying directional schedule, not under their control. This was not true in the above cited studies, where the direction was under their control. Here, another innovation for animal behavior studies was employed. Again, the light came on only after running started and in the same direction. But a variable clutch attached to the wheel axle was energized at a moderate level of torque in opposite directions (but still toward the light) every 30 min. In other words, to continue to run unidirectionally, it would require more work to turn the wheel every alternate 30 min. Despite this, the mice continued to run unidirectionally, even with moderate increase in the amount of work required to do so (Fig. 6-24).

The applied torque then was increased gradually from night-to-night. What would the mice do then? Would they keep working harder and harder to run in the same direction, would they run only during the alternate 30 min periods, would they run in opposite directions every 30 min, as permitted by the clutch, would they stop running entirely, or would different individuals respond differently? The result was clear-cut; the mice kept working harder and harder to run unidirectionally, though more and more slowly (Fig. 6-24, Apr. 1-3), until they no longer had the strength to run against the clutch's torque. Only then did they accept being compelled to run in opposite directions every 30-min (Fig. 6-24, Apr. 4-8, Apr. 8 not shown). But as soon as the clutch torque was decreased to a sufficiently low value, they resumed unidirectional running (Fig. 6-24, Apr. 9). By then, however, orientation to the enclosure had been reversed.

Three factors may account for this observed behavior. First, non-self-imposed changes of running regime are resisted so strongly that in order to force mice to accept them, running on any other schedule must be infeasible. Second, the tendency to run in one direction for long periods usually is so strong that the animals strive to do so in the face of severe obstacles. And, third, it is equally rewarding to run at high speeds against low frictional torque, and at low speeds against high frictional torque. Of course, the first and second factors may be merely different ways of looking at the same conservativeness of movement patterns (and even of other behavior) that could have survival value in the wild.

In the above example where the clutch torque was increased gradually, a clear-cut answer from the five possibilities was obtained. This was typical of my experimental results in general. I rarely, or never, asked a question of my animals to which they did not give a clear-cut answer yes, no, or otherwise (true, also, in my studies of birds; see Chap. 10). If the answer was not clear-cut, I felt that there was something wrong with the question, and rethought and reformulated it. The animals never failed me or, rather, nature never failed me, since the animals were merely a product of organic evolution, molded by natural selection.

As touched on earlier, these findings indicate that WF mice have a highly developed sense of direction and maintain a constant 'awareness' of immediate surroundings and directions of movements. The strong tendencies to orient to light sources and features of enclosures suggest that the moon, the sun, and near and distant landmarks are used as navigational aids in the wild. The sustained unidirectional patterns of running presumably are akin to stereotyped nightly activity regimes in the wild. Further light on these matters was cast by the above cited studies of program clocks in small mammals and further findings in Chap. 7.

Whereas most studies of animal behavior typically employ statistical analyses to obtain confidence limits, few of mine did. They were irrelevant when clear-cut answers were being obtained. Nor was a paper ever returned to me for, or a referee request, a statistical analysis to obtain confidence limits. [It was at about this time, March 27, 1968, that John R. Olive, Executive Director of the American Institute of Biological Sciences informed me that the Western Regional Council had recommended me as a prospective experimenter for the NASA space flight program. A week later, as mentioned earlier, John E. Naugle, Associate Administrator for Space Science and Applications at NASA invited me to propose a flight experiment for a biosatellite program Earth Orbiting Mission. I had to decline.]

I presented a paper on this work at the Xth International Ethological Congress in Stockholm in 1967 (Sept. 16-24), before the paper appeared in Nature. One of the letters I received after this presentation was of particular interest, as it came from the then Dr. Christian Backer Carus. He eventually went into sleep research, as did I, and became Professor and Director of the Psychological Institute II, Sleep Laboratory of the Westfalian Friedrich Wilhelms University. He wrote the books, "General Psychology" and "Who Dreams, Sleeps Better." His letter of Jan. 23, 1968, from the Psychological Institute of the Univ. of Hamburg follows:

I listened to your interesting paper you presented in Stockholm at the Xth Interntional Ethological Congress last year. Now I should like to study your paper: "Activity and orientational.....to light," more thoroughly for referring it among others in my lecture on: "Neuere Untersuchingen zur vergleichenden und physiologischen Tierpsychologie." Beyond this it will be valuable for my own studies. Kindly send me a copy of your valuable paper which is more in detail than the short summary we all got in the conference map. Moreover, I will be greatly thankful to you if you possibly could include some pictures of your animals and the experimental situations, which I could us for demonstrations.

Thanking you in advance for your kindness, I remain yours very truly.

Titles of newspaper reports:
"Artificial dusk, dawn reset biological clock"
"Twilight busy time for small animals"
"Animals' touchy tune - just a song at twilight"
"Mice may navigate by moon and stars"