Articles in PresS. Am J Physiol Regul Integr Comp Physiol (February 2, 2006). doi:10.1152/ajpregu.00073.2006
THE SEARCH FOR THE FEEDING-ENTRAINABLE CIRCADIAN
OSCILLATOR:
A COMPLEX PROPOSITION
Alec J. Davidson, PhD
Neuroscience Institute
Morehouse School of Medicine
720 Westview Dr. S.W.
Atlanta, GA. 30310
[email protected]
Copyright © 2006 by the American Physiological Society.
Working in the laboratory of John B. Watson in the early 1920s, Curt P. Richter first
observed the phenomenon of rats engaged in what would later be called food-anticipatory
activity: “It is seen that immediately following the daily feeding period there is a period of
relative inactivity lasting from four to five hours…….During the last two to three hours of
the twenty-four the activity increases very rapidly right up to the time of the next feeding
period” (24).
More recently it has become clear that food-anticipatory activity (FAA) exhibits the
defining characteristics of a circadian rhythm.
Circadian rhythms are oscillations of
physiological or behavioral functions that are timed by biological clocks, the best studied of
which is found in the hypothalamic suprachiasmatic nucleus (SCN). While these clocks
can operate in the absence of external input, to be useful in the anticipation of expected
environmental changes they must be synchronized by the environment in response to
cues called zeitgebers (Ger. time-giver). Light is the strongest zeitgeber for the SCN.
Working through specialized retinal photoreceptors (10) it causes an adjustment to the
phase of the clock in the SCN each day to maintain a precisely 24h period. However the
effect of this light exposure each day is limited; the SCN takes several transient cycles to
fully resynchronize to abrupt large changes in environmental time, a process we
experience as jet-lag. FAA also displays transients for several cycles following an abrupt
change in feeding time (29). Furthermore, FAA persists during several days of total food
deprivation (25) (1), the equivalent to constant darkness for rhythms synchronized by light
exposure.
The search for the FEO: A complex proposition
2
While the SCN is established as the main light-entrainable circadian oscillator in the
mammal, it is not the source of the timing signal that triggers FAA (31) (for a detailed
discussion see Landry et al. (14), this issue). Determining the anatomical location of the
food-entrainable oscillator (FEO) (30) (25) has been surprisingly difficult. The attempts to
do so are well reviewed in (19) and (28) and again in the comprehensive introduction to
the Landry report (14). The most valid conclusion we can draw from this literature is that
we know more about the where the FEO is not, than where it is.
In a forthcoming article in Nature Neuroscience, Gooley and colleagues present
data indicating a significant role for the dorsomedial hypothalamic nuclei (DMH) in the
generation of FAA (11). In their study the authors report that cell-specific lesions of this
structure abolish FAA as measured by general cage activity. Furthermore these authors
measured EEG and did not observe increased wakefulness prior to mealtime in their DMHlesioned rats.
However Landry and colleagues, in this issue of American Journal of Physiology –
Regulatory, Integrative and Comparative Physiology, once again demonstrate the
complexity of this system and the elusiveness of the FEO. Using an overhead motion
sensor and a microswitch at the food bin as behavioral measures, they show that DMHlesioned rats can still anticipate mealtime, and that the anticipation persists during total
food deprivation. One potentially important difference in the paradigm utilized by Landry is
the presence of a sleeping tube in the cage. Rats will avoid light exposure during daytime,
and therefore the sleeping tube may serve to minimize general cage activity related to
light-avoidance, and select for more purpose-driven (e.g. food seeking) behavior.
Kindly relegated to the supplemental materials section of their paper, the Gooley
study also reports on some experiments in which they fail to reproduce the abolition of
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FAA following lesions of the brainstem parabrachial nuclei (PBN). This finding stands in
stark contrast to those reported by me and my colleagues a few years earlier (4) in which
FAA was abolished after PBN lesions. This latter study indexed FAA with two different
measures of feeder-approach behavior.
The disparate findings on PBN lesions ((11) vs. (4)) and on DMH lesions ((11) vs.
(14, this issue)) do not stand alone as examples of inconsistent findings in this area. An
earlier report by Mistlberger and colleagues (20) showed that large limbic system lesions,
including the accumbens core and shell, failed to affect FAA in rats using feederapproaches as the behavioral measure. However, Mendoza et al. (18) reported that more
specific excitotoxic lesions of the core region of nucleus accumbens reduced the intensity
of FAA. The Mendoza study utilized infrared beam-breaks as their measure of activity.
Furthermore, while lesions of the hypothalamic paraventricular region abolished
anticipation measured by tilt-cage activity, food-bin approach measures revealed that the
rats were still predicting mealtime (21).
A common feature among these pairs of seemingly inconsistent results is the
difference in the specific behavioral measurements being made.
While parabrachial
lesions abolish food-directed behavioral anticipation (4), they do not abolish the increase in
general cage activity prior to mealtime. While PVN lesions abolish tilt-cage anticipation,
they do not block more meal-directed activity (21). Likewise, while FAA is eliminated by
DMN lesions when measured by general cage activity and even wakefulness (11), the
findings published in this issue show that rats still exhibit anticipation when measured
using food-bin-directed behavior, and in the presence of a sleeping tube that may increase
the selectivity of the behavior being measured (14).
4
In summary, all of these lesion studies reveal structures that are involved in FEO
output, but that cannot fully account for the oscillation. One of the elegant aspects of a
lesion study is that if it is performed well, a negative result provides a wealth of information.
If the rat can still demonstrate the capability, in this case predict mealtime, that structure is
not uniquely necessary for that function. The site of the FEO remains elusive!
FEO: Behavioral versus physiological rhythmicity
Despite the failure of lesion studies to unambiguously identify a central site
necessary for the generation of FAA (demonstrated once again by Landry in this issue
(14)), recent studies suggest that the focus of this search should remain in the central
nervous system. While digestive structures do have independent circadian clocks, and
these clocks are sensitive to the timing of food access (32) (2) (5) (27) (3), a clear
distinction needs to be drawn between these peripheral clocks and the black box we refer
to as the FEO.
Several lines of evidence suggest functional independence of these
systems from one another.
First,
while metabolism is clearly altered in restricted-fed rats such that most
rhythmic functions reset to mealtime (7, 8) (3, 6), entrainment of metabolism is not
necessary for FAA. Several studies suggest that FAA can be induced using a highly
palatable meal on a background of ad libitum food access (22) (33) (17), eliminating the
metabolic rhythms and the catabolic state commonly associated with timed and limited
access to food.
Second, while the clock mutant mouse has altered circadian behavioral rhythms in
constant conditions (34), behavioral anticipation of mealtime persists (23). However the
livers of Clock/Clock mice exhibit a rapidly damped oscillation in clock gene rhythms once
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the feeding schedule is terminated (13). Furthermore, while Per1 rhythms in digestive
tissues such as liver, stomach and colon entrain to daytime feeding in a fashion similar to
FAA, these rhythms quickly return to a nighttime peak phase once the rats are released to
ad libitum meals(5). In contrast, when the rat is food deprived after 1 week of this adlibitum access to food, FAA reemerges at the correct daytime phase, while molecular
rhythms in all of the digestive tissues remain nocturnal.
These findings suggest that
molecular rhythms in digestive tissues exhibit different characteristics from the rhythm in
behavior.
Since there are clearly a multitude of circadian clocks sensitive to feeding time, and
these systems may operate independently and serve different physiological functions, I
propose that for clarity the term FEO be reserved for the clock system responsible for the
generation of FAA, a use of the term consistent with its meaning when it was conceived
(30) (25).
Is the FEO a single structure?
The failure of lesion studies to identify a single necessary site for FAA suggests that
the timing system underlying it may be distributed rather than localized to one site in the
brain.
Despite the critical differences described above between rhythms in peripheral
structures and FAA, the common feature of sensitivity to feeding time among the many
oscillating structures in the body is supportive of a distributed or even ubiquitous nature of
the FEO; perhaps every neuron in the nervous system or indeed every cell in the organism
contributes to this timing function. Certainly the availability of a circulating energy source is
a widely available zeitgeber.
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This notion is inconsistent with localization of function, a characteristic of the
mammalian nervous system beautifully illustrated by the suprachiasmatic nuclei, a very
small structure in the brain with profound functional importance. However the examples
mentioned above of brain lesions where certain behavioral outputs of the FEO can be
abolished while others are spared helps to resurrect the idea of localization of function:
even if the clock is a distributed or ubiquitous system, its control over physiological and
behavioral functions appears to be organized in a highly specific manner.
The importance of understanding entrainment of circadian rhythmicity by food access
The importance of a thorough understanding of the effects of feeding schedules on
circadian rhythmicity cannot be overstated. The ubiquity of the phenomenon underscores
its importance in biology. Anticipation of mealtime has been observed in a wide range of
species, suggesting a long phylogenetic history. For a thorough review of these studies
refer to an excellent chapter by Stephan (28). In addition to those studies covered by
Stephan, a recent report describes robust FAA in a species of nocturnal fish (12).
Food restriction dramatically increases lifespan in many species including laboratory
rodents, dogs and primates
(15) (16).
The connections between the effects of food
restriction on biological timekeeping and on longevity are understudied and may be of
great importance. The connection between food restriction and health is reinforced by the
recent demonstration that food restriction schedules attenuate tumor development in mice
(9, 35). While this effect may be partially due to caloric restriction, the timing of food intake
was clearly important in those studies. Since food intake patterns have been shown to
regulate rhythms of cell division (26), it seems that restricted feeding may well prove to be
a valuable tool for the control of cancer.
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References Cited
1.
Clarke JD and Coleman GJ. Persistent meal-associated rhythms in SCN-lesioned rats.
Physiol Behav 36: 105-113., 1986.
2.
Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, and Schibler U.
Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker
in the suprachiasmatic nucleus. Genes Dev 14: 2950-2961., 2000.
3.
Davidson AJ, Cantenon-cervantes O, and Stephan FK. Daily oscillations in liver
function: diurnal versus circadian rhythmicity. Liver International 24: 179-186, 2004.
4.
Davidson AJ, Cappendijk SL, and Stephan FK. Feeding-entrained circadian rhythms are
attenuated by lesions of the parabrachial region in rats. Am J Physiol 278: R1296-1304, 2000.
5.
Davidson AJ, Poole A, Yamazaki S, and Menaker M. Is the food-entrainable oscillator in
the digestive system? Genes, Brain and Behavior 2: 1-8, 2003.
6.
Davidson AJ and Stephan FK. Plasma glucagon, glucose, insulin, and motilin in rats
anticipating daily meals. Physiol Behav 66: 309-315, 1999.
7.
Diaz-Munoz M, Vazquez-Martinez O, Aguilar-Roblero R, and Escobar C. Anticipatory
changes in liver metabolism and entrainment of insulin, glucagon, and corticosterone in foodrestricted rats. Am J Physiol Regul Integr Comp Physiol 279: R2048-2056, 2000.
8.
Escobar C, Diaz-Munoz M, Encinas F, and Aguilar-Roblero R. Persistence of metabolic
rhythmicity during fasting and its entrainment by restricted feeding schedules in rats. Am J Physiol
274: R1309-1316, 1998.
9.
Filipski E, Innominato PF, Wu M, Li XM, Iacobelli S, Xian LJ, and Levi F. Effects of light
and food schedules on liver and tumor molecular clocks in mice. J Natl Cancer Inst 97: 507-517,
2005.
10.
Gooley JJ, Lu J, Chou TC, Scammell TE, and Saper CB. Melanopsin in cells of origin of
the retinohypothalamic tract. Nat Neurosci 4: 1165., 2001.
11.
Gooley JJ and Saper CB. The dorsomedial hypothalamic nucleus is critical for the
expression of food-entrainable circadian rhythms. Nature Neuroscience In Press, 2006.
12.
Herrero MJ, Pascual M, Madrid JA, and Sanchez-Vazquez FJ. Demand-feeding rhythms
and feeding-entrainment of locomotor activity rhythms in tench (Tinca tinca). Physiol Behav 84:
595-605, 2005.
13.
Horikawa K, Minami Y, Iijima M, Akiyama M, and Shibata S. Rapid damping of foodentrained circadian rhythm of clock gene expression in clock-defective peripheral tissues under
fasting conditions. Neuroscience 134: 335-343, 2005.
14.
Landry GJ, Simon M, Webb IC, and Mistlberger RE. Persistence of a behavioral food
anticipatory circadian rhythm following dorsomedial hypothalamic ablation in rats. American
Journal of Physiology - Regulatory, Integrative and Comparative Physiology In Press, 2006.
15.
Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol 35: 299-305, 2000.
16.
Masoro EJ. Overview of caloric restriction and ageing. Mech Ageing Dev 126: 913-922,
2005.
17.
Mendoza J, Angeles-Castellanos M, and Escobar C. A daily palatable meal without food
deprivation entrains the suprachiasmatic nucleus of rats. Eur J Neurosci 22: 2855-2862, 2005.
18.
Mendoza J, Angeles-Castellanos M, and Escobar C. Differential role of the accumbens
Shell and Core subterritories in food-entrained rhythms of rats. Behav Brain Res 158: 133-142,
2005.
19.
Mistlberger RE. Circadian food-anticipatory activity: formal models and physiological
mechanisms. Neurosci Biobehav Rev 18: 171-195, 1994.
20.
Mistlberger RE and Mumby DG. The limbic system and food-anticipatory circadian
rhythms in the rat: ablation and dopamine blocking studies. Behav Brain Res 47: 159-168, 1992.
21.
Mistlberger RE and Rusak B. Food-anticipatory circadian rhythms in rats with
paraventricular and lateral hypothalamic ablations. J Biol Rhythms 3: 277-291, 1988.
8
22.
Mistlberger RE and Rusak B. Palatable daily meals entrain anticipatory activity rhythms in
free- feeding rats: dependence on meal size and nutrient content. Physiol Behav 41: 219-226,
1987.
23.
Pitts S, Perone E, and Silver R. Food-entrained circadian rhythms are sustained in
arrhythmic Clk/Clk mutant mice. Am J Physiol Regul Integr Comp Physiol 285: R57-67, 2003.
24.
Richter CP. A behavioristic study of the rat. Comp Psychol Mono 1: 1-55, 1922.
25.
Rosenwasser AM, Pelchat RJ, and Adler NT. Memory for feeding time: possible
dependence on coupled circadian oscillators. Physiol Behav 32: 25-30., 1984.
26.
Scheving LA. Biological clocks and the digestive system. Gastroenterology 119: 536-549.,
2000.
27.
Scheving LE, Tsai TH, and Scheving LA. Rhythmic Behavior in the Gastrointestinal Tract.
In: Ulcer Disease: New Aspects of Pathogenesis and Pharmacology, edited by Szabo S and
Pfeiffer CJ. Boca Raton, FL: CRC Press, Inc., 1989, p. 239-270.
28.
Stephan FK. Food Entrainable Oscillators in Mammals. In: Handbook of Behavioral
Neurobiology 12: Circadian Clocks, edited by J. T, Turek FW and Moore RY. New York: Kluwer
Academic / Plenum Publishers, 2001, p. 223-241.
29.
Stephan FK. Phase shifts of circadian rhythms in activity entrained to food access. Physiol
Behav 32: 663-671, 1984.
30.
Stephan FK. The role of period and phase in interactions between feeding- and lightentrainable circadian rhythms. Physiol Behav 36: 151-158, 1986.
31.
Stephan FK, Swann JM, and Sisk CL. Anticipation of 24-hr feeding schedules in rats with
lesions of the suprachiasmatic nucleus. Behav Neural Biol 25: 346-363, 1979.
32.
Stokkan KA, Yamazaki S, Tei H, Sakaki Y, and Menaker M. Entrainment of the Circadian
Clock in the Liver by Feeding. Science 291: 490-493, 2001.
33.
Verwey M, Khoja Z, and Amir S. Feeding-induced c-FOS activation is insufficient for
reentrainment of Per2 rhythms in the limbic forebrain. Program # 60.6. 2005 SFN Abstract Viewer /
Itinerary planner, 2005.
34.
Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove
WF, Pinto LH, Turek FW, and Takahashi JS. Mutagenesis and mapping of a mouse gene, Clock,
essential for circadian behavior. Science 264: 719-725, 1994.
35.
Wu MW, Li XM, Xian LJ, and Levi F. Effects of meal timing on tumor progression in mice.
Life Sci 75: 1181-1193, 2004.
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