Neurofibrillary pathology [paired helical filaments (PHFs)] formed by the microtubule-associated protein tau in a hyperphosphorylated form is a major hallmark of Alzheimer's disease and related disorders. The process of tau phosphorylation, thought to be of critical importance for PHF formation, and its potential link to neurodegeneration, however, is not understood very well, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. Here we describe the formation of highly phosphorylated tau, containing a number of PHF-like epitopes in torpor during hibernation. PHF-like phosphorylation of tau was not associated with fibril formation and was fully reversible after arousal. Distribution of PHF-like tau followed a consistent pattern, being most intense in the entorhinal cortex, hippocampus, and isocortical areas. Within the hippocampus, a particularly high labeling was seen in CA3 pyramidal cells. Somewhat lesser reactivity was present in CA1 neurons while dentate gyrus granule cells were not reactive. Formation of PHF-like tau in CA3 neurons was paralleled by the regression of synaptic contacts of the mossy fiber system terminating on CA3 apical dendrites. Mossy fiber afferentation was re-established during arousal, concomitantly with the decrease of PHF-like tau in CA3 neurons. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau. The repeated formation and degradation of PHF-like tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. Hibernation will, therefore, be a valuable model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological in vivo conditions.

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Nocturnal rodents show diurnal food anticipatory activity when food access is restricted to a few hours in daytime. Timed food access also results in reduced food intake, but the role of food intake in circadian organization per se has not been described. By simulating natural food shortage in mice that work for food we show that reduced food intake alone shifts the activity phase from the night into the day and eventually causes nocturnal torpor (natural hypothermia). Release into continuous darkness with ad libitum food, elicits immediate reversal of activity to the previous nocturnal phase, indicating that the classical circadian pacemaker maintained its phase to the light-dark cycle. This flexibility in behavioral timing would allow mice to exploit the diurnal temporal niche while minimizing energy expenditure under poor feeding conditions in nature. This study reveals an intimate link between metabolism and mammalian circadian organization.

Hibernation is an energy-conserving behavior consisting of periods of inhibited metabolism ('torpor') with lowered body temperature. Torpor bouts are interspersed by arousal periods, in which metabolism increases and body temperature returns to euthermia. In deep torpor, the body temperature typically decreases to 2-10°C, and major physiological and immunological changes occur. One of these alterations constitutes an almost complete depletion of circulating lymphocytes that is reversed rapidly upon arousal. Here we show that torpor induces the storage of lymphocytes in secondary lymphoid organs in response to a temperature-dependent drop in plasma levels of sphingosine-1-phosphate (S1P). Regulation of lymphocyte numbers was mediated through the type 1 S1P receptor (S1P 1 ), because administration of a specific antagonist (W146) during torpor (in a Syrian hamster at ∼8°C) precluded restoration of lymphocyte numbers upon subsequent arousal. Furthermore, S1P release from erythrocytes via ATP-binding cassette (ABC)-transporters was significantly inhibited at low body temperature (4°C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at ± 25°C), during forced hypothermia in anesthetized (summer-active) hamsters (at ± 9°C), and in a nonhibernator (rat at ∼19°C). Our results demonstrate that lymphopenia during hibernation in small mammals is driven by body temperature, via altered plasma S1P levels. S1P is recognized as an important bioactive lipid involved in regulating several other physiological processes as well and may be an important factor regulating additional physiological processes in hibernation as well as in mediating the effects of therapeutic hypothermia in patients.ibernation is an energy-conserving behavior consisting of periods of significantly inhibited metabolism (torpor) that result in a largely reduced heart and ventilation rate (1-3) and body temperature. Torpor bouts are interspersed by arousal periods with durations of 8-24 h, during which metabolism increases and body temperature rapidly returns to euthermia (2, 4). Hibernating mammals display major changes in their physiology that lead (among other changes) to an increased resistance to ischemia/reperfusion (5, 6) and a reduced immune function (7). Remarkably, despite the repetitive cycles of cooling and rewarming, hibernating animals do not show gross signs of organ damage (8). In humans, therapeutic hypothermia is used frequently to limit neuronal injury in cardiac arrest and major surgery of brain and heart (9). However, hypothermia as used during cardiac surgery is associated with increased renal injury postoperatively (10). Therefore, unraveling the mechanisms underlying the changes in physiology of hibernating mammals might be of substantial clinical relevance.

Polyunsaturated fatty acids (PUFA) have strong effects on hibernation and daily torpor. Increased dietary uptake of PUFA of the n-6 class, particularly of Linoleic acid (LA, C18:2 n-6) lengthens torpor bout duration and enables animals to reach lower body temperatures (Tb) and metabolic rates. As previously hypothesized, this well-known influence of PUFA may be mediated via effects of the membrane fatty acid composition on sarcoplasmic reticulum (SR) Ca2+−ATPase 2a (SERCA) in the heart of hibernators. We tested the hypotheses that high proportions of n-6 PUFA in general, or specifically high proportions of LA (C18:2 n-6) in SR phospholipids (PL) should be associated with increased cardiac SERCA activity, and should allow animals to reach lower minimum Tb in torpor. We measured activity of SERCA from hearts of hibernating and non-hibernating Syrian hamsters (Mesocricetus auratus) in vitro at 35°C. Further, we determined the PL fatty acid composition of the SR membrane of these hearts. We found that SERCA activity strongly increased as the proportion of LA in SR PL increased but was negatively affected by the content of Docosahexaenoic acid (DHA; C22:6 n-3). SR PL from hibernating hamsters were characterized by high proportions of LA and low proportions of DHA. As a result, SERCA activity was significantly higher during entrance into torpor and in torpor compared to inter-bout arousal. Also, animals with increased SERCA activity reached lower Tb during torpor. Interestingly, a subgroup of hamsters which never entered torpor but remained euthermic throughout winter displayed a phenotype similar to animals in summer. This was characterized by lower proportions of LA and increased proportions of DHA in SR membranes, which is apparently incompatible with torpor. We conclude that the PUFA composition of SR membranes affects cardiac function via modulating SERCA activity, and hence determines the minimum Tb tolerated by hibernators.

The relationship between body size and basal metabolic rate (BMR) in homeotherms has been treated in the literature primarily by comparison between species of mammals or birds. This paper focuses on the intraindividual changes in BMR when body mass (W) varies with different maintenance regimens. BMR varied in individual kestrels in proportion to W 1.67 , which is considerably steeper than the mass exponents for homomorphic change (0.667; Heusner, 1984) for interspecific comparison among all birds (0.677) or raptors (0.678), for interindividual comparison of kestrels on ad libitum maintenance regimens (0.786), and for mass proportionality (1.00). The circadian range of telemetered core temperature also varied more strongly with intraindividual than with interspecific (Aschoff, 1981a) variation in mass. This was due to reduced nocturnal core temperature at low-maintenance regimens, which was, however, insufficient to account for the excessive reduction in BMR. Carcass analysis of eight birds sacrificed revealed a disproportionate reduction in heart and kidney lean mass at low-maintenance regimens. We surmise that variation in BMR primarily reflects variation in these metabolically highly active tissues. This may account for positive correlations found between heart, kidney, and BMR residuals relative to interspecific allometric prediction, and between α and p residuals, as expected on the basis of the constant excess of BMR during α above BMR during p (Aschoff & Pohl, 1970a).In the broad diversity of scientific contributions by Jfrgen Aschoff, the one with greatest impact in animal ecology has been his analysis, jointly with Hermann Pohl, of basal metabolic rates (BMRs) in birds and their dependence on body mass and phase of the circadian cycle (Aschoff and Pohl, 1970a, b). This analysis refined earlier allometric relationships established by Kleiber (1947), Brody (1945), and Lasiewski and Dawson (1967 by demonstrating that BMRs, measured in darkness, at rest, at thermoneutral temperature, and without food being digested, were reduced during the circadian rest phase compared with the active phase. BMRs during the rest phase and their allometric relation with body mass soon became a standard for 1. This paper is dedicated to Professor Jürgen Aschoff, whose breadth of scientific interests and warm intellectual support have become an inexhaustible source of inspiration for us.

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