Arjen M. Strijkstra

Warming up for sleep? - ground squirrels sleep during arousals from hibernation

Hypothermia during mammalian hibernation is periodically interrupted by arousals to euthermy, the function of which is unknown. We report that arctic ground squirrels (Spermophilus parryii) consistently sleep during these arousals, and that their EEG shows the decrease in slow wave activity (delta power) that is characteristic of a declining requirement for sleep. These results are consistent with the novel hypothesis that the need for sleep slowly accumulates during torpor, and that returning to euthermy is periodically required to allow sleep. Sleep thus seems to be energetically expensive for a hibernating mammal, and cannot be considered solely a strategy for saving energy.

Subjective sleepiness correlates negatively with global alpha (8–12 Hz) and positively with central frontal theta (4–8 Hz) frequencies in the human resting awake electroencephalogram

Subjective sleepiness is part of the system controlling the decision to go to sleep in humans. Extended periods of waking lead to increased sleepiness, as well as to changes in cortical electroencephalogram (EEG) during waking. We investigated the association of sleepiness and awake EEG spectra during 40 h of wakefulness using multi-electrode EEG recordings for full coverage of the scalp. We found: (1). strong negative correlations of alpha (8-12 Hz) power with subjective sleepiness at all scalp locations, suggesting a negative association between sleepiness and general cortical activation; and (2). positive correlations of theta (4-8 Hz) power with subjective sleepiness with a focus on frontal locations, suggesting additional location specific associations between sleepiness and cortical activation. These findings support the notion that sleepiness is directly represented in the awake EEG.

Intraspecific Allometry of Basal Metabolic Rate: Relations with Body Size, Temperature, Composition, and Circadian Phase in the Kestrel, Falco tinnunculus

The relationship between body size and basal metabolic rate (BMR) in homeo therms 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 W1.67, 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).

A social conflict increases EEG slow-wave activity during subsequent sleep

Electroencephalogram (EEG) slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep is widely viewed as an indicator of sleep debt and sleep intensity. In a previous study, we reported a strong increase in SWA during NREM sleep after a social conflict in rats. To test whether this increase in SWA reflects normal physiological sleep or an unrelated by-product of the stress, we now measured the effect of a conflict in combination with extended sleep deprivation by means of gentle handling. We anticipated that if the social defeat-induced SWA reflects a true sleep debt, the drive for it would persist during the extended wakefulness. Male rats were subjected to a 1-h social conflict followed by 5 h of sleep deprivation by gentle handling or to 6 h gentle handling alone. The manipulations took place during the second half of the dark phase and recovery sleep was recorded during the subsequent light phase. Neither of the two procedures caused a significant change in the total duration of NREM or REM sleep thereafter. Yet, both modes of sleep deprivation induced a strong increase in SWA during NREM sleep. This SWA was significantly higher for 6 h after sleep deprivation consisting of a social conflict followed by gentle handling, as compared to sleep deprivation by handling alone. Thus, the SWA increasing effect of the conflict persisted during the extended wakefulness. The data confirm that social defeat stress accelerates the build up of sleep debt and support the notion that sleep debt and subsequent NREM sleep intensity not only depend on the duration of prior wakefulness but also on what animals experience during that waking.

Working for Food Shifts Nocturnal Mouse Activity into the Day

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 model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons – implications for Alzheimer's disease

Neurofibrillar tangles made up of ‘paired helical filaments’ (PHFs) consisting of hyperphosphorylated microtubule‐associated protein tau are major hallmarks of Alzheimers disease (AD). Tangle formation selectively affects certain neuronal types and systematically progresses throughout numerous brain areas, which reflects a hierarchy of neuronal vulnerability and provides the basis for the neuropathological staging of disease severity. Mechanisms underlying this selective neuronal vulnerability are unknown. We showed previously that reversible PHF‐like phosphorylation of tau occurs during obligate hibernation. Here we extend these findings to facultative hibernators such as Syrian hamsters (Mesocricetus auratus) forced into hibernation. In this model, we showed in the basal forebrain projection system that cholinergic neurons are selectively affected by PHF‐like phosphorylated tau, while γ‐aminobutyric acid (GABA)ergic neurons are largely spared, which shows strong parallels to the situation in AD. Formation of PHF‐tau in these neurons apparently does not affect their function as pacemaker for terminating hibernation. We conclude that although formation of PHF‐like phosphorylated tau in the mammalian brain follows a certain hierarchy, affecting some neurons more frequently than others, it is not necessarily associated with impaired neuronal function and viability. This indicates a more general link between PHF‐like phosphorylation of tau and the adaptation of neurons under conditions of a ‘vita minima’.

Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate

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 (S1P1), 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.

Dissimilarity of slow-wave activity enhancement by torpor and sleep deprivation in a hibernator

Sleep regulation processes have been hypothesized to be involved in function and timing of arousal episodes in hibernating ground squirrels. We investigated the importance of sleep regulation during arousal episodes by sleep deprivation experiments. After sleep deprivation of 4, 12, and 24 h, starting 4 h after onset of euthermy, a duration-dependent enhancement of slow-wave activity (SWA) of the cortical electroencephalogram during non-rapid eye movement sleep was found, as expected for normal sleep regulation. When sleep deprivation was applied during the initial phase of the arousal episode, in which effects of prior torpor were present in undisturbed recordings, no subsequent recurrence of SWA was found. In addition, prior torpor induced a reduction in the spectral activity of the sigma frequency range (7-14 Hz), which was not observed after sleep deprivation. The effects of torpor and sleep deprivation on subsequent SWA appear qualitatively different. This indicates that effects of deep torpor on sleep are dissimilar to normal sleep regulation.

Sex and age differences in mass, morphology, and annual cycle in European ground squirrels, Spermophilus citellus

We collected 6 years of data (1990-1995) on survival, hibernation, body-mass changes, and morphological parameters for a suburban population of European ground squirrels (Spermophilus citellus) using censusing and capture-recapture techniques. We attempted to determine differences in sex and age in these parameters. In the focal population, sex ratios of adults and yearlings were female-biased, but the sex ratio of juveniles was balanced. Overwinter mortality was low, but losses during the active season were high in all sex and age groups. Male and female juveniles disappeared from their natal area in roughly equal proportions. Among older individuals, more males disappeared than females. Hibernation patterns were similar to other Spermophilus species, except that females began hibernation before males. Therefore, females had significantly longer hibernation periods and higher proportional overwinter losses of mass than males. All adult (greater than or equal to 2 years) but only a few yearling males were reproductively active. Yearling males emerged from hibernation with a lower mass than adults but were indistinguishable from them before subsequent immergence. Adult and yearling females reproduced and lost mass during late lactation, a pattern more pronounced in older than yearling females. Juvenile males were heavier than juvenile females before hibernation, although no difference was found at weaning. Skull size increased in the first two active seasons but did not change thereafter. Differences in sex and age resembled those of most hibernating,ground squirrels in many aspects but also showed some unusual patterns that probably have evolved due to specific environmental constraints in this species.

The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress

The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer’s disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases.