Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats.

OBJECTIVE: Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch). METHODS: Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep-wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining. RESULTS: Repeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group. CONCLUSION: Delayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery.

TNFR1 is essential for CD40, but not for lipopolysaccharide-induced sickness behavior and clock gene dysregulation.

Autoimmune and infectious diseases are associated with behavioral changes referred to as sickness behavior syndrome (SBS). In autoimmunity, the generation of anti-self T lymphocytes and autoantibodies critically involves binding of CD40 ligand on T-cells to its receptor CD40 on B-cells, dendritic cells and macrophages. Activation of CD40 leads to production of proinflammatory cytokines and, as shown here, induces SBS. Here we report that these behavioral changes depend on the expression of tumor necrosis factor alpha receptor 1 (TNFR1), but not on interleukin-1 receptor 1 or interleukin-6. Moreover, the intensity of SBS correlates with suppression of E-box controlled clock genes, including Dbp, and upregulation of Bmal1. However, the absence of TNFR1 does not interfere with the development of SBS and dysregulation of clock genes in mice treated with lipopolysaccharide. Thus, our results suggest that TNFR1 mediates SBS and dysregulation of clock genes in autoimmune diseases.

Manipulation of adenosine kinase affects sleep regulation in mice.

Sleep and sleep intensity are enhanced by adenosine and its receptor agonists, whereas adenosine receptor antagonists induce wakefulness. Adenosine kinase (ADK) is the primary enzyme metabolizing adenosine in adult brain. To investigate whether adenosine metabolism or clearance affects sleep, we recorded sleep in mice with engineered mutations in Adk. Adk-tg mice overexpress a transgene encoding the cytoplasmic isoform of ADK in the brain but lack the nuclear isoform of the enzyme. Wild-type mice and Adk(+/-) mice that have a 50% reduction of the cytoplasmic and the nuclear isoforms of ADK served as controls. Adk-tg mice showed a remarkable reduction of EEG power in low frequencies in all vigilance states and in theta activity (6.25-11 Hz) in rapid eye movement (REM) sleep and waking. Adk-tg mice were awake 58 min more per day than wild-type mice and spent significantly less time in REM sleep (102 ± 3 vs 128 ± 3 min in wild type). After sleep deprivation, slow-wave activity (0.75-4 Hz), the intensity component of non-rapid eye movement sleep, increased significantly less in Adk-tg mice and their slow-wave energy was reduced. In contrast, the vigilance states and EEG spectra of Adk(+/-) and wild-type mice did not differ. Our data suggest that overexpression of the cytoplasmic isoform of ADK is sufficient to alter sleep physiology. ADK might orchestrate neurotransmitter pathways involved in the generation of EEG oscillations and regulation of sleep.

Sleep deprivation in the dark period does not impair memory in OF1 mice.

There is increasing evidence that sleep facilitates memory acquisition and consolidation. Moreover, the sleep-wake history preceding memory acquisition and retention as well as circadian timing may be important. We showed previously that sleep deprivation (SD) following learning in OF1 mice impaired their performance on an object recognition task. The learning task was scheduled at the end of the 12 h dark period and the test 24 h later. To investigate the influence of the prominent circadian sleep-wake distribution typical for rodents, we now scheduled the learning task at the beginning of the dark period. Wakefulness following immediately after the learning task was attained either by gentle interference (SD; n = 20) or by spontaneous wheel running (RW; n = 20). Two control groups were used: one had no RW throughout the experiment (n = 23), while the other group's wheel was blocked immediately after acquisition (n = 16), thereby preventing its use until testing. Recognition memory, defined as the difference in exploration of a novel and of familiar objects, was assessed 24 h later during the test phase. Motor activity and RW use were continuously recorded. Remarkably, performance on the object recognition task was not influenced by the protocols; the waking period following acquisition did not impair memory, independent of the method inducing wakefulness (i.e., sleep deprivation or spontaneous running). Thus, all groups explored the novel object significantly longer than the familiar ones during the test phase. Interestingly, neither the amount of rest lost during the SD interventions nor the amount of rest preceding acquisition influenced performance. However, the total amount of rest obtained by the control and SD mice subjected to acquisition at "dark offset" correlated positively (r = 0.66) with memory at test, while no such relationship occurred in the corresponding groups tested at dark onset. Neither the amount of running nor intermediate rest correlated with performance at test in the RW group. We conclude that interfering with sleep during the dark period does not affect object recognition memory consolidation.

Sleep deprivation impairs object recognition in mice.

Many studies in animals and humans suggest that sleep facilitates learning, memory consolidation, and retrieval. Moreover, sleep deprivation (SD) incurred after learning, impaired memory in humans, mice, rats, and hamsters. We investigated the importance of sleep and its timing in an object recognition task in OF1 mice subjected to 6h SD either immediately after the acquisition phase (0-6 SD) or 6h later (7-12 SD), and in corresponding undisturbed controls. Motor activity was continuously recorded with infrared sensors. All groups explored two familiar, previously encountered objects to a similar extent, both at the end of the acquisition phase and 24h later during the test phase, indicating intact familiarity detection. During the test phase 0-6 SD mice failed to discriminate between the single novel and the two familiar objects. In contrast, the 7-12 SD group and the two control groups explored the novel object significantly longer than the two familiar objects. Plasma corticosterone levels determined after SD did not differ from time-matched undisturbed controls, but were significantly below the level measured after learning alone. ACTH did not differ between the groups. Therefore, it is unlikely that stress contributed to the memory impairment. We conclude that the loss of sleep and the activities the mice engaged in during the SD, impaired recognition memory retrieval, when they occurred immediately after acquisition. The delayed SD enabled memory consolidation during the 6h when the mice were allowed to sleep, and had no detrimental effect on memory. Neither SD schedule impaired object familiarity processing, suggesting that only specific cognitive abilities were sensitive to the intervention. Sleep may either actively promote memory formation, or alternatively, sleep may provide optimal conditions of non-interference for consolidation.

Sleep deprivation and daily torpor impair object recognition in Djungarian hamsters.

Sleep has been shown to play a facilitating role in memory consolidation, whereas sleep deprivation leads to performance impairment both in humans and rodents. The effects of 4-h sleep deprivation on recognition memory were investigated in the Djungarian hamster (Phodopus sungorus). Because sleep during the first hours after daily torpor has many similarities to recovery from sleep deprivation, the effects of spontaneous torpor on object recognition were also assessed. A 4-h sleep deprivation, starting immediately after an object learning task, diminished the ability of the hamsters to: (1) discriminate between an already encountered object (target) and a novel object presented in a novel context, (2) retrieve a target within a complex spatial scene, and (3) detect a spatial rearrangement of familiar objects in a familiar context. Plasma stress hormone levels were similar in sleep-deprived and control hamsters. The occurrence of a daily torpor episode during retention was associated with impaired old-new object discrimination performance in the more effortful complex spatial scene task only, and in a two-object choice situation in a novel context no torpor-induced deficit was found. Our results show that post learning sleep deprivation and daily torpor induce a deficit in familiar object retrieval performance in a complex spatial scene, while sparing familiarity-based recognition and novelty processing. Sleep deprivation during the first 4 h of memory consolidation hampered also recency memory for discrete objects. Stress was not a factor contributing to the sleep deprivation-induced impairment.

Seasonal aspects of sleep in the Djungarian hamster.

BACKGROUND: Changes in photoperiod and ambient temperature trigger seasonal adaptations in the physiology and behaviour of many species, including the Djungarian hamster. Exposure of the hamsters to a short photoperiod and low ambient temperature leads to a reduction of the polyphasic distribution of sleep and waking over the light and dark period. In contrast, a long photoperiod enhances the daily sleep-wake amplitude leading to a decline of slow-wave activity in NREM sleep within the light period. It is unknown whether these changes can be attributed specifically to photoperiod and/or ambient temperature, or whether endogenous components are contributing factors. The influence of endogenous factors was investigated by recording sleep in Djungarian hamsters invariably maintained at a low ambient temperature and fully adapted to a short photoperiod. The second recording was performed when they had returned to summer physiology, despite the maintenance of the 'winter' conditions. RESULTS: Clear winter-summer differences were seen in sleep distribution, while total sleep time was unchanged. A significantly higher light-dark cycle modulation in NREM sleep, REM sleep and waking was observed in hamsters in the summer physiological state compared to those in the winter state. Moreover, only in summer, REM sleep episodes were longer and waking bouts were shorter during the light period compared to the dark period. EEG power in the slow-wave range (0.75-4.0 Hz) in both NREM sleep and REM sleep was higher in animals in the summer physiological state than in those in the 'winter' state. In winter SWA in NREM sleep was evenly distributed over the 24 h, while in summer it decreased during the light period and increased during the dark period. CONCLUSION: Endogenous changes in the organism underlie the differences in sleep-wake redistribution we have observed previously in hamsters recorded in a short and long photoperiod.

Selective sleep deprivation after daily torpor in the Djungarian hamster.

Sleep, daily torpor and hibernation are no longer considered homologous processes. Animals emerging from these states spend most of their time in sleep. After termination of the torpor-associated hypothermia, there is an initial high electroenecephalogram (EEG) slow-wave activity (SWA; 0.75-4.0 Hz) and a subsequent monotonic decline. Both of these features are similar to the effects elicited by prolonged waking. It was previously shown that when hamsters are not allowed to sleep immediately after emerging from torpor, an additional SWA increase above the level reached after sleep deprivation (SD) alone occurs during the delayed recovery. A similar manipulation in hibernating ground squirrels abolished the subsequent SWA increase, shedding doubt on the similarity of the regulatory aspects following torpor and hibernation. To further investigate the extent to which SWA is homeostatically regulated after torpor, Djungarian hamsters were subjected to 1.5 h partial non-rapid eye movement (NREM) sleep deprivation (NSD) that either immediately followed the emergence from torpor (T + NSD) or 4-h SD (SD + NSD). The NSD was attained by disturbing the animals when they exhibited NREM sleep with high amplitude slow-waves. To investigate whether regional aspects of sleep homeostasis are similar after torpor and SD, the EEG was recorded from a parietal and frontal derivation after 4-h SD. An increase in SWA in NREM sleep occurred after all conditions in both EEG derivations. There was no significant difference in SWA during the initial 1.5-h recovery when torpor, T + NSD and SD + NSD were compared. During recovery from torpor and SD, SWA was higher in the frontal than in the parietal derivation. Our results provide further evidence that torpor and SD have similar effects on sleep. The SWA increase did not disappear after the NSD; therefore, SWA is homeostatically regulated after daily torpor. The frontal predominance of slow waves encountered both after torpor and SD indicates that waking and torpor induce similar regional changes in EEG SWA.