Biomedical subjects

Paul Franken

Publications and source records attributed to Paul Franken.

15 recordsLinked to original sources

PubMed2006

Glycogen content in the cerebral cortex increases with sleep loss in C57BL/6J mice.

We hypothesized that a function of sleep is to replenish brain glycogen stores that become depleted while awake. We have previously tested this hypothesis in three inbred strains of mice by measuring brain glycogen after a 6h sleep deprivation (SD). Unexpectedly, glycogen content in the cerebral cortex did not decrease with SD in two of the strains and was even found to increase in mice of the C57BL/6J (B6) strain. Manipulations that initially induce glycogenolysis can also induce subsequent glycogen synthesis thereby elevating glycogen content beyond baseline. It is thus possible that in B6 mice, cortical glycogen content decreased early during SD and became elevated later in SD. In the present study, we therefore measured changes in brain glycogen over the course of a 6 h SD and during recovery sleep in B6 mice. We found no evidence of a decrease at any time during the SD, instead, cortical glycogen content monotonically increased with time-spent-awake and, when sleep was allowed, started to revert to control levels. Such a time-course is opposite to the one predicted by our initial hypothesis. These results demonstrate that glycogen synthesis can be achieved during prolonged wakefulness to the extent that it outweighs glycogenolysis. Maintaining this energy store seems thus not to be functionally related to sleep in this strain.

Analysis of Variance↗

PubMed2006

NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions.

Because the transcription factor neuronal Per-Arnt-Sim-type signal-sensor protein-domain protein 2 (NPAS2) acts both as a sensor and an effector of intracellular energy balance, and because sleep is thought to correct an energy imbalance incurred during waking, we examined NPAS2's role in sleep homeostasis using npas2 knockout (npas2-/-) mice. We found that, under conditions of increased sleep need, i.e., at the end of the active period or after sleep deprivation (SD), NPAS2 allows for sleep to occur at times when mice are normally awake. Lack of npas2 affected electroencephalogram activity of thalamocortical origin; during non-rapid eye movement sleep (NREMS), activity in the spindle range (10-15 Hz) was reduced, and within the delta range (1-4 Hz), activity shifted toward faster frequencies. In addition, the increase in the cortical expression of the NPAS2 target gene period2 (per2) after SD was attenuated in npas2-/- mice. This implies that NPAS2 importantly contributes to the previously documented wake-dependent increase in cortical per2 expression. The data also revealed numerous sex differences in sleep; in females, sleep need accumulated at a slower rate, and REMS loss was not recovered after SD. In contrast, the rebound in NREMS time after SD was compromised only in npas2-/- males. We conclude that NPAS2 plays a role in sleep homeostasis, most likely at the level of the thalamus and cortex, where NPAS2 is abundantly expressed.

Animals↗

PubMed2005

Retinoic acid signaling affects cortical synchrony during sleep.

Delta oscillations, characteristic of the electroencephalogram (EEG) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remain elusive. Here we demonstrate in the mouse that the gene encoding the retinoic acid receptor beta determines the contribution of delta oscillations to the sleep EEG. Thus, retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult.

Animals↗

PubMed2005

Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.

The Na(+)-independent alanine-serine-cysteine transporter 1 (Asc-1) is exclusively expressed in neuronal structures throughout the central nervous system (CNS). Asc-1 transports small neutral amino acids with high affinity especially for D-serine and glycine (K(i): 8-12 microM), two endogenous glutamate co-agonists that activate N-methyl-D-aspartate (NMDA) receptors through interacting with the strychnine-insensitive glycine binding-site. By regulating D-serine (and possibly glycine) levels in the synaptic cleft, Asc-1 may play an important role in controlling neuronal excitability. We generated asc-1 gene knockout (asc-1(-/-)) mice to test this hypothesis. Behavioral phenotyping combined with electroencephalogram (EEG) recordings revealed that asc-1(-/-) mice developed tremors, ataxia, and seizures that resulted in early postnatal death. Both tremors and seizures were reduced by the NMDA receptor antagonist MK-801. Extracellular recordings from asc-1(-/-) brain slices indicated that the spontaneous seizure activity did not originate in the hippocampus, although, in this region, a relative increase in evoked synaptic responses was observed under nominal Mg(2+)-free conditions. Taken together with the known neurochemistry and neuronal distribution of the Asc-1 transporter, these results indicate that the mechanism underlying the behavioral hyperexcitability in mutant mice is likely due to overactivation of NMDA receptors, presumably resulting from elevated extracellular D-serine. Our study provides the first evidence to support the notion that Asc-1 transporter plays a critical role in regulating neuronal excitability, and indicate that the transporter is vital for normal CNS function and essential to postnatal survival of mice.

Amino Acid Transport System y+↗

PubMed2004

Homeostatic regulation of sleep in arrhythmic Siberian hamsters.

Sleep is regulated by independent yet interacting circadian and homeostatic processes. The present study used a novel approach to study sleep homeostasis in the absence of circadian influences by exposing Siberian hamsters to a simple phase delay of the photocycle to make them arrhythmic. Because these hamsters lacked any circadian organization, their sleep homeostasis could be studied in the absence of circadian interactions. Control animals retained circadian rhythmicity after the phase shift and re-entrained to the phase-shifted photocycle. These animals displayed robust daily sleep-wake rhythms with consolidated sleep during the light phase beginning about 1 h after light onset. This marked sleep-wake pattern was circadian in that it persisted in constant darkness. The distribution of sleep in the arrhythmic hamsters over 24 h was similar to that in the light phase of rhythmic animals. Therefore, daily sleep amounts were higher in arrhythmic animals compared with rhythmic ones. During 2- and 6-h sleep deprivations (SD), it was more difficult to keep arrhythmic hamsters awake than it was for rhythmic hamsters. Because the arrhythmic animals obtained more non-rapid eye movement sleep (NREMS) during the SD, they showed a diminished compensatory response in NREMS EEG slow-wave activity during recovery sleep. When amounts of sleep during the SD were taken into account, there were no differences in sleep homeostasis between experimental and control hamsters. Thus loss of circadian control did not alter the homeostatic response to SD. This supports the view that circadian and homeostatic influences on sleep regulation are independent processes.

Animals↗

PubMed2003

Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice.

Animal behavior is synchronized to the 24-hour light:dark (LD) cycle by regulatory programs that produce circadian fluctuations in gene expression throughout the body. In mammals, the transcription factor CLOCK controls circadian oscillation in the suprachiasmatic nucleus of the brain; its paralog, neuronal PAS domain protein 2 (NPAS2), performs a similar function in other forebrain sites. To investigate the role of NPAS2 in behavioral manifestations of circadian rhythm, we studied locomotor activity, sleep patterns, and adaptability to both light- and restricted food-driven entrainment in NPAS2-deficient mice. Our results indicate that NPAS2 plays a substantive role in maintaining circadian behaviors in normal LD and feeding conditions and that NPAS2 is critical for adaptability to food restriction.

Adaptation, Physiological↗

PubMed2003

Changes in brain glycogen after sleep deprivation vary with genotype.

Sleep has been functionally implicated in brain energy homeostasis in that it could serve to replenish brain energy stores that become depleted while awake. Sleep deprivation (SD) should therefore lower brain glycogen content. We tested this hypothesis by sleep depriving mice of three inbred strains, i.e., AKR/J (AK), DBA/2J (D2), and C57BL/6J (B6), that differ greatly in their sleep regulation. After a 6-h SD, these mice and their controls were killed by microwave irradiation, and glycogen and glucose were quantified in the cerebral cortex, brain stem, and cerebellum. After SD, both measures significantly increased by approximately 40% in the cortex of B6 mice, while glycogen significantly decreased by 20-38% in brain stem and cerebellum of AK and D2 mice. In contrast, after SD, glucose content increased in all three structures in AK mice and did not change in D2 mice. The increase in glycogen after SD in B6 mice persisted under conditions of food deprivation that, by itself, lowered cortical glycogen. Furthermore, the strains that differ most in their compensatory response to sleep loss, i.e., AK and D2, did not differ in their glycogen response. Thus glycogen content per se is an unlikely end point of sleep's functional role in brain energy homeostasis.

Anesthesia↗

PubMed2003

Genetics of sleep and sleep disorders.

Sleep has been observed in all vertebrates studied and in several invertebrates, notably the fruit fly Drosophila melanogaster. In all species, a substantial portion of life is spent in this behavioral state and disturbed sleep or lack of sleep has immediate negative impacts on performance and health. Although it is agreed upon that sleep fulfills a fundamental biological need, the function of sleep remains an enigma. Because the expression and regulation of sleep and some sleep disorders have strong genetic components, the recent progress in human, mouse, and fruit-fly genome sequencing projects have given rise to the expectation that the molecular pathways underlying sleep disorders and sleep regulation or even function can now be more readily identified. We review here available genetic data both from basic sleep research and sleep disorders with emphasis on recent advances in our understanding of the molecular basis of the homeostatic regulation of sleep. Recent studies in the dog, the mouse, and the fruit-fly have begun to reveal exciting new molecular pathways that regulate sleep. This illustrates that only the continued use of multiple animal models and genetic approaches will ensure a rapid progress in the relatively new field of sleep genetics.

Animals↗

PubMed2003

Perchance to dream: solving the mystery of sleep through genetic analysis.

Sleep has been identified in all mammals and nonmammalian vertebrates that have been critically evaluated. In addition, sleep-like states have also been identified and described in several invertebrates. Despite this prevalence throughout the animal kingdom, the function of sleep remains a mystery. The completion of several genome sequencing projects has led to the expectation that fundamental aspects of sleep can be elucidated through genetic dissection. Indeed, studies in both the mouse and fly have begun to reveal tantalizing suggestions about the underlying principles that regulate sleep homeostasis. In this article we will review recent studies that have used genetic techniques to evaluate sleep in the fruit fly and the mouse.

Animals↗

PubMed2003

Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep.

In rodents, the electroencephalogram (EEG) during paradoxical sleep and exploratory behavior is characterized by theta oscillations. Here we show that a deficiency in short-chain acyl-coenzyme A dehydrogenase (encoded by Acads) in mice causes a marked slowing in theta frequency during paradoxical sleep only. We found Acads expression in brain regions involved in theta generation, notably the hippocampus. Microarray analysis of gene expression in mice with mutations in Acads indicates overexpression of Glo1 (encoding glyoxylase 1), a gene involved in the detoxification of metabolic by-products. Administration of acetyl-L-carnitine (ALCAR) to mutant mice significantly recovers slow theta and Glo1 overexpression. Thus, an underappreciated metabolic pathway involving fatty acid beta-oxidation also regulates theta oscillations during sleep.

Acetylcarnitine↗

PubMed2002

A role for cryptochromes in sleep regulation.

BACKGROUND: The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-) lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes. RESULTS: Under all three conditions, cry1,2-/- mice exhibit the hallmarks of high non-REM sleep (NREMS) drive (i.e., increases in NREMS time, NREMS consolidation, and EEG delta power during NREMS). This unexpected phenotype was associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and albumin d-binding protein (dbp), which are known to be transcriptionally inhibited by CRY1,2. To further examine the relationship between circadian genes and sleep homeostasis, we examined wild type mice and rats following sleep deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp mRNA specifically in the cerebral cortex; these changes subsided with recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase-1epsilon did not change with sleep deprivation. CONCLUSIONS: These results indicate that mice lacking cryptochromes are not simply a genetic model of circadian arrhythmicity in rodents and functionally implicate cryptochromes in the homeostatic regulation of sleep.

ARNTL Transcription Factors↗

PubMed2002

Role of melanopsin in circadian responses to light.

Melanopsin has been proposed as an important photoreceptive molecule for the mammalian circadian system. Its importance in this role was tested in melanopsin knockout mice. These mice entrained to a light/dark cycle, phase-shifted after a light pulse, and increased circadian period when light intensity increased. Induction of the immediate-early gene c-fos was observed after a nighttime light pulse in both wild-type and knockout mice. However, the magnitude of these behavioral responses in knockout mice was 40% lower than in wild-type mice. Although melanopsin is not essential for the circadian clock to receive photic input, it contributes significantly to the magnitude of photic responses.

Animals↗

PubMed2002

Long-term vs. short-term processes regulating REM sleep.

In cats, rats, and mice, the amount of rapid eye movement sleep (REMS) lost during a sleep deprivation (SD) predicts the subsequent REMS rebound during recovery sleep. This suggests that REMS is homeostatically regulated and that a need or pressure for REMS accumulates in its absence, i.e. during both wakefulness and non-rapid eye movement sleep (NREMS). Conversely, it has been proposed that REMS pressure accumulates exclusively during NREMS [Benington and Heller, Am. J. Physiol. 266 (1994) R1992; Prog. Neurobiol. 44 (1994b) 433]. This hypothesis is based on the analysis of the duration of successive NREMS and REMS episodes and of electroencephalogram (EEG) events preceding REMS. Pre-REMS events (PREs) do not always result in sustained REMS and can thus be regarded as REMS attempts that increase as NREMS progresses. It is assumed that two processes regulating REMS can resolve the apparent contradiction between these two concepts: a 'long-term' process that homeostatically regulates the daily REMS amount and a 'short-term' process that regulates the NREM--REMS cycle. These issues were addressed in two SD experiments in rats. The two SDs varied in length (12 and 24 h) and resulted in very similar compensatory changes in NREMS but evoked very different changes for all REMS parameters studied. The large REMS increase observed after 24-h SD was accompanied by a reduction in unsuccessful PREs and an increase in sustained REMS episodes, together resulting in a threefold increase in the success-rate to enter REMS. Changes in success-rate matched those of a theoretically derived long-term REMS pressure. The SD induced changes in sleep architecture could be reproduced by assuming that the increased long-term REMS pressure interacts with the short-term process by increasing the probability to enter and remain in REMS.

Animals↗

PubMed2002

Loss of circadian organization of sleep and wakefulness during hibernation.

We investigated circadian and homeostatic regulation of nonrapid eye movement (NREM) sleep in golden-mantled ground squirrels during euthermic intervals between torpor bouts. Slow-wave activity (SWA; 1-4 Hz) and sigma activity (10-15 Hz) represent the two dominant electroencephalographic (EEG) frequency components of NREM sleep. EEG sigma activity has a strong circadian component in addition to a sleep homeostatic component, whereas SWA mainly reflects sleep homeostasis [Dijk DJ and Czeisler CA. J Neurosci 15: 3526-3538, 1995; Dijk DJ, Shanahan TL, Duffy JF, Ronda JM, and Czeisler CA. J Physiol (Lond) 505: 851-858, 1997]. Animals maintained under constant conditions continued to display circadian rhythms in both sigma activity and brain temperature throughout euthermic intervals, whereas sleep and wakefulness showed no circadian organization. Instead, sleep and wakefulness were distributed according to a 6-h ultradian rhythm. SWA, NREM sleep bout length, and sigma activity responded homeostatically to the ultradian sleep-wake pattern. We suggest that the loss of sleep-wake consolidation in ground squirrels during the hibernation season may be related to the greatly decreased locomotor activity during the hibernation season and may be necessary for maintenance of multiday torpor bouts characteristic of hibernating species.

Animals↗

PubMed2002

Invited review: genetic dissection of sleep.

Recent advances in genomics open up new avenues in the analysis of complex behaviors such as sleep. In this analysis, the mouse is the model species of choice because it is amenable to high throughput phenotype and genotype analysis. With the use of the mouse model, unprecedented progress in our understanding of sleep physiology and the treatment of sleep disorders is awaited. This review is intended to provide an overview of available methods and techniques for genetic dissection of sleep in mice. Limits and advantages of different approaches are discussed to highlight the necessity for combining methods to avoid erroneous interpretations. The gap between understanding mechanisms of sleep and its functions may be bridged by finding its molecular bases.

Animals↗