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Fred W Turek

Publications and source records attributed to Fred W Turek.

At least 19 recordsLinked to original sources
PubMed2006

Genetic analysis of the stress-responsive adrenocortical axis.

The underlying genetic components contributing to individual variability in functions of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis are poorly understood. To determine genetic loci mediating three aspects of the adrenocortical function, we conducted a quantitative trait locus (QTL) analysis in the segregating F2 generation of a Wistar Kyoto (WKY) x Fischer 344 (F344) cross, two inbred rat strains that differ in several HPA axis measures. The following three components of adrenocortical function are known to be regulated by different mechanisms that are mediated via suprahypothalamic, hypothalamic, pituitary, and intra-adrenal influences: basal plasma corticosterone (Cort) levels, plasma Cort response to a 10-min restraint stress, and adrenal weight. Genome scans identified a complex genetic architecture for the basal Cort phenotype, including sex and maternal lineage effects. Pairwise interactions were also identified for this trait. We identified three significant and two suggestive QTLs for stress Cort, along with two pairs of interacting loci for this trait. Four highly significant and two suggestive loci were identified for adrenal weight, with no interacting loci. In contrast to basal Cort, no sex- or lineage-dependent QTL were identified for stress Cort or adrenal weight, despite the large sex differences in these phenotypes. We identified three nucleotide alterations in an obvious candidate gene mapped to the most significant QTL for stress Cort, Cort-binding globulin (CBG), one of which is known to alter CBG binding. This analysis confirms that three separate traits regulated by the HPA axis are controlled by multiple, but mainly nonoverlapping, QTLs.

Adrenal Glands↗
PubMed2006

Vasopressin regulation of the proestrous luteinizing hormone surge in wild-type and Clock mutant mice.

In the female mouse, ovulation and estrous cyclicity are under both hormonal and circadian control. We have shown that mice with a mutation in the core circadian gene Clock have abnormal estrous cycles and do not have a luteinizing hormone (LH) surge on the afternoon of proestrus due to a defect at the hypothalamic level. In the present study, we tested the hypotheses that vasopressin (AVP) can act as a circadian signal to regulate the proestrous release of LH, and that this signal is deficient in the Clock mutant. We found that Avp expression in the suprachiasmatic nucleus (SCN) and AVP 1a receptor (Avpr1a) expression in the hypothalamus is reduced in Clock mutant mice compared to wild-type mice. Intracerebroventricular (i.c.v.) injection of AVP on the afternoon of proestrus is sufficient to induce LH secretion, which reaches surge levels in 50% of Clock mutant mice. The effect of AVP on the Clock mutant LH surge is mediated by AVPR1A, as co-infusion of AVP and an AVPR1A-specific antagonist prevents AVP induction of LH release, although infusion of an AVPR1A antagonist into wild-type mice failed to prevent a proestrous LH surge. These results suggest that reduced hypothalamic AVP signaling plays a role in the absence of the proestrous LH surge in Clock mutant mice. The results also support the hypothesis that AVP produced by the SCN may be a circadian signal that regulates LH release.

Animals↗
PubMed2006

The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude.

The mouse Clock gene encodes a basic helix-loop-helix-PAS transcription factor, CLOCK, that acts in concert with BMAL1 to form the positive elements of the circadian clock mechanism in mammals. The original Clock mutant allele is a dominant negative (antimorphic) mutation that deletes exon 19 and causes an internal deletion of 51 aa in the C-terminal activation domain of the CLOCK protein. Here we report that heterozygous Clock/+ mice exhibit high-amplitude phase-resetting responses to 6-h light pulses (Type 0 resetting) as compared with wild-type mice that have low amplitude (Type 1) phase resetting. The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes, Per1 and Per2, are not affected by the Clock/+ mutation. However, the amplitude of the circadian rhythms of Per gene expression are significantly reduced in Clock homozygous and heterozygous mutants. Rhythms of PER2::LUCIFERASE expression in suprachiasmatic nuclei explant cultures also are reduced in amplitude in Clock heterozygotes. The phase-response curves to changes in culture medium are Type 0 in Clock heterozygotes, but Type 1 in wild types, similar to that seen for light in vivo. The increased efficacy of resetting stimuli and decreased PER expression amplitude can be explained in a unified manner by a model in which the Clock mutation reduces circadian pacemaker amplitude in the suprachiasmatic nuclei.

Animals↗
PubMed2006

Diurnal sex differences in the sleep-wake cycle of mice are dependent on gonadal function.

STUDY OBJECTIVES: Sex is an important determinant of the pathophysiology of several disorders that influence and/or impair sleep-wake regulation. To date, few studies have examined either the role of sex or the gonadal hormones on sleep and wakefulness. The difficulty in performing well-controlled clinical experiments on sex and sleep underscores the need for effective animal models to investigate the influence of the gonadal hormones on sleep-wake states. This study describes the influence of sex on sleep and wakefulness in mice, the primary mammalian genetic model for sleep analysis, and tests the hypothesis that gonadal function drives sex differences in sleep-wake states. DESIGN: Electroencephalogram/electromyogram sleep-wake patterns were recorded in intact and gonadectomized male and female C57BL/6J mice maintained on a 14-hour light:10-hour dark schedule. Following a 24-hour baseline recording, mice were sleep deprived during the light phase by gentle handling and given a 10-hour recovery opportunity during the immediate dark phase. MEASUREMENTS AND RESULTS: Intact female mice spent more time awake than intact males during 24 hours of baseline recording at the expense of non-rapid eye movement (NREM) sleep. Though the recovery response of NREM sleep was similar between males and females, when examined in reference to baseline levels, females exhibited a more robust recovery response. Gonadectomy in males and females reduced or eliminated the majority of sex differences in sleep architecture and homeostasis. CONCLUSIONS: These data demonstrate that the gonadal hormones influence the amount, distribution, and intensity of sleep but do not account for all sex differences in the sleep-wake cycle.

Animals↗
PubMed2005

Altered sleep regulation in leptin-deficient mice.

Recent epidemiological, clinical, and experimental studies have demonstrated important links between sleep duration and architecture, circadian rhythms, and metabolism, although the genetic pathways that interconnect these processes are not well understood. Leptin is a circulating hormone and major adiposity signal involved in long-term energy homeostasis. In this study, we tested the hypothesis that leptin deficiency leads to impairments in sleep-wake regulation. Male ob/ob mice, a genetic model of leptin deficiency, had significantly disrupted sleep architecture with an elevated number of arousals from sleep [wild-type (WT) mice, 108.2 +/- 7.2 vs. ob/ob mice, 148.4 +/- 4.5, P < 0.001] and increased stage shifts (WT, 519.1 +/- 25.2 vs. ob/ob, 748.0 +/- 38.8, P < 0.001) compared with WT mice. Ob/ob mice also had more frequent, but shorter-lasting sleep bouts compared with WT mice, indicating impaired sleep consolidation. Interestingly, ob/ob mice showed changes in sleep time, with increased amounts of 24-h non-rapid eye movement (NREM) sleep (WT, 601.5 +/- 10.8 vs. ob/ob, 669.2 +/- 13.4 min, P < 0.001). Ob/ob mice had overall lower body temperature (WT, 35.1 +/- 0.2 vs. ob/ob, 33.4 +/- 0.2 degrees C, P < 0.001) and locomotor activity counts (WT, 25125 +/- 2137 vs. ob/ob, 5219 +/- 1759, P < 0.001). Ob/ob mice displayed an attenuated diurnal rhythm of sleep-wake stages, NREM delta power, and locomotor activity. Following sleep deprivation, ob/ob mice had smaller amounts of NREM and REM recovery sleep, both in terms of the magnitude and the duration of the recovery response. In combination, these results indicate that leptin deficiency disrupts the regulation of sleep architecture and diurnal rhythmicity.

Animals↗
PubMed2005

Obesity and metabolic syndrome in circadian Clock mutant mice.

The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

Adipocytes↗
PubMed2004

Circadian rhythms: from the bench to the bedside and falling asleep.

The discovery of the molecular core machinery underlying the generation of circadian rhythms in mammals, and the ability to alter the genes and protein products that comprise the circadian clock, has led to a new appreciation of the role of the clock in regulating many parameters of the sleep-wake cycle, beyond just the timing of sleep. The journal, Sleep, with its mission of publishing papers on basic and translational research in the field of sleep, is in an ideal position to insure that advances in the field of circadian rhythms are used to improve human sleep and in the treatment of sleep-wake disorders.

Circadian Rhythm↗