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Potassium, rubidium, and 4-aminopyridine effects on the circadian running rhythm in the hamster.

The period of the circadian rhythm of wheel-running was shortened when golden hamsters were given supplemental dietary potassium or rubidium for two weeks. Treatment with 4-aminopyridine, a potassium channel blocker, significantly increased circadian period. These period changes (0.17 h for potassium treatment, 0.14 h for rubidium, and 0.07 h for 4-aminopyridine) support previous data indicating that potassium is a component of the mammalian biological clock mechanism.

4-Aminopyridine↗

Morphological characteristics of the bovine corpus luteum during the estrous cycle and pregnancy.

The corpus luteum, one of the biological clocks of the estrous cycle and pregnancy, is known foremost for its production of progesterone that blocks the pituitary release of gonadotropins and prepares the uterus for a pregnancy. The cellular sources of this progesterone are the steroidogenic small and large luteal cells. Other luteal cells that are not steroidogenic, but are believed to have an important role in the function of this gland are the fibroblast, macrophages and endothelial cells. The most prominent luteal cell is the large steroidogenic cell characterized by an abundance of smooth endoplasmic reticulum and densely packed spherical mitochondria that are indicative of its contribution to most of the circulating progesterone believed to be constitutively secreted and not under the control of LH. Other distinguishing features of the large luteal cell are the presence of rough endoplasmic reticulum, prominent Golgi, and secretory granules that are indicative of endocrine cells. This cell undergoes dynamic changes across the estrous cycle and pregnancy, believed to reflect a change in progesterone and protein secretion that will eventually influence a successful pregnancy or another ovulation if pregnancy fails. The morphological characteristics of the bovine luteal cells are the focus of this review.

Journal Article↗

Relations between depressed mood and vocal parameters before, during and after sleep deprivation: a circadian rhythm study.

The mechanism underlying improvement after total sleep deprivation (TSD) was studied in 14 major depressed patients. The suggestions that (1) circadian processes and/or (2) dimensions of arousal may play a role in the response to TSD were investigated. Diurnal variation of depressed mood and of mood- and arousal-related vocal parameters was studied in relation to the effect of TSD on depressed mood and vocal parameters. During 3 baseline days, during TSD and 2 days after TSD vocal parameters and depressed mood were assessed 6 and 3 times daily respectively. The mean fundamental frequency (frequency of vocal fold vibration, F0) (presumably reflecting aspects of arousal) as well as the range of the F0 (proposed to reflect sadness) showed a clear circadian pattern with a peak at about 4.00 p.m. TSD affected the circadian organization of the mean F0 and advanced the peak of the curve. After one night of subsequent sleep this effect disappeared. In addition, improvement after TSD coincided with an increase of the mean F0. The diurnal variation of mood before TSD predicted the mood response to TSD, whereas diurnal variation of vocal parameters did not. Moreover, circadian changes in vocal parameters were not related to changes in depressed mood. These findings suggest that the diurnal variations in mood and vocal parameters are regulated by different mechanisms. Data support the presumption that circadian as well as arousal processes are involved in the mood response to TSD. Circadian changes in vocal parameters due to TSD are not likely to reflect changes in the biological clock.

Adult↗

A longitudinal study of diurnal mood variation in depression; characteristics and significance.

The course of 39 depressed in-patients' daily mood was recorded by means of frequent self-ratings during their entire stay (in total 3718 days). The frequency of diurnal variations largely varies between subjects without clear dichotomy in 'diurnal' and 'non-diurnal' subjects and the occurrence of diurnal variations is rather irregular. Mood variability measures rather than average daily mood improvement correlate with the response to sleep deprivation. These observations do not support theories of chronobiological rhythm disturbances in depression. It is argued that depressed subjects largely vary in susceptibility to stimuli. Signals generated by the biological clock or by processes related to the sleep-wake cycle are considered examples of such stimuli.

Adult↗

Circadian variation of plasma cobalamin, transcobalamin-bound cobalamin and unsaturated binding capacity of transcobalamin and haptocorrin in healthy elderly.

Blood samples were drawn every second hour during a 24-h period from healthy elderly subjects. Plasma levels of cobalamin, albumin, transcobalamin-bound cobalamin and unsaturated binding capacity of transcobalamin and haptocorrin were determined. During night, all components decreased in parallel with plasma albumin. The nocturnal decreases were therefore ascribed to plasma volume changes due to bed-rest. Reports on the recently proposed role of cobalamin for the biological clock were reviewed, but the proposed role could not be explained by this study.

Aged↗

Direct in utero perception of light by the mammalian fetus.

The primary neural pathway for entrainment of circadian rhythms in rodents is the retinohypothalamic tract, which conveys lighting information from the retina to a biological clock in the hypothalamic suprachiasmatic nuclei (SCN). In a precocious rodent species, the spiny mouse, the retinohypothalamic tract is present and functioning within the SCN on the day of birth, as assessed by HRP histochemistry and 14C-labeled 2-deoxyglucose autoradiography, respectively. Furthermore, direct perception of environmental lighting was observed in fetal spiny mice late in gestation. Direct, retina-mediated fetal light perception appears to be a less potent entraining agent than maternal cues communicating time-of-day information to the fetal spiny mouse. Nevertheless, direct fetal light perception may reinforce maternal entraining signals during the prenatal period and therefore be of physiological significance for entrainment of circadian rhythmicity in the fetus.

Animals↗

Circadian actions of melatonin at the suprachiasmatic nucleus.

The biological clock in the suprachiasmatic nucleus (SCN) of the hypothalamus plays a well-defined role in regulating melatonin production by the pineal. Emerging evidence indicates that melatonin itself can feed back upon the SCN and thereby influence circadian functions. Melatonin administration has been shown to entrain activity rhythms in rodents and humans. Melatonin binds specifically within the SCN and alters SCN physiology by both acute and clock-resetting mechanisms. The circadian clock in the SCN appears to temporally restrict its own sensitivity to melatonin, such that physiological sensitivity is greatest in the subjective dusk period.

Animals↗

Impact of age-related changes in serotonin and norepinephrine metabolism on reproductive function in female rats: an analytical review.

This review attempts to reconcile changes in brain NE and 5HT metabolism with the effects of aging, drug treatment and altered photoperiods on phasic and tonic release of LH in the female. A hypothesis is presented in which 5HT has "indirect" and "direct" effects on LH surges. The "indirect" ones facilitate LH surges via a generalized effect of 5HT on temporal organization within multiple neuroendocrine axes. Thus, 5HT promotes circadian rhythmicity in many systems due to its participation in the biological "clock" mechanism of the hypothalamus. The "direct" ones that are specific to the LH releasing mechanism also occur for 5HT (inhibitory) as well as for NE (facilitory) due to the interaction of these transmitters with LH-RH secreting neurons. It is proposed that metabolic changes during aging that favor 5HT at the expense of NE obliterate the facilitatory effects of both amines while enhancing the inhibitory component of 5HT's influence on LH secretion.

Aging↗

Light-induced gene expression in the suprachiasmatic nucleus of young and aging rats.

We investigated age-related changes in a molecular mechanism associated with synchronization of circadian rhythms to the environment. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that regulates a variety of physiological and behavioral rhythms. Recent studies have demonstrated photic induction of immediate early genes (IEGs) such as c-fos in the SCN in a circadian-phase dependent manner, suggesting that IEGs may be part of the pathway for entrainment of circadian rhythms. We find that there is a decreased response of the IEGs c-fos, and NGFI-A but not NGFI-B in the SCN of old animals after photic stimulation. Changes in gene transcription indicated by IEGs may provide insights into the molecular machinery of the biological clock and ultimately elucidate mechanisms underlying the age-dependent decay of circadian organization.

Aging↗

Influence of aging on the seasonal rhythm of the vasopressin-expressing neurons in the human suprachiasmatic nucleus.

The mammalian suprachiasmatic nucleus (SCN) is considered to be a major component of the biological clock implicated in the temporal organization of a variety of physiological, endocrine, and behavioral processes. There is now a great deal of evidence indicating that many of these rhythms are progressively disturbed during senescence. The present study was aimed at investigating the influence of aging on the seasonal rhythm of the vasopressin (VP)-expressing neurons in the human SCN. To that end, brains obtained at autopsy of 48 human subjects, ranging in age from 6 to 91 years, were studied. Subjects were divided into two age groups, viz. "young subjects" (up to 50 years) and "elderly subjects" (over 50 years). It is shown that the number of VP-immunoreactive neurons in the human SCN exhibits a marked annual oscillation in young but not in elderly people. Whereas in young subjects low VP-immunoreactive neuron numbers were found during the summer (May-July) and peak values in autumn (September-November), the SCN of elderly people showed a disrupted annual cycle with a reduced amplitude. These data suggest that the biosynthesis of vasopressin in the human SCN exhibits a seasonal rhythm that becomes disturbed later in life.

Adolescent↗

Seasonal changes in the suprachiasmatic nucleus of man.

The mammalian suprachiasmatic nucleus (SCN) is considered to be the principal component of the biological clock, generating a wide variety of physiological and behavioral circadian rhythms. In addition to its implication in circadian rhythms, the SCN is also involved in the expression of some seasonal cycles. In the present study we show that the volume of the human SCN and the number of vasopressin-immunoreactive neurons contained within it fluctuate significantly over the year, with values being about twice as high in the autumn as in the summer. In contrast, no seasonal variations could be detected in the paraventricular nucleus (PVN), another major vasopressinergic cell group in the hypothalamus. The present findings suggest that the human SCN is influenced by seasonal variations in photoperiod.

Adolescent↗

Distribution of arginine-vasopressin and vasoactive intestinal peptide messenger RNA in the suprachiasmatic nucleus of the sheep.

The distribution of mRNAs for vasoactive intestinal peptide (VIP) and arginine-vasopressin (VP) was studied in the hypothalamus of the sheep by in situ hybridization. VIP mRNA was detected in the supraoptic nucleus (SON) and in the median part of the suprachiasmatic nucleus (SCN). VP mRNA was observed in the magnocellular system of the hypothalamus and in the dorso-lateral part of the SCN. These results confirm that the SCN is a site of synthesis of both peptides. Therefore, VIP and VP may be involved in diverse physiological functions including the functioning of the biological clock constituted by the SCN.

Animals↗

Annual variations in the vasopressin neuron population of the human suprachiasmatic nucleus.

The mammalian suprachiasmatic nucleus is considered to be the major component of the biological clock, involved in the temporal organization of a wide variety of physiological and behavioral processes. The present study was conducted to investigate whether there are diurnal or annual variations in the morphology of the vasopressin-containing neuron population of the suprachiasmatic nucleus in human beings. To that end, the brains of 48 human subjects were investigated. A marked annual variation was observed in the volume and vasopressin cell number of the human suprachiasmatic nucleus: the volume of the vasopressin cell population was, on average, 2.5 times larger in October-November than in May-June and contained 2.7 times as many vasopressin-immunoreactive neurons. In general, the annual cycle of the human suprachiasmatic nucleus showed a non-sinusoidal pattern with a maximum in early autumn, a lower plateau in winter and a deep trough in late spring and early summer. In contrast, no such seasonal variations could be detected in suprachiasmatic nucleus vasopressin numerical cell density or cell-nuclear diameter. The number of vasopressin-immunoreactive neurons in the paraventricular nucleus of the hypothalamus, on the other hand, did not show any significant periodic changes over the year, indicating the specificity of the suprachiasmatic nucleus rhythm. In contrast with the annual cycle of the suprachiasmatic nucleus, no significant diurnal variations were observed in any of these parameters. In conclusion, the findings indicate that photoperiod may be considered a potential environmental factor controlling the activity of the vasopressin system of the human suprachiasmatic nucleus.

Adolescent↗

On the aging of organisms and their cells.

An explanation of organismic ageing based on a limited division capacity of dividing cells is difficult to reconcile with much of the available data. The physiology of cells in ageing organisms tends, on the contrary, to suggest that organisms age as a result of degeneration in their non-dividing cell populations. Senescence in these non-mitotic cells resmebles the ageing of the non-dividing fraction of cell cultures clonally senescing, or maintained in long-term quiescence in vitro. As cultures of diploid human fibroblasts senesce there is an accumulation of non-dividing cells. Alterations in these post-mitotic cells can explain the senescent properties of late passage cultures. It is proposed that during the in vitro senescence of fibroblast cultures, cell ageing results from, as opposed to causes, the absence of mitosis. Cell ageing may primarily result from changes in the chromatin induced by the non-mitotic state.

Aged↗

Olfactory bulbectomy increases basal suprachiasmatic cyclic AMP levels in male rats.

For further characterization of the olfactory bulb's role in the medication of chronobiological phenomena, we examined basal cyclic- 3',5'-adenosine monophosphate (cAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal cAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for cAMP. We report a 83.6% increase in basal cAMP levels in the SCN following OBX (OBX = 63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p less than 0.01). No significant differences in LHIP cAMP levels were found. This specific increase in SCN cAMP, at the time of maximum cAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.

Animals↗

Effects of excitatory and inhibitory amino acids on neuronal discharges in the cultured suprachiasmatic nucleus.

The influence of amino acids on neuronal activity was studied microiontophoretically in the cultured suprachiasmatic nucleus (SCN). Three types of SCN neurons could be characterized: silent (glutamate responsive), irregular, and regular neurons. Glutamate excited about 70% of the regular and 60% of the irregular cells. GABA inhibited both the spontaneous and the glutamate-evoked activity of more than 90% of all three types of SCN neurons. MK-801 partially blocked glutamate responses. N-acetyl-aspartyl-glutamate (NAAG), a new neurotransmitter found in the retinohypothalamic fibers, directly increased firing rate and potentiated glutamate responses in the SCN neurons that were studied. These results indicate the potential significance of the amino acids in neuronal transmission within the biological clock.

Amino Acids↗

Circadian rhythms in early human development.

The body temperature, heart rate and rest-activity cycles of 12 low-risk preterm infants (29-35 weeks) were continuously recorded in the neonatal intensive care unit over a period of 1-2 weeks. Throughout the recordings the light was on continuously, the feeding was done intra-gastrically every 2 h and the incubator temperature was constant. Under such conditions a significant circadian rhythm was found in the body temperature and heart rate of more than 50% of the infants. These findings indicate the possible existence of an endogenous circadian rhythm in early human infancy. Since lights are continuously on in the neonatal intensive care unit, this might impair the time of emergence of day-night entrainment of the biological clock in preterm infants.

Body Temperature↗

Sleep and circadian rhythms.

The human biological clock or "circadian system" serves the function of preparing the body and mind for restful sleep at some times of day and active wakefulness at others. The observed circadian rhythms result from three interacting processes: endogenous rhythm generation mechanisms, entrainment mechanisms to keep these rhythms "on track," and exogenous masking processes stemming from changes in environment and behavior. In both advanced age and extraterrestrial travel these processes, particularly the latter two, can be dramatically effected with a consequent disruption in sleep and daytime functioning. We are currently studying the age-related effects on these processes in healthy 80 year olds using two different protocols. The first involved 36 h of constant wakeful bedrest which "unmasked" the endogenous component of circadian rhythms in various physiological and psychological functions. This experiment revealed little difference between nine old men and four young men in the endogenous body temperature rhythm, but revealed quite marked differences between the age groups in subjective activation and objective performance rhythms. A similar pattern occurred in the second experiment, which was a phase shift study comparing five old women with eight middle-aged men in their response to an acute 6 h phase advance in routine. Despite rather short-lived age-related differences in circadian rhythms, there were dramatic differences between the age groups in measures of sleep, mood, activation, and performance efficiency lasting for a week or more after the phase shift.

Adult↗