Realizar modelo en 3DSom Pro mediante Plantilla

Diagram 12; Mean melatonin, cortisol and core body temperature (CBT). The figure shows transverse mean profiles (n=8) o f melatonin, cortisol and CBT in baseline conditions of continuous constant routine, a low- intensity 3 hour exercise stimulus (23:30 - 02:30 hours) and a high-intensity 1 hour exercise stimulus (00:30 - 01:30 hours). Black bars represent periods of darkness in which sleep was allowed. Open rectangles represent

BASELINE LOW INTENSITY HIGH INTENSITY

,2 20 200 c 150 i

i

I 100 ^ 50 - .mm. 0 -t—I- 37 .36 I ^ 4- 10 10 18 02 10 18 02 10 02 10

exercise sessions (from: Buxton et al, 1997)

(Cagnacci et al 1997). Thus, light-influenced SCN activity is relayed to the pineal gland primarily via a peripheral sympathetic tract in the superior cervical ganglion, although there is an element of direct central innervation via projections o f the lateral geniculate nucleus (Arendt, 1998). In mammals, melatonin is synthesised primarily within the pineal, although some is also produced by the retina, and possibly at some other sites (Arendt, 1998).

Melatonin has been credited with a very wide range of effects in humans, from acting as a contraceptive (through its stimulation of prolactin, and partial inhibition of

gonadotrophins), to an onchostatic (Arendt, 1998). It is reputed to hasten re-entrainment following eastward (transmeridional) travel across several time zones (Lewy and Sack,

1996), and alteration of its normal circadian patterns of secretion have been reported in psychiatric disease and in sudden infant death syndrome (Garcia-Patterson et al, 1996). It does not appear to show toxicity in humans, if administered exogenously, even at supra- physiological doses (Guardiola-Lemaitre, 1997)

All functions which appear to be directly influenced by day length can be influenced by modifying melatonin levels (Steinlechner, 1996). But although it inhibits, and phase shifts, SCN neuronal activity ihytiims (Steinlechner, 1996), the release of melatonin occurs as the effect of SCN output, not the reverse (see review: Reuss, 1996). The most notable

abnormalities in human melatonin secretion are observed in blind subjects who have no light perception (NLP). Blind subjects produce the same amount of melatonin as sighted individuals, even though the majority of the blind subjects are in free run (Lockley et al,

1997). Yet some of these subjects retain the ability to suppress melatonin in response to light stimuli (Lockley et al, 1997; Czeisler et al, 1995). The mechanisms by which this is achieved are not defined. Humoral influences (see above) are suggested by some

researchers (Oren and Terman, 1998; Campbell and Murphy, 1998), whilst others indicate that the physical presence of eyes (regardless o f the paucity of their visual perception function) is the influential fector (Lockley et al, 1997). Thus melatonin appears to be involved in the control of circadian rhythms in mammals by an as yet not fully known mechanism.

Administered melatonin can inhibit SCN metabolic activity in humans (Cassone, 1990), induce phase shift (McArthur et al, 1991), and increase the anq)litude of body ten^erature rhythm (Samel et al, 1991). It has only weak zeitgeber effects in humans (Middleton et al, 1997), although it can be shown to affect the phase of sleep (Middleton et al 1995), and consistently improve subjective sleep, alertness and performance, even in the presence of inappropriately timed bright light (Deacon and Arendt, 1996a and b). These observed

effects are thought to be due to the acute phase adaptation effects of melatonin on body temperature in particular (Arendt, 1998), as a suitably timed pharmacological does of melatonin (5mg) will increase the rate of re-entrainment of body temperature in subjects in environmental isolation (Samel et al, 1991). It principal effect appears to be to shorten tau, and emphasise adaptation to phase shift in both sighted (Lewy et al, 1992; Zaidan et al,

1994) and blind subjects (Sack et al, 1991), when administered at the appropriate circadian time (Arendt et al, 1997). Overall, it induces a short-lived reinforcement of the physiology

and behaviours associated with darkness. (Please see also: Liu et al, 1997; Arendt et al, 1997; Deacon and Arendt, 1995a; Reppert, Godson et al, 1995; Slaugenhaupt et al, 1995; Dollins, 1994; Reppert et al, 1994; Weaver et al, 1993; Tzichinsky et al, 1992a; Lewy et al, 1992; Cagnacci et al, 1992; McArthur et al, 1991; Reppert et al, 1988).

There is a body of evidence indicating that melatonin feeds back to, and influences SCN function (Gillette and McArthur, 1996), as there is a clear link between pineal N-

acetykransferase [NAT] rhythms and the intrinsic rhythmicity of light-induced c-fos gene expression with in the SCN (lllnerova and Sumova, 1997). The daily re-entrainment of the biological clock (tau ~ 24.3 hrs) to the 24 hour day is achieved through exposure to daylight (Minors et al, 1991). The subsequent rise in evening melatonin levels (which is itself induced by the decrease in SCN activity) may reinforce this effect, giving a definite physiological role for pineal and melatonin in circadian organisation in mammals (Arendt,

1998). The circadian effects of melatonin appear to be mediated by the e?q)ression and activity of melatonin receptors in the SCN (please refer to: Reppert et al, 1996; Reppert and Weaver, 1995; Reppert, Godson et al, 1995; Slaugenhaupt et al, 1995; Krause and

Dubocovich, 1990; Reppert et al, 1988), with melatonin appearing to act directly at the SCN, to entrain circadian rhythms to the light / dark cycle (Reppert et al, 1994). The density of SCN melatonin receptors peaks at the light / dark transition, coinciding with the time of the decrease of spontaneous electrical activity at the SCN, and creating a window for melatonin effects (see eg: McArthur et al, 1991). Melatonin binding sites have also been identified at the synapse of bipolar and ganglion cells in the irmer plexiform layer of the mammalian retina (luvone and Gan, 1995), and retinal melatonin, which shows a 24-hr rhythmicity, inhibits the release of dopamine to regulate the metabolism and position of photoreceptors. This mechanism may modulate visual processing throughout the 24 hrs (see review: Reuss, 1996).

In spite of the notable short-term effects of exogenous melatonin, the exact function of endogenous melatonin in humans is not immediately obvious, as the sensitive zone of the melatonin PRC fells at a time in the circadian day when endogenous melatonin is not

secreted (McArthur et al, 1991). It is hypothesised that, as it exerts an inhibitory effect on SCN neurones, melatonin could help define SCN sensitivity (i.e.: ‘set the gain’) to phase- shifting stimuli (Ding et al, 1994). As light causes levels of circulating melatonin to fell precipitously (Klein, 1993), hght exposure at night actively potentiates its own

effectiveness at the SCN, at the time in the circadian cycle when the clock is most

responsive to the phase shifting effect of light (Liu et al, 1997). But it is difficult to make a case for a major role of the pineal or melatonin mammalian circadian control (Arendt,

1998), as the entraining effect of melatonin on the biological clock is very weak, compared to that of light (Reppert and Weaver, 1995).

2.4.2: Circadian Variation in Core Bodv Temperature (CBT)

There is a link between the pattern of pineal gland activity, melatonin levels, and the regulation of the diurnal ihythm of core body temperature (CBT) (please refer to Diagram 9, above). Exogenous melatonin always suppresses core body temperature (please refer to Cagnacci et al, 1997; Myers, 1995; Strassman et al, 1991; McIntyre et al, 1989). In humans, the circadian rhythm of melatonin is strictly associated with the rhythm of CBT, with the nocturnal decline in CBT inversely related to, and caused by, the rise in melatonin levels (Arendt, 1998). Heat loss occurs as the dependent variable of heat production, with heat production being driven by the circadian activity of the SCN and its effects on levels of circulating melatonin (Cagnacci et al, 1997). SCN efferents input to the thermoregulatory pre-optical areas of the hypothalamus, and melatonin (indirectly) affects their

thermoregulatory activity through the feedback loop, to modify the metabolic and electrical activity of SCN neurones (Cagnacci et al, 1997; Krause and Dubocovich, 1990). The nocturnal rise in melatonin both enhances heat loss and reduces heat production through its action at the thermoregulatory centres of the hypothalamus, to cause peripheral

vasodilatation (Cagnacci et al, 1997). It is postulated that almost half of the observed amplitude of body temperature ihythm in the non-free running (i.e.: normal) situation is due to the effect of the 24 hour pattern of endogenous melatonin levels (Minors et al, 1993; Cagnacci et al, 1992).

Body temperature shows a constant increase from the early morning low (at 03:00 - 06:00 hours), through to the late afternoon. This peak is followed by a steady decrease back to minimum (Diagram 9). The unmasked amplitude of body temperature, morning to late afternoon is 0.38®C +/- 0.02®C (see, for example, Krauchi and Wirz-Justice, 1994; Cagnacci et al, 1992; Brown and Czeisler, 1992). This pattern of change in temperature reflects the circadian rhythm of heat production and heat loss, itself the product of hypothalamic

activity (see above), observed even under constant routine regimes (Krauchi and Wirz- Justice, 1994). The evening decline in CBT is not due solely to passive heat loss from peripheral tissues. It is actively associated with changes in circulating melatonin levels (Cagnacci, 1997; Krauchi et al, 1997c; Krauchi et al, 1997d; Cagnacci, 1996). The fell in CBT normally begins approximately 4 - 5 hours before onset sleep, in diurnal subjects and thus precedes the night-time rise of melatonin (Cagnacci et al, 1992). This timing pattern persists in the sleep deprived, in night-workers, and under conditions of constant routine. The decline in melatonin levels, that occurs later in the subjective night, is immediately followed by the increase in CBT (Cagnacci et al 1997), both in subjects normally entrained to the light/ dark period, and also in those subjected to light-induced phase shifts

(Shanahan, and Czeisler, 1991). This phenomenon persists under conditions of forced desynchrony, where the rest / activity cycle lengthens to match the imposed artificial day / night cycle (Arendt, 1995). Thus CBT, like melatonin, gives a reliable marker of the endogenous rhythm of the master ‘clock’ (Krauchi and Wirz-Justice, 1994; Cagnacci et al, 1992; Shanahan, and Czeisler, 1991), and is used (Cagnacci et al 1997), in both normal and phase shifted subjects (Shanahan, and Czeisler, 1991), to indicate the phase of circulating melatonin.

There is a close relationship between the timing of the circadian ihythm of core body temperature and the ihythm of sleep propensity (Nakao et al, 1995) and both appear to be governed by a common oscillator (Lack and Lushington, 1996). The period of the sleep- wake cycle seldom differs from 24 hours (Ashkenazi et al 1993). Activity / rest, and sleep / wake, cycles are entrained to the 24 hour light / dark period of the solar cycle (Klein et al,

1991), so that sleep tendency is controlled by SCN activity (Edgar, Mement and Fuller, 1993), and the thermoregulatory mechanisms o f the pre-optic / anterior hypothalamus (Nakao et al, 1995). Overall subject performance tends to show positive relationship with core body temperature and an inverse relationship with raised levels of melatonin and cortisol (Arendt and Deacon, 1997; Monk et al, 1997).

2.4.3: Cortisol

Cortisol, like melatonin, is secreted in a pulsatile manner, but to a different diurnal rhythm. The secretion pattern and baseline values of cortisol are high in the early part of the day, and low in the later evening (Diagram 9, above). This contrasts with the pattern of melatonin release which begins to rise when cortisol levels are at their lowest, peaking when cortisol levels begin to rise, and decreasing when cortisol levels peak (Diagram 9, above). The hormones appear to be in anti-phase with one another, and the different

patterns of release suggest that they may be under different controlling mechanisms (Rivest et al, 1989)

2.5: INDUCED CHANGES IN CIRCADIAN RHYTHMS:

The phase of circadian rhythms is not fixed, as zeitgeber induce circadian rhythm

adaptations in response to changes in light e?q)osure (see above). But, internal rhythms will be out of phase with the external environment during the adaptation period to the new time phase. Subjects tend to complain of poor sleep, reduced alertness and a decrement of performance during the adaptation period - they are ‘jet lagged’ (Arendt et al, 1997). The desynchrony with solar time is particularly marked in night workers and some blind subjects. Night workers have to work when the core body temperature and performance rhythms are lowest, and fatigue, sleep propensity and melatonin secretion rhythms are maximal (Arendt et al, 1997). And some totally blind subjects free run (Lockley et al,

1997), so that their circadian rhythms are out of phase with the mass of the population the majority of the time, synchronising with the norm for only a few days in every 6 - 7 week period (Lewy and Sack, 1996).

2.5.1: Shiftwork

75% of the working population live a diurnal life style. In contrast the remaining 25% work shifts (Maurice, 1981), having to sleep during the hours of daylight, and work during the night. The effect of this inversion of the diurnal pattern extracts a toll from night workers. They are exposed to altered lighting patterns. Daytime retinal light is absent, when they sleep, and they are exposed to domestic levels of light (of approximately 500 lux all night) whilst at work. Zeitgeber changes tend to induce phase delays in some, but not all, aspects of the circadian timing system (Barnes, et al, 1998; Arendt et al, 1997; Roller et al 1994). Most night-workers do not sleep well (Monk et al, 1996; Barak et al, 1995; Czeisler et al, 1990; Knauth and Rutenfranz, 1976), as they have to sleep during the day, when levels of melatonin are low and core body temperature is raised (see below) (Sack, Blood and Lewy,

1992). As a result, circadian ihythm disorders are very common in night woricers (van Cauter et al, 1997; Sack et al, 1992; Waldhauser et al, 1986) (Diagram 11). For example, both day and night workers have similarly timed peaks and troughs o f cortisol production (Touitou et al 1990; Sharma et al, 1989; Fibiger et al, 1984), but the peak to trough difference of night workers is about only 70% of that of day workers (Touitou et al, 1990).

DIAGRAM 11: SLEEP NO SLEEP 135 UJ 125 ~ J TJ o 115

3 E

< 105 ^ 175 100 75 20 15 5 0 -3 0 +3 +6

THE EFFECTS OF SLEEP DEPRIVATION ON PLASMA GLUCOSE LEVELS, INSULIN

In document Modelado 3D a partir de fotografías con 3DSOM (página 44-69)