Chapter 028. Sleep Disorders (Part 3) pot

Sleep Disorders Part 3 Physiology of Circadian Rhythmicity The sleep-wake cycle is the most evident of the many 24-h rhythms in humans.. At the molecular level, endogenous circadian rh

Chapter 028 Sleep Disorders

(Part 3)

Physiology of Circadian Rhythmicity

The sleep-wake cycle is the most evident of the many 24-h rhythms in humans Prominent daily variations also occur in endocrine, thermoregulatory, cardiac, pulmonary, renal, gastrointestinal, and neurobehavioral functions At the molecular level, endogenous circadian rhythmicity is driven by self-sustaining transcriptional/translational feedback loops (Fig 28-2) In evaluating a daily variation in humans, it is important to distinguish between those rhythmic components passively evoked by periodic environmental or behavioral changes (e.g., the increase in blood pressure and heart rate upon assumption of the upright posture) and those actively driven by an endogenous oscillatory process (e.g., the circadian variation in plasma cortisol that persists under a variety of environmental and behavioral conditions)

Figure 28-2

Model of the molecular feedback loop at the core of the mammalian circadian clock

The positive element of the feedback loop (+) is the transcriptional

activation of the Per1 gene (and probably other clock genes) by a heterodimer of

the transcription factors CLOCK and BMAL1 (also called MOP3) bound to an

E-box DNA regulatory element The Per1 transcript and its product, the clock

component PER1 protein, accumulate in the cell cytoplasm As it accumulates, the PER1 protein is recruited into a multiprotein complex thought to contain other

circadian clock component proteins such as cryptochromes (CRYs), Period proteins (PERs), and others This complex is then transported into the cell nucleus (across the dotted line), where it functions as the negative element in the feedback loop (–) by inhibiting the activity of the CLOCK-BMAL1 transcription factor heterodimer As a consequence of this action, the concentration of PER1 and other clock proteins in the inhibitory complex falls, allowing CLOCK-BMAL1 to

activate transcription of Per1 and other genes and begin another cycle The

dynamics of the 24-h molecular cycle are controlled at several levels, including regulation of the rate of PER protein degradation by casein kinase-1 epsilon (CK1E) Additional limbs of this genetic regulatory network, omitted for the sake

of clarity, are thought to contribute stability Question marks denote putative clock proteins, such as Timeless (TIM), as yet lacking genetic proof of a role in the

mammalian clock mechanism (Copyright Charles J Weitz, Ph.D., Department of Neurobiology, Harvard Medical School.)

While it is now recognized that many peripheral tissues in mammals have circadian clocks that regulate diverse physiologic processes, these independent tissue-specific oscillations are coordinated by a central neural pacemaker located

in the suprachiasmatic nuclei (SCN) of the hypothalamus Bilateral destruction of these nuclei results in a loss of the endogenous circadian rhythm of locomotor activity, which can be restored only by transplantation of the same structure from a donor animal The genetically determined period of this endogenous neural

oscillator, which averages ~24.2 h in humans, is normally synchronized to the

24-h period of t24-he environmental lig24-ht-dark cycle Small differences in circadian period underlie variations in diurnal preference, with the circadian period shorter

in individuals who typically rise early compared to those who typically go to bed late Entrainment of mammalian circadian rhythms by the light-dark cycle is mediated via the retinohypothalamic tract, a monosynaptic pathway that links specialized, photoreceptive retinal ganglion cells directly to the SCN Humans are exquisitely sensitive to the resetting effects of light, particularly at the blue end (~460–480 nm) of the visible spectrum

The timing and internal architecture of sleep are directly coupled to the output of the endogenous circadian pacemaker Paradoxically, the endogenous circadian rhythms of sleep tendency, sleepiness, and REM sleep propensity all peak near the habitual wake time, just after the nadir of the endogenous circadian temperature cycle, whereas the circadian wake propensity rhythm peaks 1–3 h before the habitual bedtime

These rhythms are thus timed to oppose the homeostatic decline of sleep tendency during the habitual sleep episode and the rise of sleep tendency throughout the usual waking day, respectively Misalignment of the output of the endogenous circadian pacemaker with the desired sleep-wake cycle can, therefore, induce insomnia, decreased alertness, and impaired performance evident in night-shift workers and airline travelers