Timing, Sleep, and Respiration in Health and Disease - Progress in Molecular Biology and Translational Science - page 203

concentrations in vivo . 49,55,143-145 The timing of sensitivity as well as the
direction of the response (i.e., phase advance) for both 5-HT and hypercap-
nia is similar. Thus it stands to reason that hypercapnia could activate 5-HT
neurons leading to 5-HT release onto neurons within the suprachiasmatic
nucleus and subsequently the phase shift.
Chronic exposure to hypoxia and hypercapnia can also affect circadian
rhythms. Hypoxia has been shown to abolish circadian rhythms of not just
respiratory measures, but also of core body temperature, activity, and cor-
tisol secretion. 124,146 As discussed above, hypoxia is sensed primarily via
peripheral chemoreceptors in the carotid body. However, sino-aortic node
denervation in rats, and thus elimination of output from peripheral chemo-
receptors, did not prevent blunting of circadian rhythms of body tempera-
ture and locomotor activity. These authors concluded that this suggests
direct effect of hypoxia on thermoregulatory centers in the hypothala-
mus. 147 Certainly, as mentioned above, hypothalamic sites have been shown
to be hypoxia chemosensors. 21,148,149 Chronic low-level hypercapnia blunts
circadian activity and temperature rhythms in humans 122 but has no effect on
rat temperature, activity, or respiratory rhythms. 119 It does, however,
increase the baseline and phase amplitude of the circadian rhythms of RR
and tidal volume. 119
4. SLEEP AND BREATHING
4.1. State-dependent control of breathing
Breathing regulation is modulated in a state-dependent manner. 150 As one
transitions to light NREM from wakefulness, breathing can be unsta-
ble. 151,152 This is termed periodic breathing or Cheyne-Stokes respira-
tion. 153 Breathing instability at the extreme manifests as obstructive,
central, or mixed apneas. 154 In deeper NREM, breathing becomes more
regular with larger V T and slower RR. In NREM, these changes are accom-
panied by a relative increase in arterial P CO ð Þ and a concomitant decrease in
arterial P O 2 . There is an increase in total airway resistance in NREM due
largely to the increase in upper airway resistance that results from decreased
tonic activity to upper airway muscles. 155-157 Intercostal muscle activity is
increased during NREM as evidenced by EMG studies with little or no
increase in diaphragmatic muscle activity. 158,159 In contrast to deeper
NREM, in REM, respiration is profoundly irregular 151,160 and can be asso-
ciated with sudden changes in RR and V T . There can also be apneic