Timing, Sleep, and Respiration in Health and Disease - Progress in Molecular Biology and Translational Science - page 196

nuclei have properties consistent with being central CO 2 chemoreceptors,
though the relative importance of the specific sites and neuronal cell types
responsible for central respiratory chemoreception have been the subject of
debate. 15,23-26 Candidate chemoreceptive nuclei include the medullary
raph´, 27,28 NTS, 29 locus coeruleus, 30-32 RTN, 33-35 hypothalamus, 21,36-39
and cerebellar fastigial nucleus. 40 The sensitivity of central chemoreceptors
to CO 2 is increased by hypoxia. 41 Just as there is evidence for a central com-
ponent of O 2 chemoreception, there is evidence for a peripheral component
of CO 2 chemoreception. 42,43
Serotonergic medullary raph ´ neurons are intrinsically chemosensitive
in vitro . 27,44-46 While the respiratory stimulus that leads to activation of che-
moreceptors is hypercapnia, it is the change in brain tissue pH that results
from the

change that stimulates central chemoreceptors and not
CO 2 itself. Indeed, medullary 5-HT neurons respond to changes in intracel-
lular pH, but do not respond to stimulation with CO 2 . 47,48

ð P CO 2 Þ

In vivo , hyper-
capnia increases the firing rate of 5-HT neurons in the awake, behaving
cat, 49 leads to increased c-fos expression in medullary 5-HT neurons 50-53
and causes 5-HT release within the mouse hypoglossal nucleus. 54 Direct
application of acetazolamide 55 or CO 2 -rich artificial cerebrospinal fluid to
the medullary raph´ induces a focal acidification of the region and increases
breathing. 56,57 Acute 5-HT neuron lesion or inactivation with 5,7-
dihydroxytryptamine, lidocaine, ibotenic acid, muscimol, 8-OH-DPAT,
or saporin conjugated to a 5-HT transporter antibody reduces the hypercap-
nic ventilatory response (HCVR). 57-62 Mice with a subtotal (Pet1-KO
mice) or nearly complete ( Lmx1b f/f/p mice) genetic deletion of 5-HT neu-
rons within the central nervous system 63,64 have an impaired HCVR com-
pared to WT mice. 65,66
Hypercapnia stimulates LC neurons in vivo and in vitro . 30,31,67-69 Like-
wise, neurons within the NTS are also stimulated by acidosis, 29,70 as are neu-
rons in the RTN. 33,35 Neurons in each of these regions, except the RTN, 71
have been shown to retain their chemosensitivity after chemical synaptic
blockade or physical isolation. RTN neurons are strongly stimulated by
5-HT, SP, and TRH, 72 and as recently discussed, it is possible that some
of their pH sensitivity is due to synaptic input from 5-HT or other
neurons. 73,74
Neurons in the caudal hypothalamus of rabbits, 75 cats, 76 and rats 21 are
stimulated by hypercapnia. There are also chemosensitive neurons in the lat-
eral hypothalamus that contain orexin. 36 Stimulation of orexin neurons with