State-dependent central chemoreception: a role of orexin

Abstract

Sites involved in central chemoreception (CCR) are widely distributed in the brain. One possible explanation for the existence of multiple central chemoreceptor sites is the vigilance state-dependent hypothesis, that some sites are of greater importance in wakefulness others in sleep. We briefly summarize the evidence for a distributed network of central chemoreceptor sites and a vigilance state-dependent differentiation among them. We then discuss the role of orexin in vigilance state-dependent CCR based on our recent studies using orexin knockout mice and focal microdialysis of an orexin receptor antagonist at the retrotrapezoid nucleus and medullary raphe in rats. Orexin affects CCR in a vigilance state-dependent manner that varies with circadian time. Orexin also contributes to emotional stress- and other state-dependent related regulation of ventilation, e.g., the defense response. Diversity in central chemoreception including orexin neurons and the synaptic control of respiratory and cardiovascular output neurons appears to be necessary for animals to adapt themselves to constantly changing situations and behavioral states.

Figure 1. Vigilance-state-dependent central chemoreception

The top panel shows a schematized view of a medullary cross section at the level of the facial nucleus ~11 mm caudal to bregma. NTS refers to nucleus of the tractus solitarius; RTN to the retrotrapezoid nucleus; VII to the facial nucleus. The rectangles show the approximate size of the dialysis probe placed either in the medullary raphe or in the RTN. The circular shaded areas show the approximate area of decreased pH when the dialysis solution contains 25% CO₂, based on pH measurements obtained under anesthesia. The panel at lower left shows the ventilatory responses to focal acidification of the RTN in wakefulness and sleep. Note that ventilation increases only in wakefulness and predominantly via an increase in tidal volume. The panel at lower right shows the ventilatory response to focal acidification of the medullary raphe in wakefulness and sleep. Note that ventilation increases only in sleep and predominantly via an increase in breathing frequency. (Adapted from Nattie 2001)

Figure 2. Relationship between vigilance states and minute ventilation under various gas conditions

Note that vigilance-state-dependent changes in minute ventilation (QW > SWS ≥ REM) is well preserved under hypoxic and hypercapnic conditions. Data are expressed means ± SEM of 5 wild-type mice. * P < 0.05 compared with QW. (Adapted from Kuwaki, 2008)

Figure 3. Vigilance-state-dependent changes in hypercapnic ventilatory responsiveness in wild-type (WT) mice and prepro-orexin knockout mice (ORX-KO)

Hypercapnic responsiveness was evaluated by calculating the slope of the relationship between the inspired CO₂ concentration (0-10%) and minute ventilation. Data are presented as means ± SEM of 5 WT mice and 5 ORX-KO mice. * P < 0.05 compared with WT mice. † P < 0.05 compared with the data during awake (ANOVA with repeated measures design). Abbreviations: SWS, slow-wave sleep; REM, rapid-eye-movement sleep. (Adapted from (Nakamura et al. 2007))

Figure 4. Pivotal role of orexin in connecting state-dependent behavioral regulation system and cardiorespiratory homeostatic reflex pathways

Among known connections from/to orexinergic neurons in the hypothalamus, selected brain nuclei are depicted that are relevant to this review (thick lines). Many nuclei located at both of input (MR, RTN, LC, NTS) and output (cardiorespiratory motor neurons) interfaces in the homeostatic cardiorespiratory reflex pathway receive projections from orexinergic neurons (right half). Simultaneously, orexinergic connections are engaged in sleep/wake regulation and emotional stress-induced behavioral changes (left half). Thus, orexin can modulate cardiorespiratory homeostasis in a state-dependent manner. Arrows indicate a probable excitatory connection and circles indicate an inhibitory connection. Connections shown in thin lines are either direct or indirect. Abbreviations: AMG, amygdala; BNST, bed nucleus of the stria terminalis; DR, dorsal raphe; LC, locus coeruleus; MLR, medullary locomotor region; MR, medullary raphe; NTS, nucleus tractus solitarius; PAG, periaqueductal gray; PVN, paraventricular nucleus; RTN, retrotrapezoid nucleus; RVLM, rostral ventrolateral medulla where sympathetic premotor neurons are located; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; VLPO, ventrolateral preoptic nucleus.