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Orexin in Respiratory and Autonomic Regulation, Health and Diseases

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Abstract

Orexin neurons, located in the hypothalamus, produce orexin‐A and orexin‐B neuropeptides and send widespread projections throughout the central nervous system, including many nuclei that are critically involved in sleep‐wake, cardiorespiratory, and autonomic regulation. Significant progress has been made to better understand the roles of orexins in the control of breathing and autonomic functions since the discovery of orexins in 1998. Orexin neurons are CO2/pH chemosensitive and blockade of orexin receptors with orexin receptor antagonists can significantly attenuate ventilatory response to hypercapnia or CO2 chemoreflex. Animal models with orexin abnormalities, for example, too little or too much, have all been reported to have significant alterations in breathing, central chemoreception (hypercapnic chemoreflex), blood pressure, thermoregulation, and cardiorespiratory responses to stress. More recent studies further show that abnormalities of the orexin system are linked to many neurological disorders in addition to narcolepsy, for example, sleep disorders, neurodegenerative disorders, neurogenic hypertension, and sudden infant death syndrome. These new findings have significantly advanced the knowledge in understanding the underlying mechanism of orexin‐associated health and diseases while providing a new pathway for possible treatments. In this article, we will discuss some of the progresses in basic research and in health and diseases. © 2020 American Physiological Society. Compr Physiol 10:345‐363, 2020.

Keywords: orexin; control of breathing and autonomic functions; central chemoreception; neurogenic diseases

Figure 1. Figure 1. Schematic representation showing the broad anatomical and functional connections between orexin neurons and other neuronal systems. It summarizes how the orexin system may be critically linked with the cardiorespiratory and autonomic regulatory system and the vigilance‐state dependent behavioral regulatory system. Arrows indicate the excitatory connections, while circles indicate the inhibitory connections. AMG, amygdala; BAT, brown adipose tissue; 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; PBC, pre‐Bötzinger complex; PBN, parabrachial nucleus; PVN, paraventricular nucleus; RTN, retrotrapezoid nucleus; RVLM, rostral ventrolateral medulla where sympathetic cardiovascular premotor neurons are located; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; VLPO, ventrolateral preoptic nucleus. Adapted, with permission, from Kuwaki, 2015 78.
Figure 2. Figure 2. Transgenic orexin deficient mice have lower mean arterial blood pressure and attenuated ventilatory response to CO2 or hypercapnic chemoreflex. (A) Ventilatory response to hypercapnia is severely attenuated in Orexin‐KO than wild‐type (WT) controls only in wakefulness. (*P < 0.05 compared with WT mice. P < 0.05 compared with the data during awake). (B) Resting blood pressure is significantly lower in orexin‐KO than WT controls in both light and dark diurnal cycles. ORX‐KO, orexin knockout mice; WT, wild‐type mice; SWS, slow‐wave sleep; REM, rapid‐eye movement sleep. Adapted, with permission, from Kayaba et al. 2013 71, and Kuwaki et al. 2010 79.
Figure 3. Figure 3. Spontaneously hypertensive rats have an excessive number of orexin‐producing neurons, high mean arterial blood pressure (MABP), and exaggerated ventilatory response to hypercapnia. (A) Distribution of OX‐ir neurons in three hypothalamic zones and whole hypothalamus in SHR (dark gray bar) and WKY (white bar) at young and adult age. (B) Resting MABP with (hatched bars) and without (black bars) treatment of a dual OXR antagonist, almorexant (Amxt), in young and adult SHRs versus that in age‐matched WKY rats (gray bars) in wakefulness, NREM, and REM sleep. (C) Ventilatory response (% change of V˙E) in normoxic hypercapnia with Amxt treatment (hatched bars) and without (black bars) in young and adult SHRs versus that in normotensive young and adult WKY rats (gray bars). DMH, dorsomedial hypothalamus; f, fornix; Hyp, hypothalamus (all three zones); LHA, lateral hypothalamic area; PeF, perifornical hypothalamus 94.
Figure 4. Figure 4. Orexins are involved in regulation of central chemoreception. Schematic sagittal brain section shows the location of orexin neurons and two brainstem putative central chemoreceptor sites, the RTN and medullary raphe. (E) Adapted, with permission, from Nambu et al. 115. Orexin neurons themselves are CO2/pH chemosensitive in brain slices of the hypothalamus of transgenic mice that express GFP only in orexin neurons. Demonstrates the effect of CO2‐induced low pHe on orexin neurons (A‐a). Effect of HEPES‐buffered low pHe on orexin neurons (A‐b). (a,b) Adapted, with permission, from Williams et al. 2007 172. Blocking OXRs with a dual OXR antagonist, Amxt, via oral administration significantly lowers the ventilatory response to hypercapnia only in wakefulness in the dark period (B). Focal inhibition of OX1R in the RTN (C) or medullary raphe (D) significantly attenuated CO2 chemoreflex. (B) Adapted, with permission, from Li and Nattie 2010 91; (C) Adapted, with permission, from Dias et al. 2009 36; (D) Adapted, with permission, from Dias et al. 2010 35. aCSF, artificial cerebrospinal fluid; RTN, retrotrapezoid nucleus.
Figure 5. Figure 5. The effects of OXA on hypoglossal motor (HMNs) neuronal activity and of eliminating orexin neurons on genioglossal muscle activity (GG‐EMG). Orexin‐A concentration‐dependently increased the firing rate of HMNs in brain slices of neonatal rats (A). Bilateral lesions of orexin neurons in the hypothalamus of adult rats via orexin‐B‐SAP (400 nL per side, 0.43 mg/mL) decreased the respiratory‐related GG‐EMG (B, lower panel) compared to control‐injected rats (B, top panel). Tonic activity of GG‐EMG is not affected while respiratory‐related activity is significantly attenuated post‐lesion (C). Adapted, with permission, from Zhang et al. 2014 181.
Figure 6. Figure 6. The effects of OX1R antagonist and OXB agonist on orexin‐induced increase in mean arterial pressure (MAP) and sympathetic nerve activity (SNA) in the RVLM (A) and spinal cord (B). OX1R antagonist, SB334867, can significantly attenuate the orexin A‐induced MAP and sSNA effects in the RVLM (A). OXA dose‐dependently increased MAP and sSNA and OX1R antagonism can block such OXA‐induced effects in the spinal cord (B). ***P < 0.001, **P < 0.01, *P < 0.05, significantly different from PBS. Adapted, with permission, from Shahid et al. 2011 151 and Shahid et al. 2012 152.
Figure 7. Figure 7. OX‐KO and OX neuron‐ablated (ORX‐AB) mice differentially respond to cold stress. Mice were exposed to a cold environment (5°C) for 4 h while the abdominal temperature was continuously monitored with a telemetric system. The thin lines indicate the data from an individual animal, and the thick lines are the mean ± SEM of orexin‐knockout mice (ORX‐KO), orexin neuron‐ablated mice (ORX‐AB), and their corresponding wild‐type littermates (WTKO and WTAB). Adapted, with permission, from Kuwaki 78.
Figure 8. Figure 8. Change of number of orexin neurons in the hypothalamus and orexin processes in the pons in SIDS and non‐SIDS cases. Box and whisker plot shows that total number of OXA and OXB immunoreactivity was decreased by up to 21% within the hypothalamus in SIDS versus non‐SIDS cases (A and B). In the pons, a 40% to 50% decrease in OXA in all pontine nuclei (C), similar OXB findings in the LC, LDT, DTg, and Pn (D) in SIDS cases compared to non‐SIDS cases. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001. Adapted, with permission, from Hunt et al. 2015 66 with permission.


Figure 1. Schematic representation showing the broad anatomical and functional connections between orexin neurons and other neuronal systems. It summarizes how the orexin system may be critically linked with the cardiorespiratory and autonomic regulatory system and the vigilance‐state dependent behavioral regulatory system. Arrows indicate the excitatory connections, while circles indicate the inhibitory connections. AMG, amygdala; BAT, brown adipose tissue; 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; PBC, pre‐Bötzinger complex; PBN, parabrachial nucleus; PVN, paraventricular nucleus; RTN, retrotrapezoid nucleus; RVLM, rostral ventrolateral medulla where sympathetic cardiovascular premotor neurons are located; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; VLPO, ventrolateral preoptic nucleus. Adapted, with permission, from Kuwaki, 2015 78.


Figure 2. Transgenic orexin deficient mice have lower mean arterial blood pressure and attenuated ventilatory response to CO2 or hypercapnic chemoreflex. (A) Ventilatory response to hypercapnia is severely attenuated in Orexin‐KO than wild‐type (WT) controls only in wakefulness. (*P < 0.05 compared with WT mice. P < 0.05 compared with the data during awake). (B) Resting blood pressure is significantly lower in orexin‐KO than WT controls in both light and dark diurnal cycles. ORX‐KO, orexin knockout mice; WT, wild‐type mice; SWS, slow‐wave sleep; REM, rapid‐eye movement sleep. Adapted, with permission, from Kayaba et al. 2013 71, and Kuwaki et al. 2010 79.


Figure 3. Spontaneously hypertensive rats have an excessive number of orexin‐producing neurons, high mean arterial blood pressure (MABP), and exaggerated ventilatory response to hypercapnia. (A) Distribution of OX‐ir neurons in three hypothalamic zones and whole hypothalamus in SHR (dark gray bar) and WKY (white bar) at young and adult age. (B) Resting MABP with (hatched bars) and without (black bars) treatment of a dual OXR antagonist, almorexant (Amxt), in young and adult SHRs versus that in age‐matched WKY rats (gray bars) in wakefulness, NREM, and REM sleep. (C) Ventilatory response (% change of V˙E) in normoxic hypercapnia with Amxt treatment (hatched bars) and without (black bars) in young and adult SHRs versus that in normotensive young and adult WKY rats (gray bars). DMH, dorsomedial hypothalamus; f, fornix; Hyp, hypothalamus (all three zones); LHA, lateral hypothalamic area; PeF, perifornical hypothalamus 94.


Figure 4. Orexins are involved in regulation of central chemoreception. Schematic sagittal brain section shows the location of orexin neurons and two brainstem putative central chemoreceptor sites, the RTN and medullary raphe. (E) Adapted, with permission, from Nambu et al. 115. Orexin neurons themselves are CO2/pH chemosensitive in brain slices of the hypothalamus of transgenic mice that express GFP only in orexin neurons. Demonstrates the effect of CO2‐induced low pHe on orexin neurons (A‐a). Effect of HEPES‐buffered low pHe on orexin neurons (A‐b). (a,b) Adapted, with permission, from Williams et al. 2007 172. Blocking OXRs with a dual OXR antagonist, Amxt, via oral administration significantly lowers the ventilatory response to hypercapnia only in wakefulness in the dark period (B). Focal inhibition of OX1R in the RTN (C) or medullary raphe (D) significantly attenuated CO2 chemoreflex. (B) Adapted, with permission, from Li and Nattie 2010 91; (C) Adapted, with permission, from Dias et al. 2009 36; (D) Adapted, with permission, from Dias et al. 2010 35. aCSF, artificial cerebrospinal fluid; RTN, retrotrapezoid nucleus.


Figure 5. The effects of OXA on hypoglossal motor (HMNs) neuronal activity and of eliminating orexin neurons on genioglossal muscle activity (GG‐EMG). Orexin‐A concentration‐dependently increased the firing rate of HMNs in brain slices of neonatal rats (A). Bilateral lesions of orexin neurons in the hypothalamus of adult rats via orexin‐B‐SAP (400 nL per side, 0.43 mg/mL) decreased the respiratory‐related GG‐EMG (B, lower panel) compared to control‐injected rats (B, top panel). Tonic activity of GG‐EMG is not affected while respiratory‐related activity is significantly attenuated post‐lesion (C). Adapted, with permission, from Zhang et al. 2014 181.


Figure 6. The effects of OX1R antagonist and OXB agonist on orexin‐induced increase in mean arterial pressure (MAP) and sympathetic nerve activity (SNA) in the RVLM (A) and spinal cord (B). OX1R antagonist, SB334867, can significantly attenuate the orexin A‐induced MAP and sSNA effects in the RVLM (A). OXA dose‐dependently increased MAP and sSNA and OX1R antagonism can block such OXA‐induced effects in the spinal cord (B). ***P < 0.001, **P < 0.01, *P < 0.05, significantly different from PBS. Adapted, with permission, from Shahid et al. 2011 151 and Shahid et al. 2012 152.


Figure 7. OX‐KO and OX neuron‐ablated (ORX‐AB) mice differentially respond to cold stress. Mice were exposed to a cold environment (5°C) for 4 h while the abdominal temperature was continuously monitored with a telemetric system. The thin lines indicate the data from an individual animal, and the thick lines are the mean ± SEM of orexin‐knockout mice (ORX‐KO), orexin neuron‐ablated mice (ORX‐AB), and their corresponding wild‐type littermates (WTKO and WTAB). Adapted, with permission, from Kuwaki 78.


Figure 8. Change of number of orexin neurons in the hypothalamus and orexin processes in the pons in SIDS and non‐SIDS cases. Box and whisker plot shows that total number of OXA and OXB immunoreactivity was decreased by up to 21% within the hypothalamus in SIDS versus non‐SIDS cases (A and B). In the pons, a 40% to 50% decrease in OXA in all pontine nuclei (C), similar OXB findings in the LC, LDT, DTg, and Pn (D) in SIDS cases compared to non‐SIDS cases. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001. Adapted, with permission, from Hunt et al. 2015 66 with permission.
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Teaching Material

Savannah Barnett and Aihua Li. Orexin in Respiratory and Autonomic Regulation, Health and Diseases. Compr Physiol 10 : 2020, 345-363.

Didactic Synopsis

Major Teaching Points:

1. Understanding the hypothalamic neuropeptides, e.g., orexins, is necessary to master the underline mechanism of vigilance state-dependent control of cardiorespiratory and autonomic function and orexin-associated diseases.

2. Orexins play important roles in regulation cardio-respiratory and autonomic functions in different vigilance state.

    a) Many neurons in the cardio-respiratory and sleep-wake control centers are innervated by orexin neurons and express orexin receptors.
    b) Orexins excite cardio-respiratory and sympathetic activity, promote wakefulness and maintain upper airway patency.

3. Animals with orexin deficiency have hypotension, attenuated hypercapnic chemoreflex and fight-or-flight stress response, while animals with too much orexin, e.g., spontaneous hypertensive rats, have exaggerated CO2 chemoreflex, hyperactive and hypertension.

4. Dysfunctional orexin system are associated with many neurogenic disorders, including

    a) Sleep disorders, e.g., narcolepsy and obstructive sleep apnea
    b) Neurodegenerative diseases, e.g., Parkinson's disease and Alzheimer's disease
    c) Neurogenic hypertension
    d) Sudden infant death syndrome

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching point: Orexin neurons are anatomical and functional connected with many other neuronal systems e.g., cardio-respiratory and autonomic regulatory system and the vigilance-state dependent behavioral regulatory system.

Figure 2. Teaching point: Orexin deficiency leads to a severely attenuated ventilatory response to hypercapnia or hypercapnic chemoreflex during wakefulness, and lower resting blood pressure in both light and dark diurnal cycles in transgenic orexin knockout mice.

Figure 3. Teaching point: An overactive orexin system has been linked to neurogenic hypertension. Spontaneously hypertensive rats, the most commonly used animal model for human essential hypertension, have excess orexin neurons from young. Treating with a dual orexin receptor blocker can significantly lower higher blood pressure and exaggerated hypercapnic chemoreflex in these hypertensive rats.

Figure 4. Teaching point: Orexin is importantly involved in CO2 chemoreception or hypercapnic chemoreflex. Orexin neurons in the hypothalamus are pH/CO2 chemosensitive, and block orexin receptors with orexin receptor antagonist focally in two chemosensitive sites or systemically can significantly attenuate CO2 chemoreflex.

Figure 5. Teaching point: Orexin signaling is important in the control of airway patency, and decreased orexin inputs may have pathological impacts on the airway reflexes.

Figure 6. Teaching point: Administration of orexin can dose-dependently increase sympathetic activity and blood pressure, and administration of orexin receptor antagonist can block such orexin-induced excitatory effects.

Figure 7. Teaching point: The role of orexin in thermoregulation is complex, that loss of orexin producing neurons can significantly attenuate cold-stress response.

 

Figure 8. Teaching point: Dysfunctional orexin system is also linked to SIDS, and the total number of orexin neurons was significantly lower within the hypothalamus in SIDS cases (up to ~ 21%) compare to non-SIDS cases. 


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How to Cite

Savannah Barnett, Aihua Li. Orexin in Respiratory and Autonomic Regulation, Health and Diseases. Compr Physiol 2020, 10: 345-363. doi: 10.1002/cphy.c190013