Cumulative effects of repetitive intermittent hypercapnic hypoxia on orexin in the developing piglet hypothalamus

Du, Man; Hunt, Nicholas J.; Waters, Karen A.; Machaalani, Rita

doi:10.1016/j.ijdevneu.2015.10.007

Cited by 13 publications

(7 citation statements)

References 67 publications

(105 reference statements)

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“…There are only a limited number of previous studies that have examined the effect of combined H/H on identified orexin neurons. Consistent with our findings, immunohistochemical results indicate that animals exposed to intermittent H/H have decreased expression of orexin-A and -B in lateral hypothalamus, as well as in dorsomedial hypothalamus and the perifornical area (Du et al 2016). The findings from a recent in vitro study (Williams et al 2007) conducted on mice showed that the change in bath solution from 10% to 5% CO 2 induces membrane hyperpolarization and decreases firing activity of orexin neurons in the lateral hypothalamus.…”

Section: Discussionsupporting

confidence: 91%

Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats

Dergacheva

Yamanaka

Schwartz

et al. 2016

Journal of Neurophysiology

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Evidence of impaired function of orexin neurons has been found in individuals with cardiorespiratory disorders, such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS), but the mechanisms responsible are unknown. Individuals with OSA and SIDS experience repetitive breathing cessations and/or rebreathing of expired air, resulting in hypoxia/hypercapnia (H/H). In this study, we examined the responses of fluorescently identified rat orexin neurons in the lateral hypothalamus to acute H/H to test if and how these neurons alter their activity and function during this challenge. Experiments were conducted in an in vitro slice preparation using voltage-clamp and current-clamp configurations. H/H (10 min) induced hyperpolarization, accompanied by rapid depression, and finally, cessation of firing activity in orexin neurons. Hypoxia alone had similar but less potent effects. H/H did not alter the frequency of inhibitory glycinergic postsynaptic currents. The frequency of GABAergic currents was diminished but only at 8-10 min of H/H. In contrast, the frequency of excitatory glutamatergic postsynaptic events was diminished as early as 2-4 min of H/H. In the presence of glutamatergic receptor blockers, the inhibitory effects of H/H on the firing activity and membrane potential of orexin neurons persisted but to a lesser extent. In conclusion, both direct alteration of postsynaptic membrane properties and diminished glutamatergic neurotransmission likely contribute to the inhibition of orexin neurons by H/H. These mechanisms could be responsible for the decreased function of orexin in individuals at risk for OSA and SIDS.

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Section: Discussionsupporting

confidence: 91%

Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats

Dergacheva

Yamanaka

Schwartz

et al. 2016

Journal of Neurophysiology

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“…Our finding that Ox immunoreactivity is decreased in the hypothalamus and pons after IHH without changes in the total number of neurons in the C‐THT is consistent with findings reported after hypoxic or hypercapnic exposures alone (Table S2). In addition, the IHH data in this study provide confirmation of our previous work (Du et al ., ). Owing to the paucity of tissue available for all of the groups, a two‐dimensional counting method was used previously to determine the percentage of positive neurons, and we therefore only reported the percentage of Ox‐positive neurons, and not the total number of neurons.…”

Section: Discussionmentioning

confidence: 97%

“…According to the literature, excitation of Ox-positive neurons is mediated by intermittent rather than continuous hypoxia (Yamaguchi et al, 2015), but exposure to intermittent hypoxia must be coupled with hypercapnia before decreased Ox immunoreactivity is observed (Du et al, 2016). Neither intermittent hypoxia alone nor severe hypoxia promote decreased Ox immunoreactivity (Hundahl et al, 2011;Yamaguchi et al, 2015).…”

Section: Effects Of Ihhmentioning

confidence: 99%

“…This model serves to simulate the effects of the rebreathing of expired air seen in prone‐sleeping infants (Thompson et al ., ), and recurring apnoeas such as occur in OSA (Waters & Gozal, ). With previous use of this model, chronic IHH exposure (number of days of exposure) was found to decrease the percentage of OxA/OxB‐immunoreactive neurons in the hypothalamus by up to 25% (Du et al ., ) and increase the percentage of Ox receptors by 20–40% (Hunt et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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Changes in orexinergic immunoreactivity of the piglet hypothalamus and pons after exposure to chronic postnatal nicotine and intermittent hypercapnic hypoxia

Hunt

Russell

et al. 2016

Eur J of Neuroscience

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We recently showed that orexin expression in sudden infant death syndrome (SIDS) infants was reduced by 21% in the hypothalamus and by 40-50% in the pons as compared with controls. Orexin maintains wakefulness/sleeping states, arousal, and rapid eye movement sleep, abnormalities of which have been reported in SIDS. This study examined the effects of two prominent risk factors for SIDS, intermittent hypercapnic hypoxia (IHH) (prone-sleeping) and chronic nicotine exposure (cigarette-smoking), on orexin A (OxA) and orexin B (OxB) expression in piglets. Piglets were randomly assigned to five groups: saline control (n = 7), air control (n = 7), nicotine [2 mg/kg per day (14 days)] (n = 7), IHH (6 min of 7% O2 /8% CO2 alternating with 6-min periods of breathing air, for four cycles) (n = 7), and the combination of nicotine and IHH (N + IHH) (n = 7). OxA/OxB expression was quantified in the central tuberal hypothalamus [dorsal medial hypothalamus (DMH), perifornical area (PeF), and lateral hypothalamus], and the dorsal raphe, locus coeruleus of the pons. Nicotine and N + IHH exposures significantly increased: (i) orexin expression in the hypothalamus and pons; and (ii) the total number of neurons in the DMH and PeF. IHH decreased orexin expression in the hypothalamus and pons without changing neuronal numbers. Linear relationships existed between the percentage of orexin-positive neurons and the area of pontine orexin immunoreactivity of control and exposure piglets. These results demonstrate that postnatal nicotine exposure increases the proportion of orexin-positive neurons in the hypothalamus and fibre expression in the pons, and that IHH exposure does not prevent the nicotine-induced increase. Thus, although both nicotine and IHH are risk factors for SIDS, it appears they have opposing effects on OxA and OxB expression, with the IHH exposure closely mimicking what we recently found in SIDS.

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“…Consistent with the results from this study, both orexin receptor expressions (orexin receptors 1 and 2) are increased in the PVN after intermittent exposure to H/H (Hunt et al, 2013). The authors speculated that upregulation of these orexin receptors is the result of decreased level of orexin release and receptor density compensation due to H/H exposures (Du et al, 2016). Similar results have been obtained with acute exposure to hypercapnia alone.…”

Section: Discussionmentioning

confidence: 99%

Combined hypoxia and hypercapnia, but not hypoxia alone, suppresses neurotransmission from orexin to hypothalamic paraventricular spinally-projecting neurons in weanling rats

Dergacheva

Mendelowitz

2018

Brain Research

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Both orexin neurons in the lateral hypothalamus and spinally-projecting pre-sympathetic neurons (PSNs) in the paraventricular nucleus of the hypothalamus (PVN) play an important role in the regulation of cardiovascular function under normal conditions and during cardiovascular challenges such as hypoxia and/or hypercapnia. We have previously established, using selective optogenetic excitation of orexin neurons and pathways, there is a heterogeneous neurotransmission from orexin neurons to PSNs in the PVN. This study was undertaken to test whether this pathway is altered by acute exposure to hypoxia alone and/or combined hypoxia and hypercapnia (H/H). To test this hypothesis, we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in the lateral hypothalamus and photoactivated ChR2-expressing fibers to evoke postsynaptic currents in spinally-projecting PSNs in an in vitro slice preparation in rats. In accordance with previously published data, two subpopulations of spinally-projecting PSNs were established, including those with glutamatergic or GABAergic inputs from orexin neurons. Hypoxia alone did not alter the peak amplitude of either glutamatergic or GABAergic neurotransmission, however, H/H significantly inhibited both glutamatergic and GABAergic neurotransmission from orexin neurons to SPNs. In conclusion, H/H may modulate cardiovascular function by affecting heterogeneous pathways from orexin neurons to spinally-projecting PSNs in the PVN.

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Cumulative effects of repetitive intermittent hypercapnic hypoxia on orexin in the developing piglet hypothalamus

Cited by 13 publications

References 67 publications

Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats

Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats

Changes in orexinergic immunoreactivity of the piglet hypothalamus and pons after exposure to chronic postnatal nicotine and intermittent hypercapnic hypoxia

Combined hypoxia and hypercapnia, but not hypoxia alone, suppresses neurotransmission from orexin to hypothalamic paraventricular spinally-projecting neurons in weanling rats

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