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We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R. [ABSTRACT FROM AUTHOR]

We recently showed that in male rats, orexin contributes to the hypoxic ventilatory response (HVR), with a stronger effect in the active phase. The effect of orexin on the HVR in females has not been investigated. As estrogen can inhibit orexin neurons, here we hypothesized that orexin neurons are activated by hypoxia and facilitate the HVR only in diestrus, when estrogen is low. We exposed female rats (n = 10) to near-isocapnic hypoxia (FIO2 from 0.21 to 0.09) over _5 min, after vehicle and again after suvorexant (a dual OxR antagonist; 20 mg/kg ip), with ventilation measured using whole body plethysmography. Each rat was tested in proestrus or estrus (p/estrus), and again in diestrus, during both inactive and active phases. We also performed immunohistochemistry (IHC) to determine the proportion of orexin neurons activated by acute hypoxia during diestrus (n = 6) or proestrus/estrus (n = 6) in the active phase. In the inactive phase, the HVR was unaffected by OxR blockade, irrespective of estrus stage. In the active phase, the effect of OxR blockade depended on stage: the slope of the HVR was significantly reduced by OxR blockade only during diestrus. IHC revealed that hypoxia activated more orexin neurons during diestrus compared with p/estrus. We conclude that in females, orexin neurons are activated by hypoxia and contribute to the HVR only in diestrus when estrogen levels are low. Stage of the estrus cycle should be considered when examining the physiological function of orexin neurons in females. NEW & NOTEWORTHY We previously showed that orexin facilitates the hypoxic ventilatory response (HVR) of adult male rats during the active phase. Others have shown that estrogen inhibits orexin neurons. Here we show that orexin neurons are activated by hypoxia and facilitate the HVR of adult female rats during the active phase, but only in diestrus. These data suggest that orexin neurons facilitate the HVR in females when they are free from the inhibitory effects of estrogen. [ABSTRACT FROM AUTHOR]

Salmonella enterica remains a formidable public health challenge, resulting in [approximately equals] 1.2 million illnesses and 400 deaths annually in the United States alone (1). Disease manifestations include diarrhea, fever, [...]

Eupnea and gasping in infancy depend on central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT). Although previous in vitro preparations have provided some evidence that 5-HT acts through type 2A receptors (5-HT2A) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT2A receptor activation is necessary for eupnea and the proper generation of gasping in vivo. To test this, we administered 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25 mg/kg i.p.), a 5-HT2A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT1A agonist, or vehicle (saline) to 7-9-day-old tryptophan hydroxylase 2 knockout (TPH2-/-) mice. A second experiment assessed the effect of MDL-11,939 (MDL; 10 mg/kg i.p.), the specific 5-HT2A antagonist, or vehicle (DMSO) on the gasping of wild-type (TPH2þ/þ) animals. Drugs were given 15 min prior to five episodes of severe hypoxia that elicited gasping. TPH2-/- breathed more slowly but had the same VE and VE/VO2 compared with TPH2þ/þ. As previously reported, the gasping of TPH2-/- was significantly delayed (P < 0.001) and occurred at a significantly lower frequency compared with TPH2þ/þ (P = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on VE or VE/VO2. The gasping of TPH2-/-, although unaffected by 8-OH-DPAT, was indistinguishable from the gasping of TPH2þ/þ following DOI. In TPH2þ/þ, application of MDL led to hypoventilation (P = 0.01), a delay in the appearance of gasping (P = 0.005), and reduced gasp frequency (P = 0.05). These data show that, in vivo, 5-HT2A receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT2A probably promotes gasping by exciting hypoxia-resistant pacemaker neurons. [ABSTRACT FROM AUTHOR]

Infant rat pups lacking central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT) have unstable breathing during prolonged periods of active sleep. Given that cholinergic neurons are drivers of active sleep and project to respiratory patterning regions in the brainstem, we hypothesized that 5-HT preserves respiratory stability in active sleep by dampening central cholinergic drive. We used whole-body plethysmography coupled with nuchal electromyography to monitor the breathing pattern of 2-wk-old tryptophan hydroxylase 2 (TPH2)±/± and TPH2-deficient (TPH2=/=) pups in active sleep, before and after muscarinic blockade. For the group 1 experiment we injected methylatropine (Ap-M), a CNS-impermeant form of atropine, followed ~30 min later by an injection of atropine sulfate (Ap-S), the CNS-permeant form (both 1 mg/kg, 10 μl bolus iv); both injections occurred within an active sleep episode. We analyzed the effect of each drug on the coefficient of variation of the respiratory period (CV-P) during active sleep. For the group 2 experiment rats were cycled through several episodes of active and quiet sleep before administration of Ap-S (1 mg/kg, 200 μl ip) or vehicle. We assessed the effect of Ap-S on the apnea indices of both genotypes during quiet and active sleep. In group 1 Ap-S significantly reduced the CV-P of TPH2=/= pups (P + 0.03), an effect not observed in TPH2±/± pups or following Ap-M. In group 2 the apnea index of TPH2=/= pups was significantly reduced following Ap-S injection (P + 0.04), whereas the apnea index of TPH2±/± littermates was unaffected (P + 0.58). These findings suggest that central 5-HT reduces apnea and stabilizes breathing by reducing cholinergic signaling through muscarinic receptors. [ABSTRACT FROM AUTHOR]