This project will test the hypothesis that specific neurons in three neuroanatomical sites important in the ventilatory CO2 chemoreflex also participate in the regulation of sympathetic nerve activity (SNA) and blood pressure (BP) in normal rats and mice, and in Spontaneously Hypertensive Rats (SHR). The three central chemoreceptor sites (and neurons) are: 1) orexin neurons of the lateral hypothalamus (LHA);2) Phox2b- expressing neurons of the retrotrapezoid nucleus (RTN);and 3) serotonergic (5-HT) neurons of the medullary raphe (MR). The measurements, obtained in unanesthetized rodents during wakefulness, REM and NREM sleep include ventilation, SNA and BP at rest while breathing air and in response to breathing 5% CO2. The experiments involve focal disruption of: 1) orexin neuron function by siRNA induced inhibition of prepro-orexin in the lateral hypothalamus, 2) Phox2b-expressing neurons of the RTN by viral transfection of a PRS8/allatostatin receptor construct followed by subsequent allatostatin injection to inhibit the neurons reversibly;3) 5-HT neuron function in: a) mice by transgenic insertion of the inhibitory HM4D receptor in all 5-HT neurons or in 5-HT neurons derived from rhombomeres 3 and 5 (DREADD: Designer Receptor Activated by Designer Drug), and b) rats by siRNA/shRNA to block activity of tryptophan hydroxylase 2 the enzyme for 5-HT synthesis (TPH2). In addition, the experiments involve antagonism of orexin receptors by almorexant administered systemically and focally within the medullary raphe and retrotrapezoid nucleus. The major goals are to further the understanding of the link between chemoreception and blood pressure regulation, and to begin to relate this understanding to the development of some forms of hypertension, which has relevance to the mission of the agency and to medical practice.

Public Health Relevance

Breathing is regulated, in part, by central chemoreceptors, which detect changes in carbon dioxide. In addition, we examine here the role of three chemoreceptor sites in the regulation of blood pressure in response to carbon dioxide in normal rodents and in the development of essential hypertension (as in the spontaneously hypertensive rat). Hypertension is a major health concern.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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Dartmouth College
Schools of Medicine
United States
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Ma, Tian; Lopez-Aguiar, Alexandra G N; Li, Aihua et al. (2014) Mice lacking G0S2 are lean and cold-tolerant. Cancer Biol Ther 15:643-50
Li, Aihua; Nattie, Eugene (2014) Orexin, cardio-respiratory function, and hypertension. Front Neurosci 8:22
Li, Ningjing; Nattie, Eugene; Li, Aihua (2014) The role of melanin concentrating hormone (MCH) in the central chemoreflex: a knockdown study by siRNA in the lateral hypothalamus in rats. PLoS One 9:e103585
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Nattie, Eugene; Li, Aihua (2012) Respiration and autonomic regulation and orexin. Prog Brain Res 198:25-46
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Nattie, Eugene; Li, Aihua (2012) Central chemoreceptors: locations and functions. Compr Physiol 2:221-54
Cummings, Kevin J; Hewitt, Julie C; Li, Aihua et al. (2011) Postnatal loss of brainstem serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia. J Physiol 589:5247-56

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