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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL028066-33A1
Application #
8760429
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
1994-07-01
Project End
2018-04-30
Budget Start
2014-08-15
Budget End
2015-04-30
Support Year
33
Fiscal Year
2014
Total Cost
$393,153
Indirect Cost
$150,466
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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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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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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