Any condition that threatens homeostasis such as tissue injury, hemorrhage, hypoxia, infection, hypothermia, or psychological stress elicits changes in autonomic nervous system (ANS) function and specific behaviors. These changes can be beneficial for survival if transient but pathogenic if sustained, as in hypertension. The main new idea tested is that C1 neurons, a group of catecholaminergic/glutamatergic neurons within the rostral ventrolateral medulla of all mammals, including humans, are a nodal point for expression of these stress responses. That is, C1 neurons function like a switchboard enabling the expression of a large variety of ANS responses to acute physical and psychological stresses mediated by both sympathetic and parasympathetic divisions the ANS. The proposed experiments will use innovative methods (e.g. intersectional genetics, optogenetics, pharmacogenetics) designed to test key aspects of this theory, with particular emphasis on such novel topics as anti-inflammation, the prevention of hypoxic tissue damage and behavioral effects elicited by C1 cell activation. This knowledge is central to our understanding of how blood pressure and other physiological functions are regulated by the autonomic nervous system in healthy, diseased or stressed states.
The specific aims tested are: 1: Is C1 cell stimulation sufficient to elicit physiological and behavioral signs of stress? Do C1 cells produce these effects by releasing glutamate or a catecholamine? Activation of C1 cells with optogenetics in unanesthetized transgenic mice is expected to result in signs of stress. 2: Are C1 cells necessary for responses to physiological or psychological stressors? Using loss of function optogenetics (archaerhodopsin) C1 cell activation is expected to be necessary to maintain BP and HR in awake rats subjected to non-hypotensive hemorrhage, hypoxia or bacterial infection. We will also test whether C1 cells are required for the autonomic (e.g. cardiovascular, respiratory, GI and anti-inflammatory components) and behavioral manifestations of restraint stress in conscious mice by either inhibiting (pharmacogenetically) or selectively destroying these neurons. 3: Which C1 cells regulate blood pressure? Using mouse intersectional genetics and Boolean vectors, subgroups of C1 cells defined by peptide expression or CNS projection will be transduced to selectively express ChannelRhodopsin2. These subgroups are expected to have distinct projections and their optogenetic activation is expected to elicit highly specific physiological and behavioral responses.

Public Health Relevance

Any condition that threatens homeostasis such as tissue injury, hemorrhage, hypoxia, infection, hypothermia, or psychological stress elicits changes in autonomic nervous system function and behavior. These changes can be beneficial for survival if transient but pathogenic if sustained, as in hypertension. The proposed research focuses on neurons in the brainstem of humans and other mammals that are activated by physical and psychological stresses and will test whether these neurons are indispensable to the production of adaptive autonomic nervous system responses to stress and essential for certain behaviors associated with stress such as anxiety or sleep disruption. These neurons could be a productive focus of therapeutic intervention for conditions in which the autonomic nervous system is inappropriately activated e.g., hypertension, irritable bowel syndrome, heart failure or obstructive sleep apnea.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL028785-36
Application #
9610671
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Charette, Marc F
Project Start
1989-04-01
Project End
2020-08-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
36
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Stornetta, Ruth L; Guyenet, Patrice G (2018) C1 neurons: a nodal point for stress? Exp Physiol 103:332-336
Guyenet, Patrice G (2017) Putative Mechanism of Salt-Dependent Neurogenic Hypertension: Cell-Autonomous Activation of Organum Vasculosum Laminae Terminalis Neurons by Hypernatremia. Hypertension 69:20-22
Valentino, Rita J; Guyenet, Patrice; Hou, Xun Helen et al. (2017) Central Network Dynamics Regulating Visceral and Humoral Functions. J Neurosci 37:10848-10854
Abe, Chikara; Inoue, Tsuyoshi; Inglis, Mabel A et al. (2017) C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat Neurosci 20:700-707
Wenker, Ian C; Abe, Chikara; Viar, Kenneth E et al. (2017) Blood Pressure Regulation by the Rostral Ventrolateral Medulla in Conscious Rats: Effects of Hypoxia, Hypercapnia, Baroreceptor Denervation, and Anesthesia. J Neurosci 37:4565-4583
Guyenet, Patrice G; Bayliss, Douglas A; Stornetta, Ruth L et al. (2016) Proton detection and breathing regulation by the retrotrapezoid nucleus. J Physiol 594:1529-51
Inoue, Tsuyoshi; Abe, Chikara; Sung, Sun-Sang J et al. (2016) Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through ?7nAChR+ splenocytes. J Clin Invest 126:1939-52
Basting, Tyler M; Abe, Chikara; Viar, Kenneth E et al. (2016) Is plasticity within the retrotrapezoid nucleus responsible for the recovery of the PCO2 set-point after carotid body denervation in rats? J Physiol 594:3371-90
Stornetta, Ruth L; Inglis, M Andrews; Viar, Kenneth E et al. (2016) Afferent and efferent connections of C1 cells with spinal cord or hypothalamic projections in mice. Brain Struct Funct 221:4027-4044
Zheng, H; Stornetta, R L; Agassandian, K et al. (2015) Glutamatergic phenotype of glucagon-like peptide 1 neurons in the caudal nucleus of the solitary tract in rats. Brain Struct Funct 220:3011-22

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