The long-term objective of this research is to improve our understanding of the neural circuits regulating body temperature and how their function is altered during the fever response. Fever is a component of the acute-phase response to inflammatory stimuli. In uncontrolled conditions, it can threaten cellular homeostasis and survival. Treating the dysregulation of body temperature during fever will be aided by an understanding of the functional organization of the neural pathways that are activated by pyrogens and of the neurotransmitters mediating their effects. The proposed research plan will test the hypothesis that a population of neurons in the raphe pallidus (RPa) constitutes the sympathetic premotor pathway that is necessary for the activation of the sympathetic outflow to brown adipose tissue (BAT) in response to icv. PGE2, an intermediary in the """"""""fever cascade"""""""". These data will provide the cornerstone for further investigations to determine (a) the pathways by which hypothalamic neurons regulating thermal homeostasis activate sympathetically-regulated thermogenesis during fever and (b) the principal neurotransmitters and receptors that regulate the activity of RPa thermogenic neurons during fever. The proposed studies to elucidate the function and pharmacology of the longitudinally-organized core pathway for the regulation of thermogenesis in BAT will use electrophysiological recordings from the sympathetic nerves to BAT and from single neurons in the medulla in combination with microinjection techniques to activate and interrupt neuronal activity in restricted regions of the neuraxis. The first specific aim will determine the role of RPa neurons in the increases in BAT SNA and BAT heat production evoked by icv. PGE2. The sympathetic premotor neurons that project to the spinal cord to mediate these effects will be identified and their responses to febrile stimuli will be determined.
The second aim will identify the source of the tonic, GABAergic inhibition of RPa neurons and determine how this inhibition is modulated to produce fever-related increases in the sympathetic outflow to BAT. In the third aim, we will test the hypothesis that glutamate neurotransmission mediates the excitation of RPa neurons seen during the febrile response and that this excitation can be modulated by serotonergic inputs to thermogenic neurons in RPa. Understanding the pharmacology within pathways determining BAT sympathetic outflow will be a foundation for developing strategies to alter sympathetically- mediated heat production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS040987-02
Application #
6589947
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Edwards, Emmeline
Project Start
2001-07-15
Project End
2004-06-30
Budget Start
2002-01-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$207,000
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Townsend, Kristy L; Madden, Christopher J; Blaszkiewicz, Magdalena et al. (2017) Reestablishment of Energy Balance in a Male Mouse Model With POMC Neuron Deletion of BMPR1A. Endocrinology 158:4233-4245
Nakamura, Yoshiko; Yanagawa, Yuchio; Morrison, Shaun F et al. (2017) Medullary Reticular Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication. Cell Metab 25:322-334
Morrison, Shaun F (2016) Central neural control of thermoregulation and brown adipose tissue. Auton Neurosci 196:14-24
Tupone, Domenico; Cetas, Justin S; Morrison, Shaun F (2016) Hibernation, Hypothermia and a Possible Therapeutic ""Shifted Homeostasis"" Induced by Central Activation of A1 Adenosine Receptor (A1AR). Nihon Shinkei Seishin Yakurigaku Zasshi 36:51-4
Tupone, Domenico; Morrison, Shaun (2014) Hypothermia, torpor and the fundamental importance of understanding the central control of thermoregulation. Temperature (Austin) 1:89-91
Morrison, Shaun F; Madden, Christopher J (2014) Central nervous system regulation of brown adipose tissue. Compr Physiol 4:1677-713
Morrison, Shaun F; Madden, Christopher J; Tupone, Domenico (2014) Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 19:741-756
Tupone, Domenico; Madden, Christopher J; Morrison, Shaun F (2014) Autonomic regulation of brown adipose tissue thermogenesis in health and disease: potential clinical applications for altering BAT thermogenesis. Front Neurosci 8:14
Tupone, Domenico; Madden, Christopher J; Morrison, Shaun F (2013) Central activation of the A1 adenosine receptor (A1AR) induces a hypothermic, torpor-like state in the rat. J Neurosci 33:14512-25
Madden, Christopher J; Tupone, Domenico; Cano, Georgina et al. (2013) ?2 Adrenergic receptor-mediated inhibition of thermogenesis. J Neurosci 33:2017-28

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