Central Sympathetic Regulation of Thermogenesis

Project: Research project

Description

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.
StatusFinished
Effective start/end date12/1/005/31/15

Funding

  • National Institutes of Health: $207,000.00
  • National Institutes of Health: $351,575.00
  • National Institutes of Health: $314,269.00
  • National Institutes of Health: $226,500.00
  • National Institutes of Health: $355,163.00
  • National Institutes of Health: $10,292.00
  • National Institutes of Health: $339,270.00
  • National Institutes of Health: $27,941.00
  • National Institutes of Health: $297,984.00
  • National Institutes of Health: $76,995.00
  • National Institutes of Health: $297,984.00
  • National Institutes of Health: $306,883.00
  • National Institutes of Health: $351,575.00
  • National Institutes of Health: $358,750.00
  • National Institutes of Health: $226,500.00

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Thermogenesis
Fever
Brown Adipose Tissue
Dinoprostone
Neurons
Body Temperature
Preoptic Area
Skin
Vasoconstriction
Hot Temperature
Neurotransmitter Agents
Neural Pathways
Shivering
Heart Rate
Body Temperature Regulation
Acute-Phase Reaction
Hypothalamus
Middle Hypothalamus
Homeostasis
Pharmacology

ASJC

  • Medicine(all)
  • Neuroscience(all)