Fever is a defended elevation in body temperature that plays a significant role in the acute phase reaction stimulated by a cascade of endogenous pyrogens released during infection. The febrile increase in body temperature is the result of a patterned autonomic and somatic motor response orchestrated by the central nervous system in response to an increased production of the pyrogenic mediator, prostaglandin E2 (PGE2), in the preoptic area (POA), a principal thermoregulatory integration center in the brain. PGE2 binding to EP3 inhibitory receptors on neurons in the POA increases core body temperature by activating neural pathways to four principal thermoregulatory effectors: increased heat production from brown adipose tissue (BAT) thermogenesis, from shivering in skeletal muscle and from a marked tachycardia and increased heat conservation through cutaneous vasoconstriction (CVC). This same constellation of responses: augmented sympathetic outflows to BAT, to the heart and to skin blood vessels and increased somatic motorneuron discharge to muscle, also constitutes the cold defense homeostatic reflex response to stimulation of cutaneous cold receptors or falls in core temperature. In the previous funding period, we have made significant progress in understanding the functional organization and neurotransmitters regulating the activity in the thermoregulatory pathways mediating the increases in BAT thermogenesis, heart rate and CVC contributing to the febrile response to PGE2 in the POA and to cold defense responses to skin cooling. We propose to extend these studies by using the fruitful in vivo electrophysiological, anatomical and neuropharmacological approaches we have perfected over the past several years to address three specific aims that will provide new and important insights into the brain mechanisms effecting fever and performing the critical homeostatic function of thermoregulation.
The first aim will test the hypothesis that somatic, as well as sympathetic febrile and cold defense responses are organized through a hierarchical pathway between the POA and the medullary raphe by determining the central neural mechanism underlying the PGE2- and cold-evoked shivering response.
The second aim will determine the neural basis for the fundamental differences in performance between the thermoregulatory network regulating skin blood flow and that driving BAT thermogenesis.
The third aim will focus on the key integrative neurons in thermoregulation: the output neurons of the POA, to understand the mechanism for the differential control of thermoregulatory effectors and to determine their role in mediating effector responses to neurotransmitter systems implicated in conditions of thermal dysregulation.

Public Health Relevance

Understanding the central neural mechanisms mediating fever and cold defense is relevant to the development of therapeutic approaches to combat life-threatening excessive fevers (as during sepsis, toxemia, meningitis, some cancers) and to the management of the effects of thermal dysregulation that occurs during a variety of other clinically significant conditions such as cerebral ischemia and stroke, the abuse of amphetamine-based drugs, the hot flashes accompanying menopause and prostate surgery and the hypothermia induced during surgical anesthesia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Gnadt, James W
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Oregon Health and Science University
Schools of Medicine
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Morrison, Shaun F; Madden, Christopher J; Tupone, Domenico (2014) Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 19:741-56
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
Morrison, Shaun F; Madden, Christopher J; Tupone, Domenico (2012) Central control of brown adipose tissue thermogenesis. Front Endocrinol (Lausanne) 3:
Morrison, Shaun F; Nakamura, Kazuhiro (2011) Central neural pathways for thermoregulation. Front Biosci (Landmark Ed) 16:74-104
Nakamura, Kazuhiro; Morrison, Shaun F (2011) Central efferent pathways for cold-defensive and febrile shivering. J Physiol 589:3641-58
Tupone, Domenico; Madden, Christopher J; Cano, Georgina et al. (2011) An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J Neurosci 31:15944-55
Morrison, Shaun F (2011) 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. J Appl Physiol 110:1137-49
Cao, Wei-Hua; Madden, Christopher J; Morrison, Shaun F (2010) Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol 299:R277-90
Madden, Christopher J; Morrison, Shaun F (2010) Endogenous activation of spinal 5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 298:R776-83

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