The long-term objective of this research is to improve our understanding of the regulation of energy metabolism and body-weight by neural circuits in the brain and spinal cord. Obesity is a common, complex disorder with consequences that are becoming a public health problem of increasing significance. Development of treatments for the dysregulation of energy metabolism in this condition will be aided by an understanding of the functional organization of the pathways that control energy expenditure and an elucidation of the neurotransmitters mediating their effects. The proposed research will test the hypothesis that neurons in the rostral raphe pallidus (RPa) constitute a common sympathetic premotor pathway necessary for the activation of sympathetically-regulated thermogenesis in response to both metabolic/energy balance-related and thermoregulatory stimuli. The model to be studied is the sympathetic regulation of brown adipose tissue (BAT) in the rat. These data will provide the cornerstone for further studies to determine (a) the pathways by which hypothalamic neurons regulating energy and thermal homeostasis effect changes in BAT thermogenesis and (b) the principal neurotransmitters and their receptor subtypes that regulate the discharge of RPa thermogenic neurons and through which they, in turn, control the activity of spinal sympathetic preganglionic neurons for BAT. Experiments to elucidate the function and pharmacology of the longitudinally-organized core pathway for the regulation of energy utilization in BAT will involve electrophysiological recordings from the sympathetic nerves to BAT and from single neurons in the medulla and spinal cord in combination with microstimulation and microinjection techniques to alter neuronal activity in restricted regions of the brainstem, hypothalamus and spinal cord. The first specific aim will establish the role of RPa neurons in the changes in BAT SNA evoked by metabolic stimuli that influence energy expenditure in BAT and by cold stimuli that induce BAT thermogenesis. The sympathetic premotor neurons that mediate these effects will be identified and their responses to these stimuli will be determined.
The second aim will localize the source of the strong, tonic GABAergic inhibition of RPa neurons and determine how this inhibition is modulated to produce changes in the sympathetic outflow to BAT. Anatomical tract tracing techniques will be used to identify the afferent pathways to RPa that mediate metabolic and thermoregulatory homeostatic reflexes. Determining the effects of these inputs on RPa neuronal activity and BAT sympathetic outflow will help to understand their function in the network controlling BAT energy utilization. In the third specific aim, we will test the hypothesis that glutamate is the principal neurotransmitter in mediating both the excitation of RPa neurons and their effects on BAT sympathetic preganglionic neurons in the spinal cord. Understanding the neurotransmitter pharmacology within pathways determining BAT sympathetic outflow will be a foundation for development of strategies to alter energy balance in this model tissue.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-T (02))
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Yanovski, Susan Z
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Oregon Health and Science University
Schools of Medicine
United States
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Morrison, Shaun F (2016) Central neural control of thermoregulation and brown adipose tissue. Auton Neurosci 196:14-24
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
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
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
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
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
Nakamura, Kazuhiro; Morrison, Shaun F (2010) A thermosensory pathway mediating heat-defense responses. Proc Natl Acad Sci U S A 107:8848-53
Madden, C J; Morrison, S F (2009) Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 296:R831-43

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