A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia

Natalia L.S Machado; Stephen B.G Abbott; Jon M Resch; Lin Zhu; Elda Arrigoni; Bradford B Lowell; Patrick M Fuller; Marco A.P Fontes; Clifford B Saper

doi:10.1016/j.cub.2018.05.064

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A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia

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A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia

Natalia L.S Machado, Stephen B.G Abbott, Jon M Resch, Lin Zhu, Elda Arrigoni, Bradford B Lowell, Patrick M Fuller, Marco A.P Fontes and Clifford B Saper

Current biology, Vol.28(14), pp.2291-2301.e5

07/23/2018

DOI: 10.1016/j.cub.2018.05.064

PMCID: PMC6085892

PMID: 30017482

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Abstract

Stress elicits a variety of autonomic responses, including hyperthermia (stress fever) in humans and animals. In this present study, we investigated the circuit basis for thermogenesis and heat conservation during this response. We first demonstrated the glutamatergic identity of the dorsal hypothalamic area (DHAVglut2) neurons that innervate the raphe pallidus nucleus (RPa) to regulate core temperature (Tc) and mediate stress-induced hyperthermia. Then, using chemogenetic and optogenetic methods to manipulate this hypothalamomedullary circuit, we found that activation of DHAVglut2 neurons potently drove an increase in Tc, but surprisingly, stress-induced hyperthermia was only reduced by about one-third when they were inhibited. Further investigation showed that DHAVglut2 neurons activate brown adipose tissue (BAT) but do not cause vasoconstriction, instead allowing reflex tail artery vasodilation as a response to BAT-induced hyperthermia. Retrograde rabies virus tracing revealed projections from DHAVglut2 neurons to RPaVglut3, but not to RPaGABA neurons, and identified a set of inputs to DHAVglut2 → RPa neurons that are likely to mediate BAT activation. The dissociation of the DHAVglut2 thermogenic pathway from the thermoregulatory vasoconstriction (heat-conserving) pathway may explain stress flushing (skin vasodilation but a feeling of being too hot) during stressful times. [Display omitted] •DHA glutamatergic neurons that innervate RPa are selectively activated by stress•DHAVglut2 neurons activation promotes BAT thermogenesis, but not vasoconstriction•Inhibition of DHAVglut2 neurons or their terminals in the RPa reduces stress fever•DHAVglut2 neurons project to the RPaVglut3 but do not innervate RPaVGAT neurons Machado et al. describe that DHAVglut2 neurons are critical for the regulation of body temperature and stress-induced hyperthermia through their direct projections to glutamatergic neurons in the RPa, which in turn regulate thermogenesis from brown adipose tissue, but not cutaneous vasoconstriction.

medulla

dorsal hypothalamic area

fever

stress-induced hyperthermia

raphe pallidus

hypothalamus

Details

Title: Subtitle: A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia
Creators: Natalia L.S Machado - Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Stephen B.G Abbott - Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Jon M Resch - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Lin Zhu - Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Elda Arrigoni - Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Bradford B Lowell - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Patrick M Fuller - Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Marco A.P Fontes - Department of Physiology and Biophysics, Federal University of Minas Gerais, Antonio Carlos Avenue, Belo Horizonte 31270-901, Brazil
Clifford B Saper - Department of Neurology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Blackfan Circle, Boston, MA 02215, USA
Resource Type: Journal article
Publication Details: Current biology, Vol.28(14), pp.2291-2301.e5
Publisher: Elsevier Inc
DOI: 10.1016/j.cub.2018.05.064
PMID: 30017482
PMCID: PMC6085892
ISSN: 0960-9822
eISSN: 1879-0445
Grant note: DOI: 10.13039/100000002, name: NIH, award: NS085477, NS072337; name: CNPq (National Council for Scientific and Technological Development/Brazil, award: 200881/2014-0, PQ306000/2013-0; DOI: 10.13039/501100002322, name: CAPES; name: National Health and Medical Research Council of Australia, award: GNT1052674; DOI: 10.13039/100000002, name: NIH, award: 1R01NS091126
Language: English
Date published: 07/23/2018
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984065853902771

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