Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

The preoptic area (POA) is a key region controlling body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses to regulate Tb. Known POA neuronal populations reduce Tb when activated; a population that increases Tb upon activation has not yet been reported. We now identify bombesin-like receptor 3 (BRS3)-expressing POA (POABRS3) neurons as having this missing functionality. BRS3 is an orphan receptor that regulates energy and cardiovascular homeostasis, but the relevant neural circuits are incompletely understood. In mice, we demonstrate that POABRS3 neuronal activation increases Tb, heart rate, and blood pressure sympathetically, via projections to the paraventricular nucleus of the hypothalamus and dorsomedial hypothalamus. Acute POABRS3 inhibition reduces Tb. Long-term inactivation of POABRS3 neurons increased Tb variability with exaggerated Tb changes, overshooting both increases and decreases in Tb set point. BRS3 marks preoptic populations that regulate Tb and heart rate, contribute to cold-defense and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology.

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Dorsomedial hypothalamus mediates autonomic, neuroendocrine, and locomotor responses evoked from the medial preoptic area

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00574.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. R130-R140 ◽

Cited By ~ 19

Author(s):

Joseph L. Hunt ◽

Dmitry V. Zaretsky ◽

Sumit Sarkar ◽

Joseph A. DiMicco

Keyword(s):

Heart Rate ◽

Body Temperature ◽

Preoptic Area ◽

Medial Preoptic Area ◽

Behavioral Changes ◽

Baseline Heart Rate ◽

Plasma Acth ◽

Temperature Plasma ◽

Dorsomedial Hypothalamus ◽

Inhibitory Tone

Previous studies suggest that sympathetic responses evoked from the preoptic area in anesthetized rats require activation of neurons in the dorsomedial hypothalamus. Disinhibition of neurons in the dorsomedial hypothalamus in conscious rats produces physiological and behavioral changes resembling those evoked by microinjection of muscimol, a GABAA receptor agonist and neuronal inhibitor, into the medial preoptic area. We tested the hypothesis that all of these effects evoked from the medial preoptic area are mediated through neurons in the dorsomedial hypothalamus by assessing the effect of bilateral microinjection of muscimol into the DMH on these changes. After injection of vehicle into the dorsomedial hypothalamus, injection of muscimol into the medial preoptic area elicited marked increases in heart rate, arterial pressure, body temperature, plasma ACTH, and locomotor activity and also increased c-Fos expression in the hypothalamic paraventricular nucleus, a region known to control the release of ACTH from the adenohypophysis. Prior bilateral microinjection of muscimol into the dorsomedial hypothalamus produced a modest depression of baseline heart rate and body temperature but completely abolished all changes evoked from the medial preoptic area. Microinjection of muscimol just anterior to the dorsomedial hypothalamus had no effect on autonomic and neuroendocrine changes evoked from the medial preoptic area. Thus, activity of neurons in the dorsomedial hypothalamus mediates a diverse array of physiological and behavioral responses elicited from the medial preoptic area, suggesting that the latter region represents an important source of inhibitory tone to key neurons in the dorsomedial hypothalamus.

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Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses

eLife ◽

10.7554/elife.60779 ◽

2021 ◽

Vol 10 ◽

Author(s):

Aaron J Norris ◽

Jordan R Shaker ◽

Aaron L Cone ◽

Imeh B Ndiokho ◽

Michael R Bruchas

Keyword(s):

Body Temperature ◽

Mouse Models ◽

Preoptic Area ◽

Behavioral Responses ◽

Neural Circuitry ◽

Parabrachial Nucleus ◽

Solute Carrier Family ◽

Temperature Changes ◽

Neuronal Populations ◽

Solute Carrier

Maintaining stable body temperature through environmental thermal stressors requires detection of temperature changes, relay of information, and coordination of physiological and behavioral responses. Studies have implicated areas in the preoptic area of the hypothalamus (POA) and the parabrachial nucleus (PBN) as nodes in the thermosensory neural circuitry and indicate that the opioid system within the POA is vital in regulating body temperature. In the present study we identify neurons projecting to the POA from PBN expressing the opioid peptides dynorphin and enkephalin. Using mouse models, we determine that warm-activated PBN neuronal populations overlap with both prodynorphin (Pdyn) and proenkephalin (Penk) expressing PBN populations. Here we report that in the PBN Prodynorphin (Pdyn) and Proenkephalin (Penk) mRNA expressing neurons are partially overlapping subsets of a glutamatergic population expressing Solute carrier family 17 (Slc17a6) (VGLUT2). Using optogenetic approaches we selectively activate projections in the POA from PBN Pdyn, Penk, and VGLUT2 expressing neurons. Our findings demonstrate that Pdyn, Penk, and VGLUT2 expressing PBN neurons are critical for physiological and behavioral heat defense.

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Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake

Nature Neuroscience ◽

10.1038/s41593-018-0249-3 ◽

2018 ◽

Vol 21 (11) ◽

pp. 1530-1540 ◽

Cited By ~ 21

Author(s):

Ramón A. Piñol ◽

Sebastian H. Zahler ◽

Chia Li ◽

Atreyi Saha ◽

Brandon K. Tan ◽

...

Keyword(s):

Heart Rate ◽

Food Intake ◽

Body Temperature ◽

Energy Expenditure ◽

Dorsomedial Hypothalamus ◽

Regulate Body Temperature

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2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense

Journal of Applied Physiology ◽

10.1152/japplphysiol.01227.2010 ◽

2011 ◽

Vol 110 (5) ◽

pp. 1137-1149 ◽

Cited By ~ 72

Author(s):

Shaun F. Morrison

Keyword(s):

Body Temperature ◽

Heat Loss ◽

Preoptic Area ◽

Functional Organization ◽

Inhibitory Input ◽

Neural Pathways ◽

Dorsomedial Hypothalamus ◽

Brown Adipose ◽

Premotor Neurons ◽

Raphe Pallidus

Central neural circuits orchestrate the homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the research leading to a model representing our current understanding of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for control of heat loss, and brown adipose tissue, skeletal muscle, and the heart for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific core efferent pathways within the central nervous system (CNS) that share a common peripheral thermal sensory input. The thermal afferent circuit from cutaneous thermal receptors includes neurons in the spinal dorsal horn projecting to lateral parabrachial nucleus neurons that project to the medial aspect of the preoptic area. Within the preoptic area, warm-sensitive, inhibitory output neurons control heat production by reducing the discharge of thermogenesis-promoting neurons in the dorsomedial hypothalamus. The rostral ventromedial medulla, including the raphe pallidus, receives projections form the dorsomedial hypothalamus and contains spinally projecting premotor neurons that provide the excitatory drive to spinal circuits controlling the activity of thermogenic effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a platform for further understanding of the functional organization of central thermoregulation.

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Mixing induces long-term hyperthermia in growing pigs

Animal Science ◽

10.1017/s1357729800051456 ◽

1999 ◽

Vol 69 (3) ◽

pp. 601-605 ◽

Cited By ~ 11

Author(s):

I. C. de Jong ◽

E. Lambooij ◽

S. M. Korte ◽

H. J. Blokhuis ◽

J. M. Koolhaas

Keyword(s):

Heart Rate ◽

Body Temperature ◽

Growing Pigs ◽

Activity Level ◽

Long Term Effects ◽

Deep Body Temperature ◽

Sensitive Parameter ◽

Effects Of Stress ◽

Deep Body

AbstractThe purpose of this experiment was to determine whether body temperature is a sensitive parameter to measure long-term effects of stress in pigs. Mixing of unacquainted pigs is a severe stressor that has detrimental effects on health, production and welfare. We measured deep body temperature after mixing growing pigs. Five pigs of 15 weeks of age, each individually housed with a companion pig, were mixed with two unacquainted congeners. Deep body temperature, heart rate and activity were recorded by radiotelemetry 9 days prior to until 8 days after mixing. These parameters were also recorded in five control pigs (individually housed with a companion pig) during the same time span. Behaviour during the light period was recorded on videotape on the day of mixing and on three subsequent days. Mixing induced a significant rise in body temperature that lasted for 8 h after mixing. Although heart rate and general activity level did not significantly differ between mixed and control pigs, mixing significantly increased the frequency of fighting and reduced the frequency of eating. In conclusion, the present experiment shows that mixing induces a long-lasting hyperthermia in pigs. Thus, deep body temperature may be used as a sensitive parameter to measure long-term effects of stress in pigs.

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Neurons in the dorsomedial hypothalamus promote, prolong, and deepen torpor

10.1101/2021.09.05.458994 ◽

2021 ◽

Author(s):

Michael T Ambler ◽

Timna Hitrec ◽

Andrew Wilson ◽

Matteo Cerri ◽

Anthony E Pickering

Keyword(s):

Energy Expenditure ◽

Preoptic Area ◽

Supply And Demand ◽

Daily Torpor ◽

Dorsomedial Hypothalamus ◽

Neuronal Populations ◽

Naturally Occurring ◽

Wide Range ◽

Activity Dependent ◽

Torpor Bouts

Torpor is a naturally occurring, hypometabolic, hypothermic state engaged by a wide range of animals in response to imbalance between the supply and demand for nutrients. Recent work has identified some of the key neuronal populations involved in daily torpor induction in mice, in particular projections from the preoptic area of the hypothalamus (POA) to the dorsomedial hypothalamus (DMH). The DMH plays a role in thermoregulation, control of energy expenditure, and circadian rhythms, making it well positioned to contribute to the expression of torpor. We used activity dependent genetic TRAPing techniques to target DMH neurons that were active during natural torpor bouts in female mice. Chemogenetic reactivation of torpor-TRAPed DMH neurons in calorie-restricted mice promoted torpor, resulting in longer and deeper torpor bouts. Chemogenetic inhibition of torpor-TRAPed DMH neurons did not block torpor entry, suggesting a modulatory but not a necessary role for the DMH in the control of torpor. This work adds to the evidence that a projection from the POA to the DMH forms part of a torpor-inducing circuit within the mouse hypothalamus.

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Parabrachial Opioidergic Projections to Preoptic Hypothalamus Mediate Behavioral and Physiological Thermal Defenses

10.1101/2020.06.23.167619 ◽

2020 ◽

Author(s):

Aaron J. Norris ◽

Jordan R. Shaker ◽

Aaron L. Cone ◽

Imeh B. Ndiokho ◽

Michael R Bruchas

Keyword(s):

Body Temperature ◽

Opioid Peptides ◽

Behavioral Responses ◽

Neural Circuitry ◽

Opioid System ◽

Parabrachial Nucleus ◽

Hypothalamic Area ◽

Temperature Changes ◽

Neuronal Populations

SummaryMaintaining stable body temperature through environmental thermal stressors requires detection of temperature changes, relay of information, and coordination of physiological and behavioral responses. Studies have implicated areas in the preoptic hypothalamic area (POA) and the parabrachial nucleus (PBN) as nodes in the thermosensory neural circuitry and indicate the opioid system within the POA is vital in regulating body temperate. In the present study we identify neurons projecting to the POA from PBN expressing the opioid peptides Dynorphin (Dyn) and Enkephalin (Enk). We determine that warm-activated PBN neuronal populations overlap with both Dyn and Enk expressing PBN populations. We demonstrate that Dyn and Enk expressing neurons are partially overlapping subsets of a glutamatergic population in the PBN. Using optogenetic approaches we selectively activate projections in the POA from PBN Dyn, Enk, and VGLUT2 expressing neurons. Our findings demonstrate that Dyn, Enk, and VGLUT2 expressing PBN neurons are critical for physiological and behavioral heat defense.

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Orbital bleeding in rats while under diethylether anaesthesia does not influence telemetrically determined heart rate, body temperature, locomotor and eating activity when compared with anaesthesia alone

Laboratory Animals ◽

10.1258/002367797780596284 ◽

1997 ◽

Vol 31 (3) ◽

pp. 271-278 ◽

Cited By ~ 8

Author(s):

H. Van Herck ◽

S. F. De Boer ◽

A. P. M. Hesp ◽

H. A. Van Lith ◽

A. C. Baumans ◽

...

Keyword(s):

Heart Rate ◽

Locomotor Activity ◽

Body Temperature ◽

Body Core Temperature ◽

Eating Pattern ◽

Endocrine Stress Response ◽

Body Core ◽

Roman Low Avoidance ◽

Roman High Avoidance

The question addressed was whether orbital bleeding in rats, while under diethylether anaesthesia, affects their locomotor activity, body core temperature, heart rate rhythm and eating pattern. Roman High Avoidance (RHA) and Roman Low Avoidance (RLA) rats were used to enhance generalization of the results. Orbital bleeding when the rats were under diethylether anaesthesia was compared with diethylether anaesthesia alone. To take into account any effects of handling, the rats were also subjected to sham anaesthesia. The RHA rats urinated more during anaesthesia, needed more time to recover from the anaesthesia and showed a greater endocrine stress response to diethylether anaesthesia when compared with the RLA rats. During anaesthesia, the RHA rats showed a greater fall of body temperature and bradycardia than did the RLA rats. Diethylether anaesthesia reduced locomotor activity in the RHA rats, but had no effect in the RLA rats. In neither RHA nor RLA rats did anaesthesia plus orbital puncture, versus anaesthesia alone, influence body temperature, heart rate rhythm, locomotor and eating activity. The lack of effect of orbital puncture occurred both in the short term (within 2 h) and long term (within 48 hours) and thus this study indicates that orbital puncture had, at least with respect to variables measured in the present study, no effect superimposed on that of diethylether anaesthesia.

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A subsidiary fever center in the medullary raphé?

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00141.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. R1592-R1598 ◽

Cited By ~ 19

Author(s):

Mutsumi Tanaka ◽

Robin M. McAllen

Keyword(s):

Heart Rate ◽

Body Temperature ◽

Preoptic Area ◽

Sympathetic Nerves ◽

Prostaglandin E ◽

Brown Adipose ◽

Medullary Raphe ◽

Premotor Neurons ◽

Heat Conservation ◽

Cutaneous Vasoconstriction

In fever, as in normal thermoregulation, signals from the preoptic area drive both cutaneous vasoconstriction and thermogenesis by brown adipose tissue (BAT). Both of these responses are mediated by sympathetic nerves whose premotor neurons are located in the medullary raphé. EP3 receptors, key prostaglandin E2 (PGE2) receptors responsible for fever induction, are expressed in this same medullary raphé region. To investigate whether PGE2 in the medullary raphé might contribute to the febrile response, we tested whether direct injections of PGE2 into the medullary raphé could drive sympathetic nerve activity (SNA) to BAT and cutaneous (tail) vessels in anesthetized rats. Microinjections of glutamate (50 mM, 60–180 nl) into the medullary raphé activated both tail and BAT SNA, as did cooling the trunk skin. PGE2 injections (150–500 ng in 300–1,000 nl) into the medullary raphé had no effect on tail SNA, BAT SNA, body temperature, or heart rate. By contrast, 150 ng PGE2 injected into the preoptic area caused large increases in both tail and BAT SNA (+60 ± 17 spikes/15 s and 1,591 ± 150% of control, respectively), increased body temperature (+1.8 ± 0.2°C), blood pressure (+17 ± 2 mmHg), and heart rate (+124 ± 19 beats/min). These results suggest that despite expression of EP3 receptors, neurons in the medullary raphé are unable to drive febrile responses of tail and BAT SNA independently of the preoptic area. Rather, they appear merely to transmit signals for heat production and heat conservation originating from the preoptic area.

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