Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors

Matsuo, Tomohiro; Isosaka, Tomoko; Tang, Lijun; Soga, Tomoyoshi; Kobayakawa, Reiko; Kobayakawa, Ko

doi:10.1038/s42003-020-01629-2

Cited by 17 publications

(15 citation statements)

References 70 publications

(36 reference statements)

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“…In addition, 2MT evokes physiological responses, as well as defensive behaviours for survival. 2MT has demonstrated resistance to critical hypoxia in cutaneous or cerebral I/R injury following hypothermia 22 . However, mechanisms underlying the systemic effect of 2MT on tissue metabolism and its potential biomedical implications in cardiovascular diseases remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

et al. 2021

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Aims Cardiac ischaemia/reperfusion (I/R) injury remains a critical issue in the therapeutic management of ischaemic heart failure. Although mild hypothermia has a protective effect on cardiac I/R injury, more rapid and safe methods that can obtain similar results to hypothermia therapy are required. 2‐Methyl‐2‐thiazoline (2MT), an innate fear inducer, causes mild hypothermia resulting in resistance to critical hypoxia in cutaneous or cerebral I/R injury. The aim of this study is to demonstrate the protective effect of systemically administered 2MT on cardiac I/R injury and to elucidate the mechanism underlying this effect. Methods and results A single subcutaneous injection of 2MT (50 mg/kg) was given prior to reperfusion of the I/R injured 10 week‐old male mouse heart and its efficacy was evaluated 24 h after the ligation of the left anterior descending coronary artery. 2MT preserved left ventricular systolic function following I/R injury (ejection fraction, %: control 37.9 ± 6.7, 2MT 54.1 ± 6.4, P < 0.01). 2MT also decreased infarct size (infarct size/ischaemic area at risk, %: control 48.3 ± 12.1, 2MT 25.6 ± 4.2, P < 0.05) and serum cardiac troponin levels (ng/mL: control 8.9 ± 1.1, 2MT 1.9 ± 0.1, P < 0.01) after I/R. Moreover, 2MT reduced the oxidative stress‐exposed area within the heart (%: control 25.3 ± 4.7, 2MT 10.8 ± 1.4, P < 0.01). These results were supported by microarray analysis of the mouse hearts. 2MT induced a transient, mild decrease in core body temperature (°C: −2.4 ± 1.4), which gradually recovered over several hours. Metabolome analysis of the mouse hearts suggested that 2MT minimized energy metabolism towards suppressing oxidative stress. Furthermore, 18F‐fluorodeoxyglucose‐positron emission tomography/computed tomography imaging revealed that 2MT reduced the activity of brown adipose tissue (standardized uptake value: control 24.3 ± 6.4, 2MT 18.4 ± 5.8, P < 0.05). 2MT also inhibited mitochondrial respiration and glycolysis in rat cardiomyoblasts. Conclusions We identified the cardioprotective effect of systemically administered 2MT on cardiac I/R injury by sparing energy metabolism with reversible hypothermia. Our results highlight the potential of drug‐induced hypothermia therapy as an adjunct to coronary intervention in severe ischaemic heart disease.

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Section: Introductionmentioning

confidence: 99%

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

et al. 2021

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“…The strong modulation of breathing through 2MT exposure in our study aligns with prior work demonstrating a reduction in breathing rate associated with 2MT. 22 , 55 Here intranasal pressure recordings highlight that the reduction in breathing frequency manifests from an increase in longer inhale pauses. Given this effect on pauses is most dramatic during 2MT freezing, an innate fear, in comparison to freezing from conditioned fear during retrieval, we investigated breathing during an additional odor-independent innate fear, foot shock.…”

Section: Discussionmentioning

confidence: 96%

“… 56 Notably, recent literature supports this potential mechanism for 2MT effects on breathing as it exerts partial action through trigeminal transient receptor potential (TRP) A1 receptors 57 and increases c-fos expression in the spinal trigeminal nucleus. 55 …”

Section: Discussionmentioning

confidence: 99%

Machine learning-based clustering and classification of mouse behaviors via respiratory patterns

Janke¹,

Zhang²,

Ryu³

et al. 2022

iScience

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“…Additional considerations are warranted concerning the role of hypothermia as part of a homeostatic, protective system. In mice a stereotypic “fear response” is induced by predator-specific odors, e.g., thiazolines, which trigger TRPA1 ion channels in sensory neurons, including vagus nociceptors (Matsuo et al 2021a , b ). As in the present study, the TRPA1 response activated by odorants is adaptive, promoting survival of stressors such as hypoxia by activating an energy conserving reflex consisting of immobility, hypothermia, bradycardia, and brain sparing hypometabolism, which also inhibits LPS-stimulated pro-inflammatory cytokines (Matsuo et al 2021a ).…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses

Silverman

Tynan²,

Hepler³

et al. 2023

Mol Med

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Background Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1β (IL-1β) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors expressing Transient Receptor Potential Ankyrin-1 (TRPA1) can initiate inflammation, comparatively little is known about the role of TRPA1 nociceptors in the physiological responses to specific cytokines. Methods To monitor body temperature in conscious and unrestrained mice, telemetry probes were implanted into peritoneal cavity of mice. Using transgenic and tissue specific knockouts and chemogenetic techniques, we recorded temperature responses to the potent pro-inflammatory cytokine IL-1β. Using calcium imaging, whole cell patch clamping and whole nerve recordings, we investigated the role of TRPA1 during IL-1β-mediated neuronal activation. Mouse models of acute endotoxemia and sepsis were used to elucidate how specific activation, with optogenetics and chemogenetics, or ablation of TRPA1 neurons can affect the outcomes of inflammatory insults. All statistical tests were performed with GraphPad Prism 9 software and for all analyses, P ≤ 0.05 was considered statistically significant. Results Here, we describe a previously unrecognized mechanism by which IL-1β activates afferent vagus nerve fibers to trigger hypothermia, a response which is abolished by selective silencing of neuronal TRPA1. Afferent vagus nerve TRPA1 signaling also inhibits endotoxin-stimulated cytokine storm and significantly reduces the lethality of bacterial sepsis. Conclusion Thus, IL-1β activates TRPA1 vagus nerve signaling in the afferent arm of a reflex anti-inflammatory response which inhibits cytokine release, induces hypothermia, and reduces the mortality of infection. This discovery establishes that TRPA1, an ion channel known previously as a pro-inflammatory detector of cold, pain, itch, and a wide variety of noxious molecules, also plays a specific anti-inflammatory role via activating reflex anti-inflammatory activity.

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Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors

Cited by 17 publications

References 70 publications

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

Machine learning-based clustering and classification of mouse behaviors via respiratory patterns

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses

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