Cyclic ADP-Ribose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus during Social or Psychological Stress in Mice
Open accessAbstract
Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulation. Previously, we showed that the intracellular free calcium concentration ([Ca(2+)]i) that seems to trigger OT release can be elevated by β-NAD(+), cADPR, and ADP in mouse oxytocinergic neurons. As these β-NAD(+) metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca(2+)]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35°C to 38.5°C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR-dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38- or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6°C to 37.8°C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8°C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress.
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The open field test is meant to assess anxious behaviour.
“The open field test is meant to assess anxious behaviour80.”
From Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice (2019) · cites this paper as [80]
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- Authors
- Zhong, J., Amina, S., Liang, M., Akther, S., Yuhi, T., Nishimura, T., Tsuji, C., Tsuji, T., Liu, H.-X., Hashii, M., Furuhara, K., Yokoyama, S., Yamamoto, Y., Okamoto, H., Zhao, Y. J., Lee, H. C., Tominaga, M., Lopatina, O., & Higashida, H.
- Affiliations
- Kanazawa University (JP)
- Peking University (CN)
- National Institutes of Natural Sciences (JP)
- Corresponding author
- Higashida, Haruhiro
- ORCID
- Venue
- Frontiers in Neuroscience
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- Frontiers Media SA
- Published
- 2016-07-22
- Volume
- 10
- Pages
- 304-304
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC4956647
- OpenAlex
- W2468642893
- Cited by
- 42
- References
- 86
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- 9.95
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- en
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- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) (submittedVersion, cc-by-nc-nd)
- Greater South Information System
- Funders
- Japan Agency for Medical Research and Development
- Shenzhen Government
- Ministry of Education, Culture, Sports, Science and Technology
- National Natural Science Foundation of China (31571438, 31301156, 91413114, 31470815)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- cyclic ADP-ribose, CD38, TRPM2, oxytocin release, hypothalamus, heat, stress, social stress, social dominance, lipopolysaccharide-induced fever, ryanodine receptor, intracellular calcium, thermosensitive ion channels, rectal temperature
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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