Abstract
Patients suffering from mood disorders and anxiety commonly exhibit hypothalamic-pituitary-adrenocortical (HPA) axis and autonomic hyperresponsiveness. A wealth of data using preclinical animal models and human patient samples indicate that p11 deficiency is implicated in depression-like phenotypes. In the present study, we used p11-deficient (p11KO) mice to study potential roles of p11 in stress responsiveness. We measured stress response using behavioral, endocrine, and physiological readouts across early postnatal and adult life. Our data show that p11KO pups respond more strongly to maternal separation than wild-type pups, even though their mothers show no deficits in maternal behavior. Adult p11KO mice display hyperactivity of the HPA axis, which is paralleled by depression- and anxiety-like behaviors. p11 was found to be highly enriched in vasopressinergic cells of the paraventricular nucleus and regulates HPA hyperactivity in a V1B receptor-dependent manner. Moreover, p11KO mice display sympathetic-adrenal-medullary (SAM) axis hyperactivity, with elevated adrenal norepinephrine and epinephrine levels. Using conditional p11KO mice, we demonstrate that this SAM hyperactivity is partially regulated by the loss of p11 in serotonergic neurons of the raphe nuclei. Telemetric electrocardiogram measurements show delayed heart rate recovery in p11KO mice in response to novelty exposure and during expression of fear following auditory trace fear conditioning. Furthermore, p11KO mice have elevated basal heart rate in fear conditioning tests indicating increased autonomic responsiveness. This set of experiments provide strong and versatile evidence that p11 deficiency leads to HPA and SAM axes hyperresponsiveness along with increased stress reactivity.
Original language | English |
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Pages (from-to) | 3253-3265 |
Number of pages | 13 |
Journal | Molecular Psychiatry |
Volume | 26 |
Issue number | 7 |
Early online date | 1 Oct 2020 |
DOIs | |
Publication status | Published - Jul 2021 |
Funding
Acknowledgements We would like to dedicate this article to the late Professor Paul Greengard, who made major contributions for our understanding of the role of p11 in depression. The authors wish to thank Professor Michael Kaplitt and Dr. Roberta Marongiu for their expert contributions to the revision of this manuscript, and Charbel Kreidy and Dr. Xiaoqun Zhang for their valuable help with tissue collection and animal handling. This work was supported by the Swedish Research Council, the S\u00F6derberg Foundation and the Swedish Brain Fund. VCS was supported by a Wenner-Gren Foundation grant. TH was supported as early stage researcher by the European Union Seventh Framework Programs under grant agreements no. PEOPLE-ITN-2008-238055 (BrainTrain) provided to OS and PS.
Funders | Funder number |
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Söderberg Foundation | |
Wenner-Gren Foundation | |
Medicinska Forskningsrådet | |
Swedish Brain Fund | |
Vetenskapsrådet | |
European Commission | 238055 |
Seventh Framework Programme | PEOPLE-ITN-2008-238055 |