Deep Phenotyping Reveals CRH and FKBP51-dependent Behavioral Profiles Following Chronic Social Stress Exposure in Male Mice

Overview

Journal Neuropsychopharmacology

Date 2024 Oct 22

PMID 39438757

Authors

Veronika Kovarova

Joeri Bordes

Shiladitya Mitra

Sowmya Narayan

Margherita Springer

Lea Maria Brix

Jan M Deussing

Mathias V Schmidt

Affiliations

Soon will be listed here.

Abstract

The co-chaperone FKBP51, encoded by FKBP5 gene, is recognized as a psychiatric risk factor for anxiety and depressive disorders due to its crucial role in the stress response. Another key modulator in stress response regulation is the corticotropin releasing hormone (CRH), which is co-expressed with FKBP51 in many stress-relevant brain-regions and cell-types. Together, they intricately influence the balance of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary stress response systems. Previous research underscores the potential moderating effects these genes have on the regulation of the stressful life events towards the vulnerability of major depressive disorder (MDD). However, the specific function of FKBP51 in CRH-expressing neurons remains largely unexplored. Here, through deep behavioral phenotyping, we reveal heightened stress effects in mice lacking FKBP51 in CRH co-expressing neurons (CRH), particularly evident in social contexts. Our findings highlight the importance of considering cell-type specificity and context in comprehending stress responses and advocate for the utilization of machine-learning-driven phenotyping of mouse models. By elucidating these intricacies, we lay down the groundwork for personalized interventions aimed at enhancing stress resilience and individual well-being.

References

Puscian A, Leski S, Kasprowicz G, Winiarski M, Borowska J, Nikolaev T . Eco-HAB as a fully automated and ecologically relevant assessment of social impairments in mouse models of autism. Elife. 2016; 5. PMC: 5092044. DOI: 10.7554/eLife.19532. View

Brix L, Hausl A, Toksoz I, Bordes J, van Doeselaar L, Engelhardt C . The co-chaperone FKBP51 modulates HPA axis activity and age-related maladaptation of the stress system in pituitary proopiomelanocortin cells. Psychoneuroendocrinology. 2022; 138:105670. DOI: 10.1016/j.psyneuen.2022.105670. View

Hartmann J, Wagner K, Liebl C, Scharf S, Wang X, Wolf M . The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology. 2011; 62(1):332-9. DOI: 10.1016/j.neuropharm.2011.07.041. View

Zannas A, Wiechmann T, Gassen N, Binder E . Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications. Neuropsychopharmacology. 2015; 41(1):261-74. PMC: 4677131. DOI: 10.1038/npp.2015.235. View

Williams K, Zou Y, Qiu B, Kono T, Guo C, Garcia D . Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways. Cells. 2024; 13(1). PMC: 10778370. DOI: 10.3390/cells13010089. View

Wagner K, Hartmann J, Labermaier C, Hausl A, Zhao G, Harbich D . Homer1/mGluR5 activity moderates vulnerability to chronic social stress. Neuropsychopharmacology. 2014; 40(5):1222-33. PMC: 4367467. DOI: 10.1038/npp.2014.308. View

Malkesman O, Scattoni M, Paredes D, Tragon T, Pearson B, Shaltiel G . The female urine sniffing test: a novel approach for assessing reward-seeking behavior in rodents. Biol Psychiatry. 2009; 67(9):864-71. PMC: 2922846. DOI: 10.1016/j.biopsych.2009.10.018. View

Pereira T, Tabris N, Matsliah A, Turner D, Li J, Ravindranath S . SLEAP: A deep learning system for multi-animal pose tracking. Nat Methods. 2022; 19(4):486-495. PMC: 9007740. DOI: 10.1038/s41592-022-01426-1. View

Deussing J, Chen A . The Corticotropin-Releasing Factor Family: Physiology of the Stress Response. Physiol Rev. 2018; 98(4):2225-2286. DOI: 10.1152/physrev.00042.2017. View

10.

van Doeselaar L, Yang H, Bordes J, Brix L, Engelhardt C, Tang F . Chronic social defeat stress in female mice leads to sex-specific behavioral and neuroendocrine effects. Stress. 2020; 24(2):168-180. DOI: 10.1080/10253890.2020.1864319. View

11.

Matosin N, Halldorsdottir T, Binder E . Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model. Biol Psychiatry. 2018; 83(10):821-830. DOI: 10.1016/j.biopsych.2018.01.021. View

12.

Guilloux J, Seney M, Edgar N, Sibille E . Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. J Neurosci Methods. 2011; 197(1):21-31. PMC: 3086134. DOI: 10.1016/j.jneumeth.2011.01.019. View

13.

Agorastos A, Chrousos G . The neuroendocrinology of stress: the stress-related continuum of chronic disease development. Mol Psychiatry. 2021; 27(1):502-513. DOI: 10.1038/s41380-021-01224-9. View

14.

Golden S, Covington 3rd H, Berton O, Russo S . A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011; 6(8):1183-91. PMC: 3220278. DOI: 10.1038/nprot.2011.361. View

15.

Fries G, Gassen N, Schmidt U, Rein T . The FKBP51-Glucocorticoid Receptor Balance in Stress-Related Mental Disorders. Curr Mol Pharmacol. 2015; 9(2):126-40. DOI: 10.2174/1874467208666150519114435. View

16.

Hausl A, Brix L, Hartmann J, Pohlmann M, Lopez J, Menegaz D . The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. Mol Psychiatry. 2021; 26(7):3060-3076. PMC: 8505251. DOI: 10.1038/s41380-021-01044-x. View

17.

Jones J, Chaturvedi S, Granados-Fuentes D, Herzog E . Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids. Nat Commun. 2021; 12(1):5763. PMC: 8486846. DOI: 10.1038/s41467-021-25959-9. View

18.

Davis M, Holmes S, Pietrzak R, Esterlis I . Neurobiology of Chronic Stress-Related Psychiatric Disorders: Evidence from Molecular Imaging Studies. Chronic Stress (Thousand Oaks). 2018; 1. PMC: 5976254. DOI: 10.1177/2470547017710916. View

19.

Heim C, Bradley B, Mletzko T, Deveau T, Musselman D, Nemeroff C . Effect of Childhood Trauma on Adult Depression and Neuroendocrine Function: Sex-Specific Moderation by CRH Receptor 1 Gene. Front Behav Neurosci. 2010; 3:41. PMC: 2821197. DOI: 10.3389/neuro.08.041.2009. View

20.

Scharf S, Liebl C, Binder E, Schmidt M, Muller M . Expression and regulation of the Fkbp5 gene in the adult mouse brain. PLoS One. 2011; 6(2):e16883. PMC: 3036725. DOI: 10.1371/journal.pone.0016883. View