The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), a main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. Using deletion, overexpression, and rescue of Fkbp5 exclusively in the PVN, we establish the fundamental importance of Fkbp5 in the HPA axis stress response. Furthermore, we show that Fkbp5 manipulation alters GR activation and elucidate the cellular complexity in the PVN, in which Fkbp5 operates.

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The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice

Molecular Psychiatry ◽

10.1038/s41380-021-01044-x ◽

2021 ◽

Author(s):

Alexander S. Häusl ◽

Lea M. Brix ◽

Jakob Hartmann ◽

Max L. Pöhlmann ◽

Juan-Pablo Lopez ◽

...

Keyword(s):

Stress Response ◽

Hpa Axis ◽

Paraventricular Nucleus ◽

Acute Stress ◽

Negative Regulator ◽

Neuron Activity ◽

Cell Type ◽

Specific Expression ◽

Acute Stress Response ◽

Cell Type Specific

AbstractDisturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.

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Linking the hemodynamic consequences of adverse childhood experiences to an altered HPA axis and acute stress response

Brain Behavior and Immunity ◽

10.1016/j.bbi.2020.12.018 ◽

2020 ◽

Author(s):

Kylie S. Dempster ◽

Deborah D. O'Leary ◽

Adam J. MacNeil ◽

Gary J. Hodges ◽

Terrance J. Wade

Keyword(s):

Stress Response ◽

Hpa Axis ◽

Adverse Childhood Experiences ◽

Acute Stress ◽

Childhood Experiences ◽

Adverse Childhood ◽

Acute Stress Response

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Voluntary wheel running initially increases adrenal sensitivity to adrenocorticotrophic hormone, which is attenuated with long-term training

Journal of Applied Physiology ◽

10.1152/japplphysiol.91128.2008 ◽

2009 ◽

Vol 106 (1) ◽

pp. 66-72 ◽

Cited By ~ 43

Author(s):

Jonathan E. Campbell ◽

Nasimeh Rakhshani ◽

Sergiu Fediuc ◽

Silvio Bruni ◽

Michael C. Riddell

Keyword(s):

Stress Response ◽

Hpa Axis ◽

Restraint Stress ◽

Acute Stress ◽

Wheel Running ◽

Male Rats ◽

Voluntary Wheel Running ◽

Acute Stress Response ◽

Voluntary Wheel

Although exercise is a common and potent activator of the hypothalamic-pituitary adrenal (HPA) axis, the effects of exercise on the acute stress response are not well understood. Here, we investigated the effects of short- (2 wk) and long-term (8 wk) voluntary wheel running on adrenal sensitivity to ACTH stimulation and the acute stress response to restraint in male rats. Diurnal glucocorticoid patterns were measured on days 7 (all groups) and 35 (8-wk groups). Rats were subjected to 20 min of restraint stress on either week 1 or on week 7 of treatment to assess HPA activation. One week later, exogenous ACTH (75 ng/kg) was administered to assess adrenal sensitivity to ACTH. Following this, adrenals were collected and analyzed for key proteins involved in corticosterone (CORT) synthesis. By the end of week 1, exercising (E) animals had twofold higher peak diurnal CORT levels compared with sedentary (S) animals ( P < 0.01). CORT values were not different between groups at week 8. In response to restraint stress at week 2, CORT values in E were approximately threefold greater than in S ( P < 0.05). No difference was found between E and S rats in the response to, or recovery from, restraint at week 8. During the ACTH challenge at week 2, E demonstrated a ∼2.5-fold increase in adrenal sensitivity compared with S, while no difference was found between E and S at week 8. The expression of steroidogenic acute regulatory protein was found to be ∼50% higher in the adrenals in E compared with S at week 2 ( P < 0.05), but no difference existed between groups at week 8. These results show that volitional wheel running initially causes hyperactivation of the HPA axis, due to enhanced adrenal sensitivity to ACTH, but that these alterations in HPA activity are completely restored by 8 wk of training.

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The Role of Alcohol Biomarkers in Detecting a Physician's COVID-19-Related Acute Stress Response

Journal of Addiction Medicine ◽

10.1097/adm.0000000000000865 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Alexis G. Polles ◽

William S. Jacobs ◽

Chad Brazle ◽

Lisa J. Merlo

Keyword(s):

Stress Response ◽

Acute Stress ◽

Acute Stress Response

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Recent life stress predicts blunted acute stress response and the role of executive control

Stress ◽

10.1080/10253890.2019.1687684 ◽

2019 ◽

Vol 23 (3) ◽

pp. 359-367

Author(s):

Yuanyuan Xin ◽

Zhuxi Yao ◽

Weiwen Wang ◽

Yuejia Luo ◽

André Aleman ◽

...

Keyword(s):

Stress Response ◽

Executive Control ◽

Life Stress ◽

Acute Stress ◽

Acute Stress Response

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Role of adrenergic mechanisms in regulation of phagocytic cell functions in acute stress response

Immunology Letters ◽

10.1016/s0165-2478(03)00027-0 ◽

2003 ◽

Vol 86 (3) ◽

pp. 229-233 ◽

Cited By ~ 7

Author(s):

Jurii I. Shilov ◽

Ekaterina G. Orlova

Keyword(s):

Stress Response ◽

Acute Stress ◽

Phagocytic Cell ◽

Adrenergic Mechanisms ◽

Cell Functions ◽

Acute Stress Response

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Behavioral coping strategies in a cichlid fish: the role of social status and acute stress response in direct and displaced aggression

Hormones and Behavior ◽

10.1016/j.yhbeh.2004.11.014 ◽

2005 ◽

Vol 47 (3) ◽

pp. 336-342 ◽

Cited By ~ 37

Author(s):

Tricia S. Clement ◽

Victoria Parikh ◽

Mark Schrumpf ◽

Russell D. Fernald

Keyword(s):

Stress Response ◽

Coping Strategies ◽

Social Status ◽

Acute Stress ◽

Cichlid Fish ◽

Displaced Aggression ◽

Acute Stress Response

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Does dehydroepiandrosterone sulfate have a role in COVID-19 prognosis and treatment?

Endocrine Regulations ◽

10.2478/enr-2021-0019 ◽

2021 ◽

Vol 55 (3) ◽

pp. 174-181

Author(s):

Sojit Tomo ◽

Mithu Banerjee ◽

Praveen Sharma ◽

Mahendra Garg

Keyword(s):

Rheumatoid Arthritis ◽

Hpa Axis ◽

Acute Stress ◽

Immunological Response ◽

Dehydroepiandrosterone Sulfate ◽

Inhibitory Effect ◽

Limited Evidence ◽

Inflammatory Conditions ◽

Acute Stress Response

Abstract The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory conditions and modulated immunological response. Limited evidence is available regarding the incidence and the effect of HPA dysfunction in COVID-19. Although the cortisol levels have only been estimated in a few studies, the dehydroepiandrosterone sulfate (DHEAS) release from the adrenal gland has not been explored yet. In this mini review, the authors discuss the role of dehydroepiandrosterone (DHEA) and DHEAS in the acute stress response and immunological modulation. Various effects of DHEAS have been demonstrated in different diseases. The specific inhibitory effect of DHEA on interleukin 6 (IL-6) could be of paramount importance in COVID-19. Further, DHEA supplementation has already been proposed in inflammatory conditions, like rheumatoid arthritis. DHEAS levels in COVID-19 may help to understand the HPA axis dysfunction as well as the possibility of repurposing DHEA as a drug for mitigating the pro-inflammatory COVID-19.

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