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

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.

Download Full-text

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

10.1101/824664 ◽

2019 ◽

Author(s):

Alexander S. Häusl ◽

Jakob Hartmann ◽

Max L. Pöhlmann ◽

Lea M. Brix ◽

Juan-Pablo Lopez ◽

...

Keyword(s):

Stress Response ◽

Hpa Axis ◽

Paraventricular Nucleus ◽

Acute Stress ◽

Negative Regulator ◽

Immune Disorders ◽

Fk506 Binding Protein ◽

Main Driver ◽

Acute Stress Response

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.

Download Full-text

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

Download Full-text

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.

Download Full-text

The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response

BMC Cell Biology ◽

10.1186/1471-2121-9-37 ◽

2008 ◽

Vol 9 (1) ◽

Cited By ~ 195

Author(s):

Mattias K Andersson ◽

Anders Ståhlberg ◽

Yvonne Arvidsson ◽

Anita Olofsson ◽

Henrik Semb ◽

...

Keyword(s):

Stress Response ◽

Expression Patterns ◽

Cell Spreading ◽

Cell Type ◽

Specific Expression ◽

Cell Type Specific Expression ◽

Cell Type Specific

Download Full-text

Decreased levels of RGS4 in the paraventricular nucleus facilitate GABAergic inhibition during the acute stress response

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2016.02.108 ◽

2016 ◽

Vol 472 (1) ◽

pp. 276-280 ◽

Cited By ~ 3

Author(s):

Soonwoong Jung ◽

Hyeonwi Son ◽

Dong Hoon Lee ◽

Gu Seob Roh ◽

Sang Soo Kang ◽

...

Keyword(s):

Stress Response ◽

Paraventricular Nucleus ◽

Acute Stress ◽

Gabaergic Inhibition ◽

Acute Stress Response

Download Full-text

Regulatory role of the G alpha 1 subunit in controlling cellular morphogenesis in Dictyostelium

Development ◽

10.1242/dev.120.12.3549 ◽

1994 ◽

Vol 120 (12) ◽

pp. 3549-3561 ◽

Cited By ~ 2

Author(s):

S. Dharmawardhane ◽

A.B. Cubitt ◽

A.M. Clark ◽

R.A. Firtel

Keyword(s):

Negative Regulator ◽

Specific Gene ◽

Wild Type ◽

Cell Type ◽

Lacz Reporter ◽

Specific Expression ◽

Multicellular Development ◽

Cell Type Specific Expression ◽

Cell Type Specific ◽

Constitutively Active

To determine the function of the Dictyostelium G alpha 1 subunit during aggregation and multicellular development, we analyzed the phenotypes of g alpha 1 null cells and strains overexpressing either wild-type G alpha 1 or two putative constitutively active mutations of G alpha 1. Strains overexpressing the wild-type or mutant G alpha 1 proteins showed very abnormal culmination with an aberrant stalk differentiation. The similarity of the phenotypes between G alpha 1 overexpression and expression of a putative constitutively active G alpha 1 subunit suggests that these phenotypes are due to increased G alpha 1 activity rather than resulting from a non-specific interference of other pathways. In contrast, g alpha 1 null strains showed normal morphogenesis except that the stalks were thinner and longer than those of wild-type culminants. Analysis of cell-type-specific gene expression using lacZ reporter constructs indicated that strains overexpressing G alpha 1 show a loss of ecmB expression in the central core of anterior prestalk AB cells. However, expression of ecmB in anterior-like cells and the expression of prestalk A-specific gene ecmA and the prespore-specific gene SP60/cotC appeared normal. Using a G alpha 1/lacZ reporter construct, we show that G alpha 1 expression is cell-type-specific during the multicellular stages, with a pattern of expression similar to ecmB, being preferentially expressed in the anterior prestalk AB cells and anterior-like cells. The developmental and molecular phenotypes of G alpha 1 overexpression and the cell-type-specific expression of G alpha 1 suggest that G alpha 1-mediated signaling pathways play an essential role in regulating multicellular development by controlling prestalk morphogenesis, possibly by acting as a negative regulator of prestalk AB cell differentiation. During the aggregation phase of development, g alpha 1 null cells display a delayed peak in cAMP-stimulated accumulation of cGMP compared to wild-type cells, while G alpha 1 overexpressors and dominant activating mutants show parallel kinetics of activation but decreased levels of cGMP accumulation compared to that seen in wild-type cells. These data suggest that G alpha 1 plays a role in the regulation of the activation and/or adaptation of the guanylyl cyclase pathway. In contrast, the activation of adenylyl cyclase, another pathway activated by cAMP stimulation, was unaffected in g alpha 1 null cells and cell lines overexpressing wild-type G alpha 1 or the G alpha 1 (Q206L) putative dominant activating mutation.(ABSTRACT TRUNCATED AT 400 WORDS)

Download Full-text