Author
L. Brix
Bio: L. Brix is an academic researcher from Max Planck Society. The author has contributed to research in topics: Biology & Medicine. The author has an hindex of 3, co-authored 7 publications receiving 15 citations.
Topics: Biology, Medicine, Hypothalamus, Glutamatergic, Glucocorticoid receptor
Papers
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TL;DR: In this article, a single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity.
Abstract: 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), 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.
32 citations
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TL;DR: There are differences in the way that female and male mice respond towards chronic social stress conditions when it comes to behavior and hormonal changes, which are partially dependent on estrous cycle stage.
Abstract: Over the years, it has become increasingly clear that males and females respond differently towards environmental stressors, highlighting the importance of including both sexes when studying the ef...
22 citations
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TL;DR: In this article , a combination of endogenous knockout and viral rescue was used to show that male mice lacking FKBP51 in Pomc-expressing cells exhibit enhanced glucocorticoid (GC)-mediated negative feedback and are protected from age-related disruption of their diurnal corticosterone (CORT) rhythm.
8 citations
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TL;DR: In this article, the FK506-binding protein 51 (FKBP51) is identified as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WipI3, thereby regulating the balance between autophagy and mTOR signaling.
Abstract: The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD) induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.
7 citations
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TL;DR: The fundamental importance of F kbp5 in the HPA axis stress response is established and it is shown that Fkbp5 manipulation alters GR activation and elucidate the cellular complexity in the PVN, in which FKBp5 operates.
Abstract: 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.
5 citations
Cited by
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TL;DR: There are two kinds of tutorial articles: those that provide a primer on an established topic and those that let us in on the ground floor of something of emerging importance.
Abstract: There are two kinds of tutorial articles: those that provide a primer on an established topic and those that let us in on the ground floor of something of emerging importance. The first type of tutorial can have a noted expert who has been gracious (and brave) enough to write a field guide about a particular topic. The other sort of tutorial typically involves researchers who have each been laboring on a topic for some years. Both sorts of tutorial articles are very much desired. But we, as an editorial board for both Systems and Transactions, know that there has been no logical place for them in the AESS until this series was started several years ago. With these tutorials, we hope to continue to give them a home, a welcome, and provide a service to our membership. We do not intend to publish tutorials on a regular basis, but we hope to deliver them once or twice per year. We need and welcome good, useful tutorial articles (both kinds) in relevant AESS areas. If you, the reader, can offer a topic of interest and an author to write about it, please contact us. Self-nominations are welcome, and even more ideal is a suggestion of an article that the editor(s) can solicit. All articles will be reviewed in detail. Criteria on which they will be judged include their clarity of presentation, relevance, and likely audience, and, of course, their correctness and scientific merit. As to the mathematical level, the articles in this issue are a good guide: in each case the author has striven to explain complicated topics in simple-well, tutorial-terms. There should be no (or very little) novel material: the home for archival science is the Transactions Magazine, and submissions that need to be properly peer reviewed would be rerouted there. Likewise, articles that are interesting and descriptive, but lack significant tutorial content, ought more properly be submitted to the Systems Magazine.
955 citations
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TL;DR: In this paper, the authors show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning mineralocorticoid receptor (MR) balance in the hippocampus.
27 citations
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TL;DR: In this article, a review summarizes the findings and analyses their methodology and proposes adherence to the Research Domain Criteria and the STRANGE framework to minimize experimental bias and increase data purview.
Abstract: Depression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework.
16 citations
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TL;DR: In this article, the role of Shati/Nat8l in stress sensitivity in mice was investigated and it was found that Shati and N8l levels in the dorsal striatum were increased in stress-susceptible mice but not in resilient mice exposed to repeated social defeat stress (RSDS).
13 citations
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TL;DR: In this article, the molecular mechanisms of glucocortin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience were discussed, and a review of these mechanisms was presented.
Abstract: This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the hypothalamus plays a central role in regulating the stress response. CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates glucocorticoid secretion from the adrenal glands. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The activated hypothalamic-pituitary-adrenal axis is suppressed by the negative feedback from glucocorticoids. Glucocorticoid-dependent repression of cAMP-stimulated Crf promoter activity is mediated by both the negative glucocorticoid response element and the serum response element. Conversely, the inducible cAMP-early repressor can suppress the stress response via inhibition of the cAMP-dependent Crf gene, as can the suppressor of cytokine signaling-3 in the hypothalamus. CRF receptor type 1 is mainly involved in a stress response, depression, anorexia, and seizure, while CRF receptor type 2 mediates “stress coping” mechanisms such as anxiolysis in the brain. Differential effects of FK506-binding immunophilins, FKBP4 and FKBP5, contribute to the efficiency of glucocorticoids under stress resilience. Together, a variety of factors contribute to stress resilience. All these factors would have the differential roles under stress resilience.
12 citations