FKBP51 in the Oval Bed Nucleus of the Stria Terminalis Regulates Anxiety-Like Behavior

Engelhardt, Clara; Tang, Fiona; Elkhateib, Radwa; Bordes, Joeri; Brix, Lea M.; Doeselaar, Lotte van; Häusl, Alexander S.; Pöhlmann, Max L.; Schraut, Karla; Yang, Huanqing; Chen, Alon; Deussing, Jan M.; Schmidt, Mathias

doi:10.1523/eneuro.0425-21.2021

Cited by 12 publications

(14 citation statements)

References 79 publications

(112 reference statements)

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“…This suggests that no tolerance develops to the pharmacological effect. Overall, our data supports the importance of FKBP51 inhibition for anxiety-like behaviors and also challenges new evidence on the role of FKBP51 in anxiety regulation [50].…”

Section: Discussionsupporting

confidence: 76%

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

et al. 2022

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Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

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Section: Discussionsupporting

confidence: 76%

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

et al. 2022

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“…This may explain why levels of Fkbp5 after acute stress return to homeostatic levels sooner in females than males ( Bourke et al, 2013 ). It is likely that increased chromatin accessibility of Fkbp5 in double-hit males is the result of a latent impact of the first hit of stress, and could itself confer protection against anxiety-like phenotypes, consistent with findings showing that overexpression of Fkbp5 in discrete brain regions induces anxiolytic phenotypes ( Engelhardt et al, 2021 ). Chromatin accessibility of Zbtb16 was also different in males and females, with double-hit stress inducing significant chromatin remodeling in males but not in females.…”

Section: Discussionsupporting

confidence: 84%

An allostatic epigenetic memory on chromatin footprints after double-hit acute stress

Caradonna

Paul

Marrocco

2022

Neurobiology of Stress

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“…Despite our findings that activation of Corticotropin-Releasing Factor (CRF)-expressing neurons contained within the oval nucleus of the Bed Nucleus of the Stria Terminalis (BNSTov) produces pro-resilient behavioral responses, several studies have reported that this activation induces negative emotional states. [3][4][5][6][7][8] Previously, we show that BNSTov CRF activation had a pro-social effect only after cumulative stress exposure 1 , suggesting a role for BNSTov CRF neurons in potentially promoting cooperative sociality under stressful conditions. This adaptive function confers an evolutionary advantage.…”

Section: Resultsmentioning

confidence: 82%

CRF neurons of the BNST promote resilience by blunting the internal experience of aversion

Haynes

Mayberg

Young

et al. 2022

Preprint

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The Bed Nucleus of the Stria Terminalis (BNST) has been studied extensively for its role in coordinating what appears to be often opposing adaptive behaviors. However, what is missing in the literature is the link between internal affective states and the adaptive stress behaviors they motivate. Previously, we uncovered a stress window during which neuronal activity of Corticotropin-Releasing Factor (CRF) expressing neurons of the oval nucleus of the BNST, (BNSTovCRF) maintains resilient behavior through self-sustained activation1. Here, we explore how BNSTovCRF neurons achieve this through shifting the valence of stress contexts to represent a less aversive experience. Using cell-type-selective optogenetics and transgenic Crf-ChR2 mice, we show that BNSTovCRF induces resiliency through dampening the deleterious effects of social defeat encoding, enhancing the positive salience of both appetitive and aversive stimuli, shifting socio-affective bias, and promoting tolerability of non-social physical stress. Adaptive responses to stress typically emanate as a response to negative internal states by external stimuli; here we show that in resilient mice, stressful environments are less aversive than susceptible mice, suggesting a different motivational capacity to endure stress in this group. Thus, we describe a novel role for BNSTovCRF neurons in resisting the emotional effects of cumulative stress by reducing the internal experience of aversion.

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FKBP51 in the Oval Bed Nucleus of the Stria Terminalis Regulates Anxiety-Like Behavior

Cited by 12 publications

References 79 publications

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

An allostatic epigenetic memory on chromatin footprints after double-hit acute stress

CRF neurons of the BNST promote resilience by blunting the internal experience of aversion

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