Identification of stress resilience module by weighted gene co-expression network analysis in Fkbp5-deficient mice

Abstract

FKBP5 encodes the FK506 binding protein 5, a glucocorticoid receptor (GR) binding protein known to play an important role in the physiological stress response. However, results from previous studies examining the association between common variants of FKBP5 and stress have been inconsistent. To investigate whether the loss of FKBP5 affects the stress response, we examined the behavior of mice following the induction of chronic restraint stress between homozygous wild-type and Fkbp5 knock-out mice. After 21 days of exposure to restraint stress, WT mice showed anhedonia, a core symptom of depression, which could be measured by a sucrose preference test. However, Fkbp5-deficient mice did not exhibit significant depressive-like behavior compared to the WT after exposure to chronic restraint stress. To investigate the molecular mechanism underlying stress resilience, we performed RNA sequencing analysis. The differentially expressed gene (DEG) analysis showed that chronic stress induced changes in various biological processes involved in cell-cell adhesion and inflammatory response. Weighted gene co-expression network analysis identified 60 characteristic modules that correlated with stress or the FKBP5 genotype. Among them, M55 showed a gene expression pattern consistent with behavioral changes after stress exposure, and the gene ontology analysis revealed that this was involved in nervous system development, gland morphogenesis, and inflammatory response. These results suggest that FKBP5 may be a crucial factor for the stress response, and that transcriptomic data can provide insight into stress-related pathophysiology.

RNA-seq co-expression network analysis reveals anxiolytic behavior of mice with Efnb2 knockout in parvalbumin+ neurons

“…To identify gene expression profiles associated with fearless and anxiolytic behaviors, we performed a WGCNA to the RNA-seq data [ 19 , 20 ]. In WGCNA, 11,527 genes (Additional file 4 ) of the transcriptome dataset are clustered according to co-expression.…”

Myelination defects in the medial prefrontal cortex of Fkbp5 knockout mice

“…10,40,41 Several rodent studies have examined the roles of Fkbp5 in mediating the stress response by manipulating Fkbp5 expression. [42][43][44][45][46] For example, mice with low or no Fkbp5 expression demonstrated resilience to stress 28,42,44,45 and better stress coping behavior compared to mice with normal expression of Fkbp5. 43,46 In addition, mice with reduced FKBP5 expression in the infralimbic medial prefrontal cortex showed enhanced extinction memory after fear memory consolidation.…”

“…All experiments were approved by the Committee on the Institutional Animal Care and Use of Chung-Ang University (Seoul, Korea). 28 2.2 | RNA extraction and small RNA sequencing (RNA-seq)…”

Regulation of behavioral response to stress by microRNA-690

“…FKBP5 also interacts with Hsp90 to interfere with glucocorticoid receptor-mediated signaling [ 3 , 4 ]. In our previous study, we found that Fkbp5 knock-out (KO) mice exhibited significantly reduced depressive-like behaviors when exposed to stress, and transcriptomic analysis showed a distinct expression module associated with stress resilience in the medial prefrontal cortex (mPFC) [ 5 ]. The mPFC has been considered an important region associated with stress responses because it connects to several brain regions, such as the amygdala and hypothalamus, which regulate neuroendocrine and autonomic functions and mediate circuit-specific effects of stress on neuronal remodeling [ 6 ].…”

“…We hypothesized that miR-690 could mediate the stress response. Therefore, to verify this hypothesis, miR-690 levels of Fkbp5 KO mice were assessed when subjected to restraint stress for 3 weeks [ 5 ]. Restraint stress, a widely used animal model of stress, can alter neurotransmission and gene regulation in the short term and can cause neuronal structure modifications over the long term [ 14 ].…”