Expression and Regulation of the Fkbp5 Gene in the Adult Mouse Brain

Scharf, Sebastian H.; Liebl, C.; Binder, Elisabeth B.; Schmidt, Mathias V.; Müller, Marianne B.

doi:10.1371/journal.pone.0016883

Cited by 181 publications

(134 citation statements)

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“…Likewise, in aged adult offspring, there was an upregulation of Fkbp5 gene expression in the PVN and ARC nuclei following CSDS on account of exposure to maternal obesity. Previous rodent studies have nicely illustrated that Fkbp5 expression is increased in select brain regions on account of both acute and chronic stress exposure [48,49]. The parallel effects of stress exposure and maternal dietary condition on Fkbp5 gene expression may contribute to the paralleled effects of CSDS and maternal diet on stress coping and anxiety-like behaviors reported here.…”

Section: Discussionsupporting

confidence: 64%

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice

et al. 2015

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Background: There is growing evidence that maternal obesity and prenatal exposure to a high-fat diet program fetal development to regulate the physiology and behavior of the offspring in adulthood. Yet the extent to which the maternal dietary environment contributes to adult disease vulnerability remains unclear. In the current study we tested whether prenatal exposure to maternal obesity increases the offspring's vulnerability to stress-related psychiatric disorders. Methods: We used a mouse model of maternal diet-induced obesity to investigate whether maternal obesity affects the response to adult chronic stress exposure in young adult (3-month-old) and aged adult (12-month-old) offspring. Results: Long-lasting, delayed impairments to anxiety-like behaviors and stress coping strategies resulted on account of prenatal exposure to maternal obesity. Although maternal obesity did not change the offspring's behavioral response to chronic stress per se, we demonstrate that the behavioral outcomes induced by prenatal exposure to maternal obesity parallel the deleterious effects of adult chronic stress exposure in aged male mice. We found that the glucocorticoid receptor (GR, Nr3c1) is upregulated in various hypothalamic nuclei on account of maternal obesity. In addition, gene expression of a known regulator of the GR, FKBP51, is increased specifically within the paraventricular nucleus. Conclusions: These findings indicate that maternal obesity parallels the deleterious effects of adult chronic stress exposure, and furthermore identifies GR/FKBP51 signaling as a novel candidate pathway regulated by maternal obesity.

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Section: Discussionsupporting

confidence: 64%

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice

et al. 2015

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“…13 Animal models have revealed the importance of placental expression of genes regulating serotonin response on fetal brain development, as the placenta acts as a transient source of serotonin during development. 44 Several other genes for which placental methylation has been associated with infant health are also expressed in the brain, such as HTR2A, 45 NR3C1, 46 FKBP5, 47 and LEP. 48 Epigenetic regulation by the placenta may influence these important neuropeptides that direct the development and function of the fetal brain.…”

Section: Discussionmentioning

confidence: 99%

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

et al. 2016

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(2016) Regions of variable DNA methylation in human placenta associated with newborn neurobehavior, Epigenetics, 11:8, 603-613, DOI: 10.1080/15592294.2016 ABSTRACTThe placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 £ 10 ¡7 ) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are overrepresented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.

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“…It is noteworthy that in our study, the effect of acute stress on WT animals differs between the PFC and the HC, with preservation of FKBP5 levels in the HC, suggesting the need for the inhibitory presence of FKBP5 in this critical brain region, and eluding to the notion that subcellular manipulation of the HPA axis in the CNS can be achieved in a region-specific manner. Indeed, in the hippocampus of mice, FKBP5 expression remains stable following restraint stress but expression is increased after other various forms of acute stress (Scharf, Liebl et al 2011). These results highlight the importance of FKBP5 in intracellular glucocorticoid signaling and the interaction of GR co-chaperones with HIV, in accordance to previous studies demonstrating differences in FKBP5 expression in HIV-infected humans (Tatro, Everall et al 2009; Tatro, Nguyen et al 2010).…”

Section: ) Discussionmentioning

confidence: 99%

HIV-1 proteins accelerate HPA axis habituation in female rats

Panagiotakopoulos

Kelly

Neigh

2015

Physiology & Behavior

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Congenital infection by the Human Immunodeficiency Virus (HIV) has been shown to lead to multiple co-morbidities, and people living with HIV have a higher incidence of affective and anxiety disorders. A marked increase in mood disorders is evident during the sensitive phase of adolescence and this is further pronounced in females. Depression has been linked to dysfunction of the intracellular response system to corticosteroids at the level of the hippocampus (HC) and prefrontal cortex (PFC) with a notable role of the glucocorticoid receptor (GR) and its co-chaperones (FKBP5 and FKBP4). The current study examined the extent to which HIV protein expression in adolescent female rats altered the stress response at both the level of corticosterone output and molecular regulation of the glucocorticoid receptor in the brain. WT and HIV-1 genotype female rats were randomly allocated in control, acute stress and repeat stress groups. Corticosterone plasma levels and expression of GR, FKBP4, and FKBP5 in the HC and PFC were measured. The presence of HIV-1 proteins facilitate habituation of the corticosterone response to repeated stressors, such that HIV-1 TG rats habituated to repeated restraint and WT rats did not. This was reflected by interactions between stress exposure and HIV-1 protein expression at the level of GR co-chaperones. Although expression of the GR was similarly reduced after acute and repeat stress in both genotypes, expression of FKBP5 and FKBP4 was altered in a brain-region specific manner depending on the duration of the stress exposure and the presence or absence of HIV-1 proteins. Collectively, the data presented demonstrate that HIV-1 proteins accelerate habituation to repeated stressors and modify the influence of acute and repeat stressors on GR co-chaperones in a brain region-specific manner.

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Expression and Regulation of the Fkbp5 Gene in the Adult Mouse Brain

Cited by 181 publications

References 46 publications

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

HIV-1 proteins accelerate HPA axis habituation in female rats

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