Impact of Fkbp5 × early life adversity × sex in humanised mice on multidimensional stress responses and circadian rhythmicity

Abstract

The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioural and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition, and sex. In humanised females carrying the CG- but not the AT-allele, ELA led to altered HPA axis functioning, exploratory behaviour, and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.

Fkbp5-humanized mice shed light on female higher vulnerability to stress

“…This fact prompted Nold and colleagues to develop Fkbp5-humanized C57BL/6 mouse lines carrying either the AT or CG allele to study the causal relationship and mechanistic impact of the human FKBP5 SNPs on stress physiology and the development of stress-related behavioral disorders. After confirming previously that in these mice the AT allele leads to increased expression of Fkbp5 in brain cells upon stimulation by GR 5 , here 3 the authors exposed mice of the two lines and of both sexes to maternal separation as an early life adversity (ELA) model to analyze the interaction of Fkbp5 genotype x ELA x sex on HPA functioning, stress-related behaviors and gene expression profiling in stress-related brain regions. Gene expression was qualitatively validated in human induced pluripotent stem cells (hiPSCs) from AT or CG carriers that had been differentiated in neurons and astrocytes.…”

“…For the last twenty years, we have known that vulnerability or resilience to early life stress is modulated by genetics; individuals carrying certain alleles of certain genes are more or less likely to present stress-associated pathologies than others 1,2 . In a new study, Nold and colleagues 3 used humanized mice to investigate the effects of genetic and environmental factors on stress responses. Such a stress vulnerability/resilience gene is the one encoding FK506-binding protein 51 (FKBP5).…”

Single nuclei transcriptomics in human and non-human primate striatum implicates neuronal DNA damage and proinflammatory signaling in opioid use disorder

“…We identified the FK506 binding protein 5, FKBP5 , as a potential factor in the role of sex in opioid use. In the brain, FKBP5 121, 122 is likely a key factor involved in stress and opioids in females 123 . FKBP5 was significantly upregulated in astrocytes, oligodendrocytes, and oligodendrocyte precursor cells of female OUD subjects (Figure 6C; log2FC F glia >1.30, FDR F glia < 0.0165, log2FC M = - 1.62, FDR M interneurons < 0.040).…”

“…We also identified the FK506 binding protein 5, FKBP5, as a potential factor in the role of sex in opioid use. FKBP5 97,98 in the brain has been proposed as a key factor mediating the relationship between sex and OUD 99 .…”

Neurobiological mechanisms of mood disorders: Stress vulnerability and resilience

“…A study with rats that experienced adversity in the first stages of life in an induced way showed the presence of both A/T and G/C alleles, and demonstrated the effect of the polymorphisms on their behavior. In addition to exhibiting decreased activity and reduced ability to adapt to their environment, mice expressing the A/T allele showed increased expression of genes related to cellular respiration, indicating a need for more energy ( Nold et al, 2022 ).…”