research

Main Projects

GR/FKBP51 function in stress vulnerability/resilience

The main focus of my research is to understand how stress hormone signaling, specifically glucocorticoid signaling, mediates the effects of stressful experiences on physiology and behavior. Glucocorticoid receptor (GR) function and sensitivity is robustly influenced by co-chaperones, such as the FK506-binding protein 51 (FKBP51, encoded by the fkbp5 gene). FKBP51 binds to heat-shock proteins during the maturation of the GR-complex, which leads to a decreased GR-complex affinity for stress hormones. Intriguingly, the expression of FKBP51 is stimulated by glucocorticoids as part of an intracellular ultra-short negative feedback loop for GR activity. Numerous independent studies report an association of fkbp5 polymorphisms with major depressive disorder and bipolar disorder, most specifically in the context of gene by environment interactions.

We have previously established FKBP51 as a key player in stress-related psychopathologies, contributing to stress susceptibility. Having generated conditional FKBP51 KO mouse lines, we now probe the function of this important and clinically validated co-chaperone in a sex-, region- and cell type-specific manner. Main research questions include:

(1) What is the function of FKBP51 in monoaminergic circuits, with a focus on social behavior?

(3) What is the contribution of FKBP51 in the hippocampus to cognitive and emotional behavior?

(4) What is the function of FKBP51 in glia, specifically microglia and astrocytes?

(5) What is the effect of FKBP51 with other steroid receptors?

(A) Schematic overview of the cellular function of FKBP51 as a GR modulator. (B) Mice lacking FKBP51 (FKBP51KO) are resilient to chronic social defeat stress exposure. Wildtype (WT) mice respond to chronic social defeat stress with increased basal corticosterone levels, an effect that is abolished in FKBP51KO mice. (C) Hippocampal FKBP51 mRNA expression following chronic stress strongly correlates with depressive-like behavior in the forced swim test. (D) Specific overexpression of FKBP51 (51OE^BLA) in the basolateral amygdala (BLA) mimics stress-induced anxiety. (E) The first potent and selective FKBP51 antagonist SAFit2 has anxiolytic properties. EPM: elevated plus maze; DaLi: dark-light box. # p<0.05,* p<0.05 . Data are presented with SEM.

Early experiences shaping stress vulnerability/resilience

The interplay between experiences during sensitive developmental periods and the later adult environment seems to be crucial in shaping individual variability in stress coping. We have investigated the acute and long-term consequences of postnatal stress exposure, and could demonstrate in various studies that an adverse early life environment leads to cognitive deficits and behavioral alterations, e.g., in aggression or social behavior. An interesting aspect is whether the long-term effects of early life adversity are universally maladaptive, or if they can be adaptive and pro-resilient under certain environmental conditions. The cumulative stress or multiple hit hypothesis states that the higher the number of stressful events during early life, the greater the vulnerability to stressors later in life. Our research has helped develop the match/mismatch hypothesis of psychiatric disease: Early life environment shapes coping strategies that enable individuals to optimally face similar environments later in life. We showed that animals with mismatched environmental conditions (e.g., only early life stress or only adult stress exposure) behaved differently from animals with matched environments, showing anxious, antisocial and depressive-like behaviors. Currently we address how genetic predisposition in both males and females interacts with both, prenatal and postnatal early life environmental conditions to shape individual physiology and behavior in adulthood. We combine deep behavioral phenotyping using the social box system in combination with telemetric, long-term recordings of physiological parameters as heart rate, blood pressure or sleep EEG, followed-up by RNA sequencing in different brain regions to map sex-specific quantitative trait locus (QTL) networks and combining mouse and human data of gene (co)expression to identify hub genes of stress resilience.

Schematic representation of two extremes in the reaction to early life adversity. The red line represents a condition where the individual has a genetic background that is insensitive to environmental experiences and therefore prone to adverse cumulative effects of stress exposure. Consequently, such an individual would thrive under mild stress conditions and become more and more vulnerable to stress with higher levels of developmental stress exposure. The blue line represents the other extreme, namely an individual that has a high sensitivity to the environment. Such an individual would benefit from moderate stress levels during development and become stress resilient. In contrast, with no meaningful stress exposure during development such an individual will have no chance to adapt its physiology to an adverse environment and will therefore be highly vulnerable to stress in adulthood. Severe early life stress exposure is expected to be harmful under most circumstances, largely independent of the genetic background of an individual.

Stress and metabolism

Chronic stress is a major risk factor for obesity and metabolism-related diseases, highlighting the shared biology between stress and metabolic regulation. Yet the relationship between stress and energy metabolism is highly complex, exemplified by diverging metabolic outcomes in response to stress. Glucocorticoids affect energy intake and expenditure to favor a positive energy balance, whereas β-adrenergic receptors increase energy expenditure via activation of thermogenesis in brown adipose tissue, thus favoring a negative energy balance. Despite clear effects of stress on metabolic outcomes, molecular mediators remain poorly defined. We have uncovered a central role of FKBP51 to orchestrate whole body metabolism by specific actions in the periphery as well as the hypothalamus.

Given the tight interplay and high co-morbidity of mood disorders with metabolic disorders, we plan to intensify our research on this topic. A specific focus will lie on unraveling the precise mechanism of central vs. peripheral FKBP51 actions on metabolism in interaction with stress or dietary challenges, and the development and testing of high-affinity FKBP51 inhibitors for the treatment of obesity-induced diabetes (funded by the recently awarded VIP+ grant, in collaboration with Dr. Felix Hausch).

Proposed model of FKBP51 as a regulator of glucose uptake. FKBP51 scaffolds Akt2, PHLPP1, and AS160. The associations between FKBP51, AKT2, PHLPP1, and AS160 may be either direct or indirect through additional intermediate proteins. In the presence of FKBP51, PHLPP1 phosphatase activity is directed towards AKT2 to favor inactive Akt2, decreased AS160 phosphorylation and reduced glucose uptake. By contrast, loss of FKBP51’s scaffolding function leads to increased AKT2. In the presence of SAFit2, a conformational change within FKBP51 disrupts its ability to form a complex with AS160, while simultaneously enhancing AKT2-AS160 binding. Ultimately, loss of FKBP51 and FKBP51 antagonism with SAFit2 both promote glucose uptake. “?” refers to possible unidentified intermediate proteins within the FKBP51 signaling complex. Curved arrows indicate PHLPP1-mediated dephosphorylation of AKT2 at Ser473. The green double arrow indicates enhanced binding between AKT2 and AS160. Green outlines reflect enhanced phosphorylation; red outlines reflect decreased phosphorylation. The width of the arrows correspond to the magnitude of downstream activation.

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