Molecular Pathways of Depression
Deciphering the molecular underpinnings of affective disorders remains a major challenge. We aim at translating questions arising from clinical observations into strategies in basic research employing tools from biochemistry, molecular biology and cell biology; we engage in collaborations wherever needed. Currently, we focus on regulatory and regulated molecules (including epigenetics) of the stress hormone axis, and in particular chaperones like FKBP51. Our strategy includes the search for novel pathways of antidepressants as another entry point into disease-relevant molecular networks. The physiological relevance of these molecular pathways is tested in animal models and clinical samples (Fig 3).
Epigenomics of Early-Life Stress
Childhood trauma, maltreatment, but also interpersonal loss, are known causes of early-life stress (ELS) and strong risk factors for depression. Maternal neglect is the most common form of maltreatment, accounting for some 80 % of all cases.
We hypothesize that ELS leaves an enduring trace in the neural cells and circuits that govern behavior and physiology, including the neuroendocrine response to challenging stimuli. Epigenetic processes involving DNA methylation and chromatin structure provide the long sought-after link between environmental stimuli and sustained changes in gene expression, physiology and behavior. Experience-dependent methyl marking of DNA is now recognized as an important contribution to the dynamic regulation of gene transcription that supports synaptic plasticity and long-term behavioral adaptation.
Our aim is to decipher the convergence of pathways and mechanisms responsible for translating early experiences into alterations in brain function through epigenetically altered gene transcription, neurocircuit reorganisation and functional outcome. The project is approached from a top-down (neural circuitry to stress-related epigenomics and phenotypes) and bottom-up scale (genetic variants encoding changes in neuronal connectivity important for the processing of future stressors) to understand the mechanisms through which early trauma and neglect encode future vulnerability or resilience to depression (Fig. 4).