Research Reports

The neuropeptide corticotropin-releasing hormone (CRH) is a central regulator of the stress response. Alterations in the CRH system have repeatedly been observed in depressed patients. Our group at the Max Planck Institute of Psychiatry identified CRH-related circuits shaping anxiety, arousal and locomotion. The detailed comprehension of CRH-dependent neural circuits is a prerequisite to establish the CRH system as a potential alternative therapeutic target beyond classical antidepressants.

The World Health Organization estimates that around 300 million people worldwide are affected by depression. Affective disorders represent one of the most significant causes for the loss of healthy life years and result in a reduced life expectancy compared to the general population. Psychotropic drugs approved for the treatment of depression do not result in disease improvement or even remission in all affected patients. The identification of specific biomarkers that provide each patient with the optimal drug would be an important milestone in personalized psychiatric medicine.

Stress-induced diseases are among the most common health problems worldwide and include both mental disorders such as depression and physical conditions such as diabetes. These diseases are causally related to each other and the mechanisms of stress regulation could be a common cause of both physical and mental disorders. We have identified a central mechanism that is decisively involved in the development of stress-induced diseases and represents a novel treatment option.

Stress can affect gene expression through epigenetic mechanisms such as DNA-methylation. New research suggests a similar regulation at the level of messenger molecules (mRNA) which are responsible for the transmission of genetic information. The most common mRNA modification N6-methyladenosine (m6A) is regulated by stress in the brain and shows a changed signature in the blood of patients suffering from depression. Future research investigating the involvement of m6A in the stress response can provide a better understanding of the origin of stress-related psychiatric disorders.

Psychiatric diseases represent one of the major public health burdens in western societies. The scientists at the Max-Planck Institute of Psychiatry are developing a new system medicine approach in order to address these challenges. In this approach, pluripotent stem cell based personalized disease models are used to generate various human brain cells in the laboratory. By combining these models with sophisticated computational analysis strategies, the scientists aim at decoding the patient specific molecular genetic basis of these diseases.

Malformations of the cerebral cortex are often associated with intellectual disability and epilepsy. These disorders arise in the course of cortical development as a consequence of disturbance of neuronal development, migration and connection. In order to develop therapeutic strategies, it is essential to understand the genetic causes and to investigate the molecular and cellular mechanisms underlying these malformations. The MPI research group uses cerebral organoids derived from induced stem cells for this purpose.

Psychiatric disorders can affect our ability to successfully and enjoyably interact with others. The neural mechanisms of social interaction and transdiagnostic social impairments are only now beginning to be studied thanks to methodological developments. In the future, interaction-based functional neuroimaging, used by scientists at the MPI of Psychiatry, may help in the selection and refinement of treatment options for psychiatric disorders.

MicroRNAs regulate the activity of genes in our cells. Thus, in nerve cells of the brain, they influence our behavior or our reaction to the environment – two processes that are disturbed in psychiatric diseases. Now microRNAs have been discovered, which for instance act as our body’s own antidepressant or allow an adequate reaction to stressful situations. Better understanding of the role of microRNAs in psychiatric disorders will help to develop new diagnostics or treatment approaches.

Childhood maltreatment not only harms mind and body but leaves long-lasting modifications on genes. Patients suffering from posttraumatic stress disorder who have or have not experienced childhood maltreatment, displayed distinct epigenetic profiles in immune cells. Thus identical psychiatric diagnosis can be accompanied by distinct biological signatures and possibly differential response to treatment. This highlights the importance of the patient’s individual biography in defining disease subtypes.

Depression is a complex psychiatric disorder that is thought to develop due to a combination of genetic risk factors with exposure to aversive environments. FKBP5, a co-chaperone of stress hormone receptors, seems to be a key mediator of depression, as polymorphisms in the gene encoding FKBP5 can increase the likelihood to develop this disease. By investigating the molecular, structural, physiological and behavioral function of FKBP5 we can support the central role of this co-chaperone in stress and depression, and pave the way for the development of novel antidepressant treatment strategies.

An impaired stress-hormone regulation plays an important role for the development of depression. Genetic variations in the FKBP5 gene expressing a modulator of the stress hormone axis contribute in interaction with environmental stress factors to increased depression susceptibility. Successful antidepressant treatment is closely related to the recovery of the stress hormone regulation, which in turn is modulated by FKBP5 activity. Thus, FKBP5 is a promising target for future antidepressant drugs, which should be particularly effective in patients with impaired stress-hormone regulation.

Behaviour and emotions result from the electrical activity of neuronal networks in the brain. Disturbances of this activity of brain circuits will thus play a causal role in the pathogenesis and pathology of psychiatric disorders. The exploration of such dysfunctions in the electrical activity will expedite the development of more effective treatments of these disorders. A modern imaging approach is now used to visualize changes in the propagation of electrical nerve cell activity through brain circuits.

Early-life stress causes attachment of elementary chemical markings – so-called methyl groups – to our genetic material, resulting in persistent alteration of the activity of genes. This discovery was possible by help of mice which were separated from their mothers shortly after birth and, as a consequence of this, showed elevated stress hormones and reduced stress tolerance all their life. In case of corresponding disposition both are precursors to major depression.

The FK506-binding protein 51 (FKBP51) regulates the signal transduction of steroid hormone receptors and is genetically associated with a variety of affective disorders. Two key steps for a better understanding of this protein in mammalian behaviour are the characterization of transgenic mice and the development of specific inhibitors. The latter further have the potential to study the role of FKBP51 in clinical studies.

The restless legs syndrome (RLS) is a common neurological disorder. Since the first description a large genetic contribution in the aetiology was suspected. For the first time genetic risk variants for RLS have been identified performing a genome wide association study by genotyping 500 000 common genetic variants. More than 1600 patients with RLS and 2600 controls of the general population have participated in this study. The identified genes MEIS1, BTBD9, and LBXCOR1 are know as control factors in embryonic development. Their role in the adult brain is still unknown.

Multiple Sclerosis (MS) is a heterogenous, chronic inflammatory, demyelinating disease of the central nervous system (CNS). Despite of many research efforts the cause of MS is unknown. Today new techniques allow the investigation of nearly the whole genome, transcriptome and proteome. The Max-Planck-Institute of Psychiatry uses these techniques to explore the pathogenesis of MS and to open the possibility for an individualized therapy.

Modern high-throughput and ultra high-throughput genetic approaches allow the identification of predictors of individual response to treatment with anti-depressants. The herein drafted studies exemplify that large cohorts of well phenotyped individuals are vital to the success of genetic analyses.

Functional neuroimaging techniques provide an excellent opportunity to investigate dynamic aspects of information processing during sleep in humans. At the Max Planck Institute of Psychiatry, a method for simultaneous recordings of the electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) during sleep has been established. Subject to the respective sleep stage, acoustic stimuli led to different regional activation or deactivation patterns in cortical and subcortical brain regions, allowing conclusions on stimuli processing during sleep. Future studies and further developments of this technique will lead to a substantial progress regarding the functional neuroanatomy of sleep and the effects of sleep deprivation and psychopharmacological drugs on cognitive functioning.

Over the past years the approach to understand complex cellular mechanisms in the life and medical sciences has shifted from a hypothesis-driven to a discovery-driven science. Instead of focussing on a selected number of genes or proteins the discovery-driven approach seeks a comprehensive analysis and global description of cellular mechanisms. The trend to a discovery-driven science has also occurred at the Max Planck Institute of Psychiatry where basic and clinical scientists are trying to understand the pathogenic mechanisms of affective and neurological disorders. Proteomics, the comprehensive analysis of the protein complement of the genome of an organism, represents such a global bioanalytical effort that has been established at the institute. Our efforts using proteomics to gain a better understanding and to search for targets for depression, anxiety and multiple sclerosis are described.