Funding & Studies

Our research is largely supported by third-party funding. We are grateful for the ongoing and closed support provided by the German Research Foundation (DFG), the Federal Ministry for Research, Technology and Space (BMFTR), the Volkswagen Foundation, the Stiftung Charité, and the Max Planck Society. Many of our projects involve conducting human studies. We primarily investigate how autophagy-inducing interventions such as exercise, diets, or dietary supplements affect mental health. Based on our findings, we aim to develop guidelines for simple and effective applications in the prevention and treatment of mental health disorders.

Ongoing Funding

Role of astrocyte mitochondrial metabolism in chronic stress

DFG, Project no. 533208662

with Mathias V. Schmidt and Michał Ślęzak

Major Depression (MDD) is among the leading causes of disease-related disability worldwide. Current treatment approaches are often ineffective and rely on a trial-and-error principle, with only about half of patients responding to initial therapy. To develop new therapeutic strategies, a deeper understanding of the neurobiological foundations of psychiatric disorders is essential. Our research demonstrates that glucocorticoid receptor (GR)-dependent signaling pathways mediate key effects of chronic stress—including alterations in cellular metabolism, mitochondrial function, and autophagy. Particularly relevant is the chaperone FKBP51, which acts as a modulator of GR function in astrocytes. These cells are located at the interface between blood vessels and brain tissue and play a crucial role in mediating communication between systemic signals and neuronal activity. We hypothesize that chronic stress impairs the metabolic performance of astrocytes via disrupted GR signaling, thereby altering neural circuits that regulate behavior. This may be especially relevant for women, who are more frequently affected by depression and metabolic disturbances. In an interdisciplinary project, three research teams from Wrocław, Bonn, and Munich are investigating the contribution of astrocyte-specific metabolic pathways to depression-like phenotypes. Using genetic manipulations in the prefrontal cortex of female mice, we analyze the effects on social behavior, metabolite profiles, mitochondrial parameters, autophagy, and neurotransmitter levels. The goal is to develop new approaches for treating stress-related disorders by specifically reversing stress-induced signaling disruptions.

Profiling the glucocorticoid receptor activation during SARS-CoV-2 infection

DFG, Project no. 535619751

with Marcel A. Müller

COVID-19 remains a global health threat, particularly for individuals with limited access to vaccines or antiviral medications. While glucocorticoids (GCs) such as dexamethasone have been successfully used to treat severe cases, their use in mild cases may be counterproductive. The precise molecular mechanisms by which GCs influence SARS-CoV-2 replication and virus-host interactions are still poorly understood. Initial studies suggest that SARS-CoV-2 manipulates the GC-activated glucocorticoid receptor (GR) signaling pathway and alters the cell’s immunometabolism to promote viral replication. This project investigates the GR signaling pathway as a therapeutic target for novel drugs with combined antiviral and anti-inflammatory effects. The aim is to analyze the activation dynamics of GR during SARS-CoV-2 infection in cell culture models, identify key host proteins involved in immunometabolic signaling pathways, and validate their function through genetic manipulation. In addition, GR-based treatment strategies will be tested in cell cultures and patient-derived organoids. The findings are expected to contribute to the development of personalized therapies that remain effective against future viral variants or newly emerging pathogens.

Modulation of Autophagy via Camelid Nanobodies Targeting Transmembranous Atg9a to Selectively Shape Stress Resilience

DFG, Project no. 542802080

with Mathias V. Schmidt

Mental disorders are widespread and pose a significant burden on individuals and society. Existing therapies are often ineffective and rely on a trial-and-error approach. To date, there is no biologically grounded strategy for the preventive enhancement of individual stress resilience. Autophagy—a cellular recycling process essential for maintaining homeostasis—is increasingly gaining attention in research on stress-related disorders. Genome-wide studies have shown that dysregulation of autophagy-related signaling pathways is associated with psychiatric conditions. However, a systematic analysis of autophagy’s role in stress and the development of targeted intervention strategies is still lacking. This project investigates the hypothesis that activation of autophagy via the transmembrane protein Atg9a improves neuroplasticity and stress coping. To this end, a multimodal toolbox using Atg9a knockouts and overexpression in cell and mouse models is being established to analyze the effects on autophagy, neurometabolism, and neuronal function. In addition, newly developed, highly selective Atg9a nanobodies (Atg9a-Nbs) will be used to specifically activate autophagy and examine its impact on stress resilience. The research groups led by PI Gassen and PI Schmidt combine their expertise in molecular biology, physiology, and behavioral science. The goal is to develop innovative, biologically based treatment strategies for stress-associated mental disorders.

Disease-predisposing or resilience-promoting? Decoding the systems biology and behavioural predictors and determinants of the tipping point of stress (PROGRESS)

DFG, Project no. 544161359

with Marianne B. Müller (Coordination), Johannes Bohacek, Iiris Hovatta, Igor Jurisica, Helena Sork

The concept of tipping points is currently receiving increased attention in the context of climate change: abrupt transitions often result from the accumulation of smaller processes that push a system beyond a critical threshold. In stress research, however, this concept has largely been overlooked, and the precise determinants that decide whether stress has positive or negative effects remain unknown. The PROGRESS project aims to close this gap by investigating the dynamics of stress-related tipping points. Using non-invasive longitudinal and single-subject monitoring, the project seeks to map the temporal progression and dynamics of events associated with social stress, including detailed behavioral and molecular changes, alterations in brain connectivity, and cardiovascular function. A central goal is to identify and validate predictive signatures of stress resilience and vulnerability in both mouse models and humans. Furthermore, the project tests the hypothesis that actively promoting resilience can shift the tipping point, potentially preventing the onset of stress-related disorders. To achieve these objectives, the research team draws on well-characterized human cohorts focused on resilience and depression, and employs translationally valid animal models alongside innovative methods for longitudinal, cross-scale phenotype analysis. The successful completion of PROGRESS will enable early prediction of tipping points and allow for personalized risk stratification. Ultimately, the findings are expected to contribute to transforming modern psychiatry into a science of prevention.

Long-term analysis of stress-induced behavioral dynamics: EVs as biomarkers

DFG, Project no. 562802756

with Mathias V. Schmidt

Chronic stress can trigger maladaptive changes in behavior and disrupt bodily homeostasis, contributing to the development of psychiatric disorders such as depression and anxiety. Existing animal models used in stress research are often short-term, artificial, and lack translational relevance. This project introduces an innovative home-cage stress model with a chronic stress reminder that accounts for the animals’ active and inactive phases and is continuously analyzed over 48 hours using deep learning algorithms (DeepLabCut, DeepOF). The goal is to capture the true dynamics of stress-induced behavioral changes. The focus lies on extracellular vesicles (EVs), whose synthesis, cargo loading, release, and uptake may serve as potential biomarkers for central stress-related processes. To assess translational relevance, EVs from the plasma of healthy human participants are proteomically analyzed before and after exposure to a bungee jump stressor. A key regulator in this context is FKBP51, a stress-associated protein linked to the HPA axis, depression, and vesicle synthesis. The role of FKBP51 in the new stress model is investigated through pharmacological (SaFIT2, Protac) and genetic (CRISPR-Cas) manipulations. By integrating behavioral, molecular, and translational approaches, the project aims to deepen our understanding of the neurobiological mechanisms underlying the stress response and to develop novel treatment strategies for stress-related disorders.

The Polyamine Hypothesis of Resilience: Autophagy-inducing Polyamines in Stress, Stress-related Diseases and Resilience

DFG, Project No. 570281506

With Marianne B. Müller

Stressful life experiences are major contributors to the rising prevalence of mental disorders, particularly depression. While current treatments combining medication and psychotherapy offer some relief, many individuals still experience poor outcomes or relapse. This is largely due to a limited understanding of the biological mechanisms that drive stress-related mental illness. This research proposes that proper regulation of brain polyamine metabolism may be critical for coping with stress. Targeted modulation of polyamine metabolism could offer a novel strategy for preventing and treating stress-induced depressive symptoms. Building on recent findings, the project aims to explore the interplay between polyamines, autophagy, and stress signaling. The study will pursue three key objectives: (1) to differentiate the effects of acute versus chronic stress on brain-region-specific regulation of the polyamine-autophagy axis; (2) to investigate the temporal dynamics of chronic stress and test whether spermidine supplementation can reverse depression-like symptoms; and (3) to explore whether polyamines can actively promote resilience through autophagy induction. By uncovering how polyamines interact with stress hormones to regulate autophagy, the research seeks to identify the tipping point where adaptive responses become harmful. This could pave the way for early interventions and innovative treatments, with spermidine supplementation emerging as a promising therapeutic approach for stress-related mental disorders.

AutoHealth - Autophagy linking peripheral metabolism and stress to mental health: from model systems to clinical application

BMFTR, Grant no. 01EW2501A

with Mathias V. Schmidt, V. Raluca Contu, Mouna Maroun, Hale Yapici Eser

Mental disorders are among the leading causes of global disease burden and often co-occur with metabolic conditions. Stress is a shared risk factor for both. According to the WHO, around 970 million people were living with a mental disorder in 2019, and the COVID-19 pandemic further increased the prevalence of anxiety and depression by 25%. Despite their widespread occurrence, the molecular connections between stress, metabolism, and mental health remain largely unexplored, hindering progress in therapeutic development. The AutoHealth project investigates how stress affects the brain and body, focusing on a cellular process called autophagy, which recycles damaged cellular components and helps maintain health. Using animal models exposed to early-life stress, project partners will study behavior and metabolism over a defined period. In parallel, studies involving individuals with various psychological and metabolic profiles—such as those conducted at University Hospital Bonn—aim to deepen understanding of stress-related effects in humans. AutoHealth leverages already approved medications that promote autophagy to mitigate stress-induced damage. Promising treatments identified in animal studies will be tested in clinical trials. The project fosters collaboration with patient organizations, healthcare professionals, and researchers to develop and disseminate innovative therapies. By specifically enhancing autophagy, AutoHealth seeks to offer new solutions for stress-related disorders.

Prophylactic autophagy-inducing therapies to tackle coronaviruses (ProATTac)

Volkswagen Foundation, Reference no. 9A889

with Marcel A. Müller

The lack of medical treatment options is a major challenge during the current COVID-19 pandemic. SARS-CoV-2, the causative agent of COVID-19, is a newly emerged highly pathogenic zoonotic coronavirus (CoV), causing mild to severe respiratory symptoms but also embolisms, pneumonia, and neurological disease through enhanced inflammatory and autoimmune responses. We previously showed that human pathogenic CoVs limit autophagy, the cellular recycling system of cells involved in the inflammatory response, and found that compound-driven autophagy induction inhibits replication of highly pathogenic CoV. To generate improved future treatments, we want to develop minimally toxic, broad-range dual antiviral, anti-inflammatory drugs suitable for long-term and prophylactic use. Within a newly established high throughput platform, antiviral activity of N=355 autophagy-inducing compounds will be analyzed with SARS-CoV, newly generated MERS-CoV and SARS-CoV-2 replicons in novel CoV-susceptible autophagy-reporter cells. Minimally toxic, efficient compounds will be further tested in CoV-infected cell cultures, primary airway epithelial cells, and organoids. Antiviral and anti-inflammatory activity of the most potent compounds will be confirmed in a CoV-susceptible autophagy-reporter mouse line. The reporter mice will serve to characterize compound-induced effects, and enable us to monitor autophagy and inflammation during CoV infection. Our project will pave the way for developing a new class of broad-range dual antiviral and anti-inflammatory drugs.

From black bile to melancholia: transmission of mood states via plasma transfer (MoodTransfer)

Volkswagen Foundation, Reference no. 9A889

with Marianne B. Müller

The alarming prevalence of stress-related depressive disorders is now being referred to as the second pandemic; the individual burden on those affected and the health and economic impact of depressive disorders are devastating. Despite decades of research, there has been no innovation, and the pharmaceutical industry is increasingly withdrawing from the development of novel antidepressants. Given this alarming situation, we propose to enable true innovation through a radical paradigm shift: we postulate that, contrary to the currently prevailing dogma that depression is a disease of the brain, depressive disorders do not originate in the brain, but in specific alterations of peripheral signatures of the metabolome and proteome (so-called peripheral mood engrams), which in turn alter brain function. We will test this hypothesis using appropriate animal models in both sexes and show that peripheral mood engrams, and thus the symptoms of depressive disorders, but also the beneficial effects of antidepressant therapy and resilience interventions, can be transferred from one organism to another by plasma transfer. Detailed analysis of peripheral alterations will also allow us to identify new candidates for causal therapies targeting systems biology alterations. If our hypothesis is confirmed, we expect a radical paradigm shift at multiple levels, from basic research to drug development and clinical treatment. In addition, by identifying a tangible biological cause of depression that lies outside the brain, this project would, for the first time, pave the way for breaking down the massive social stigma that patients with mental illness face.

Autophagy Inducers

Brain&Behaviour Research Foundation, Max-Planck Society, KAHN-I Fund

Collaboration with MPI Psychiatry & LDC Dortmund

AMPAR Inducers

Max-Planck Society, KAHN-I Fund

Collaboration with MPI Psychiatry & LDC Dortmund

Closed Funding

Impact of SARS-CoV-2 on Cellular Proteostatic Processes (with Marcel A. Müller)

BMFTR, Grant no. 01KI20434A

The stress-responsive psychiatric risk factor FKBP51 as a novel central regulator of metabolic (dys)function (with Mathias V. Schmidt)

DFG, Project no. 453645443

Bats versus humans: Stress response as target for antiviral and anti-inflammatory drugs (with Marcel A. Müller)

Funded by Charité Foundation (BIH Visiting Professors)

Human studies

An Exploratory Clinical Study on Autophagy During Fasting (AutoFast)

NCT04739852

Autophagy is considered one of the key molecular mechanisms for the broad preventive and therapeutic effects of periodic fasting. While it is generally known that fasting induces autophagy, there are no human studies that focus on the size and temporal kinetics of autophagy and its association with fasting specific signaling pathways. The kinetics of autophagy in patients with chronic diseases will now be compared with the kinetics of autophagy in healthy subjects, who both fast according to the same scheme; and further changes in metabolic and inflammatory parameters will be investigated.

An Exploratory Clinical Study on Autophagy and Multi-level Molecular Profiling During Spermidine Supplementation (StressLess)

NCT04823806

Recently, the autophagy inducing caloric restriction mimic spermidine became available. Autophagy is essential for energy and cellular homeostasis through protein catabolism and dysregulation results in compromised proteostasis, stress-coping behavior, and in excessive secretion of signaling molecules and inflammatory cytokines. Antidepressants for example effect autophagy dependent pathways to exert their beneficial effects. It can therefore be hypothesized that autophagy induction through spermidine supplementation also shows beneficial clinical effect, particularly in the field of psychiatric conditions. It would be safe, low cost and easy to implement in relay to psychotropic medication in the treatment of psychiatric patients.Therefore, the aim of the project is to analyze clinical effects of spermidine supplementation in correlation to the underlying, multi-level molecular profiling.

Multi-level Molecular Profiling of High Acute Stress: a Clinical Study (HighStress)

NCT05144022

Although it is well known that stress plays an important role in the development of neuropsychiatric diseases, the precise role and molecular effects of stress have only been poorly understood. For example, autophagy is essential for energy and cellular homeostasis through protein catabolism, and dysregulation results in compromised proteostasis, stress-coping behavior, and excessive secretion of signaling molecules and inflammatory factors. Therefore, the aim of the project is to analyze the clinical effects of a bungee jump resembling an acute stress event in correlation to autophagy and other underlying, multi-level molecular profiling. Specifically, it is planned to perform multi-level molecular profiling and sleep analysis in a cohort of healthy male individuals before, during, and after a bungee jump compared to a control cohort of healthy males not undergoing a stress event. The resulting findings will advance the role of autophagy during the stress response and hence in the development of psychiatric disorders, and possibly investigate alternative treatment venues on a molecular level, and finally contribute to a better clinical outcome.

Multi-level Molecular Profiling of Peak Performance in Endurance Sports (AutoSport)

NCT05359744

Physical activity triggers complex molecular responses, including changes in immune-, stress-, and metabolic pathways. For example, autophagy is essential for energy and cellular homeostasis through protein catabolism, and dysregulation results in compromised proteostasis, reduced exercise performance, and excessive secretion of signaling molecules and inflammatory proteins. However, previous research has been limited by the extend of molecules measured and biological processes covered. A better understanding of these processes through multi-omic analysis can improve knowledge of molecular changes in response to exercise. The main purpose of the investigators study is to analyze the effects of acute exercise in correlation to autophagy and other signaling cascades. Specifically, the investigators plan to perform multi-level molecular profiling in a cohort of healthy male elite cyclists and male and female recreational athletes, before, during, and after a bicycle ergometer test. The results will be compared to a control cohort without intervention.

Multi-level Molecular Profiling of Stress Exposure Under Standardized Food Intake: A Clinical Study (NutriMol)

NCT06016530

Nutrition plays a crucial role in preventing various diseases, including cardiovascular and metabolic conditions. Moreover, it is gaining increasing attention in the context of preventing and treating psychiatric disorders. However, limited knowledge exists concerning the effects of food intake and stress on metabolism over time. To enhance the understanding of this subject, blood components in healthy volunteers will be examined during a standardized diet, focusing on the interaction between nutrition and stress. Physiological stress will be induced by subjecting participants to sleep deprivation for over 36 hours. Hormonal influences related to the female menstrual cycle are particularly taken into account in female participants. In conclusion, comprehending these processes can improve the understanding of nutritional physiology and contribute to advancements in clinical practice.