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

• Applicants: Dr. Nils Gassen; Dr. Benjamin Jurek
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Biological Psychiatry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562802756

Background: The exposure to excessive or chronic stress can lead to maladaptive coping strategies that pose a threat to the homeostasis of an organism. Such maladaptation can result in psychiatric disorders in humans, like depression or general anxiety disorder. Current animal models for psychiatric research are limited in their assessment of the true dynamics of stress-induced behavior, as 5-minute behavioral tests are likely to miss the true dynamics of behavior, occur in artificial arenas, pose an additional stress themselves and require experimenter-animal contact. Objectives: We propose a novel acute stress paradigm that occurs in the home cage and includes a chronic reminder of the stress across the inactive and active phase of mice. Variations of stressor timing, the characteristics of the reminder, and the sex of the experimental animals will reveal the true dynamics of stress-induced behaviors over time. In contrast to classical 5-minute behavioral tests, we analyze the home cage behavior of male and female mice constantly over 48 hours by means of deep learning-based algorithms (DeepLabCut, DeepOF). The dynamics of stress-induced behavior over several hours is likely to be mirrored by the synthesis, release, and uptake of extracellular vesicles (EVs) in the brain and periphery. This easily accessible pool of potential biomarkers could be informative of central stress-related processes, opening up possibilities for innovative treatment options of stress-related disorders in humans. To raise the bar of translatability in stress research we subject male and female human probands to the stressful experience of a bungee jump and analyze release and proteomic content of plasma-derived extracellular vesicles before and after the stress. One of the stress-related candidate biomarkers that could affect EV cargo loading, release, and uptake is the co-chaperone FKBP51, which has already been linked to HPA-axis activity, depression and, as a complex with HSP90, vesicle formation. Pharmacological (via SaFIT2, Protac) and genomic manipulation (CRISPR-Cas) of FKBP51 in our novel stress paradigm will reveal its involvement in EV regulation. Significance: With this proposal we aim to combine our novel stress paradigm of unsupervised long-term home-cage behavioral analysis of male and female mice with the temporal dynamics of stress-induced EV cargo loading, release, and uptake, to create a better understanding of the neurobiological mechanisms underlying the stress response in rodents and humans.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Mathias V. Schmidt, Ph.D.