Summary: New research clarifies how three proteins coordinate the brain’s response to stress in the hippocampus and highlights potential targets for treating stress-related psychiatric conditions.
Source: McLean Hospital
Understanding the biological mechanisms that underlie stress-related mental health disorders—such as major depressive disorder and post-traumatic stress disorder (PTSD)—remains a critical challenge in neuroscience and psychiatry.
An international research team led by investigators at McLean Hospital reports new findings that map how three key proteins interact to regulate the body’s stress response in the hippocampus, a brain region central to stress regulation and emotional processing. The study, published in Cell Reports, sheds light on molecular relationships that could guide future therapeutic strategies when stress regulation becomes dysregulated.
“When the body’s response to stress is out of balance, it can harm the brain and increase vulnerability to mood and anxiety disorders,” said lead author Jakob Hartmann, PhD, an assistant neuroscientist in the Neurobiology of Fear Laboratory at McLean and an instructor in psychiatry at Harvard Medical School. The team began this work after observing notable differences in where three stress-regulating proteins are localized within the hippocampus.
Using a combination of experiments on non-human tissue and analyses of postmortem human brain samples, the investigators examined how the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the FK506-binding protein 51 (FKBP5) influence one another. Their results reveal a nuanced regulatory network in which MR plays a dominant role in controlling the expression of FKBP5 under baseline conditions, while FKBP5 modulates GR sensitivity during stress.
Specifically, the researchers found that mineralocorticoid receptors (MRs), rather than glucocorticoid receptors (GRs), drive the production of FKBP5 in normal, non-stress conditions. FKBP5 in turn reduces the sensitivity of GRs to stress hormones when stress occurs. This positions FKBP5 as a critical mediator that helps maintain balance between MR and GR signaling in the hippocampus, effectively fine-tuning the brain’s molecular response to stress.
“Our findings indicate that coordinated targeting of GR, MR, and FKBP5 may offer complementary routes to influence both central and peripheral aspects of the stress response,” said senior author Kerry J. Ressler, MD, PhD, chief scientific officer at McLean Hospital, chief of McLean’s Division of Depression and Anxiety Disorders, and a professor of psychiatry at Harvard Medical School. The study emphasizes the importance of MR signaling, which the authors note has been comparatively underappreciated in the context of stress-related psychiatric disorders.
By clarifying how these proteins interact in the hippocampus, the research opens new experimental directions for understanding susceptibility to stress-induced psychiatric conditions and for developing interventions that restore healthy stress regulation. The study’s results provide a molecular framework that can inform future preclinical and clinical investigations, while highlighting FKBP5 as a potential molecular switch that modulates receptor sensitivity in response to changing physiological states.
The investigators used well-controlled tissue-based studies to map protein localization and expression patterns and to test how these proteins influence each other under different conditions. While further research is required to translate these molecular insights into clinical treatments, the work provides foundational knowledge about the receptor interactions that govern stress signaling in a key brain area implicated in mood and anxiety disorders.
This research was supported by multiple funding sources, including a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (awarded to Hartmann, grant no. 24774), National Institutes of Health grants (R01MH108665, P50MH115874), the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01ES100221, awarded to Serena M. Dudek, PhD), and several research grants to Torsten Klengel, MD, PhD (NICHD R21HD088931, R21HD097524; NIMH R21MH117609; ERA-Net Neuron 01EW2003).
About this stress research news
Source: McLean Hospital
Contact: Press Office – McLean Hospital
Image: The image is in the public domain
Original Research: The findings will appear in Cell Reports