Groundbreaking research conducted by a joint team, comprising experts from KAIST's Department of Biological Sciences and collaborators from the National Forensic Service and Ajou University Medical Center, has significantly advanced our understanding of major depressive disorder (MDD). Their findings challenge the conventional view that MDD is solely a consequence of neuronal degradation, proposing instead that the condition may stem from the intricate dysregulation of specific neural signaling pathways. This investigation, which involved comprehensive RNA sequencing and immunohistochemical analysis of brain tissue from suicide victims, notably uncovered a molecular explanation for the observed treatment resistance to standard antidepressants in older adults. Furthermore, the study showcased the potential of optogenetic technology to restore antidepressant effects in animal models by precisely modulating these identified signaling pathways, thereby paving the way for targeted therapeutic developments, particularly those focusing on the 'Numb' protein.

The research delved into the hippocampus, a brain region pivotal for memory and emotional processing, with a specific emphasis on the dentate gyrus (DG), known for its role in neurogenesis and mood regulation. Utilizing two established mouse models of depression, the team observed a pronounced increase in the signaling receptor FGFR1 (Fibroblast Growth Factor Receptor 1) within the DG under stressful conditions. Subsequent experiments with conditional knockout mice, genetically engineered to lack the FGFR1 gene, demonstrated that the absence of this receptor heightened vulnerability to stress and accelerated the onset of depressive symptoms, underscoring FGFR1's vital role in neural regulation and resilience. Innovatively, the researchers developed an 'optoFGFR1 system,' employing light to activate FGFR1. Activating this system in FGFR1-deficient mice successfully reversed depressive behaviors, providing experimental validation that FGFR1 signaling activation alone could alleviate depression. However, a significant revelation emerged when applying this system to aged depressive mouse models: the optoFGFR1 activation failed to produce antidepressant effects. This led to the discovery of an excessive presence of the 'Numb' protein in the aged brains, which actively interfered with FGFR1 signaling. This observation was corroborated by postmortem human brain tissue analysis, which revealed an overexpression of Numb protein exclusively in elderly individuals diagnosed with depression. Critically, by suppressing Numb and simultaneously activating FGFR1 signaling in aged mouse models, the researchers were able to restore neurogenesis and normal behavior, indicating that the Numb protein functions as a critical inhibitor of the FGFR1 pathway, preventing the hippocampus from enacting its natural antidepressant mechanisms.

This study not only illuminates a critical molecular mechanism underlying depression, particularly its age-related complexities, but also inspires a renewed sense of possibility for those affected by this pervasive disorder. The identification of the 'Numb' protein as a key modulator of antidepressant efficacy in older adults offers a beacon of hope, directing future research and drug development towards more precise and effective interventions. Embracing such scientific breakthroughs fosters an environment where innovation thrives, constantly pushing the boundaries of what is medically possible and reinforcing the collective human endeavor to alleviate suffering and enhance well-being. This advancement reminds us that even in the face of long-standing challenges, persistent inquiry and interdisciplinary collaboration can unlock transformative solutions, underscoring the enduring power of knowledge to bring about positive change in the world.