Autophagic Dysregulation in Depression

Autophagy is a fundamental cellular process critical for maintaining homeostasis and has emerging relevance in stress adaptation and affective disorders. This thesis investigated how autophagy flux is modulated by acute stress, chronic stress-associated depression, pharmacological interventions, and psychedelic compounds across human, mouse, organotypic and cellular models. In humans, acute stressors such as bungee jumping and sleep deprivation transiently increased peripheral autophagy flux, with proteomic analyses revealing a coordinated sequence involving early stress-responsive autophagy proteins, lysosomal degradation, mitophagy, and proteostatic maintenance. In contrast, individuals with mild to moderate depressive symptoms exhibited reduced autophagy flux, which correlated with resilience and mental wellbeing, suggesting impaired cellular and psychological stress adaptation under chronic stress. Preclinical studies using the Chronic Social Defeat Stress (CSDS) model corroborated these findings, showing behavioral deficits, adrenal enlargement, and widespread dysregulation of autophagy-related proteins. Spermidine, an autophagy-inducing polyamine, normalized proteomic autophagic profiles, and mitigated both behavioral and physiological stress markers. Translational studies in humans demonstrated that spermidine supplementation increased autophagy flux in peripheral blood mononuclear cells (PBMCs) and reduced depressive symptom severity, with individuals exhibiting lower baseline resilience showing the strongest responses in autophagy flux. Investigations of psychedelic compounds revealed cell type-specific effects: psilocybin/psilocin enhanced autophagy flux in neuronal cells, had modest effects in astrocytic cells, and reduced flux in microglial cells. Psychedelic-induced modulation of autophagy was also corroborated in hippocampal slice cultures. Proteomic analyses of neuronal cells treated with psilocybin implicated mTORC1-ULK1 disinhibition and ERK-mediated pathways, suggesting that autophagy may contribute to the neuroplasticity mechanisms underlying psychedelic antidepressant effects. Collectively, these findings establish autophagy as a dynamic mechanism linking acute stress adaptation, chronic stress pathology, and pharmacological interventions, with autophagy flux emerging as both a biomarker of resilience and a potential therapeutic target for stress-related psychiatric disorders.