Autophagic Dysregulation in Depression
Yara Mecdad
bonndoc October 26, 2026 DOI: 10.48565/bonndoc-1014 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Thesis combining human observational and intervention studies with preclinical mouse, organotypic slice, and cellular experiments Peer reviewed |
|---|---|
| Population | Humans exposed to acute stressors or with depressive symptoms, mice in the Chronic Social Defeat Stress model, hippocampal slice cultures, and neuronal, astrocytic, and microglial cell cultures |
| Interventions | Spermidine Psilocybin/Psilocin |
| Topics | Depression |
| Key findings | Acute stress transiently increased peripheral autophagy flux, whereas mild to moderate depressive symptoms were associated with reduced flux that correlated with resilience and wellbeing. Spermidine normalized autophagy profiles and reduced behavioral and physiological stress markers in mice and increased autophagy flux and reduced depressive symptom severity in humans. Psilocybin/psilocin enhanced autophagy flux in neuronal cells, had modest effects in astrocytes, and reduced flux in microglia, with proteomics implicating mTORC1-ULK1 disinhibition and ERK-mediated pathways. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |