The Polyamine Hypothesis of Resilience: Autophagy-inducing Polyamines in Stress, Stress-related Diseases and Resilience; Running Title: Regulating stress-related outcomes through polyamines Acronym: ASTRA

• Applicants: Dr. Nils Gassen; Professorin Dr. Marianne Müller
• Subject Area: Biological Psychiatry ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570281506

Stress-related disorders are a rising global health concern, with chronic stress as a major risk factor for depression. Despite extensive research, the molecular mechanisms underlying stress resilience and vulnerability remain poorly understood, limiting effective therapeutic strategies. Emerging evidence highlights autophagy - a cellular recycling mechanism - as a key regulator of stress adaptation. However, the impact of chronic stress on autophagy and its potential as a therapeutic target remain unclear. Polyamines (PAs), including spermidine, are metabolic regulators involved in neuroplasticity, neurogenesis, and autophagy. Spermidine has been shown to enhance autophagy, counteracting cognitive decline and promoting resilience in neurodegenerative and metabolic diseases. Recent studies suggest an interaction between PAs and glucocorticoid signaling, a key regulator of the stress response. We hypothesize that chronic stress disrupts the polyamine-autophagy axis, leading to metabolic dysfunction. PA supplementation may restore autophagy, enhance resilience, and reverse stress-induced deficits. This project aims to dissect the brain region-specific and systemic effects of acute and chronic stress on the polyamine-autophagy axis using in vivo mouse models of social stress. We will apply cutting-edge methods, including genetically encoded autophagy reporters, targeted metabolomics, and high-resolution proteomics, to perform longitudinal analyses of stress-induced molecular, metabolic, and behavioral changes. Additionally, we will assess the therapeutic potential of PA supplementation in restoring autophagic function and improving cognitive and behavioral resilience. To maximize translational relevance, we will implement innovative behavioral phenotyping, combining conventional tests with deep-learning-based automated behavior analysis. The project is structured into four work packages (WPs). WP1 will assess the acute effects of social stress on autophagic signaling in specific brain regions. WP2 will extend these analyses to chronic stress, characterizing its cumulative impact on PA metabolism and autophagy in the brain and peripheral tissues. WP3 will determine whether PA supplementation can reverse stress-induced autophagic deficits and behavioral impairments. WP4 will explore targeted modulation of the PA-autophagy axis to enhance resilience and its interaction with stress signaling, including glucocorticoid receptor and chaperone regulation. By integrating molecular, metabolic, and behavioral analyses across multiple scales, this study will provide novel insights into the mechanisms of stress resilience. Identifying the transition point where adaptive stress responses become maladaptive could enable early interventions targeting PA metabolism and autophagy. Ultimately, our findings may pave the way for new therapeutic strategies to prevent and treat stress-related mental disorders, addressing a critical gap in psychiatric research.

• DFG Programme: Research Grants