From Stress to Synapse: The Neuronal Atrophy Pathway to Mood Dysregulation

Mood disorders, including major depressive disorder and bipolar disorder, are among the most prevalent mental health conditions globally, yet their underlying mechanisms remain incompletely understood. This review critically examines the neuronal atrophy hypothesis, which posits that chronic stress and associated neurobiological changes lead to structural and functional deficits in critical brain regions, contributing to mood disorder pathogenesis. Key mechanisms explored include dysregulation of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), elevated glucocorticoids from stress responses, neuroinflammation mediated by cytokines, and mitochondrial dysfunction disrupting neuronal energy metabolism. These processes collectively impair synaptic plasticity, exacerbate structural atrophy, and perpetuate mood dysregulation. Emerging evidence from neuroimaging, genetic, and epigenetic studies underscores the complexity of these interactions and highlights the role of environmental factors such as early-life stress and urbanization. Furthermore, therapeutic strategies targeting neuroplasticity, including novel pharmacological agents, lifestyle interventions, and anti-inflammatory treatments, are discussed as promising avenues for improving patient outcomes. Advancing our understanding of the neuronal atrophy hypothesis could lead to more effective, sustainable interventions for managing mood disorders and mitigating their global health burden.