Increased cellular stress responses, neuroinflammation, and altered neuronal signaling in the pathophysiology of PTSD

Post-traumatic stress disorder (PTSD) is associated with persistent dysregulation of cellular stress pathways and altered neuronal signaling within limbic and prefrontal circuits. Increasing evidence indicates that activation of endoplasmic reticulum stress responses, oxidative imbalance, and inflammasome signaling contribute to sustained neurobiological alterations underlying PTSD symptomatology. Stress-induced activation of inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) interacts with inflammatory mediators such as interleukin-18 (IL-18) and interleukin-1β (IL-1β), amplifying neuroimmune responses. Activation of the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) and caspase-1 promotes cytokine maturation and microglial activation, leading to impaired synaptic plasticity. These mechanisms are accompanied by alterations in glutamatergic and gammaaminobutyric acid (GABA) signaling, oxidative stress imbalance, and dysregulation of the hypothalamic-pituitary-adrenal axis. Neuroimaging data demonstrate volumetric and microstructural changes in the hippocampus, amygdala, and prefrontal cortex in chronic PTSD, suggesting structural correlates of prolonged inflammatory and stress-related activity. Biomarker studies further indicate associations between inflammatory mediators, coping strategies, sleep disturbances, and illness duration. These findings support the concept that increased cellular stress responses and altered neuronal signaling are central components of PTSDpathophysiology rather than secondary epiphenomena. Understanding the interaction between endoplasmic reticulum stress, inflammasome activation, oxidative imbalance, and neurotransmitter dysregulation may improve biomarker-based diagnostics and facilitate development of targeted therapeutic interventions.