Silent Regulators of Trauma: The microRNA Blueprint Underlying Post-traumatic Stress Disorder Biology

Abstract Post-traumatic stress disorder (PTSD) is a chronic and disabling psychiatric condition that affects millions of people worldwide, producing persistent disturbances in emotional regulation, cognition, and physiological functioning. Although exposure to traumatic or life-threatening events is a defining feature of PTSD, only a subset of exposed individuals develop enduring symptoms, highlighting variability in vulnerability and recovery. The biological mechanisms underlying PTSD remain incompletely understood. Increasing evidence suggests that epigenetic processes play a central role in shaping individual responses to trauma. Among these, microRNAs (miRNAs), small, noncoding RNA molecules that fine-tune gene expression by regulating the translation and stability of multiple target genes simultaneously, have emerged as important epigenetic regulators of PTSD-related neurobiology. Because a single miRNA can influence extensive gene networks, alterations in miRNA expression affect a broad range of biological processes relevant to PTSD, including hypothalamic–pituitary–adrenal axis function, synaptic plasticity, immune signaling, and memory formation. Recent studies demonstrate that dysregulated miRNAs can modify glucocorticoid receptor sensitivity, shape fear memory acquisition and extinction, and contribute to the pro-inflammatory phenotype frequently observed in PTSD. Progress of miRNA research in this field has been driven by integrative strategies that combine human peripheral tissues, plasma, and extracellular vesicles, complemented by animal models of stress and fear learning, including fear conditioning, restraint stress, and single-prolonged stress paradigms. Together, these approaches provide converging evidence for a critical role of miRNAs in PTSD pathophysiology. This review synthesizes findings across species to clarify miRNA-mediated mechanisms and highlight future directions for biomarker discovery and therapeutic development.