Preventing traumatic stress-induced behavioral abnormalities in rats with blue light phototherapy

Background: Posttraumatic stress disorder (PTSD) is a debilitating mental condition triggered by traumatic stress, and current treatments remain limited. Non-invasive phototherapy has shown promise in mood disorders, yet its efficacy in PTSD-particularly for early intervention and fear symptom mitigation-remains insufficiently explored. Objective: This study aimed to investigate the preventive and therapeutic effects of blue non-invasive phototherapy (470 nm) on PTSD-related anxiety and fear behaviors in a rat model, focusing on neuronal activation and transcriptomic changes in emotion-related brain regions. Methods: Sprague-Dawley (SD) rats (n = 100) were subjected to single inescapable electric foot shock after single prolonged stress procedure (SPS-S). Groups included control (Ctrl), SPS-S, SPS-S + immediate light therapy (SPS-S + I-LT), SPS-S + delayed light therapy (SPS-S + D-LT), and SPS-S + immediate and delayed light therapy combination (SPS-S + ID-LT). Behavioral assessments, including open field test (OFT), elevated plus maze (EPM) and fear conditioning, were conducted at week one and three post-intervention. Immunohistochemical staining for c-Fos expression and RNA sequencing of the medial prefrontal cortex (mPFC) were performed to evaluate neural activation and transcriptomic alterations. Results: I-LT and ID-LT were associated with reduced anxiety-like behaviors in the OFT and EPM compared with untreated SPS-S-exposed rats (p < 0.001). Improvements in fear-related freezing behavior were observed at 3 weeks in the I-LT group and ID-LT group (p < 0.001), whereas D-LT was associated with anxiolytic effects without significant changes in fear responses. SPS-S exposure was associated with increased c-Fos expression in the infralimbic mPFC, and this elevation was attenuated in animals receiving I-LT or ID-LT. Transcriptomic analyses revealed stress-associated alterations in synapse-related pathways, which were modulated in the I-LT group. Selected synaptic genes were further examined by quantitative real-time PCR. Conclusions: Blue light phototherapy produced distinct behavioral and molecular signatures in a rat model of traumatic stress. Immediate post-trauma intervention showed stronger associations with fear-related outcomes, supporting the potential relevance of early light-based interventions as a non-invasive adjunctive strategy for traumatic stress management.