Frequency-specific photobiomodulation at theta and gamma enhances cognitive networks and mitigates age-related decline

Photobiomodulation (PBM) is a non-invasive strategy to enhance cognitive function, yet the effects of stimulation frequency remain unclear. We applied pulsed 810 nm PBM at 5 Hz or 40 Hz to the frontal cortex of adult rats, and 40 Hz PBM to aged rats. In young adults, both stimulation frequencies enhanced cognitive flexibility, and in aged rats 40 Hz PBM improved learning speed. In terms of brain changes, we studied cytochrome c oxidase (CCO) activity, c-Fos expression and protein levels. We observed a decrease in the prefrontal CCO activity in adults, and an increase in prefrontal c-Fos expression, both with 40 Hz. Regarding protein levels in young rats, 5 Hz PBM reduced pERK expression in the hippocampus and p38 in the prefrontal cortex, while regulating interleukins and cytokines in these regions. Additionally, 5 Hz upregulated Synapsin-I expression in both the prefrontal cortex and hippocampus, and increased PSD-95 levels selectively in the hippocampus, highlighting its role in synaptic plasticity and memory consolidation. Notably, 5 Hz also increased GFAP expression in both regions, and selectively upregulated NF-κB expression. 40 Hz PBM reduced pERK expression in the hippocampus and p38 in the prefrontal cortex, also modulating interleukins and cytokines in these areas. Additionally, 40 Hz increased p38 expression in the hippocampus and reduced p53 and BAX levels in the prefrontal cortex. Also, 40 Hz upregulated Synapsin-I in both regions and increased PSD-95 expression in both the prefrontal cortex and hippocampus. As observed with 5 Hz, 40 Hz also elevated GFAP expression in both regions. In aged rats, PBM reduced Iba-1 in prefrontal cortex and hippocampus, enhanced NeuN in prefrontal cortex, and decreased p38 and BCL-2 in the hippocampus. Collectively, these results demonstrate frequency-dependent modulation of neuroinflammation, synaptic plasticity, and apoptosis, while highlighting the beneficial effects of 40 Hz PBM in aged subjects, supporting PBM as a targeted approach to improve cognitive function across the lifespan.