Low-Intensity Focused Ultrasound Enhances Hippocampal Neurogenesis via BDNF Pathways: Toward a Regenerative Modality...

Adult hippocampal neurogenesis is essential for learning, memory, and structural plasticity, yet the mechanisms through which physical neuromodulatory stimuli regulate this process remain incompletely understood. Here, we investigated whether transcranial low-intensity focused ultrasound (LIFU) modulates adult hippocampal neurogenesis in a frequency-dependent manner. Adult rats received LIFU targeting the dentate gyrus at 0.5, 1, or 5 MHz twice weekly for 4 wk. Cellular proliferation was assessed using BrdU incorporation, neuronal differentiation was evaluated by BrdU/NeuN co-labeling, and hippocampal expression of neurogenic regulators (BDNF, FGF-2, and Sox-2) was quantified by qRT-PCR. Cognitive performance was examined using the novel object recognition task. Low-frequency stimulation (0.5 MHz) produced the most pronounced increase in BrdU-positive cells across the dentate gyrus and significantly elevated BDNF, FGF-2, and Sox-2 mRNA expression compared with sham controls. Intermediate (1 MHz) and higher (5 MHz) frequencies produced more modest effects. Behavioral testing revealed improved recognition memory selectively in the 0.5 MHz group, consistent with enhanced hippocampal plasticity. These findings demonstrate that ultrasound frequency critically shapes neurogenic and cognitive responses, supporting mechanotransduction-dependent regulation of adult hippocampal plasticity.