Multisession Anodal Transcranial Direct Current Stimulation Enhances Adult Hippocampal Neurogenesis and Context Discrimination in Mice

Transcranial direct current stimulation (tDCS) is a promising noninvasive neuromodulatory treatment option for multiple neurologic and psychiatric disorders, but its mechanism of action is still poorly understood. Adult hippocampal neurogenesis (AHN) continues throughout life and is crucial for preserving several aspects of hippocampal-dependent cognitive functions. Nevertheless, the contribution of AHN in the neuromodulatory effects of tDCS remains unexplored. Here, we sought to investigate whether multisession anodal tDCS may modulate AHN and its associated cognitive functions. Multisession anodal tDCS were applied on the skull over the hippocampus of adult male mice for 20 min at 0.25 mA once daily for 10 d totally. We found that multisession anodal tDCS enhances AHN by increasing the proliferation, differentiation and survival of neural stem/progenitor cells (NSPCs). In addition, tDCS treatment increased cell cycle reentry and reduced cell cycle exit of NSPCs. The tDCS-treated mice exhibited a reduced GABAergic inhibitory tone in the dentate gyrus compared with sham-treated mice. The effect of tDCS on the proliferation of NSPCs was blocked by pharmacological restoration of GABA_B receptor-mediated inhibition. Functionally, multisession anodal tDCS enhances performance on a contextual fear discrimination task, and this enhancement was prevented by blocking AHN using the DNA alkylating agent temozolomide (TMZ). Our results emphasize an important role for AHN in mediating the beneficial effects of tDCS on cognitive functions that substantially broadens the mechanistic understanding of tDCS beyond its well-described in hippocampal synaptic plasticity.