Protracted L-methionine treatment with prelimbic cortical electrical stimulation alleviates anxiety-like behaviour and restores cognitive deficits in the aged rats.

Abstract

Introduction: Global DNA methylation decreases along aging process and is associated with cognitive decline. Although deep brain stimulation (DBS) is a promising therapy for neuropsychiatric disorders, the potential interactions of DBS and epigenetic changes remain largely unknown. Here, we tested the hypothesis that DBS enhanced memory function through a methylation-dependent mechanism in an aged animal model of cognitive deficits. Materials and Methods: We performed 4 weeks of protracted L-methionine treatment together with prelimbic cortical DBS in aged rats (n = 10 - 12 per group), and subsequently animals were behaviourally tested for anxiety and hippocampaldependent memory. For mechanisms, gene expression related to the neuroplasticityrelated functions were investigated in the hippocampus and amygdala. Result and Discussion: Our results demonstrated that L-methionine treatment and DBS contributed synergistically to the restoration of spatial learning and memory of aged animals in Morris water-maze test. Interestingly, our data showed that the anxiolytic effects of DBS were mediated in a methylation-independent mechanism. DBS altered expression of immediate early gene in both hippocampus and amygdala, whereas both treatments upregulated the expression of Bdnf exon IV transcript that associated with contextual learning. Notably, L-methionine-DBS most effectively downregulated memory suppressor gene CaN expression specifically in hippocampus. These results further support the necessity of L-methionine in mediating the effect of DBS. Conclusion: Our findings suggested that there is a certain threshold of methylation degree for DBS to effectively ameliorate age-dependent memory impairment. This study provides insight on potential interactions between DNA methylation and DBS as a novel therapeutic approach against age-related cognitive decline.