Brain pacemaker in medial prefrontal cortex enhances memory and hippocampal neuroplasticity in the aged brain

Abstract

Background: Memory dysfunction is the main symptom of dementia-related disorders. Current treatments for dementia are limited, and no therapies are known to halt or prolong the development of this neurodegenerative disease. The use of electrical stimulation to control severely debilitating neurological and psychiatric diseases is a fast-emerging field in clinical neuroscience. In this study, we tested the hypothesis that electrical stimulation of the medial prefrontal cortex enhances learning and memory-related behaviors in animal model of dementia. Materials and Methods: Aged rats received electrode implantation in the medial prefrontal cortex, and tested behaviorally for hippocampal-dependent memory and underwent mood-related tests to evaluate possible side-effects. The molecular mechanisms on hippocampal neuroplasticity and midbrain serotonergic regulation were investigated using a combination of histochemistry, electrophysiology and biochemical approaches including microarray, and western-blotting techniques. Results: Our data demonstrated that electrical stimulation targeting specifically the medial prefrontal cortex, evoking powerful antidepressant effects in experimental model, as compared to several other stimulated brain regions (cingulate cortex, nucleus accumbens core and shell parts, lateral habenula, ventral tegmental area). Further, our results have shown that it could also be used to enhance the growth of brain cells in the hippocampus, which mitigates the harmful effects of dementia-related conditions and improve the learning and memory functions in the object recognition test and Morris water maze experiments. Our results showed a remarkable increase of neural progenitors, surviving BrdU-positive cells, and dendritic arborization after chronic medial prefrontal cortex stimulation as compared to the sham. To confirm the stimulation-induced neurogenesis on memory enhancement, immunofluorescence revealed co-localization of immediate-early gene activation c-Fos with the doublecortin and the BrdU-labeled cells in the hippocampal dentate gyrus, indicating their functional roles on memory behavior. At the molecular level, the enhanced neurogenesis effects were experimentally supported by the upregulated neuroplasticity-related genes using oligonucleotide microarrays and quantitative real-time PCR techniques in rat hippocampi. Besides, our electrophysiological and histochemical investigations have found that stimulation of the medial prefrontal cortex evoked a specific brain circuitry modulation of the serotonergic networks, which linked to the dorsal raphe nucleus in regulation of mood-related and hippocampal-dependent memory behaviors. Conclusions: Our findings suggested that medial prefrontal cortex stimulation has the potential to be developed into a therapy to treat patients suffering from dementia as well as treatment-resistant depression. Importantly, its mechanisms by which stimulation improves mood and memory functions are likely to be mediated by hippocampal neuroplasticity and serotonergic neurotransmission.