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Lee Wei Lim Li Ka Shing

Abstract

INTRODUCTION

Age-related memory dysfunction is the main symptom of dementiarelated disorders. Current treatments for dementia are limited, and no therapies are known to halt the development of this neurodegenerative disease. In this study, we tested the hypothesis that electrical stimulation of the medial prefrontal cortex (mPFC) enhanced learning and memory-related behaviors in an aged animal model.

MATERIALS AND METHODS

Aged rats were stimulated in the mPFC and they were behaviorally tested for hippocampaldependent memory and anxiety-related tests to evaluate possible side-effects. The molecular mechanisms in the hippocampus along with other brain regions were investigated using a combination of in vivo electrophysiological recording, immunohistological and biochemical approaches including DNA microarraybased genome-wide analyses with realtime quantitative PCR and western-blotting techniques.

RESULTS

Our data demonstrated that electrical stimulation targeting specifically the mPFC evoking powerful memory enhancement effects in aged animal model. Our results showed a remarkable increase of neural progenitors, surviving BrdU-positive cells, and dendritic arborization after chronic stimulation as compared to the control. Principle component analyses revealed differentially expressed genes in both the dorsal and ventral hippocampi. Pathway analysis showed a distinct pattern of biological signaling mechanisms after stimulation in particular the monoamine and synaptic neurotransmission, neuroplasticityrelated functions, regulation of cyclic adenosine monophosphate metabolic and biosynthetic processes. In addition, the electrophysiological and histochemical data have also demonstrated that mPFC stimulation evoked a specific brain circuitry modulation of the serotonergic networks, which linked to the dorsal raphe nucleus in regulation of the mood and hippocampal-dependent memory behaviors.

DISCUSSION

Our findings suggested that electrical stimulation of the mPFC has the potential to be developed into a therapy to treat patients suffering from dementia. Importantly, the mechanisms by which stimulation improves memory functions are likely to be mediated by a complex hippocampal signaling pathways that underlie the process for memory acquisition, consolidation and retrieval.

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