Targeting mitochondria via methylene blue : implications in memory enhancement and neuroprotection

Memory—though seemingly simple in concept—is altogether a notoriously elusive and difficult process to understand. While some memories are fragile and changeable under certain circumstances, others are persistent and difficult to erase. This work is a comprehensive investigation into memories: how to change persistent ones, enhance complicated ones and protect delicate ones. The first objective of this work was to explore a strategy for manipulating fear memories, which are notoriously difficult to erase. This was done by testing different parameters for attenuation of fear using extinction as a strategy for interrupting fear memory reconsolidation. Briefly, by manipulating extinction parameters such that subjects were unable to predict the occurrence of fearful stimuli, we were able to maximize the degree of memory updating. Since memory processing is contingent upon specific neuronal activity, and neuronal activity is primarily fueled by products of mitochondrial respiration, the second and third objectives of this work focused largely on how manipulating mitochondrial activity enhances and protects memory processes respectively. This was done using mitochondrial enhancer methylene blue (USP grade). Methylene blue (MB) is a synthetic dye with a unique ability to cross the blood-brain barrier and diffuse into neuronal mitochondria. There, it serves as a redox electron cycler, increasing neurons’ capacity for mitochondrial respiration. The second objective of this work examined the effect of post-extinction administration of MB and its interaction with reconsolidation update mechanisms in the persistent attenuation of fear memories. Building on findings from the first objective, we found that administering MB after extinction helped subjects maintain the fear attenuation induced by extinction. The third objective explored the ability of MB to prevent the cognitive deficits arising from chronic cerebral hypoperfusion, a risk factor for mild cognitive impairment and Alzheimer’s disease. Finally, quantitative cytochrome oxidase histochemistry (a marker for mitochondrial activity) was used to map the effects of MB on brain mitochondria in the hypoperfusion model. Methylene blue attenuated some of the cognitive deficits that arose from chronic cerebral hypoperfusion, which was reflected in enhanced brain mitochondrial activity.