This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue’s action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.

After fear conditioning (e.g., by pairing a tone to a shock), memory retrieval typically leads to fear expression (e.g., freezing to the tone). Here, we examined the effect of a conditioned rat's fear memory retrieval on a naïve cage-mate's behavior to the conditioned stimulus. We show that rats exposed to a novel tone in the presence of a cage-mate previously conditioned to that same tone selectively showed increased freezing to the stimulus the next day (fear conditioning by-proxy). In addition, fear conditioning by-proxy experienced prior to pairing the tone to a mild shock increased freezing during presentation of that tone the next day. Our results suggest that, during memory retrieval, fear of a stimulus can be socially transmitted to a cage-mate. These findings may have implications for models of phobias. KeywordsSocial transmission of fear; fear conditioning; memory retrieval; observational learning In fear conditioning, the pairing of an initially neutral conditioned stimulus (e.g., an auditory tone) to an aversive unconditioned stimulus (e.g., a footshock) leads to the formation of a long-lasting fear memory, such that when the tone is later presented on its own, it elicits fear expression [11], [22], [13]. This simple paradigm has been extensively studied, since the pathways engaged during the formation of fear memories are thought to overlap greatly with those that are involved in anxiety-related disorders [11]. Certain types of anxiety-related disorders, for instance post-traumatic stress (PTSD), involve, by definition, a previous experience that led to the formation of a memory now at the source of the disorder symptoms [14]. Re-experiencing the traumatic episode, via internal or external triggering of the memory, is a key aspect of PTSD [14]. In the case of specific phobias, however, attributions of fear to stimuli is not necessarily preceded by a traumatic episode encoded in memory [21]. For example, an individual may have an extreme fear of spiders, and yet have no recollection of having ever experienced a situation in which a spider inflicted them harm.One plausible explanation for such a case may be that the individual simply does not recall the episode that would have caused the phobia initially. Another possibility would suggest that fear can be socially passed on, and thus acquired indirectly, through transmission of verbal information or vicarious learning in response to an otherwise neutral stimulus [21].Corresponding Author: Marie-H. Monfils, Department of Psychology, University of Texas at Austin, 1 University Station, A8000, Austin, TX, 78712, USA, Tel.: 512-471-4139, monfils@mail.utexas.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be...

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