Ascorbate (vitamin C) is a vital antioxidant molecule in the brain. However, it also has a number of other important functions, participating as a co-factor in several enzyme reactions including catecholamine synthesis, collagen production and regulation of HIF-1α. Ascorbate is transported into the brain and neurons via the Sodium-dependent Vitamin C Transporter-2 (SVCT2), which causes accumulation of ascorbate within cells against a concentration gradient. Dehydroascorbic acid, the oxidized form of ascorbate, is transported via glucose transporters of the GLUT family. Once in cells, it is rapidly reduced to ascorbate. The highest concentrations of ascorbate in the body are found in the brain and neuroendocrine tissues such as adrenal, although the brain is the most difficult organ to deplete of ascorbate. Combined with regional asymmetry in ascorbate distribution within different brain areas, these facts suggest an important role for ascorbate in the brain. Ascorbate is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic and GABAergic transmission and related behaviors. Neurodegenerative diseases typically involve high levels of oxidative stress and thus ascorbate has been posited to have potential therapeutic roles against ischemic stroke, Alzheimer's disease, Parkinson's disease and Huntingdon's disease.

Mice co-expressing the Swedish amyloid precursor protein mutation (APP Swe ) and exon 9 deletion (DE9) of the PSEN1 gene begin to develop amyloid plaques at 6-7 months of age. We demonstrate here a spatial learning deficit in 7-month-old APP Swe + PSEN1DE9 bigenic mice using an adaptation of the Barnes maze. Mice were first trained on a cued target followed by a hidden-target condition. Although bigenic mice quickly learned the cued-target version of the task, they were significantly impaired when switched to the hidden-target version. In contrast, a separate group of double-transgenic mice trained first on the spatial hidden-target version of the task were unimpaired relative to wild-type controls. We propose that processes such as general rule learning, context learning and exploratory habituation exert a greater influence when the testing environment is novel and overshadow the spatial memory deficit in naive bigenic mice. However, when cued-target training is conducted first, these processes habituate and the spatial learning deficit is unmasked. Seven-month-old APP Swe + PSEN1DE9 mice were unimpaired on tests of memory that did not involve learning the rules governing spatial associations.

The effects of abnormally high or low stress on learning are well established. The Barnes maze and Morris water maze are two commonly-used tests of spatial memory, of which the water maze is considered more stressful; however, until now this has not been demonstrated empirically. In the present study, mice matched for performance on commonly-used anxiety tasks were trained on either the Barnes maze or water maze or received no cognitive testing. Water-maze training induced greater increases in plasma corticosterone than did Barnes maze training, assessed 30 min. after the final session. Importantly, spatial learning was inversely correlated with corticosterone levels in the water maze but not the Barnes maze, suggesting that performance on the water maze may be more affected by test-induced stress even within wild-type subjects of the same age and gender. These findings are important when considering the appropriate cognitive tasks for any experiment in which stress responses may differ systematically across groups. KeywordsAnxiety; stress; corticosterone; Barnes maze; Morris water maze; Elevated plus maze; Light-dark activity; social dominance; behaviour The Barnes maze [3] and Morris water maze [19] are similar tasks in that they both measure the ability of a mouse to learn and remember the location of a target zone using a configuration of distal visual cues located around the testing area [11,23]. Both tasks rely on hippocampaldependent spatial reference memory and on the inherent tendencies of the subjects to escape from an aversive environment [2,27]. It has been suggested that the Barnes maze is less anxiogenic [13,21]; however, we know of no data that support this assumption.Innate anxiety and cognitive ability differ considerably among mouse strains [5,13,18] highlighting the fact that the selection of a background strain and the choice of behavioural Corresponding author: Fiona Harrison, PhD, Vanderbilt University, Division of Diabetes, Endocrinology & Metabolism, 7465 Medical Research Building IV, 2213 Garland Avenue, Nashville, TN, 37232-0475, Fiona.Harrison@Vanderbilt.edu, Phone: 615-936-1660, FAX: 615-936-1667. 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 discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The subjects were thirty 7-week-old male, C57BL/6J mice obtained from Jackson Laboratory (Bar Harbor, ME, USA; stock #000664) and left undisturbed for 1 week before testing began. Mice were housed five per cage until 1 day before testing in the Barnes or water maze, when mice were singly housed to eliminate any additional stress that may arise from test order within the cage as other mice are r...

A key focus for future studies of ascorbate and the vascular endothelium will likely be to determine the mechanisms and clinical relevance of ascorbate effects on endothelial function, permeability, and survival in diseases that cause endothelial dysfunction.

The Barnes maze is a spatial memory task that requires subjects to learn the position of a hole that can be used to escape the brightly lit, open surface of the maze. Two experiments assessed the relative importance of spatial (extra-maze) versus proximal visible cues in solving the maze. In Experiment 1, four groups of mice were trained either with or without a discrete visible cue marking the location of the escape hole, which was either in a fixed or variable location across trials. In Experiment 2, all mice were trained with the discrete visible cue marking the target hole location. Two groups were identical to the cued-target groups from Experiment 1, with either fixed or variable escape locations. For these mice, the discrete cue either was the sole predictor of the target location or was perfectly confounded with the spatial extra-maze cues. The third group also used a cued variable target, but a curtain was drawn around the maze to prevent the use of spatial cues to guide navigation. Probe trials with all escape holes blocked were conducted to dissociate the use of spatial and discrete proximal cues. We conclude that the Barnes maze can be solved efficiently using spatial, visual cue, or serial-search strategies. However, mice showed a strong preference for using the distal room cues, even when a discrete visible cue clearly marked the escape location. Importantly, these data show that the cued-target control version of the Barnes maze as typically conducted does not dissociate spatial from nonspatial abilities.

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Oxidative stress is implicated in the cognitive deterioration associated with normal aging as well as neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. We investigated the effect of ascorbic acid (vitamin C) on oxidative stress, cognition, and motor abilities in mice null for gulono‐γ‐lactone oxidase (Gulo). Gulo−/− mice are unable to synthesize ascorbic acid and depend on dietary ascorbic acid for survival. Gulo−/− mice were given supplements that provided them either with ascorbic acid levels equal to‐ or slightly higher than wild‐type mice (Gulo‐sufficient), or lower than physiological levels (Gulo‐low) that were just enough to prevent scurvy. Ascorbic acid is a major anti‐oxidant in mice and any reduction in ascorbic acid level is therefore likely to result in increased oxidative stress. Ascorbic acid levels in the brain and liver were higher in Gulo‐sufficient mice than in Gulo‐low mice. F4‐neuroprostanes were elevated in cortex and cerebellum in Gulo‐low mice and in the cortex of Gulo‐sufficient mice. All Gulo−/− mice were cognitively normal but had a strength and agility deficit that was worse in Gulo‐low mice. This suggests that low levels of ascorbic acid and elevated oxidative stress as measured by F4‐neuroprostanes alone are insufficient to impair memory in the knockouts but may be responsible for the exacerbated motor deficits in Gulo‐low mice, and ascorbic acid may have a vital role in maintaining motor abilities.

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