Dataset Information

Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice.

ABSTRACT: Metformin is an oral anti-diabetic used as first-line therapy for type 2 diabetes. Because benefits of metformin extend beyond diabetes to other age-related pathology, and because its effect on gene expression profiles resembles that of caloric restriction, metformin has a potential as an anti-aging intervention and may soon be assessed as an intervention to extend healthspan. However, beneficial actions of metformin in the central nervous system have not been clearly established. The current study examined the effect of chronic oral metformin treatment on motor and cognitive function when initiated in young, middle-aged, or old male mice. C57BL/6 mice aged 4, 11, or 22 months were randomly assigned to either a metformin group (2 mg/ml in drinking water) or a control group. The mice were monitored weekly for body weight, as well as food and water intake and a battery of behavioral tests for motor, cognitive and visual function was initiated after the first month of treatment. Liver, hippocampus and cortex were collected at the end of the study to assess redox homeostasis. Overall, metformin supplementation in male mice failed to affect blood glucose, body weights and redox homeostasis at any age. It also had no beneficial effect on age-related declines in psychomotor, cognitive or sensory functions. However, metformin treatment had a deleterious effect on spatial memory and visual acuity, and reduced SOD activity in brain regions. These data confirm that metformin treatment may be associated with deleterious effect resulting from the action of metformin on the central nervous system.

SUBMITTER: Thangthaeng N

PROVIDER: S-EPMC5287385 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice.

Thangthaeng Nopporn N Rutledge Margaret M Wong Jessica M JM Vann Philip H PH Forster Michael J MJ Sumien Nathalie N

Aging and disease 20170201 1

Metformin is an oral anti-diabetic used as first-line therapy for type 2 diabetes. Because benefits of metformin extend beyond diabetes to other age-related pathology, and because its effect on gene expression profiles resembles that of caloric restriction, metformin has a potential as an anti-aging intervention and may soon be assessed as an intervention to extend healthspan. However, beneficial actions of metformin in the central nervous system have not been clearly established. The current st ...[more]

PMID: 28203479

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Project description:BackgroundAs one of the environmental risk factors for human health, atmospheric fine particulate matter (PM2.5) contributes to cognitive deterioration in addition to respiratory and cardiovascular injuries. Recently, increasing evidence implicates that PM2.5 inhalation can affect neurological functions in offspring, but the sex-specific outcomes and the underlying biological processes are largely unknown.ObjectivesTo observe the influence of prenatal PM2.5 exposure on cognitive performance in offspring, to elucidate the neuronal morphological alterations and possible transcriptional regulation based on mRNA-sequencing (mRNA-Seq) data after birth, and to determine the key components of PM2.5 contributing to the adverse effects.MethodsPregnant C57BL/6J mice were exposed to sterile saline or PM2.5 suspension. Morris water maze test was used to assess the cognitive function in weanling offspring. Microscopic observation was applied to detect neuronal morphogenesis in vivo and in vitro. The cortex tissues from male offspring were collected on postnatal days (PNDs) 1, 7, and 21 for mRNA-Seq analysis. The organic and inorganic components of PM2.5 were separated to assess their contributions using primary cultured neurons.ResultsPrenatal PM2.5 exposure impaired spatial learning and memory in weanling male mice, but not female mice. The sex-specific outcomes were associated with mRNA expression profiles of the cortex during postnatal critical windows, and the annotations in Gene Ontology (GO) of differentially expressed genes (DEGs) revealed that the exposure persistently disrupted the expression of genes involved in neuronal features in male offspring. Consistently, axonal growth impairment and dendritic complexity reduction were observed. Importantly, Homeobox A5 (Hoxa5), a critical transcription factor regulating all of the neuronal morphogenesis-associated hub genes on PNDs 1, 7, and 21, significantly decreased in the cortex of male offspring following PM2.5 exposure. In addition, both inorganic and organic components were harmful to axonal and dendritic growth, with organic components exhibiting stronger inhibition than inorganic ones.ConclusionPrenatal PM2.5 exposure affected spatial learning and memory in male mice by disrupting Hoxa5-mediated neuronal morphogenesis, and the organic components, including polycyclic aromatic hydrocarbons (PAHs), posed more adverse effects than the inorganic components.

Project description:Ample research in visual working memory (VWM) has demonstrated that the memorized items are maintained in integrated spatial configurations, even when the spatial context is task irrelevant. These insights were obtained in studies in which participants were provided with the information they memorized. However, the encoding of provided information is only one aspect of memory. In everyday life, individuals often construct their own memory representations, an aspect of memory we have previously termed self-initiated (SI) working memory. In this study, we employed a SI VWM task in which participants selected the visual targets they memorized. The spatial locations of the targets were task irrelevant. Nevertheless, we were interested to see whether participants would construct spatially structured memory representations, which would suggest that they intended to maintain the visual targets as integrated spatial configurations. The results of two experiments demonstrated that participants constructed spatially structured configurations relative to random displays. Specifically, participants selected visual targets in close spatial proximity and constructed spatial sequences with short distances and fewer path crossings. When asked to construct configurations for a hypothetical competitor in a memory contest, participants disrupted the spatial structure by selecting visual targets that were further apart and by increasing the distances between them, which suggests that these characteristics were under their control. At the end of each experiment, participants provided verbal descriptions of the strategies they used to construct the memory displays. While the spatial structure of the SI memory representations was robust, it was absent from the participants' explicit descriptions, which focused on non-spatial strategies. Participants reported selecting items based, most frequently, on semantic categories and visual features. Taken together, these results demonstrated that participants had access to the metacognitive knowledge on the spatial structure of VWM representations, knowledge they manipulated to construct memory representations that enhanced or disrupted memory performance. While having a profound impact on behavior, this metacognitive knowledge on spatial structure remained implicit, as it was absent from the participants' verbal reports. Viewed from a larger perspective, this study explores how individuals interact with the world by actively structuring their surroundings to maximize cognitive performance.

Dataset Information

Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice.

Publications

Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice.

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