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Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

Nature Neuroscience volume 11, pages 309–317 (2008)Cite this article

Abstract

Many organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic-pituitary-adrenal axis, the role of this neuroendocrine system in diabetes-induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced insulin and show hyperglycemia, increased corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity.

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Figure 1: Maintaining normal physiological corticosterone prevents learning deficits in rodent models of diabetes.
Figure 2: Lowering corticosterone regulates synaptic plasticity in diabetic rodents.
Figure 3: AraC treatment reduces cell proliferation, without altering synaptic marker immunoreactivity.
Figure 4: Antimitotic treatment selectively impairs dentate gyrus LTP recorded in the absence of picrotoxin.
Figure 5: Elevated corticosterone contributes to the suppression of dentate gyrus cell proliferation in diabetic rodents.
Figure 6: Hippocampal cell proliferation and neurogenesis is reduced in a mouse model of type 2 diabetes.
Figure 7: A high replacement dose of corticosterone reinstates learning deficits in adrenalectomized db/db mice.

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Acknowledgements

This research was supported by US National Institutes of Health National Research Service Award Predoctoral fellowship F31AG024690-03 to A.M.S. through Princeton University, and by the Intramural Research Program of the US National Institute on Aging. We thank D.L. Longo for suggestions and T. Lamb, O. Carlson, J.S. Villareal and R. Telljohann for technical assistance. We are also grateful to E. Gould and H. van Praag for comments on the manuscript.

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  1. Thiruma V Arumugam

    Present address: Present address: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79430, USA.,

Authors and Affiliations

  1. Psychology Department, Princeton University, Green Hall Washington Road, Princeton, 08544, New Jersey, USA

    Alexis M Stranahan

  2. Laboratory of Neurosciences, Cellular and Molecular Neurosciences Section, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Alexis M Stranahan, Thiruma V Arumugam, Roy G Cutler, Kim Lee & Mark P Mattson

  3. Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Josephine M Egan

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Contributions

A.M.S., M.P.M. and J.M.E. contributed to the conceptual design and development of the experiments. A.M.S., K.L., T.V.A. and R.G.C. performed surgeries, ran experiments and contributed data. All authors assisted with writing and revising the manuscript.

Corresponding author

Correspondence to Mark P Mattson.

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Stranahan, A., Arumugam, T., Cutler, R. et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11, 309–317 (2008). https://doi.org/10.1038/nn2055

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