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

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.

References

  1. Reaven, G.M. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu. Rev. Nutr. 25, 391–406 (2005).

    CAS  Article  Google Scholar 

  2. Messier, C. Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging. Neurobiol. Aging 26 (suppl. 1), S26–S30 (2005).

    CAS  Article  Google Scholar 

  3. Greenwood, C.E. & Winocur, G. High-fat diets, insulin resistance and declining cognitive function. Neurobiol. Aging 26 (suppl. 1), 45 (2005).

    Google Scholar 

  4. Desrocher, M. & Rovet, J. Neurocognitive correlates of type 1 diabetes mellitus in childhood. Child Neuropsychol. 10, 36–52 (2004).

    Article  Google Scholar 

  5. Biessels, G.J. et al. Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 45, 1259–1266 (1996).

    CAS  Article  Google Scholar 

  6. Biessels, G.J. et al. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res. 800, 125–135 (1998).

    CAS  Article  Google Scholar 

  7. Li, X.L. et al. Impairment of long-term potentiation and spatial memory in leptin receptor–deficient rodents. Neuroscience 113, 607–615 (2002).

    CAS  Article  Google Scholar 

  8. Hummel, K.P., Dickie, M.M. & Coleman, D.L. Diabetes, a new mutation in the mouse. Science 153, 1127–1128 (1966).

    CAS  Article  Google Scholar 

  9. Leuner, B., Gould, E. & Shors, T.J. Is there a link between adult neurogenesis and learning? Hippocampus 16, 216–224 (2006).

    Article  Google Scholar 

  10. Kamal, A., Biessels, G.J., Urban, I.J. & Gispen, W.H. Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression. Neuroscience 90, 737–745 (1999).

    CAS  Article  Google Scholar 

  11. Zhang, W.J., Tan, Y.F., Yue, J.T., Vranic, M. & Wojtowicz, J.M. Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol. Scand., published online 14 September 2007 (doi:10.1111/j.1600-0404.2007.00928.x).

  12. van Praag, H., Christie, B.R., Sejnowski, T.J. & Gage, F.H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 96, 13427–13431 (1999).

    CAS  Article  Google Scholar 

  13. Fontan-Lozano, A. et al. Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor. J. Neurosci. 27, 10185–10195 (2007).

    CAS  Article  Google Scholar 

  14. Lee, J., Duan, W. & Mattson, M.P. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 1367–1375 (2002).

    CAS  Article  Google Scholar 

  15. Stranahan, A.M., Khalil, D. & Gould, E. Social isolation delays the positive effects of running on adult neurogenesis. Nat. Neurosci. 9, 526–533 (2006).

    CAS  Article  Google Scholar 

  16. Magarinos, A.M. & McEwen, B.S. Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress. Proc. Natl. Acad. Sci. USA 97, 11056–11061 (2000).

    CAS  Article  Google Scholar 

  17. Chan, O. et al. Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA response to insulin-induced hypoglycemia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R235–R246 (2005).

    CAS  Article  Google Scholar 

  18. Tokuyama, K. & Himms-Hagen, J. Increased sensitivity of the genetically obese mouse to corticosterone. Am. J. Physiol. 252, 202–208 (1987).

    Google Scholar 

  19. Langley, S.C. & York, D.A. Effects of antiglucocorticoid RU486 on development of obesity in obese fa/fa Zucker rats. Am. J. Physiol. 259, 539–544 (1990).

    Google Scholar 

  20. Watts, L.M. et al. Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. Diabetes 54, 1846–1853 (2005).

    CAS  Article  Google Scholar 

  21. Oei, N.Y., Everaerd, W.T., Elzinga, B.M., van Well, S. & Bermond, B. Psychosocial stress impairs working memory at high loads: an association with cortisol levels and memory retrieval. Stress 9, 133–141 (2006).

    CAS  Article  Google Scholar 

  22. MacLullich, A.M. et al. Plasma cortisol levels, brain volumes and cognition in healthy elderly men. Psychoneuroendocrinology 30, 505–515 (2005).

    CAS  Article  Google Scholar 

  23. Elgh, E. et al. Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer's disease. Biol. Psychiatry 59, 155–161 (2006).

    CAS  Article  Google Scholar 

  24. Oitzl, M.S., Fluttert, M., Sutanto, W. & de Kloet, E.R. Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats. Eur. J. Neurosci. 10, 3759–3766 (1998).

    CAS  Article  Google Scholar 

  25. Wright, R.L., Lightner, E.N., Harman, J.S., Meijer, O.C. & Conrad, C.D. Attenuating corticosterone levels on the day of memory assessment prevents chronic stress–induced impairments in spatial memory. Eur. J. Neurosci. 24, 595–605 (2006).

    Article  Google Scholar 

  26. Alfarez, D.N., Joels, M. & Krugers, H.J. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur. J. Neurosci. 17, 1928–1934 (2003).

    Article  Google Scholar 

  27. Kerr, D.S., Campbell, L.W., Hao, S.Y. & Landfield, P.W. Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science 245, 1505–1509 (1989).

    CAS  Article  Google Scholar 

  28. Korz, V. & Frey, J.U. Stress-related modulation of hippocampal long-term potentiation in rats: Involvement of adrenal steroid receptors. J. Neurosci. 23, 7281–7287 (2003).

    CAS  Article  Google Scholar 

  29. Pavlides, C., Watanabe, Y. & McEwen, B.S. Effects of glucocorticoids on hippocampal long-term potentiation. Hippocampus 3, 183–192 (1993).

    CAS  Article  Google Scholar 

  30. Gould, E., Cameron, H.A., Daniels, D.C., Woolley, C.S. & McEwen, B.S. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J. Neurosci. 12, 3642–3650 (1992).

    CAS  Article  Google Scholar 

  31. Montaron, M.F. et al. Lifelong corticosterone level determines age-related decline in neurogenesis and memory. Neurobiol. Aging 27, 645–654 (2006).

    CAS  Article  Google Scholar 

  32. Tanapat, P., Hastings, N.B., Rydel, T.A., Galea, L.A. & Gould, E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J. Comp. Neurol. 437, 496–504 (2001).

    CAS  Article  Google Scholar 

  33. Karten, Y.J., Jones, M.A., Jeurling, S.I. & Cameron, H.A. GABAergic signaling in young granule cells in the adult rat and mouse dentate gyrus. Hippocampus 16, 312–320 (2006).

    CAS  Article  Google Scholar 

  34. Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).

    CAS  Article  Google Scholar 

  35. Saxe, M.D. et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. USA 103, 17501–17506 (2006).

    CAS  Article  Google Scholar 

  36. Snyder, J.S., Kee, N. & Wojtowicz, J.M. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 85, 2423–2431 (2001).

    CAS  Article  Google Scholar 

  37. Moosavi, M., Naghdi, N., Maghsoudi, N. & Zahedi Asl, S. Insulin protects against stress-induced impairments in water maze performance. Behav. Brain Res. 176, 230–236 (2007).

    CAS  Article  Google Scholar 

  38. Revest, J.M. et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat. Neurosci. 8, 664–672 (2005).

    CAS  Article  Google Scholar 

  39. Piroli, G.G. et al. Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus. Neuroendocrinology 85, 71–80 (2007).

    CAS  Article  Google Scholar 

  40. Sapolsky, R.M. Glucocorticoid toxicity in the hippocampus: reversal by supplementation with brain fuels. J. Neurosci. 6, 2240–2244 (1986).

    CAS  Article  Google Scholar 

  41. McNay, E.C., Fries, T.M. & Gold, P.E. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc. Natl. Acad. Sci. USA 97, 2881–2885 (2000).

    CAS  Article  Google Scholar 

  42. Reagan, L.P. et al. Localization and regulation of GLUTx1 glucose transporter in the hippocampus of streptozotocin diabetic rats. Proc. Natl. Acad. Sci. USA 98, 2820–2825 (2001).

    CAS  Article  Google Scholar 

  43. Shors, T.J., Townsend, D.A., Zhao, M., Kozorovitskiy, Y. & Gould, E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12, 578–584 (2002).

    Article  Google Scholar 

  44. Kee, N., Teixeira, C.M., Wang, A.H. & Frankland, P.W. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat. Neurosci. 10, 355–362 (2007).

    CAS  Article  Google Scholar 

  45. Bruel-Jungerman, E., Laroche, S. & Rampon, C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur. J. Neurosci. 21, 513–521 (2005).

    Article  Google Scholar 

  46. Sandeep, T.C. et al. 11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc. Natl. Acad. Sci. USA 101, 6734–6739 (2004).

    CAS  Article  Google Scholar 

  47. Cameron, H.A. & McKay, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417 (2001).

    CAS  Article  Google Scholar 

  48. Kozorovitskiy, Y. et al. Experience induces structural and biochemical changes in the adult primate brain. Proc. Natl. Acad. Sci. USA 102, 17478–17482 (2005).

    CAS  Article  Google Scholar 

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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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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.

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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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