Time-dependent impairments in learning and memory in Streptozotocin-induced hyperglycemic rats

Abstract

The sedentary lifestyle is responsible for the high prevalence of diabetes which also impairs cognition including learning and memory. Various studies have highlighted the learning and memory impairments in rodent models but data regarding the timeline of their development and their correlation to biochemical parameters are scarce. So, the present study was designed to investigate the type of memory which is more susceptible to hyperglycemia and its correlation with biochemical parameters such as inflammatory cytokines, cAMP response element binding (CREB) and protein kinase B (Akt) activation. Hyperglycemia was induced using streptozotocin (STZ, 45 mg/kg i.p.) and confirmed by measuring fasting blood glucose levels after 1 week of STZ injection. Learning and memory deficits were evaluated using the Novel Object Recognition Test (NORT) and Morris water maze (MWM), and correlated with biochemical parameters (TNF-α, IL-1β, and dopamine) at 3, 6 and 9 weeks. STZ-injected rats after 3 weeks of injection demonstrated moderate hyperglycemia (blood glucose = 7.99 ± 0.62 mM) with intact learning and reference memory; however, their working memory was impaired in MWM. Severe hyperglycemia (blood glucose = 11.51 ± 0.69 mM) accompanied by impaired short, long, and working memory was evident after 6 weeks whereas learning was intact. After 9 weeks of STZ injection, hyperglycemia was more pronounced (13.69 ± 1.43 mM) and accompanied by a learning deficit in addition to short, long, and working memory impairments. The extent of hyperglycemia either in terms of duration or severity resulted in enhanced inflammation, down-regulation of the level of dopamine, protein expression of AKT and CREB, which possibly affected learning and memory negatively.

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Acknowledgements

This work was supported by CAMS Initiatives for Innovation Medicine (2016-12 M-2-006), the National Key Research and Development Program of China (2016YFE0131800), the Joint Funds of the Southwest Medical University & Luzhou Municipal Government of China 2015LZCYD-S04 (7/15), Hunan Province Science and Technology Plan Projects of China (2015DK3010, the High - end Talents Recruitment Program (Chen Chen group) of Luzhou Municipal People’s Government. We would like to thank Dr. Radhakrishnan Rajan, College of Medicine, MBR University, Dubai, UAE, for his kind help to revise the manuscript. We would also like to thank the editor and reviewers of this manuscript whose critical reviews help us to make the draft better.

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Correspondence to Xinmin Liu or Qiong Wang.

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Ayaz Ahmed and Guirong Zeng shared the first author

Research highlights

• Learning and memory impairment is time and hyperglycemia severity dependent.

• Working memory impaired firstly among other cognitive declines.

• Early and enhanced inflammation might be responsible for cognitive decline.

• AKT and CREB expressions is reduced with hyperglycemia severity.

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Ahmed, A., Zeng, G., Jiang, D. et al. Time-dependent impairments in learning and memory in Streptozotocin-induced hyperglycemic rats. Metab Brain Dis 34, 1431–1446 (2019). https://doi.org/10.1007/s11011-019-00448-7

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Keywords

  • Hyperglycemia
  • Learning and memory
  • Novel object recognition test
  • Morris water maze
  • Dopamine
  • AKT
  • CREB