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Published online: 2023-06-05

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Changes in myelinated fibers in the hippocampus of streptozotocin-induced diabetic rats: a stereological investigation

Hui Zhao1, Ting Zhang2, Feng Zhao2, Min Tan2, Shijuan Du3, Yunzi Wang3, Juan Li3, Jiang Du4, Yong Tang5, Yuanyu Zhao6


Diabetes causes cognitive impairment, and the hippocampus is important for long-term and permanent memory function. However, the mechanism of their interaction is still unclear. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin (STZ). This study aims to explore the changes in myelinated fibers in the hippocampus of type 1 diabetic rats. The unbiased stereological methods and transmission electron microscopy were used to obtain the total volume of the hippocampus, the total volume of the myelin sheath, the total length of the myelinated nerve fibers, the distribution of the length with different diameters of the myelinated fibers, and the distribution of the length with different thickness of the myelin sheath. Stereological analysis revealed that, compared to that of the control group, the total myelinated fibers volumes and the total myelinated fibers length were decreased slightly, while the total volume and the thickness of myelin sheaths were significantly decreased in the diabetic group. Finally, when compared with the control group, the total length of myelinated fibers in the diabetes group was significantly reduced, with diameters ranging from 0.7 to 1.1 μm and thicknesses of myelin sheaths from 0.15 to 0.17 μm. This study provides the first experimental evidence by stereological means to demonstrate that myelinated nerve fibers may be the key factor in cognitive dysfunction in diabetes.

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  1. Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006; 98(3): 641–653.
  2. Frøkjær JB, Brock C, Søfteland E, et al. Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study. Exp Clin Endocrinol Diabetes. 2013; 121(6): 354–360.
  3. Gao H, Jiang Q, Ji H, et al. Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(12): 165541.
  4. Guan Yi, Ebrahimzadeh SA, Cheng CH, et al. Alzheimer's Disease Neuroimaging Initiative. Association of Diabetes and Hypertension With Brain Structural Integrity and Cognition in the Boston Puerto Rican Health Study Cohort. Neurology. 2022; 98(15): e1534–e1544.
  5. Ho N, Sommers MS, Lucki I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev. 2013; 37(8): 1346–1362.
  6. Kodl CT, Franc DT, Rao JP, et al. Diffusion tensor imaging identifies deficits in white matter microstructure in subjects with type 1 diabetes that correlate with reduced neurocognitive function. Diabetes. 2008; 57(11): 3083–3089.
  7. Koellisch U, Laustsen C, Nørlinger TS, et al. Investigation of metabolic changes in STZ-induced diabetic rats with hyperpolarized [1-13C]acetate. Physiol Rep. 2015; 3(8).
  8. Li C, Yang S, Chen L, et al. Stereological methods for estimating the myelin sheaths of the myelinated fibers in white matter. Anat Rec (Hoboken). 2009; 292(10): 1648–1655.
  9. Lisman J, Buzsáki G, Eichenbaum H, et al. Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci. 2017; 20(11): 1434–1447.
  10. Moheet A, Mangia S, Seaquist ER. Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci. 2015; 1353: 60–71.
  11. Morris RG, Garrud P, Rawlins JN, et al. Place navigation impaired in rats with hippocampal lesions. Nature. 1982; 297(5868): 681–683.
  12. Morton H, Kshirsagar S, Orlov E, et al. Defective mitophagy and synaptic degeneration in Alzheimer's disease: Focus on aging, mitochondria and synapse. Free Radic Biol Med. 2021; 172: 652–667.
  13. Northam EA, Rankins D, Cameron FJ. Therapy insight: the impact of type 1 diabetes on brain development and function. Nat Clin Pract Neurol. 2006; 2(2): 78–86.
  14. Qiu X, Huang CX, Lu W, et al. Effects of a 4 month enriched environment on the hippocampus and the myelinated fibers in the hippocampus of middle-aged rats. Brain Res. 2012; 1465: 26–33.
  15. Teh K, Wilkinson ID, Heiberg-Gibbons F, et al. Central nervous system involvement in diabetic neuropathy. Curr Diab Rep. 2011; 11(4): 310–322.
  16. Stranahan AM. Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience. 2015; 309: 125–139.
  17. Tang Y, Nyengaard JR. A stereological method for estimating the total length and size of myelin fibers in human brain white matter. J Neurosci Methods. 1997; 73(2): 193–200.
  18. Tang Y, Pakkenberg B, Nyengaard JR. Myelinated nerve fibres in the subcortical white matter of cerebral hemispheres are preserved in alcoholic subjects. Brain Res. 2004; 1029(2): 162–167.
  19. Xie K, Perna L, Schöttker B, et al. Type 2 diabetes mellitus and cognitive decline in older adults in Germany — results from a population-based cohort. BMC Geriatr. 2022; 22(1): 455.
  20. Zhao F, Li J, Mo L, et al. Changes in neurons and synapses in hippocampus of streptozotocin-induced type 1 diabetes rats: a stereological investigation. Anat Rec (Hoboken). 2016; 299(9): 1174–1183.
  21. Zhao Y, Liu J, Li J, et al. Changes in hippocampal capillaries in transgenic type 2 diabetic mice: a stereological investigation. Anat Rec (Hoboken). 2021; 304(5): 1071–1083.
  22. Zhao YY, Shi XY, Qiu X, et al. Enriched environment increases the myelinated nerve fibers of aged rat corpus callosum. Anat Rec (Hoboken). 2012; 295(6): 999–1005.
  23. Zheng H, Lin Q, Wang D, et al. NMR-based metabolomics reveals brain region-specific metabolic alterations in streptozotocin-induced diabetic rats with cognitive dysfunction. Metab Brain Dis. 2017; 32(2): 585–593.