title: Spatial memory impairments in a prediabetic rat model.
abstract: Diabetes is associated with an increased risk for brain disorders, namely cognitive impairments associated with hippocampal dysfunction underlying diabetic encephalopathy. However, the impact of a prediabetic state on cognitive function is unknown. Therefore, we now investigated whether spatial learning and memory deficits and the underlying hippocampal dysfunction were already present in a prediabetic animal model. Adult Wistar rats drinking high-sucrose (HSu) diet (35% sucrose solution during 9 weeks) were compared to controls' drinking water. HSu rats exhibited fasting normoglycemia accompanied by hyperinsulinemia and hypertriglyceridemia in the fed state, and insulin resistance with impaired glucose tolerance confirming them as a prediabetic rodent model. HSu rats displayed a poorer performance in hippocampal-dependent short- and long-term spatial memory performance, assessed with the modified Y-maze and Morris water maze tasks, respectively; this was accompanied by a reduction of insulin receptor-β density with normal levels of insulin receptor substrate-1 pSer636/639, and decreased hippocampal glucocorticoid receptor levels without changes of the plasma corticosterone levels. Importantly, HSu animals exhibited increased hippocampal levels of AMPA and NMDA receptor subunits GluA1 and GLUN1, respectively, whereas the levels of protein markers related to nerve terminals (synaptophysin) and oxidative stress/inflammation (HNE, RAGE, TNF-α) remained unaltered. These findings indicate that 9 weeks of sucrose consumption resulted in a metabolic condition suggestive of a prediabetic state, which translated into short- and long-term spatial memory deficits accompanied by alterations in hippocampal glutamatergic neurotransmission and abnormal glucocorticoid signaling.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Subunit1-Pólo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Soares
authors.forename: R D
authors.initials: RD
authors.lastname: Prediger
authors.forename: S
authors.initials: S
authors.lastname: Nunes
authors.forename: A A
authors.initials: AA
authors.lastname: Castro
authors.forename: S D
authors.initials: SD
authors.lastname: Viana
authors.forename: C
authors.initials: C
authors.lastname: Lemos
authors.forename: C M
authors.initials: CM
authors.lastname: De Souza
authors.forename: P
authors.initials: P
authors.lastname: Agostinho
authors.forename: R A
authors.initials: RA
authors.lastname: Cunha
authors.forename: E
authors.initials: E
authors.lastname: Carvalho
authors.forename: C A
authors.initials: CA
authors.lastname: Fontes Ribeiro
authors.forename: F
authors.initials: F
authors.lastname: Reis
authors.forename: F C
authors.initials: FC
authors.lastname: Pereira
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004032:Diet; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000523:psychology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011236:Prediabetic State / Q000097:blood / Q000150:complications / Q000523:psychology*; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013028:Space Perception / Q000502:physiology*; D013395:Sucrose / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D006442:Glycated Hemoglobin; D008055:Lipids; D009419:Nerve Tissue Proteins; D011972:Receptor, Insulin; D018091:Receptors, AMPA; D011965:Receptors, Glucocorticoid; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013395:Sucrose; C121673:Gprin1 protein, mouse
keywords: ANOVA; AUC; BBB; Cont; EGTA; ELISA; GAPDH; GFAP; GR; GS; GTT; HFD; HNE; HOMA; HPA; HSu; IGT; ITT; N-methyl-d-aspartate receptor; NMDAR; PBS-T; PSD-95; RAGE; STZ; T2DM; TGs; TNF-α; ZDF; Zucker Diabetic Fatty; analysis of variance; area under the curve; blood–brain barrier; control; diabetic encephalopathy; enzyme-linked immunosorbent assay; ethylene glycol tetraacetic acid; glial fibrillary acidic protein; glucocorticoid receptor; glucose tolerance test; glutamine synthetase; glyceraldehyde-3-phosphate dehydrogenase; high-fat diet; high-sucrose; high-sucrose diet; hippocampus; homeostasis model assessment index; hydroxynonenal; hypothalamic–pituitary–adrenal; impaired glucose tolerance; insulin tolerance test; memory; phosphate-buffered saline with 0.1% Tween-20; postsynaptic density protein 95; prediabetes; receptor for advanced glycation end products; streptozotocin; triglycerides; tumor necrosis factor α; type 2 diabetes mellitus