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Impairment of cognitive flexibility in type 2 diabetic db/db mice.

ABSTRACT: Impaired executive function is a major peril for patients with type 2 diabetes, reducing quality of life and ability for diabetes management. Despite the significance of this impairment, few animal models of type 2 diabetes examine domains of executive function such as cognitive flexibility or working memory. Here, we evaluated these executive function domains in db/db mice, an established model of type 2 diabetes, at 10 and 24 weeks of age. The db/db mice showed impaired cognitive flexibility in the Morris water maze reversal phase. However, the db/db mice did not show apparent working memory disturbance in the spatial working memory version of the Morris water maze or in the radial water maze. We also examined axon initial segments (AIS) and nodes of Ranvier, key axonal domains for action potential initiation and propagation. AIS were significantly shortened in medial prefrontal cortex and hippocampus of 26-week-old db/db mice compared with controls, similar to our previous findings in 10-week-old mice. Nodes of Ranvier in corpus callosum, previously shown to be unchanged at 10 weeks, were elongated at 26 weeks, suggesting an important role for this domain in disease progression. Together, the findings help establish db/db mice as a model of impaired cognitive flexibility in type 2 diabetes and advance our understanding of its pathophysiology.

SUBMITTER: Yermakov LM

PROVIDER: S-EPMC6579681 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Impairment of cognitive flexibility in type 2 diabetic db/db mice.

Yermakov Leonid M LM Griggs Ryan B RB Drouet Domenica E DE Sugimoto Chiho C Williams Michael T MT Vorhees Charles V CV Susuki Keiichiro K

Behavioural brain research 20190526

Impaired executive function is a major peril for patients with type 2 diabetes, reducing quality of life and ability for diabetes management. Despite the significance of this impairment, few animal models of type 2 diabetes examine domains of executive function such as cognitive flexibility or working memory. Here, we evaluated these executive function domains in db/db mice, an established model of type 2 diabetes, at 10 and 24 weeks of age. The db/db mice showed impaired cognitive flexibility i ...[more]

PMID: 31141724

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Project description:IntroductionThe rapid expansion of Type 2 Diabetes (T2D), that currently affects 90% of people suffering from diabetes, urges us to develop a better understanding of the metabolic processes involved in the disease process in order to develop better therapies. The most commonly used model for T2D research is the db/db (BKS.Cg-Dock7 < m > +/+ Lepr < db >/J) mouse model. Yet, a systematic 1H NMR based metabolomics characterisation of most tissues in this animal model has not been published. Here, we provide a systematic organ-specific metabolomics analysis of this widely employed model using NMR spectroscopy.ObjectivesThe aim of this study was to characterise the metabolic modulations associated with T2D in db/db mice in 18 relevant biological matrices.MethodsHigh-resolution 1H-NMR and 2D-NMR spectroscopy were applied to 18 biological matrices of 12 db/db mice (WT control n = 6, db/db = 6) aged 22 weeks, when diabetes is fully established.Results61 metabolites associated with T2D were identified. Kidney, spleen, eye and plasma were the biological matrices carrying the largest metabolomics modulations observed in established T2D, based on the total number of metabolites that showed a statistical difference between the diabetic and control group in each tissue (16 in each case) and the strength of the O-PLS DA model for each tissue. Glucose and glutamate were the most commonly associated metabolites found significantly increased in nine biological matrices. Investigated sections where no increase of glucose was associated with T2D include all intestinal segments (i.e. duodenum, jejunum, ileum and colon). Microbial co-metabolites such as acetate and butyrate, used as carbon sources by the host, were identified in excess in the colonic tissues of diabetic individuals.ConclusionsThe metabolic biomarkers identified using 1H NMR-based metabolomics will represent a useful resource to explore metabolic pathways involved in T2D in the db/db mouse model.

Project description:IntroductionDiabetic cognitive impairment (DCI) is a chronic complication of the central nervous system (CNS) caused by diabetes that affects learning and memory capacities over time. Recently, acupuncture has been shown to improve cognitive impairment in streptozotocin-induced diabetic rats. However, the effects of electroacupuncture on DCI and its underlying mechanism have not yet been elucidated in detail.MethodsIn this study, we used db/db mice as DCI animal models which showed low cognitive, learning and memory functions. Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. The db/db mice with cognitive impairment were randomly divided into a model group (Mod) and an electroacupuncture treatment group (Acup), while db/m mice were used as a normal control group (Con). First, the mice were subjected to behavioural tests using the Morris water maze (MWM), and body weight, blood glucose, insulin, triglycerides (TG) and total cholesterol (TC) were observed; HE, Nissl, and TUNEL staining were used to observe the morphological changes and neuronal apoptosis in the mice hippocampus; Finally, Western blot and rt-PCR were applied to detect the essential proteins and mRNA of ERS and insulin signalling pathway, as well as the expression levels of Tau and Aβ.ResultsElectroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. Moreover, electroacupuncture attenuated diabetes-induced morphological structure change, neuronal apoptosis in the hippocampus of db/db mice. Our results revealed that electroacupuncture could regulate the expression levels of Tau and Aβ by improving hippocampal ERS levels in db/db mice, inhibiting JNK activation, attenuating IRS1 serine phosphorylation, and restoring normal transduction of the insulin signaling pathway.DiscussionIn summary, ERS and insulin signaling pathway paly causal roles in DCI development. Electroacupuncture can significantly alleviate the pathogenesis of DCI, improve mice's learning and memory ability, and improve cognitive dysfunction. This study adds to our understanding of the effect of acupuncture on DCI and opens the door to further research on DCI.

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Impairment of cognitive flexibility in type 2 diabetic db/db mice.

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Impairment of cognitive flexibility in type 2 diabetic db/db mice.

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