Increased anxiety-like behavior is associated with the metabolic syndrome in non-stressed rats

Rebolledo-Solleiro, Daniela; Díaz, Daniel; Velasco, Manuel; Larqué, Carlos; Rico-Rosillo, Guadalupe; Vega-Robledo, Gloria Bertha; Zambrano, Elena; Hiriart, Marcia; Mora, Miguel Pérez de la

doi:10.1371/journal.pone.0176554

Cited by 56 publications

(38 citation statements)

References 80 publications

(126 reference statements)

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“…Impaired metabolic regulation is associated with anxiety behavior (46,47). Therefore, it is possible that the severe glucose intolerance in TauKO and hTau mice (21) is involved in the increase of anxiety-related behavior reported in this study.…”

Section: Discussionmentioning

confidence: 73%

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Behavioral Abnormalities in Knockout and Humanized Tau Mice

et al. 2020

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Microtubule-associated protein tau assists in stabilizing microtubules and has been particularly implicated in Alzheimer's disease (AD). Given the importance of tau to AD pathogenesis and therapies, it is important to understand non-classic physiological functions for this protein inside and outside the central nervous system (CNS). Our group has previously shown that tau ablation triggers glucose intolerance and pancreatic dysfunction in mice, suggesting that tau plays a role in peripheral metabolic regulation. Little is known about the role of tau in anxiety. Moreover, inconsistent results have been generated regarding the effects of tau deletion in memory. Here, we characterize systemic insulin resistance, anxiety-related behavior and memory in 15 to 20 weeks old Wild-Type (WT), Tau knockout (TauKO) and a distinct hTau mouse model consisting of tau knockout expressing the longest isoform (2N4R) of a non-mutant WT human Tau protein under the prion promoter (hTau). Our findings demonstrate that tau deletion leads to anxiety-related behavior, impaired contextual and cued fear memory. The presence of a human Tau transgene did not ameliorate the phenotypes observed in animals lacking the mouse tau protein and it elicited impairments in learning, memory, and peripheral insulin sensitivity. Our results suggest that tau protein plays a role in memory and anxiety-related behavior. Our findings also indicate that previously unrecognized functions for tau protein may be a complicating factor in using animal models on the TauKO background. Understanding the link between tau pathophysiology and cognitive and metabolic alterations is of great importance to establish the complete contribution of tau protein to AD pathogenesis.

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Section: Discussionmentioning

confidence: 73%

“…Impaired metabolic regulation is associated with anxiety symptoms (46,47). Therefore, we investigated anxiety-related behavior in 15-19 weeks old WT and TauKO mice at the open field (OF), elevated zero maze (EZM), forced swim, and tail suspension behavior tests.…”

Section: Patterns Of Anxiety-related Behaviors In Tauko and Htau Micementioning

confidence: 99%

Behavioral Abnormalities in Knockout and Humanized Tau Mice

et al. 2020

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“…Cognitive impairment in the diabetic milieu has been amply recognized in diabetes mellitus (DM) 1 and 2 [22,23]. In rats, feeding a diet high in sucrose or fat was shown to increase anxiety-like behavior [24,25] but the relationship between hyperglycemia in the intrauterine milieu, as in the case of gestational diabetes (GD), and its impact in the cognitive development and behavior of offspring and a possible mechanism has been poorly studied. The aim of this study was to evaluate the effects of gestational diabetes on cognitive performance, focusing on anxiety-like behavior and learning in juvenile and adult offspring rats.…”

Section: Introductionmentioning

confidence: 99%

Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects

et al. 2020

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Gestational diabetes (GD) has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. Oxidative stress is strongly associated with neurodegeneration and cognitive disruption. In the offspring brains in a GD experimental rat model, increased oxidative stress in the prenatal and postnatal stages was reported. However, long-term alterations to offspring behavior and oxidative stress, caused by changes in the cerebral cortex and hippocampus, remain unclear. In this study, we evaluated the effect of GD on young and adult male and female rat offspring in metabolic parameters, cognitive behavior, and oxidative stress. GD was induced using streptozotocin in dams. Next, the offspring were evaluated at two and six months of age. Anxiety-like behavior was evaluated using the elevated plus maze and open field maze; spatial learning and short-term memory were evaluated using the Morris water maze and radial maze, respectively. We determined oxidative stress biomarkers (reactive oxygen species (ROS), lipid peroxidation and glutathione status) and antioxidant enzymes (superoxide dismutase and catalase) in the brain of offspring. We observed that male GD offspring showed a reduced level of anxiety at both ages as they spent less time in the closed arms of the elevated plus maze at adult age ((P = 0.019, d = 1.083 ( size effect)) and spent more time in the open area of an open field (P = 0.0412, d = 0.743) when young and adult age (P = 0.018, d = 0.65). Adult female GD offspring showed a reduced level of anxiety (P = 0.036; d = 0.966), and young female GD offspring showed a deficiency in spatial learning (P = 0.0291 vs. control, d = 3.207). Adult male GD offspring showed a deficiency in short-term memory (P = 0.017, d = 1.795). We found an increase in ROS and lipid peroxidation, a disruption in the glutathione status, and decreased activity of catalase and superoxide dismutase (P < 0.05 vs. control, d > 1.0), in the cerebral cortex and hippocampus of male and female GD offspring. GD altered metabolism; male offspring of both ages and adult females showed a high level of triglycerides and a lower level of high-density lipoprotein-cholesterol (P < 0.05 vs. control, d > 1.0). Young and adult female offspring displayed higher insulin levels (P < 0.05, d > 1.0). These results suggest that gestational diabetes modifies oxidative stress and cognitive behavior in an age- and sex-dependent manner.

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“…There is growing recognition for a reciprocal, bidirectional link between anxiety disorders and proinflammatory diets (4), and obesity and related metabolic diseases (5; 6). Studies in humans and rodents have shown that obesity and the consumption of obesogenic diets are risk factors for the development of anxiety-related psychopathology (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Endocrine, metabolic, and endocannabinoid alterations in rats exhibiting high anxiety-related behaviors

Vega-Torres

Kalyan-Masih

Argueta

et al. 2019

Preprint

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Anxiety disorders are major risk factors for obesity. However, the mechanisms accounting for this susceptibility remain unclear. Animal models have proved to be useful tools for understanding the role of emotional functioning in the development and maintenance of metabolic alterations implicated in obesity. Here we sought to determine the predictive value of behavioral indices of anxiety for hormonal and metabolic imbalances in rats.Adult Lewis rats were screened on the elevated plus maze (EPM). K-means clustering was used to divide the rats into two groups based on their anxiety index in the EPM: low (LA) and high anxiety (HA) rats. This proxy of anxiety combines individual EPM parameters and accepted ratios into a single score. Four weeks later, we measured markers of endocrine and metabolic function. We found that relative LA rats, the HA rats exhibited reduced latencies to exit a modified light-dark conflict test. Our results show that the HA rats displayed increased corticosterone levels when compared to LA rats. Furthermore, the HA rats weighted more and exhibited an enhanced glycemic response to exogenously administered glucose during the glucose tolerance test, indicating glucose intolerance. Notably, when compared to LA rats, the HA rats showed higher circulating levels of the endogenous cannabinoid, 2-arachidonoyl-sn-glycerol (2-AG). Together, these data indicate that patterns of emotional reactivity associated with anxiety may share common pathological pathways with metabolic complications implicated in obesity.Uncovering metabolic risk factors for anxiety disorders have the potential to strongly impact how we treat mental illnesses. ObjectiveTo test the hypothesis that indices of anxiety in the elevated plus maze have predictive value for alterations implicated in obesity, which include heightened emotional reactivity, and dysregulated corticosterone, glucose metabolism, and circulating endocannabinoid levels.

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Increased anxiety-like behavior is associated with the metabolic syndrome in non-stressed rats

Cited by 56 publications

References 80 publications

Behavioral Abnormalities in Knockout and Humanized Tau Mice

Behavioral Abnormalities in Knockout and Humanized Tau Mice

Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects

Endocrine, metabolic, and endocannabinoid alterations in rats exhibiting high anxiety-related behaviors

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