Autism-Like Behaviours and Memory Deficits Result from a Western Diet in Mice

Abstract

Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder.

Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?

“…These observations will be discussed, in turn, below. The present study on aged mice has, in general, replicated the principal findings reported for young mice fed the WD, such as impaired glucose tolerance, altered expression of Tlr4, Ppargc1a, and Ppargc1b (Strekalova et al, , 2016, and signs of emotional and cognitive abnormalities (Strekalova et al, , 2016Veniaminova et al, 2016Veniaminova et al, , 2017Veniaminova et al, , 2020. In comparison with young mice, aged animals exposed to WD gained weight and exhibited less profound changes in the expression of markers of inflammation and mitochondrial function.…”

“…Mice were fed with a standard laboratory diet (control diet, CD) with an energy content of 3.8 kcal/g, 4.3% of fat (1.3% of saturated fat) (D18071801, Research Diet Inc., New Brunswick, NJ, United States) or with a diet containing 0.2% of cholesterol, 21.3% of fat (10.5% of saturated fat), and an energy content of 4.6 kcal/g, Western diet (D11012302, Research Diet Inc., New Brunswick, NJ, United States) for 3 weeks as described elsewhere (Strekalova et al, , 2016Veniaminova et al, 2017). The content of the nutrients in calories and weight and the ingredients are indicated in Supplementary Table S1.…”

“…Oral glucose tolerance test (OGTT) was performed as described elsewhere (Veniaminova et al, 2017(Veniaminova et al, , 2020. The test mice were fasted overnight for 18 h, beginning at 1600.…”

“…In the present study, we sought to investigate metabolic, molecular, and behavioral changes induced by the WD in aged mice with complete or partial genetic SERT deficit. We employed a previously validated model that involves feeding mice with the WD for 3 weeks, and we evaluated metabolic and neurobiological hallmarks of the WD-induced syndrome in vitro and ex vivo assays (Strekalova et al, , 2016Veniaminova et al, 2016Veniaminova et al, , 2017Veniaminova et al, , 2020. In this model, impaired glucose tolerance, increases in cholesterol and leptin blood levels, brain and liver overexpression of Toll-like receptor 4 (Tlr4), decreased expression of mitochondrial markers peroxisome proliferatoractivated receptor gamma coactivator 1 (Ppargc1) a and b, and decreased Sert expression in the brain are all features.…”

“…In this model, impaired glucose tolerance, increases in cholesterol and leptin blood levels, brain and liver overexpression of Toll-like receptor 4 (Tlr4), decreased expression of mitochondrial markers peroxisome proliferatoractivated receptor gamma coactivator 1 (Ppargc1) a and b, and decreased Sert expression in the brain are all features. These molecular changes are accompanied by depressive-and anxietylike behaviors, signs of impulsivity, lowered sociability, and cognitive deficits (Strekalova et al, , 2016Veniaminova et al, 2016Veniaminova et al, , 2017Veniaminova et al, , 2020. Here, in view of the changes observed in 5-HT receptor densities in aging and in those with SERT deficiency, we also studied gene expression of serotonin receptors Htr1a, Htr1b, and Htr2a in the brain.…”