High-fat diet administration induces compulsive-like behaviors and affects hippocampal neuronal plasticity and cognitive abilities in adult female mice

Excessive consumption of a high-fat diet (HFD) has been associated with an increased risk for the development of several diseases, including psychiatric disorders and behavioral alterations. Excess fat results in systemic chronic low-grade inflammation, which can trigger central inflammation. We hypothesize that such immune activation may, in turn, affect brain functioning by impairing neuronal plasticity, ultimately leading to behavioral and cognitive deficits. Thirty-one female C57/Bl6 mice received either an HFD (58% fat; 16 females) or a control diet (CD: 11% fat; 15 females) for 4 weeks [1]. Mice, according to diet, were housed in two IntelliCages, automated behavioral monitoring systems with four operant chambers at the corners containing drinking bottles [2]. We evaluated the effects of HFD administration on compulsive-like behaviors and cognitive abilities. Compulsive-like behaviors have been measured as an increased frequency of licks per visit, despite unchanged total licks and visits activity at the four corners. Cognitive functions were evaluated using the place learning test, during which access to drinking bottles was restricted to only one designated corner and learning is evidenced by an increased preference for this corner over time. The impact of HFD exposure on brain plasticity was assessed by evaluating the hippocampal long-term potentiation (LTP) induced by high-frequency stimulation consisting of two trains of stimuli (100 Hz, 1 s) at Schaffer collateral-CA1 synapses. Data was analyzed with Student’s t-test or repeated measures one-way ANOVA followed by Sidak's post-hoc. As expected, HFD exposure induced increased body weight (p < 0.01 HFD vs CD). Moreover, HFD-fed mice exhibited increased compulsive-like behaviors, as they performed an increased frequency of licks per visit (p < 0.01 HFD vs CD) with no differences in the number of visits and licks per day. As for cognitive abilities, in the acquisition phase of the place learning test, both the CD and HFD groups gradually increased their visits to the target corner. However, in the reversal phase, where the target corner is changed and is opposite to that of the acquisition phase, HFD-fed mice exhibited fewer incorrect visits (p < 0.05 HFD vs CD), suggesting improved extinction ability. Electrophysiological recordings revealed that HFD induced an enhancement of LTP amplitude at Schaffer collateral-CA1 synapses after two stimulation trains (p < 0.01 HFD vs CD). Our findings suggest that HFD consumption induced compulsive-like behaviors and affected cognitive abilities as well as hippocampal neuronal plasticity. We are currently investigating the effects of HFD consumption on the immune-metabolic profile both in the brain and peripheral tissues. Furthermore, we are exploring whether stressful environmental conditions may interact with unhealthy dietary patterns to reveal a vulnerable phenotype both in males and females, and whether administration of anti-inflammatory treatment could ameliorate the adverse effects of HFD.