The apolipoprotein E (APOE) ε4 allele hastens cognitive decline, but other non-cognitive behaviours, as well as underpinning interactions with the cholinergic system, have not been systematically addressed. Both C57BL/6 and humanised apoE4 female mice were transiently exposed to subclinical doses (0 or 1 mg/kg body weight) of the cholinesterase inhibitor chlorpyrifos (CPF), a widely-used pesticide, from postnatal days 10-15. At 5 months of age, we assessed the impact of APOE4 genotype, postnatal CPF exposure and APOE4 x CPF interactions on anxiety (open field and light-dark tests), stereotypes (digging test) and neophobia (sucrose preference test), as well as on high-fat diet (HFD)-seeking and consumption (scheduled-feeding paradigm). We found that control APOE4 female carriers displayed a robust anxiety-like phenotype, which was accompanied by exaggerated stereotypes and a subtle neophobic response to rewarding foods. In parallel, we observed an amplified "wanting" response for HFD in these mice, which did not entail enhanced "liking". Notably, postnatal CPF ameliorated the anxiety-like and the heightened HFD-seeking responses in adult apoE4 female mice, while caused them to gain weight steadily compared to control peers. In turn, an early-life transient exposure to CPF fostered the over-consumption of HFD during adulthood without affecting how much this reward was "wanted" or the total caloric intake. These data reveal a role for CPF towards fostering "unhealthy" dietary choices. We conclude that the APOE4 genotype modulates non-cognitive behaviours and we provide support for an APOE4-dependent cholinergic dysfunction.

中文翻译：

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产后胆碱能刺激雌性小鼠改善APOE4依赖性非认知行为特征。

载脂蛋白E（APOE）ε4等位基因加速了认知功能下降，但尚未系统解决其他非认知行为以及与胆碱能系统相互作用的基础。从出生后的第10-15天开始，将C57BL / 6和人源化apoE4雌性小鼠短暂暴露于亚临床剂量（0或1 mg / kg体重）的胆碱酯酶抑制剂毒死rif（CPF），一种广泛使用的农药。在5个月大时，我们评估了APOE4基因型，出生后CPF暴露和APOE4 x CPF相互作用对焦虑（开放视野和明暗测试），刻板印象（挖掘测试）和新恐惧症（蔗糖偏爱测试）的影响，以及寻求高脂饮食（HFD）和食用（计划喂养范例）。我们发现对照APOE4女性携带者表现出强大的焦虑样表型，伴随着夸张的刻板印象和对奖励食品的微妙的新恐惧感反应。同时，我们在这些小鼠中观察到了对HFD的放大的“想要的”反应，但这并没有增强“喜欢”的感觉。值得注意的是，出生后的CPF改善了成年apoE4雌性小鼠的焦虑样症状和HFD寻求反应的增强，但与对照组相比，它们却稳定地增加了体重。反过来，生命早期对CPF的短暂暴露会导致成年期HFD的过度消费，而不会影响“想要”多少奖励或总热量摄入。这些数据揭示了CPF在促进“不健康”饮食选择方面的作用。我们得出的结论是，APOE4基因型调节非认知行为，并为依赖APOE4的胆碱能功能障碍提供支持。