Zieba Jerzy, Morris Margaret J, Karl Tim
Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Medical Sciences, UNSW Sydney, NSW 2052, Australia; Schizophrenia Research Institute, Randwick, NSW 2031, Australia.
School of Medical Sciences, UNSW Sydney, NSW 2052, Australia.
Behav Brain Res. 2019 Nov 5;373:112074. doi: 10.1016/j.bbr.2019.112074. Epub 2019 Jul 5.
A limited number of studies suggest that poor diet choices may impact on the mental state of schizophrenia patients. Our own work found that high fat diet (HFD) reversed social recognition memory deficits in female mice mutant for the schizophrenia risk gene neuregulin 1 (i.e. Nrg1 transmembrane domain: Nrg1 TM HET). Sex effects are common in schizophrenia and adolescence is a period of increased sensitivity to environmental risk factors. Thus, we investigated whether adolescent HFD exposure modulates schizophrenia-relevant behaviours of male and female Nrg1 TM HET mice. Male and female Nrg1 TM HET and their control littermates were exposed to either HFD or a standard chow diet from late adolescence onwards. After 8 weeks, adult mice were tested for locomotion and exploration, social behaviours, sensorimotor gating (i.e. prepulse inhibition), and fear-associated learning and memory. Nrg1 TM HET mice exhibited hyper-locomotion and an anxiolytic-like phenotype across sex and Nrg1 males tended to show deficient fear-associated memory. HFD increased body weight over time in all mice, an effect less pronounced in Nrg1 female mice. The moderately suppressive effect of HFD on females' exploration was less evident in Nrg1 mutants. Nrg1 TM HET female mice also displayed a less pronounced increase in HFD-induced cue freezing and HFD modulated the response to the cue in a complex genotype-dependent manner. In conclusion, HFD exposure starting in late adolescence has sex-specific effects on exploration and fear-associated memory, which was less pronounced in females mutant for Nrg1. This suggests that research into the role of diets in schizophrenia-relevant domains should consider genetic risk factors for the disease as schizophrenia risk genes such as Nrg1 may modulate dietary effects.
少数研究表明，不良的饮食选择可能会影响精神分裂症患者的精神状态。我们自己的研究发现，高脂肪饮食（HFD）逆转了精神分裂症风险基因神经调节蛋白1突变的雌性小鼠（即Nrg1跨膜结构域：Nrg1 TM HET）的社会认知记忆缺陷。性别效应在精神分裂症中很常见，而青春期是对环境风险因素敏感度增加的时期。因此，我们研究了青春期接触HFD是否会调节雄性和雌性Nrg1 TM HET小鼠与精神分裂症相关的行为。从青春期后期开始，将雄性和雌性Nrg1 TM HET小鼠及其对照同窝小鼠分别置于HFD或标准饲料饮食中。8周后，对成年小鼠进行运动和探索、社交行为、感觉运动门控（即前脉冲抑制）以及恐惧相关学习和记忆的测试。Nrg1 TM HET小鼠在性别上均表现出运动亢进和类似抗焦虑的表型，Nrg1雄性小鼠往往表现出恐惧相关记忆缺陷。随着时间的推移，HFD使所有小鼠体重增加，在Nrg1雌性小鼠中这种影响不太明显。HFD对雌性探索的中度抑制作用在Nrg1突变体中不太明显。Nrg1 TM HET雌性小鼠在HFD诱导的线索冻结方面的增加也不太明显，并且HFD以复杂的基因型依赖方式调节对线索的反应。总之，青春期后期开始接触HFD对探索和恐惧相关记忆有性别特异性影响，这在Nrg1突变的雌性小鼠中不太明显。这表明，在研究饮食在精神分裂症相关领域的作用时，应考虑该疾病的遗传风险因素，因为诸如Nrg1等精神分裂症风险基因可能会调节饮食效应。
