Mooney Sandra M, Billings Elanaria, McNew Madison, Munson Carolyn A, Shaikh Saame R, Smith Susan M
Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States.
Department of Nutrition, University of North Carolina at Chapel Hill, Kannapolis, NC, United States.
Front Neurosci. 2023 Jul 6;17:1187220. doi: 10.3389/fnins.2023.1187220. eCollection 2023.
Prenatal alcohol exposure (PAE) causes neuroinflammation that may contribute to the pathophysiology underlying Fetal Alcohol Spectrum Disorder. Supplementation with omega-3 polyunsaturated fatty acids (PUFAs) has shown success in mitigating effects of PAE in animal models, however, the underlying mechanisms are unknown. Some PUFA metabolites, specialized pro-resolving mediators (SPMs), play a role in the resolution phase of inflammation, and receptors for these are in the brain.
To test the hypothesis that the SPM receptors FPR2 and ChemR23 play a role in PAE-induced behavioral deficits, we exposed pregnant wild-type (WT) and knockout (KO) mice to alcohol in late gestation and behaviorally tested male and female offspring as adolescents and young adults.
Maternal and fetal outcomes were not different among genotypes, however, growth and behavioral phenotypes in the offspring did differ and the effects of PAE were unique to each line. In the absence of PAE, ChemR23 KO animals showed decreased anxiety-like behavior on the elevated plus maze and FPR2 KO had poor grip strength and low activity compared to age-matched WT mice. WT mice showed improved performance on fear conditioning between adolescence and young adulthood, this was not seen in either KO.
This PAE model has subtle effects on WT behavior with lower activity levels in young adults, decreased grip strength in males between test ages, and decreased response to the fear cue indicating an effect of alcohol exposure on learning. The PAE-mediated decreased response to the fear cue was also seen in ChemR23 KO but not FPR2 KO mice, and PAE worsened performance of adolescent FPR2 KO mice on grip strength and activity. Collectively, these findings provide mechanistic insight into how PUFAs could act to attenuate cognitive impairments caused by PAE.
产前酒精暴露（PAE）会引发神经炎症，这可能导致胎儿酒精谱系障碍的病理生理过程。补充ω-3多不饱和脂肪酸（PUFA）已显示出在减轻动物模型中PAE影响方面取得成功，然而，其潜在机制尚不清楚。一些PUFA代谢产物，即特殊的促消退介质（SPM），在炎症消退阶段发挥作用，且其受体存在于大脑中。
为了检验SPM受体FPR2和ChemR23在PAE诱导的行为缺陷中起作用这一假设，我们在妊娠晚期将怀孕的野生型（WT）和基因敲除（KO）小鼠暴露于酒精中，并在青少年期和成年早期对雄性和雌性后代进行行为测试。
不同基因型之间的母体和胎儿结局并无差异，然而，后代的生长和行为表型确实存在差异，且PAE的影响因品系而异。在无PAE的情况下，与年龄匹配的WT小鼠相比，ChemR23基因敲除动物在高架十字迷宫中表现出焦虑样行为减少，而FPR2基因敲除动物握力差且活动量低。WT小鼠在青少年期和成年早期之间的恐惧条件反射测试中表现有所改善，而在任一基因敲除小鼠中均未观察到这种情况。
该PAE模型对WT行为有微妙影响，成年后活动水平较低，测试年龄之间雄性握力下降，对恐惧线索的反应降低，表明酒精暴露对学习有影响。在ChemR23基因敲除小鼠中也观察到PAE介导的对恐惧线索反应降低，但在FPR2基因敲除小鼠中未观察到，且PAE使青少年FPR2基因敲除小鼠在握力和活动方面的表现变差。总的来说，这些发现为PUFA如何减轻PAE引起的认知障碍提供了机制性见解。
