Ukezono Masatoshi, Kasahara Yoshiyuki, Yoshida Chihiro, Murakami Yuki, Okada Takashi, Takano Yuji
Department of Developmental Disorders, National Center of Neurology and Psychiatry, National Institute of Mental Health, Kodaira, Japan.
Department of Maternal and Fetal Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan.
Front Behav Neurosci. 2024 Aug 29;18:1430267. doi: 10.3389/fnbeh.2024.1430267. eCollection 2024.
A rodent autism spectrum disorder (ASD) model based on prenatal exposure to valproic acid (VPA) is widely recognized as a prominent model. Social behavior in rodent ASD models has primarily been evaluated through a three-chamber approach test. However, in this study, we focused on social attention in the VPA model of ASD.
In male C57BL/6 J mice, attentional behaviors toward conspecifics were examined through reaching tasks around 9-11 weeks of age. On embryonic day 12.5, pregnant mice underwent a subcutaneous injection of 600 mg/kg VPA sodium salt dissolved in 0.9% saline solution (VPA group) or saline solution alone (Sal group) into their neck fat. Thirty-six mice-nine each in the VPA and saline groups, and 18 partners-underwent training in reaching behavior. Subsequently, we examined whether the VPA or Sal group demonstrated focused attention toward their partners during reaching tasks. A two-way analysis of variance (ANOVA) (condition [VPA/Sal] × situation [face-to-face (attention)/not paying attention (not attention)]) was conducted on the average success rate of the situation. Additionally, we measured the duration of sniffing behavior between pairs of mice in an open field twice in total at 4 and 8 weeks of age before reaching task. The pairs were constructed by pairing a VPA or Sal group mouse with its partner, with the objective of facilitating initial encounters between the mice. A one-way ANOVA was conducted on the average duration of sniffing behavior data from 4 weeks and a second one-way ANOVA on data from 8 weeks.
The analysis revealed a significant interaction between condition and situation in the reaching task [ (1, 28) = 6.75, = 0.015, η = 0.19]. The simple main effect test exhibited that the "not paying attention" rate was significantly higher than that of the "face-to-face" in the VPA group ( < 0.01). The results revealed a not significant difference in the average duration of sniffing behavior at 4 weeks [ (3, 32) = 2.71, = 0.06, , η = 0.20], but significant difference at 8 weeks [ (3, 32) = 4.12, < 0.05, η = 0.28]. Multiple comparisons using the Bonferroni method revealed significant differences in the sniffing duration at 8 weeks between from the partner toward the VPA mouse and from the partner toward the Sal mouse ( < 0.05).
The VPA rodent model of ASD exhibited differences in social attention compared to the saline group. By focusing on social attention and exploring various ASD models, insights can be gained from the neural mechanisms underlying gaze abnormalities during social interaction in individuals with ASD.
基于产前暴露于丙戊酸（VPA）的啮齿动物自闭症谱系障碍（ASD）模型被广泛认为是一种重要的模型。啮齿动物ASD模型中的社交行为主要通过三室法测试进行评估。然而，在本研究中，我们关注的是ASD的VPA模型中的社会注意力。
在9至11周龄左右的雄性C57BL/6 J小鼠中，通过伸手任务来检查对同种个体的注意力行为。在胚胎第12.5天，将怀孕小鼠颈部脂肪皮下注射溶解于0.9%盐溶液中的600 mg/kg VPA钠盐（VPA组）或仅注射盐溶液（Sal组）。36只小鼠——VPA组和盐溶液组各9只，以及18只伙伴——接受伸手行为训练。随后，我们检查了VPA组或Sal组在伸手任务期间是否对其伙伴表现出集中注意力。对该情境的平均成功率进行了双向方差分析（ANOVA）（条件[VPA/Sal]×情境[面对面（注意力）/不关注（不注意）]）。此外，在进行伸手任务前，我们在4周和8周龄时总共两次测量了成对小鼠在开放场中的嗅探行为持续时间。通过将VPA组或Sal组小鼠与其伙伴配对来构建对子，目的是促进小鼠之间的初次接触。对4周龄嗅探行为数据的平均持续时间进行单向ANOVA，对8周龄数据进行第二次单向ANOVA。
分析显示，伸手任务中条件和情境之间存在显著交互作用[F(1, 28) = 6.75, p = 0.015, η² = 0.19]。简单主效应检验表明，VPA组中“不关注”率显著高于“面对面”组（p < 0.01）。结果显示，4周龄时嗅探行为的平均持续时间无显著差异[F(3, 32) = 2.71, p = 0.06, η² = 0.20]，但8周龄时有显著差异[F(3, 32) = 4.12, p < 0.05, η² = 0.28]。使用Bonferroni方法进行的多重比较显示，8周龄时伙伴对VPA小鼠和伙伴对Sal小鼠的嗅探持续时间存在显著差异（p < 0.05）。
与盐溶液组相比，ASD的VPA啮齿动物模型在社会注意力方面表现出差异。通过关注社会注意力并探索各种ASD模型，可以深入了解ASD个体在社交互动中凝视异常背后的神经机制。
