Zachar Gergely, Tóth András S, Gerecsei László I, Zsebők Sándor, Ádám Ágota, Csillag András
Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
Department of Systematic Zoology and Ecology, Institute of Biology, Faculty of Science, Eötvös Loránd University, Budapest, Hungary.
Front Physiol. 2019 Jul 16;10:881. doi: 10.3389/fphys.2019.00881. eCollection 2019.
Embryonic exposure to valproic acid (VPA) is known to produce sociability deficits, resembling human autistic phenotypes, in several vertebrate species. Animals living in groups prefer the proximity of peers and have the ability to perceive and to respond to social signals for modifying behavior. Chicks of Galliform birds, known to display early preference behaviors, have been used extensively for adaptive learning studies. Young precocial birds seem to be useful models also for studying the effect of embryonic VPA treatment. Here, domestic chicken eggs were injected with sodium valproate (200 μl of 35 μmol/L solution) or with vehicle (distilled water) on the 14th day of incubation. After hatching, the chicks were tested for one-trial passive avoidance learning at day 1, vocalization due to isolation as a measure of stress level (day 2), approach preference to large versus small groups of age-matched conspecifics (day 5), and to those with normal versus blurred head features (day 7). In addition, we tested the preference of birds to conspecifics reared in group versus those reared in isolation (day 9), as well as the preference of chicks to familiar versus non-familiar conspecifics (day 21). Our findings confirm previous reports concerning an adverse effect of VPA on embryonic development, including a tendency for aborted or delayed hatching and, occasionally, for locomotor disorders in a small percentage of birds (eliminated from later studies). Otherwise, VPA treatment did not impair motor activity or distress level. Memory formation for the aversive stimulus and discrimination of colors were not impaired by VPA treatment either. Innate social predispositions manifested in approach preferences for the larger target group or for the birds with natural facial features remained unaffected by VPA exposure. The most prominent finding was attenuation of social exploration in VPA-exposed birds (expressed as the frequency of positional switches between two stimulus chicks after the first choice), followed by a deficit in the recognition of familiar conspecifics, unfolding at the end of the third week. Social exploration and recognition of familiar individuals are the key elements impaired at this stage. The results underline the importance of early social exploration in ASD.
已知胚胎期暴露于丙戊酸（VPA）会在几种脊椎动物物种中产生社交缺陷，类似于人类自闭症表型。群居动物更喜欢与同伴亲近，并有能力感知和响应社交信号以改变行为。已知具有早期偏好行为的鸡形目鸟类的雏鸡已被广泛用于适应性学习研究。幼龄早成鸟似乎也是研究胚胎期VPA处理效果的有用模型。在此，在孵化第14天给家鸡蛋注射丙戊酸钠（35 μmol/L溶液200 μl）或溶剂（蒸馏水）。孵化后，在第1天对雏鸡进行一次性被动回避学习测试，在第2天测试因隔离引起的鸣叫作为应激水平的指标，在第5天测试对年龄匹配的同种大群体与小群体的接近偏好，以及在第7天测试对头部特征正常与模糊的同种个体的接近偏好。此外，我们测试了鸟类对群居饲养的同种个体与单独饲养的同种个体的偏好（第9天），以及雏鸡对熟悉的同种个体与不熟悉的同种个体的偏好（第21天）。我们的研究结果证实了先前关于VPA对胚胎发育有不良影响的报道，包括孵化流产或延迟的倾向，以及在一小部分鸟类中偶尔出现运动障碍（在后续研究中排除）。否则，VPA处理不会损害运动活动或应激水平。VPA处理也不会损害对厌恶刺激的记忆形成和颜色辨别。对较大目标群体或具有自然面部特征的鸟类的接近偏好所表现出的先天社交倾向不受VPA暴露的影响。最显著的发现是暴露于VPA的鸟类的社交探索减弱（表示为第一次选择后在两只刺激雏鸡之间位置转换的频率），其次是在第三周结束时出现对熟悉同种个体识别的缺陷。社交探索和对熟悉个体的识别是这个阶段受损的关键因素。这些结果强调了早期社交探索在自闭症谱系障碍中的重要性。
