青春期双酚A暴露对社会行为的影响及其神经机制

The study of the influence of bisphenol-A (BPA) on the development of brain and behavior focused currently on the effects of perinatal exposure of BPA on adult behavior, especially the cognition and emotion. Social behavior is necessary for animal survival and reproduction. Adolescence is critical period of social behavior formation, in which time gonadal hormones activate the neural circuits and function related to behavior. Thus we speculate that adolescent exposed to BPA, a environmental compound with weak estrogen activity, may influence the formation of social behavior; however little is known about this. The present project aims to study the effects of early pubertal exposure to BPA on social behavior (especially social play) and even enduring influence on social behavior adulthood, including social interactions, aggressive behavior, sexual behaviour, etc. In order to investigate the mechanism underlying BPA-induced changes in social behavior, the main neural links of social information, such as neuropeptides AVP and OT of amygdala (MeA) and DA signal system of limbic system-midbrain (VTA, NAc), which are related to social cognition, motivation and reward, are analyzed. Furthermore, to confirm the critical brain regions of BPA influence social behavior, the morphologic change of dendritic spines of brain area NAc is observed with Dil fluorescent scattering technology and field potential long-term potentiation (LTP) of NAc is detected with electrophysiological technology in vitro. Finally the signaling pathways through which BPA affects social behavior are analyzed using specific agonists and antagonists of receptors to reveal the molecular mechanisms of adolescent BPA exposure affecting social behavior development.

双酚A(BPA)对脑和行为发育的影响引起关注，但目前研究主要聚焦在出生前后暴露的作用。社会行为异常是自闭症等早期精神发育障碍的主要症状，青春期是社会行为形成关键期，此时性激素对相关神经环路功能成熟起激活作用。因此青春期暴露于弱雌激素活性的BPA可能影响社会行为形成，但目前对此缺乏认识。项目以整体动物研究青春期BPA暴露对早期社会行为(社会玩耍)的影响并导致成年后社会行为(社会互作、攻击、性行为等)改变；通过分析其神经信息流主要环节——社会认知识别和社会动机及相关脑区杏仁核的神经肽OT和AVP与中脑-边缘DA奖赏系统(VTA、NAc)、以及神经肽对DA信号的作用研究BPA影响社会行为的神经机制；再用Dil荧光散射和电生理技术借助特异性工具药分析离体脑片NAc区神经元树突棘形态和场电位长时程增强(LTP)，从形态和功能确认BPA影响社会行为的关键脑区及其信号通路，揭示BPA影响社会行为发育机制

环境内分泌干扰物双酚A(BPA)具有拟雌激素、抗雌激素和抗雄激素活性，其神经毒性已引起极大关注。动物社会行为最具性别二态性，青春期是其形成的关键窗，此时性激素对行为相关神经环路成熟和功能起激活作用。故推测青春期BPA暴露可能会影响动物社会行为发育。 .本研究设0.04、0.4、4 mg/kg/day 3个剂量BPA青春期暴露，发现BPA抑制青春期雄鼠同性间的玩耍，促进雄鼠成年后同性间的交互偏好，减弱攻击性；抑制雌鼠成年后的异性交往和母性行为，提高防御性。同时BPA损伤小鼠分辨同性/异性尿液气味和识别熟悉/陌生个体能力。进一步去势小鼠模型研究发现青春期BPA暴露消除睾酮对雄鼠社交和社会新奇偏好、求偶、性行为、攻击行为的促进，使其性取向偏好于同性。.青春期BPA暴露不改变社会嗅觉相关的副嗅球细胞形态和数量，但显著下调嗅觉信息集中和社会识别的关键脑区MeA的神经肽OT受体(OTR/雌)和AVP受体(V1aR/雄)表达水平，减少中枢AVP/OT主要来源下丘脑PVN的OT-ir神经元(雌)和AVP-ir神经元(雄)数目，提示PVN和MeA的OT/AVP系统可能与BPA损伤雌/雄性的个体识别能力有关。.中脑-边缘系统奖赏通路的伏隔核(NAc)DA响应神经元是社会动机的关键，决定动物社会行为取向，而其突触形态和活动决定功能效应。青春期0.4和4.0 mg/kgBPA暴露明显缩短NAc神经元树突棘直径，并上调其DA转运体、下调D1受体水平；电生理研究发现100 nM的BPA消除100 nM的DA对青春期小鼠脑片NAc区高频刺激诱导长时程增强(LTP)的促进作用，提示BPA不仅改变社会识别相关脑区神经肽活动，还改变社会动机相关脑区DA神经元突触可塑性。 .青春期BPA暴露降低雄鼠脑睾酮、升高脑17beta-E2水平，下调杏仁核和纹状体雄激素受体(AR)表达。在无性激素条件下，低剂量BPA快速促进NAc区LTP，但在性激素条件下经雌激素相关γ受体和AR介导的MAPK/ERKs 信号通路影响中脑-边缘系统DA信号和神经肽对突触可塑性的调节而影响社会行为发育。本研究首次阐明，在社会行为形成的关键期——青春期暴露于环境水平BPA可长远影响成年后雌/雄性的社会行为，研究成果为BPA的神经发育毒性防治提供科学依据。