成年慢性疾病（如神经精神性疾病和代谢性疾病）具有宫内起源，HPA轴高应激敏感性是其主要诱因。然而，HPA轴高敏感性的发生机制至今尚未明了。我们近期发现，孕期尼古丁暴露可升高子代大鼠出生前、后下丘脑PVN兴奋性，引起成年HPA轴高敏感性变化；进一步发现，子代大鼠出生前、后海马GABA合成限速酶GAD67表达也增加。综合文献，我们推测：尼古丁与其受体a4b2nAChR结合，引起胎海马GAD67表观遗传修饰及表达改变，继而减弱海马对胎下丘脑PVN-projecting区Glu-GABA的突触联系，使PVN兴奋性增加。这些改变可延续至出生后，是引起成年HPA轴高敏感性的重要原因。本项目拟在整体水平证实海马GAD67宫内编程改变在孕期尼古丁暴露致子代HPA轴高敏感性中的核心作用，进一步从细胞水平研究尼古丁上调胎海马GAD67表达的表观遗传机制，以阐明孕期尼古丁暴露所致HPA轴高敏感性的宫内发生机制。

Chronic adult diseases (neuropsychiatry disorder and metabolic diseases) have a fetal origin, and high stress sensitivity of hypothalamic-pituitary-adrenal (HPA) axis is the major cause. However, the mechanism involved in the high sensitivity of HPA axis has been not reported yet. Previous studies in our lab demonstrated that prenatal nicotine exposure can cause a permanent change of set point and sensitivity in hypothalamic paraventricular nucleus (PVN) and cause high sensitivity of HPA axis in offspring. Recently, we found that nicotine can increase the expression hippocampal GAD67 in fetal rats and also the adult rats. Based on literatures, we hypothesized that nicotine can combine with hippocampus a4b2nAChR and induce the epigenetic alteration of GAD67 promoter and enhance the expression of GAD67. The enhanced expression of hippocampus GAD67 can decrease the Glu-GABA synaptic connections in the hypothalamus PVN-projecting region, and increase the sensitivity of PVN. Moreover, the epigenetic alteration and enhanced expression of hippocampus GAD67 can continue to after birth, and contribute to the high sensitivity of HPA axis in offspring. In the present study, we will use lab animals to confirm the important role of hippocampus GAD67 intrauterine programming alteration in the high sensitivity of HPA axis induced by prenatal nicotine exposure. Meanwhile, we will clarify the epigenetic mechanism for the enhanced expression of fetal hippocampus GAD67 in cellular and molecular levels, to clarify the introuterine mechanism of high sensitivity of HPA axis induced by prenatal nicotine?exposure.