Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice
Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice
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DOI：
10.1101/2021.06.20.449139
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发表时间：
2021-06
期刊：
影响因子：
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通讯作者：
D. Ivanova;Xiao-feng Li;C. McIntyre;Yali Liu;Ling-Ling Kong-Ling;K. O'Byrne
中科院分区：
文献类型：
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作者：
D. Ivanova;Xiao-feng Li;C. McIntyre;Yali Liu;Ling-Ling Kong-Ling;K. O'Byrne
暴露于心理社会压力会破坏生殖功能，并干扰哺乳动物的脉冲式促黄体生成激素（LH）分泌。内侧杏仁核（MePD）的后背亚核是边缘脑的一部分，是生殖轴以及压力和焦虑状态的上游调节器。促肾上腺皮质激素释放因子2型受体（CRFR 2）在心理社会应激的存在下被激活，同时啮齿动物的MePD中CRFR 2配体尿皮质素3（Ucn 3）的表达增加。我们调查是否Ucn 3信号在MePD参与介导的心理社会应激暴露LH脉动的抑制作用。首先，我们将Ucn 3施用到MePD中并监测对卵巢切除小鼠中脉冲式LH分泌的影响。接下来，我们在捕食者气味2，4，5-三甲基噻唑（TMT）存在下在MePD内递送Astressin 2B（一种高度选择性CRFR 2拮抗剂），并检查对LH脉冲的影响。随后，我们用靶向MePD Ucn 3神经元的抑制性DREADD病毒感染卵巢切除的Ucn 3-cre-tdTomato小鼠，同时将小鼠暴露于TMT或束缚应激，并检查对LH脉动性以及皮质酮（CORT）释放的影响。MePD内给予Ucn 3剂量依赖性地抑制LH脉动分泌，MePD内给予Astressin 2B可阻断TMT对LH脉动的抑制作用。此外，DREADDs抑制MePD Ucn 3神经元阻断TMT和束缚应激诱导的LH脉冲抑制以及在TMT存在下CORT释放。这些结果首次证明MePD中的Ucn 3神经元介导心理社会应激诱导的GnRH脉冲发生器抑制和心理社会应激诱导的CORT分泌。Ucn 3信号在MePD中起着调节下丘脑-垂体-性腺轴和下丘脑-垂体-肾上腺轴的基本作用，并且该脑位点可能代表生殖轴和应激轴之间串扰的节点中心。
Exposure to psychosocial stress disrupts reproductive function and interferes with pulsatile luteinising hormone (LH) secretion in mammals. The posterodorsal sub-nucleus of the medial amygdala (MePD) is part of the limbic brain and is an upstream modulator of the reproductive axis as well as stress and anxiety states. Corticotropin releasing factor type-2 receptors (CRFR2) are activated in the presence of psychosocial stress together with an increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress exposure on LH pulsatility. Firstly, we administered Ucn3 into the MePD and monitored the effect on pulsatile LH secretion in ovariectomised mice. Next, we delivered Astressin2B, a highly selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-Trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected ovariectomised Ucn3-cre-tdTomato mice with inhibitory DREADDs targeting the MePD Ucn3 neurons while exposing the mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone (CORT) release. Administration of Ucn3 into the MePD dose-dependently inhibited pulsatile LH secretion and intra-MePD administration of Astressin2B blocked the suppressive effect TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses as well as CORT release in the presence of TMT. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and psychosocial stress-induced CORT secretion. Ucn3 signalling in the MePD plays a fundamental role in modulating the hypothalamic-pituitary-ganadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal centre in the crosstalk between the reproductive and stress axes.