Department of Women and Children's Health, Faculty of Life Science and Medicine, King's College London, London, United Kingdom.
Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2022 May 17;13:893029. doi: 10.3389/fendo.2022.893029. eCollection 2022.
Post-traumatic stress disorder impedes pubertal development and disrupts pulsatile LH secretion in humans and rodents. The posterodorsal sub-nucleus of the medial amygdala (MePD) is an upstream modulator of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator, pubertal timing, as well as emotional processing and anxiety. Psychosocial stress exposure alters neuronal activity within the MePD increasing the expression of Urocortin3 (Ucn3) and its receptor corticotropin-releasing factor type-2 receptor (CRFR2) while enhancing the inhibitory output from the MePD to key hypothalamic reproductive centres. We test the hypothesis that psychosocial stress, processed by the MePD, is relayed to the hypothalamic GnRH pulse generator to delay puberty in female mice. We exposed C57Bl6/J female mice to the predator odor, 2,4,5-Trimethylthiazole (TMT), during pubertal transition and examined the effect on pubertal timing, pre-pubertal LH pulses and anxiety-like behaviour. Subsequently, we virally infected Ucn3-cre-tdTomato female mice with stimulatory DREADDs targeting MePD Ucn3 neurons and determined the effect on pubertal timing and pre-pubertal LH pulse frequency. Exposure to TMT during pubertal development delayed puberty, suppressed pre-pubertal LH pulsatility and enhanced anxiety-like behaviour, while activation of MePD Ucn3 neurons reduced LH pulse frequency and delayed puberty. Early psychosocial stress exposure decreases GnRH pulse generator frequency delaying puberty while inducing anxiety-behaviour in female mice, an effect potentially involving Ucn3 neurons in the MePD.
创伤后应激障碍会阻碍人类和啮齿动物的青春期发育，并破坏促性腺激素释放激素（GnRH）脉冲分泌。内侧杏仁核后背核（MePD）是下丘脑促性腺激素释放激素（GnRH）脉冲发生器、青春期时间以及情绪处理和焦虑的上游调节因子。社会心理应激会改变 MePD 内的神经元活动，增加 Urocortin3（Ucn3）及其受体促肾上腺皮质激素释放因子 2 型受体（CRFR2）的表达，同时增强 MePD 对关键下丘脑生殖中心的抑制性输出。我们测试了这样一个假设，即由 MePD 处理的社会心理应激会传递到下丘脑 GnRH 脉冲发生器，以延迟雌性小鼠的青春期。我们在青春期过渡期间让 C57Bl6/J 雌性小鼠暴露于捕食者气味 2,4,5-三甲基噻唑（TMT），并检查其对青春期时间、青春期前 LH 脉冲和焦虑样行为的影响。随后，我们用靶向 MePD Ucn3 神经元的兴奋性 DREADD 病毒感染 Ucn3-cre-tdTomato 雌性小鼠，并确定其对青春期时间和青春期前 LH 脉冲频率的影响。在青春期发育期间暴露于 TMT 会延迟青春期、抑制青春期前 LH 脉冲性并增强焦虑样行为，而激活 MePD Ucn3 神经元会降低 LH 脉冲频率并延迟青春期。早期社会心理应激暴露会降低 GnRH 脉冲发生器的频率，从而延迟青春期，同时在雌性小鼠中诱导焦虑行为，这种效应可能涉及 MePD 中的 Ucn3 神经元。
