Department of Women and Children's Health, Faculty of Life Science and Medicine, King's College London, London, UK.
Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
J Neuroendocrinol. 2024 May;36(5):e13384. doi: 10.1111/jne.13384. Epub 2024 Mar 22.
Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety. We investigate whether NK3R activation in the MePD is involved in mediating the inhibitory effect of psychosocial stress on LH pulsatility in ovariectomised female mice. First, we administered senktide, an NK3R agonist, into the MePD and monitored the effect on pulsatile LH secretion. We then delivered SB222200, a selective NK3R antagonist, intra-MePD in the presence of predator odour, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Senktide administration into the MePD dose-dependently suppresses pulsatile LH secretion. Moreover, NK3R signalling in the MePD mediates TMT-induced suppression of the GnRH pulse generator, which we verified using a mathematical model. The model verifies our experimental findings: (i) predator odour exposure inhibits LH pulses, (ii) activation of NK3R in the MePD inhibits LH pulses and (iii) NK3R antagonism in the MePD blocks stressor-induced inhibition of LH pulse frequency in the absence of ovarian steroids. These results demonstrate for the first time that NK3R neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator.
心理社会应激通过抑制脉冲式黄体生成素 (LH) 分泌而对生殖功能产生负面影响。后背侧内侧杏仁核（MePD）部分负责处理应激并调节生殖轴。在雌激素水平低下的情况下，神经激肽 3 受体（NK3R）的激活抑制促性腺激素释放激素（GnRH）脉冲发生器，而杏仁核中的 NK3R 活性已被证明在应激和焦虑中发挥作用。我们研究了 MePD 中的 NK3R 激活是否参与介导心理社会应激对去卵巢雌性小鼠 LH 脉冲性的抑制作用。首先，我们将 NK3R 激动剂 senktide 注入 MePD 并监测其对脉冲式 LH 分泌的影响。然后，我们在存在捕食者气味、2,4,5-三甲基噻唑（TMT）的情况下将选择性 NK3R 拮抗剂 SB222200 注入 MePD，并检查其对 LH 脉冲的影响。将 senktide 注入 MePD 可剂量依赖性地抑制脉冲式 LH 分泌。此外，MePD 中的 NK3R 信号传导介导了 TMT 诱导的 GnRH 脉冲发生器的抑制，我们使用数学模型验证了这一点。该模型验证了我们的实验发现：（i）捕食者气味暴露抑制 LH 脉冲，（ii）MePD 中的 NK3R 激活抑制 LH 脉冲，以及（iii）在没有卵巢类固醇的情况下，MePD 中的 NK3R 拮抗作用阻止了应激源诱导的 LH 脉冲频率抑制。这些结果首次表明，MePD 中的 NK3R 神经元介导了心理社会应激诱导的 GnRH 脉冲发生器抑制。
