State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Exp Neurol. 2019 Nov;321:113030. doi: 10.1016/j.expneurol.2019.113030. Epub 2019 Aug 1.
Perimenopause is characterized by a gradual depletion of ovarian follicles with increased vulnerability to anxiety. However, the underlying mechanisms remain poorly understood. Herein, we show that chronic exposure to 4-vinylcycloxene diepoxide (VCD) in adult female mice (VCD-mice) caused follicles depletion and decline of serum estradiol (E2) and progesterone levels. Serotonin (5-HT) synthesis in dorsal raphe nucleus (DRN) and serotonergic afferents to basolateral amygdala complex (BLA) were reduced in VCD-mice, which were recovered by the supplement E2. VCD-mice appeared anxiety-like behaviors, which was relieved by the treatment with E2 or the co-administration of 5-HT1Ar agonist 8-OH-DPAT and 5-HT2A/Cr agonist DOI. The bath-application of 8-OH-DPAT in the slices obtained from VCD-mice (VCD-slices) corrected the increase in presynaptic glutamate release at external capsule-BLA synaptic transmission. Threshold to induce NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was declined in VCD-mice with elevation of CaMKII phosphorylation, which was sensitive to 8-OH-DPAT. Notably, the bath-application of 8-OH-DPAT in VCD-slices caused a decrease in the GABAergic feedback inhibition, which was restored by adding DOI. In addition, NMDAr-independent long-term depression (LTD) could not be induced in VCD-mice, which was rescued by the co-application of 8-OH-DPAT with DOI or the GABA receptor agonist muscimol. Furthermore, the treatment of VCD-mice with E2 could prevent the facilitation of LTP and recover the LTD induction. Thus, the results indicate that the 5-HT deficiency in the BLA of VCD-mice causes the facilitation of LTP via enhanced glutamate release and impairs the LTD induction through diminished GABAergic inhibition, leading to anxiety-like behaviors.
围绝经期的特征是卵巢卵泡逐渐耗竭，对焦虑的易感性增加。然而，其潜在机制仍知之甚少。在此，我们发现成年雌性小鼠（VCD 小鼠）慢性暴露于 4-乙烯环氧化物二环氧（VCD）会导致卵泡耗竭和血清雌二醇（E2）和孕酮水平下降。VCD 小鼠背侧中缝核（DRN）中 5-羟色胺（5-HT）的合成和 5-HT 能传入外侧杏仁核复合体（BLA）减少，但这些变化可通过补充 E2 得到恢复。VCD 小鼠出现焦虑样行为，而用 E2 或 5-HT1Ar 激动剂 8-OH-DPAT 和 5-HT2A/Cr 激动剂 DOI 联合治疗可缓解这些行为。将 8-OH-DPAT 应用于 VCD 小鼠切片（VCD 切片）中，纠正了外侧裂-BLA 突触传递中外侧囊谷氨酸释放的增加。N-甲基-D-天冬氨酸受体（NMDAr）依赖性长时程增强（LTP）的诱导阈值在 VCD 小鼠中降低，其对 8-OH-DPAT 敏感。值得注意的是，8-OH-DPAT 在 VCD 切片中的应用会导致 GABA 能反馈抑制减弱，而 DOI 可恢复这种抑制。此外，VCD 小鼠不能诱导 NMDAr 非依赖性长时程抑制（LTD），但 8-OH-DPAT 与 DOI 或 GABA 受体激动剂 muscimol 联合应用可恢复 LTD 诱导。此外，用 E2 治疗 VCD 小鼠可防止 LTP 的易化并恢复 LTD 诱导。因此，结果表明 VCD 小鼠 BLA 中的 5-HT 缺乏导致 LTP 的易化，通过增强谷氨酸释放来实现，通过减少 GABA 能抑制来损害 LTD 诱导，导致焦虑样行为。
