Liu Xiaofeng, Song Meiying, Chen Xiaowei, Sun Yanfei, Fan Renfei, Wang Liping, Lin Weihong, Hu Zheng, Zhao Hua
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Neuroscience Research Center, The First Hospital of Jilin University, Changchun, China.
Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Front Behav Neurosci. 2022 May 9;16:817859. doi: 10.3389/fnbeh.2022.817859. eCollection 2022.
Loss of estrogen due to menopause or ovarian resection is involved in the development of anxiety, which negatively impacts work productivity and quality of life. Estrogen modulates mood by binding to estrogen receptors in the brain. Estrogen receptor beta (ERβ) is highly expressed in the lateral habenula (LHb), a key site for controlling the activities of dopaminergic neurons in the ventral tegmental area (VTA) and serotoninergic neurons in the dorsal raphe nucleus (DRN) that are known to be involved in anxiety.
In this study, we examined the role of LHb in the anxiolytic-like effect of estrogen in ovariectomized (OVX) rats. The establishment of OVX anxiety model was validated in behavioral tests, including elevated plus maze (EPM) and mirror chamber maze (MCM) tasks. The expression of c-Fos in the LHb neurons was analyzed by immunohistochemistry, and monoamine neurotransmitter levels in related nuclei were analyzed using high-performance liquid chromatography (HPLC).
Estrogen-treated OVX rats showed a lower degree of anxiety-like behavior than OVX rats. OVX rats showed anxiety-like behavior and low monoamine levels in the DRN and VTA compared with sham operated and estrogen-treated OVX rats. c-Fos expression in the LHb was higher than that in the sham operated and estrogen-treated OVX rats. Intra-LHb injection of the ERβ-selective agonist diarylprepionitrile (DPN) reduced expression of c-Fos (a neuronal activity marker) and anxiety-like behavior in OVX rats, but not in normal rats, as evidenced by increased time spent in EPM open areas and the MCM mirror chamber. These changes coincided with higher levels of serotonin and dopamine in the DRN and higher dopamine levels in the VTA in OVX rats receiving intra-LHb DPN compared with those receiving vehicle injection.
These results suggest that OVX-induced anxiety-like behavior may be associated with increased LHb activity. DPN may inhibit LHb activity to improve anxiety-like behavior in OVX rats by increasing monoamine neurotransmitter levels in the DRN and VTA.
绝经或卵巢切除导致的雌激素缺失与焦虑的发生有关，这对工作效率和生活质量产生负面影响。雌激素通过与大脑中的雌激素受体结合来调节情绪。雌激素受体β（ERβ）在外侧缰核（LHb）中高度表达，外侧缰核是控制腹侧被盖区（VTA）多巴胺能神经元和中缝背核（DRN）5-羟色胺能神经元活动的关键部位，已知这些神经元与焦虑有关。
在本研究中，我们研究了LHb在雌激素对去卵巢（OVX）大鼠抗焦虑样作用中的作用。通过行为测试，包括高架十字迷宫（EPM）和镜像箱迷宫（MCM）任务，验证了OVX焦虑模型的建立。采用免疫组织化学法分析LHb神经元中c-Fos的表达，并用高效液相色谱法（HPLC）分析相关核团中的单胺类神经递质水平。
雌激素处理的OVX大鼠比OVX大鼠表现出更低程度的焦虑样行为。与假手术和雌激素处理的OVX大鼠相比，OVX大鼠表现出焦虑样行为，且DRN和VTA中的单胺水平较低。LHb中c-Fos的表达高于假手术和雌激素处理的OVX大鼠。向LHb内注射ERβ选择性激动剂二芳基丙腈（DPN）可降低OVX大鼠中c-Fos（一种神经元活动标志物）的表达和焦虑样行为，但对正常大鼠无效，这通过EPM开放区域和MCM镜像箱中停留时间的增加得以证明。与接受载体注射的OVX大鼠相比，接受LHb内DPN注射的OVX大鼠的这些变化与DRN中5-羟色胺和多巴胺水平升高以及VTA中多巴胺水平升高相一致。
这些结果表明，OVX诱导的焦虑样行为可能与LHb活性增加有关。DPN可能通过增加DRN和VTA中的单胺类神经递质水平来抑制LHb活性，从而改善OVX大鼠的焦虑样行为。
