The balance of major excitatory (glutamate, Glu) and inhibitory (γ-aminobutyric acid, GABA), named as E/I neurotransmission, is critical for proper information processing. Anxiety-like responses upon stress are accompanied by abnormal alterations in the formation and function of synapses, resulting in the imbalance of E/I neurotransmission in the amygdala. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are nuclear receptors responsible for regulating central nervous system (CNS) functions besides maintaining metabolic homeostasis. However, little is known about the contribution of LXRs in E/I balance in regulating anxiety-related behaviors induced by stress. In this study, we found stress-induced anxiety led to the expression reduction of LXRβ not LXRα in mice amygdala. GW3965, a dual agonist for both LXRα and LXRβ, alleviated anxiety-like behaviors of stressed mice through activation of LXRβ, confirmed by the knockdown of LXRβ mediated by lentiviral shRNAs in the basolateral amygdala (BLA). This was paralleled by correcting the disequilibrium of E/I neurotransmission in the stressed BLA. Importantly, GW3965 exerted anxiolytic effects by correcting the promoted amplitude and frequency of miniature excitatory postsynaptic current (mEPSC), and augmenting the decreased that of miniature inhibitory postsynaptic current (mIPSC) in the stressed BLA. This suggests that stress-induced anxiety-like behaviors can largely be ascribed to the deficit of LXRβ signaling in E/I neurotransmission in BLA. These findings highlight the deficiency of LXRβ signaling in the amygdala linked to anxiety disorder, and LXRβ activation may represent a potential novel target for anxiety treatment with an alteration in synaptic transmission in the amygdala.

中文翻译：

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杏仁核中 LXRβ 信号的激活通过在急性压力下重新平衡兴奋性和抑制性神经传递来产生抗焦虑作用。


主要兴奋性（谷氨酸，Glu）和抑制性（γ-氨基丁酸，GABA）的平衡，称为 E/I 神经传递，对于正确的信息处理至关重要。应激时的焦虑样反应伴随着突触形成和功能的异常改变，导致杏仁核中 E/I 神经传递的不平衡。肝脏 X 受体 (LXR)，包括 LXRα 和 LXRβ 亚型，是核受体，除了维持代谢稳态外，还负责调节中枢神经系统 (CNS) 功能。然而，人们对 LXR 在 E/I 平衡调节压力引起的焦虑相关行为中的贡献知之甚少。在这项研究中，我们发现压力引起的焦虑会导致小鼠杏仁核中 LXRβ 的表达减少，而不是 LXRα 的表达减少。 GW3965 是 LXRα 和 LXRβ 的双重激动剂，通过激活 LXRβ 减轻应激小鼠的焦虑样行为，这一点通过基底外侧杏仁核 (BLA) 中慢病毒 shRNA 介导的 LXRβ 敲低得到证实。同时纠正受压 BLA 中 E/I 神经传递的不平衡。重要的是，GW3965 通过纠正应激 BLA 中微型兴奋性突触后电流 (mEPSC) 的增强幅度和频率，并增强微型抑制性突触后电流 (mIPSC) 的降低来发挥抗焦虑作用。这表明压力诱发的焦虑样行为很大程度上可归因于 BLA 中 E/I 神经传递中 LXRβ 信号传导的缺陷。这些发现强调了杏仁核中 LXRβ 信号传导的缺陷与焦虑症有关，并且 LXRβ 激活可能代表了通过改变杏仁核突触传递来治疗焦虑的潜在新靶点。