Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional “glial-neuron microcircuit” in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.

中文翻译：

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腹内侧下丘脑中的星形胶质细胞与小鼠慢性应激引起的焦虑和骨质流失有关

慢性压力是骨质流失的主要危险因素之一。虽然下丘脑腹内侧 (VMH) 的神经元和神经回路介导慢性压力引起的骨丢失，但 VMH 核内的详细内在机制仍需探索。大脑区域的星形胶质细胞通过与周围神经元的相互作用在调节新陈代谢和焦虑样行为中发挥重要作用。然而，VMH 中的星形胶质细胞是否会影响神经元活动并因此调节慢性压力引起的焦虑和骨质流失仍然难以捉摸。在这项研究中，我们发现 VMH 星形胶质细胞在慢性压力引起的焦虑和骨质流失期间被激活。VMH 星形胶质细胞中 Gi 和 Gq 通路的药物遗传学激活分别降低和增加了焦虑和骨质流失的水平。此外，光遗传学激活 VMH 星形胶质细胞诱导邻近的类固醇生成因子-1 (SF-1) 神经元去极化，通过施用 N-甲基-D-天冬氨酸 (NMDA) 受体阻滞剂而减少，但不通过 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体阻滞剂。这些结果表明，VMH 细胞核中可能存在一个功能性的“神经胶质-神经元微电路”，可介导慢性压力引起的焦虑和骨质流失。这项研究不仅增进了我们对神经胶质细胞功能的理解，而且为慢性压力引起的焦虑和骨质流失治疗提供了潜在的干预目标。通过施用 N-甲基-D-天冬氨酸 (NMDA) 受体阻滞剂而减少，但不通过 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体阻滞剂。这些结果表明，VMH 细胞核中可能存在一个功能性的“神经胶质-神经元微电路”，可介导慢性压力引起的焦虑和骨质流失。这项研究不仅增进了我们对神经胶质细胞功能的理解，而且为慢性压力引起的焦虑和骨质流失治疗提供了潜在的干预目标。通过施用 N-甲基-D-天冬氨酸 (NMDA) 受体阻滞剂而减少，但不通过 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体阻滞剂。这些结果表明，VMH 细胞核中可能存在一个功能性的“神经胶质-神经元微电路”，可介导慢性压力引起的焦虑和骨质流失。这项研究不仅增进了我们对神经胶质细胞功能的理解，而且为慢性压力引起的焦虑和骨质流失治疗提供了潜在的干预目标。