Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
Program in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences and Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA.
J Clin Invest. 2018 Jul 2;128(7):2914-2926. doi: 10.1172/JCI99366. Epub 2018 Jun 4.
Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states.
糖尿病的并发症会影响到全身的组织，包括中枢神经系统。流行病学研究表明，糖尿病患者患抑郁症、焦虑症、与年龄相关的认知能力下降和阿尔茨海默病的风险增加。大脑中缺乏胰岛素受体 (IR) 或下丘脑神经元缺乏胰岛素受体的小鼠会表现出一系列代谢异常；然而，胰岛素对星形胶质细胞和神经行为的作用仍研究得不够充分。在这里，我们证明星形胶质细胞是大脑中胰岛素的直接靶标，并且星形胶质细胞上的 IR 缺失会导致小鼠出现焦虑和抑郁样行为增加。这在一定程度上可以通过删除伏隔核中的星形胶质细胞上的 IR 来重现。在分子水平上，星形胶质细胞中胰岛素信号的丧失会损害 Munc18c 的酪氨酸磷酸化。这导致从星形胶质细胞中释放的 ATP 减少，从而导致多巴胺能神经元上的嘌呤能信号减少。这些减少导致脑片中多巴胺释放减少。ATP 类似物的中枢给药可以逆转星形胶质细胞 IR 敲除小鼠的抑郁样行为。因此，星形胶质细胞胰岛素信号在多巴胺能信号传递中起着重要作用，为星形胶质细胞胰岛素作用可能导致糖尿病、肥胖症和其他胰岛素抵抗状态人群中抑郁发生率增加提供了潜在机制。
