Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden; Present address: Department of Forensic Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany.
Immunity. 2021 Feb 9;54(2):225-234.e6. doi: 10.1016/j.immuni.2020.12.016. Epub 2021 Jan 20.
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.
小胶质细胞在许多神经疾病中被激活，并被认为在包括重度抑郁症在内的情感障碍的发展中发挥重要作用。为了研究小胶质细胞信号如何调节情绪，我们使用双向化学遗传学方法操纵小鼠小胶质细胞的活性。背侧纹状体中小胶质细胞的激活诱导局部细胞因子表达和快感缺失和厌恶为特征的消极情绪状态，而小胶质细胞的失活阻止了全身炎症引起的厌恶。小胶质细胞中的白细胞介素 6 信号和环氧化酶 1 介导的前列腺素合成对于炎症诱导的厌恶是至关重要的。相应地，小胶质细胞的激活导致纹状体神经元兴奋性的前列腺素依赖性降低。这些发现表明，小胶质细胞激活通过前列腺素依赖性调节纹状体神经元引起消极情绪的机制，并表明干扰这种机制可能减轻涉及小胶质细胞激活的躯体和精神疾病中的抑郁症状。
