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系统疾病中被激活，并被认为在包括重性抑郁症在内的情感障碍的发展中起重要作用。为了研究小胶质细胞信号如何调节情绪，我们使用了小鼠小胶质细胞活性的双向化学遗传操作。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以快感缺乏和厌恶为特征的负面情感状态，而小胶质细胞的失活阻止了全身炎症诱导的厌恶。小胶质细胞中白细胞介素 6 信号传导和环氧合酶 1 介导的前列腺素合成对于炎症诱导的厌恶至关重要。相应地，小胶质细胞激活导致纹状体神经元兴奋性的前列腺素依赖性降低。