Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found that chronic restraint stress (RS) induces significant increases in serum cell-free mitochondrial DNA (cf-mtDNA) levels in mice, and systemic Deoxyribonuclease I (DNase I) treatment attenuated RS-induced social behavioral deficits. Our findings revealed potential roles of mitophagy and Mitochondrial antiviral-signaling protein (MAVS) in mediating chronic stress-induced changes in cf-mtDNA levels and social behavior. Furthermore, we showed that inhibition of Toll-like receptor 9 (TLR9) attenuates mtDNA-induced social behavior deficits. Together, these findings show that cf-mtDNA-TLR9 signaling is critical in mediating stress-induced social behavior deficits.

炎症和社会行为缺陷与许多神经精神疾病有关。慢性压力是抑郁症和其他心理健康状况的主要危险因素，已知会增加炎症反应和社会行为障碍。在慢性应激条件下已发现线粒体功能紊乱，但将线粒体功能障碍与应激引起的社会行为缺陷联系起来的机制尚不清楚。在这项研究中，我们发现慢性束缚应激 (RS) 会导致小鼠血清无细胞线粒体 DNA (cf-mtDNA) 水平显着增加，而全身脱氧核糖核酸酶 I (DNase I) 治疗可减轻 RS 引起的社会行为缺陷。我们的研究结果揭示了线粒体自噬和线粒体抗病毒信号蛋白（MAVS）在介导慢性压力引起的 cf-mtDNA 水平和社会行为变化中的潜在作用。此外，我们发现抑制 Toll 样受体 9 (TLR9​​) 可以减轻 mtDNA 诱导的社会行为缺陷。总之，这些发现表明 cf-mtDNA-TLR9 信号传导对于调节压力引起的社会行为缺陷至关重要。