Deficient mitochondrial respiration in astrocytes impairs trace fear conditioning and increases naloxone-precipitated aversion in morphine-dependent mice.
Deficient mitochondrial respiration in astrocytes impairs trace fear conditioning and increases naloxone-precipitated aversion in morphine-dependent mice.
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星形胶质细胞线粒体呼吸不足损害吗啡依赖小鼠的微量恐惧条件反射并增加纳洛酮诱发的厌恶
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线粒体在星形胶质细胞的精细突起中含量丰富，然而，对星形胶质细胞线粒体的潜在作用仍知之甚少。在本研究中，我们对星形胶质细胞氧化磷酸化异常对小鼠行为的影响进行了系统的研究。受损的星形胶质细胞氧化磷酸化是通过星形胶质细胞特异性缺失核线粒体基因Cox10而产生的，Cox10编码复合体IV的辅助蛋白，原血红素：血红素-O-法尼基转移酶。正如预期的那样，COX10基因在小鼠(CKO小鼠)中的条件性缺失显著降低了COX10和复合体IV的细胞色素C氧化酶I亚单位(MTCO1)的表达，导致氧化磷酸化降低，但不显著影响糖酵解。没有观察到缺失对运动活动、焦虑样行为、痛觉或自发交替的影响。Cox10 CKO雌性小鼠表现出轻度损害的新物体识别，而Cox10 CKO雄性小鼠在痕迹恐惧条件反射方面存在中度缺陷。在评估吗啡对奖赏影响的条件位置偏好(CPP)中，没有观察到与组相关的变化。与CPP相比，Cox10 CKO小鼠在长期接触吗啡后，纳洛酮催促戒断所产生的厌恶行为显著增加，即通过条件性场所厌恶(CPA)评估跳跃和回避行为。我们的研究表明，星形胶质细胞氧化磷酸化可能与更大的认知负荷和/或厌恶和应激条件相关的行为有关。
Mitochondria are abundant in the fine processes of astrocytes, however, potential roles for astrocyte mitochondria remain poorly understood. In the present study, we performed a systematic examination of the effects of abnormal oxidative phosphorylation in astrocytes on several mouse behaviors. Impaired astrocyte oxidative phosphorylation was produced by astrocyte-specific deletion of the nuclear mitochondrial gene, Cox10, that encodes an accessory protein of complex IV, the protoheme:heme-O-farnesyl transferase. As expected, conditional deletion of the Cox10 gene in mice (cKO mice) significantly reduced expression of COX10 and Cytochrome c oxidase subunit I (MTCO1) of Complex IV, resulting in decreased oxidative phosphorylation without significantly affecting glycolysis. No effects of the deletion were observed on locomotor activity, anxiety-like behavior, nociception, or spontaneous alternation. Cox10 cKO female mice exhibited mildly impaired novel object recognition, while Cox10 cKO male mice were moderately deficient in trace fear conditioning. No group-related changes were observed in conditional place preference (CPP) that assessed effects of morphine on reward. In contrast to CPP, Cox10 cKO mice demonstrated significantly increased aversive behaviors produced by naloxone-precipitated withdrawal following chronic exposure to morphine, that is, jumping and avoidance behavior as assessed by conditional place aversion (CPA). Our study suggests that astrocyte oxidative phosphorylation may contribute to behaviors associated with greater cognitive load and/or aversive and stressful conditions.