Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring.
Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring.
复制标题
产前阿片类药物暴露选择性抑制青春期男性后代多巴胺系统的小胶质细胞塑造。
DOI：
10.1038/s41386-022-01376-4
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Chartoff,ElenaH
中科院分区：
文献类型：
--
作者：
Smith,CarolineJ;Lintz,Tania;Clark,MadelineJ;Malacon,KarenE;Abiad,Alia;Constantino,NicholasJ;Kim,VeronicaJ;Jo,YoungC;Alonso-Caraballo,Yanaira;Bilbo,StaciD;Chartoff,ElenaH
当前的阿片类药物流行已大大增加了产前接触阿片类药物（包括羟考酮）的儿童数量。这些儿童在成年初期就出现了许多社交和认知异常。然而，人们对产前阿片类药物暴露对发育影响的机制知之甚少。小胶质细胞是大脑的常驻免疫细胞，对成年后急性阿片类药物暴露做出反应。此外，众所周知，小胶质细胞在典型发育过程中会塑造神经回路。事实上，我们最近发现，伏隔核 (NAc) 中的小胶质细胞对多巴胺 D1 受体 (D1R) 的吞噬作用是大鼠青春期和成年期之间发生的 NAc-D1R 自然发育衰退所必需的。这种小胶质细胞修剪仅发生在雄性中，并且是社交游戏行为正常发育轨迹所必需的。然而，对于这种发育程序是否会因产前接触阿片类药物而改变，几乎一无所知。在这里，我们在大鼠中发现，妊娠期间母体自行施用羟考酮会导致青少年小胶质细胞对 D1R 的吞噬作用减少，并随后在成年雄性（而非雌性）后代的 NAc 内增加 D1R 密度。最后，我们显示了暴露于阿片类药物的后代的产前和成年行为缺陷，包括男性羟考酮条件性位置偏好的消退受损。这项工作首次证明小胶质细胞在将产前阿片类药物暴露转化为神经系统和行为变化方面发挥着关键作用。
The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.