Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
Department of Psychiatry, Harvard Medical School and Basic Neuroscience Division, Mclean Hospital, Belmont, MA, USA.
Neuropsychopharmacology. 2022 Sep;47(10):1755-1763. doi: 10.1038/s41386-022-01376-4. Epub 2022 Jul 14.
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.
当前的阿片类药物泛滥极大地增加了胎儿暴露于阿片类药物（包括羟考酮）的儿童数量。这些儿童在进入青年期后，已经被记录存在许多社交和认知异常。然而，对于产前阿片类药物暴露对发育的影响机制却知之甚少。小胶质细胞是大脑的常驻免疫细胞，会对成年期的急性阿片类药物暴露做出反应。此外，小胶质细胞在正常发育过程中塑造神经回路是已知的。事实上，我们最近发现，伏隔核（NAc）中小胶质细胞对多巴胺 D1 受体（D1R）的吞噬作用对于大鼠在青春期到成年期之间自然发生的 NAc-D1R 下降是必需的。这种小胶质细胞修剪仅发生在雄性中，是正常社交玩耍行为发育轨迹所必需的。然而，几乎没有人知道这个发育程序是否会因胎儿暴露于阿片类药物而改变。在这里，我们在大鼠中表明，怀孕期间母亲自行服用羟考酮会导致青春期雄性后代 NAc 中小胶质细胞对 D1R 的吞噬作用减少，随后 D1R 密度增加。最后，我们还观察到阿片类药物暴露的后代存在产前和成年行为缺陷，包括雄性的羟考酮条件性位置偏好的消退受损。这项工作首次表明，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。
