Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet.
Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet.
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DOI：
10.1016/j.bbi.2019.11.010
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发表时间：
2020-03
期刊：
影响因子：
--
通讯作者：
Reyes TM
中科院分区：
文献类型：
--
作者：
Smith BL;Laaker CJ;Lloyd KR;Hiltz AR;Reyes TM
在人类中，妊娠期体重过度增加与后代执行功能缺陷的风险增加有关。我们以前的工作已经证实了这一发现在小鼠中，作为后代从母鼠喂养60%高脂肪（HF）的饮食在繁殖，妊娠和哺乳期表现出冲动样的行为，在5选择系列反应时间任务（5CSRTT）。由于前额叶皮层（PFC），这在执行功能中起着关键作用，经历了大量的出生后青春期修剪和小胶质细胞积极参与突触细化，我们假设，小胶质细胞可能发挥作用，在调解母亲HF饮食后的大脑发育的变化，特别是在青春期的小胶质细胞的活动。因此，我们在出生后第23-45天用PLX 3397配制饲料（PLX）处理HF或对照饲料（CD）母鼠的雄性和雌性后代，以消除小胶质细胞。在PLX去除和小胶质细胞再增殖后，成年小鼠进行测试以评估执行功能。青少年PLX治疗没有增加控制男性辍学率在学习基本的FR 1任务，但在控制后代的行为有一个最小的影响。在男性中，HF后代学习更快，在一个简单的操作性任务（固定比例1）没有PLX的影响，表现更好。然而，在HF后代中，FR 1反应的增加与5CSRTT中更多的冲动错误相关，而PLX消除了这种关联，并降低了HF后代中的冲动错误。这表明青少年PLX治疗改善了成年男性HF后代的执行功能，特别是冲动行为，而没有围产期饮食的总体影响。在女性中，母亲HF饮食损害逆转学习，但PLX没有影响性能。然后，我们测量了成年男性PFC，杏仁核（NAC）和杏仁核（AMG）的基因表达，检查与突触功能，奖励和炎症相关的目标。母亲HF饮食增加PFC突触素和AMG psd 95表达。PFC突触素表达与HF后代5CSRTT中更多的脉冲错误相关，PLX治疗消除了这种相关性。这些数据表明，青春期小胶质细胞可能在介导围产期高脂饮食后的男性执行功能中发挥关键作用。
In humans, excessive gestational weight gain during pregnancy is associated with an increased risk for executive function deficits in the offspring. Our previous work has confirmed this finding in mice, as offspring from dams fed a 60% high fat (HF) diet during breeding, gestation, and lactation demonstrate impulsive-like behavior in the 5 choice serial reaction time task (5CSRTT). Because the prefrontal cortex (PFC), which plays a key role in executive function, undergoes substantial postnatal adolescent pruning and microglia are actively involved in synaptic refinement, we hypothesized that microglia may play a role in mediating changes in brain development after maternal HF diet, with a specific focus on microglial activity during adolescence. Therefore, we treated male and female offspring from HF or control diet (CD) dams with PLX3397-formulated diet (PLX) to ablate microglia during postnatal days 23–45. After PLX removal and microglial repopulation, adult mice underwent testing to evaluate executive function. Adolescent PLX treatment did increase the control male dropout rate in learning the basic FR1 task, but otherwise had a minimal effect on behavior in control offspring. In males, HF offspring learned faster and performed better on a simple operant task (fixed ratio 1) without an effect of PLX. However, in HF offspring this increase in FR1 responding was associated with more impulsive errors in the 5CSRTT while PLX eliminated this association and decreased impulsive errors specifically in HF offspring. This suggests that adolescent PLX treatment improves executive function and particularly impulsive behavior in adult male HF offspring, without an overall effect of perinatal diet. In females, maternal HF diet impaired reversal learning but PLX had no effect on performance. We then measured gene expression in adult male PFC, nucleus accumbens (NAC), and amygdala (AMG), examining targets related to synaptic function, reward, and inflammation. Maternal HF diet increased PFC synaptophysin and AMG psd95 expression. PFC synaptophysin expression was correlated with more impulsive errors in the 5CSRTT in the HF offspring only and PLX treatment eliminated this correlation. These data suggest that adolescent microglia may play a critical role in mediating executive function after perinatal high fat diet in males.
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