Hypothalamic CCL2/CCR2 Chemokine System: Role in Sexually Dimorphic Effects of Maternal Ethanol Exposure on Melanin-Concentrating Hormone and Behavior in Adolescent Offspring
Hypothalamic CCL2/CCR2 Chemokine System: Role in Sexually Dimorphic Effects of Maternal Ethanol Exposure on Melanin-Concentrating Hormone and Behavior in Adolescent Offspring
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DOI：
10.1523/jneurosci.0637-18.2018
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发表时间：
2018-10-17
影响因子：
5.3
通讯作者：
Leibowitz, Sarah F.
中科院分区：
文献类型：
--
作者：
Chang, Guo-Qing;Karatayev, Olga;Leibowitz, Sarah F.
临床和动物研究表明，怀孕期间的乙醇暴露和炎症会导致后代出现类似的行为障碍。虽然乙醇被证明可以刺激成年人的神经免疫和神经化学系统，但对它们在子宫内对乙醇的反应的解剖关系以及神经免疫因子是否介导乙醇对后代神经元发育和行为的影响知之甚少。在这里，我们研究了在女性和男性青春期大鼠集中在外侧下丘脑，共表达炎性趋化因子C-C基序配体2（CCL 2）或其受体CCR 2与食欲神经肽，黑色素浓缩激素（MCH），促进乙醇饮用行为的神经元的特定群体。我们证明，母亲给药乙醇（2克/千克/天）从胚胎第10天（E10）到E15，而对神经胶质细胞的影响不大，刺激神经元CCL 2和CCR 2的表达，增加密度的大CCL 2神经元共定位MCH和小CCL 2神经元周围MCH神经元，并刺激酒精饮用和焦虑的青少年后代。我们表明，这些神经元和行为的变化，同样产生了母亲管理的CCL 2（4或8微克/公斤/天，E10-E15）和母亲管理的CCR 2拮抗剂INCB 3344（1毫克/公斤/天，E10-E15），乙醇和CCL 2的这些影响是性别二态性，一贯强于女性。这些结果表明，这种与MCH神经元密切相关的神经元CCL 2/CCR 2系统在介导母体乙醇暴露对青少年后代的影响中发挥作用，并导致女性中描述的酒精使用障碍的青少年风险因素水平较高。
Clinical and animal studies show that ethanol exposure and inflammation during pregnancy cause similar behavioral disturbances in the offspring. While ethanol is shown to stimulate both neuroimmune and neurochemical systems in adults, little is known about their anatomical relationship in response to ethanol in utero and whether neuroimmune factors mediate ethanol's effects on neuronal development and behavior in offspring. Here we examined in female and male adolescent rats a specific population of neurons concentrated in lateral hypothalamus, which coexpress the inflammatory chemokine C-C motif ligand 2 (CCL2) or its receptor CCR2 with the orexigenic neuropeptide, melanin-concentrating hormone (MCH), that promotes ethanol drinking behavior. We demonstrate that maternal administration of ethanol (2 g/kg/d) from embryonic day 10 (E10) to E15, while having little impact on glia, stimulates expression of neuronal CCL2 and CCR2, increases density of both large CCL2 neurons colocalizing MCH and small CCL2 neurons surrounding MCH neurons, and stimulates ethanol drinking and anxiety in adolescent offspring. We show that these neuronal and behavioral changes are similarly produced by maternal administration of CCL2 (4 or 8 mu g/kg/d, E10-E15) and blocked by maternal administration of a CCR2 antagonist INCB3344 (1 mg/kg/d, E10-E15), and these effects of ethanol and CCL2 are sexually dimorphic, consistently stronger in females. These results suggest that this neuronal CCL2/CCR2 system closely linked to MCH neurons has a role in mediating the effects of maternal ethanol exposure on adolescent offspring and contributes to the higher levels of adolescent risk factors for alcohol use disorders described in women.