Rockefeller University, New York, New York 10065.
Rockefeller University, New York, New York 10065
J Neurosci. 2018 Oct 17;38(42):9072-9090. doi: 10.1523/JNEUROSCI.0637-18.2018. Epub 2018 Sep 10.
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 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 μg/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. Ethanol consumption and inflammatory agents during pregnancy similarly increase alcohol intake and anxiety in adolescent offspring. To investigate how neurochemical and neuroimmune systems interact to mediate these disturbances, we examined a specific population of hypothalamic neurons coexpressing the inflammatory chemokine CCL2 and its receptor CCR2 with the neuropeptide, melanin-concentrating hormone. We demonstrate in adolescent offspring that maternal administration of CCL2, like ethanol, stimulates these neurons and increases ethanol drinking and anxiety, and these effects of ethanol are blocked by maternal CCR2 antagonist and consistently stronger in females. This suggests that neuronal chemokine signaling linked to neuropeptides mediates effects of maternal ethanol exposure on adolescent offspring and contributes to higher levels of adolescent risk factors for alcohol use disorders in women.
临床和动物研究表明，妊娠期间乙醇暴露和炎症会导致后代出现类似的行为障碍。虽然乙醇被证明会刺激成人的神经免疫和神经化学系统，但对于它们对乙醇的反应的解剖学关系以及神经免疫因素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，我们在雌性和雄性青春期大鼠中检查了集中在外侧下丘脑的特定神经元群体，这些神经元与食欲肽黑素浓缩激素（MCH）共表达炎症趋化因子 C-C 基序配体 2（CCL2）或其受体 CCR2，促进乙醇饮用行为。我们证明，从胚胎第 10 天（E10）到 E15 期间，母体给予乙醇（2 g/kg/d），虽然对神经胶质几乎没有影响，但会刺激神经元 CCL2 和 CCR2 的表达，增加大 CCL2 神经元与 MCH 共定位的密度和围绕 MCH 神经元的小 CCL2 神经元的密度，并刺激青春期后代的乙醇饮用和焦虑。我们表明，这些神经元和行为变化同样是由母体给予 CCL2（4 或 8 μg/kg/d，E10-E15）产生的，并被母体给予 CCR2 拮抗剂 INCB3344（1 mg/kg/d，E10-E15）阻断，这些乙醇和 CCL2 的作用具有性别二态性，在女性中更明显。这些结果表明，与 MCH 神经元紧密相关的这种神经元 CCL2/CCR2 系统在介导母体乙醇暴露对青春期后代的影响方面具有作用，并导致女性中描述的青春期酒精使用障碍风险因素水平更高。妊娠期间乙醇消耗和炎症剂同样会增加青春期后代的酒精摄入量和焦虑。为了研究神经化学和神经免疫系统如何相互作用来介导这些干扰，我们检查了外侧下丘脑神经元的一个特定群体，这些神经元共表达炎症趋化因子 CCL2 和其受体 CCR2 与神经肽黑素浓缩激素。我们在青春期后代中证明，母体给予 CCL2，就像乙醇一样，刺激这些神经元并增加乙醇摄入和焦虑，而乙醇的这些作用被母体 CCR2 拮抗剂阻断，并且在女性中更明显。这表明与神经肽相关的神经元趋化因子信号传导介导了母体乙醇暴露对青春期后代的影响，并导致女性中青春期酒精使用障碍风险因素水平升高。
