Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling.
Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling.
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DOI：
10.1016/j.bbi.2016.07.152
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Pittman QJ
中科院分区：
文献类型：
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作者：
Doenni VM;Gray JM;Song CM;Patel S;Hill MN;Pittman QJ
早期炎症已被证明对大脑发育和行为产生深远的影响，包括改变情绪行为，应激反应和神经化学/神经肽受体表达和功能。目前的研究通过检查出生后第14天（P）细菌化合物脂多糖（LPS）引发的炎症对青春期社会行为的影响来扩展这项研究。我们研究了内源性大麻素（eCB）系统在早期LPS后的社会性中所起的作用。为了测试这一点，在P14用LPS注射多组Sprague道利大鼠。在青春期，大鼠进行行为测试，在互惠的社会互动模式以及开放的领域。我们定量了P14和青春期动物（花生四烯酸和2-花生四烯酸甘油）杏仁核中的eCB水平，以及青春期杏仁体类大麻素受体1（CB 1）结合位点密度和脂肪酸酰胺水解酶（FAAH）的水解活性，该酶代谢eCB花生四烯酸。此外，我们还研究了FAAH抑制对社会行为改变的影响。我们的研究结果表明，P14 LPS减少青少年的社会行为（玩和社会非玩）在P40的男性和女性。这种行为改变伴随着CB 1结合减少，大麻素水平增加和FAAH活性增加。在社交任务前全身给予FAAH抑制剂PF-04457845（1 mg/kg）可使LPS诱导的社交行为改变正常化，而不影响对照组的社交行为。将10 ng PF-04457845输注至基底外侧杏仁核使LPS注射雌性动物的社会行为正常化。这些数据表明，出生后炎症后eCB信号的改变有助于青春期社会行为的损害，FAAH可能是涉及社交缺陷的疾病（如社交焦虑症或自闭症）的新靶点。
Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Systemic administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.