Doenni V M, Gray J M, Song C M, Patel S, Hill M N, Pittman Q J
Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; Department of Neuroscience, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
Brain Behav Immun. 2016 Nov;58:237-247. doi: 10.1016/j.bbi.2016.07.152. Epub 2016 Jul 21.
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 investigated 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. Oral 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 inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.
早期炎症已被证明会对大脑发育和行为产生深远影响，包括改变情绪行为、应激反应以及神经化学/神经肽受体的表达和功能。当前的研究通过检测出生后第14天（P14）用细菌化合物脂多糖（LPS）引发的炎症对青春期社交行为的影响，扩展了这一研究。我们研究了内源性大麻素（eCB）系统在早期LPS暴露后社交能力中所起的作用。为了验证这一点，多组斯普拉格-道利大鼠在P14时注射LPS。在青春期，大鼠在相互社交互动范式以及旷场实验中接受行为测试。我们对P14和青春期动物杏仁核中的eCB水平（花生四烯乙醇胺和2-花生四烯酸甘油酯）以及青春期杏仁核大麻素受体1（CB1）结合位点密度和代谢eCB花生四烯乙醇胺的脂肪酸酰胺水解酶（FAAH）的水解活性进行了定量。此外，我们研究了FAAH抑制对社交行为改变的影响。我们的结果表明，P14 LPS降低了P40时雄性和雌性大鼠的青春期社交行为（玩耍和非玩耍社交行为）。这种行为改变伴随着CB1结合减少、花生四烯乙醇胺水平升高以及FAAH活性增加。在社交互动任务前口服FAAH抑制剂PF-04457845（1mg/kg）可使LPS诱导的社交行为改变恢复正常，而不影响对照组的社交行为。向基底外侧杏仁核注射10ng PF-04457845可使注射LPS的雌性大鼠的社交行为恢复正常。这些数据表明，出生后炎症后eCB信号的改变导致青春期社交行为受损，并且抑制FAAH可能是涉及社交缺陷（如社交焦虑症或自闭症）疾病的一个新靶点。
