Harmatz Elia S, Stone Lauren, Lim Seh Hong, Lee Graham, McGrath Anna, Gisabella Barbara, Peng Xiaoyu, Kosoy Eliza, Yao Junmei, Liu Elizabeth, Machado Nuno J, Weiner Veronica S, Slocum Warren, Cunha Rodrigo A, Goosens Ki A
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge; Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts.
Biol Psychiatry. 2017 Jun 15;81(12):1003-1013. doi: 10.1016/j.biopsych.2016.11.009. Epub 2016 Nov 29.
There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories.
We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats.
In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism.
These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.
关于激素胃饥饿素在厌恶加工中的作用存在许多相互矛盾的研究结果，一些研究表明胃饥饿素信号传导既能抑制厌恶，也能增强厌恶。在此，我们对胃饥饿素在恐惧记忆形成中的矛盾作用进行了表征和梳理。
我们在听觉恐惧学习前后的时间点，使用酶联免疫吸附测定法测量内源性酰基胃饥饿素和皮质酮。我们对胃饥饿素信号传导进行了药理学（全身和杏仁核内）操作，并检测了几种厌恶和食欲行为。我们还使用生物素标记的胃饥饿素来可视化杏仁核冠状脑切片中的胃饥饿素结合位点。所有实验均在大鼠身上进行。
在未受应激的啮齿动物中，内源性外周酰基胃饥饿素通过在杏仁核中的作用强烈抑制恐惧记忆巩固，并且几乎解释了长期恐惧记忆强度的所有个体间差异。恐惧学习后内源性胃饥饿素水平较高与较弱的长期恐惧记忆相关，并且在记忆巩固期胃饥饿素受体的药理学激动作用降低了恐惧记忆强度。这些恐惧抑制作用不能通过食欲行为的变化来解释。相反，我们发现慢性应激会增加循环内源性酰基胃饥饿素和恐惧记忆形成，促进杏仁核中胃饥饿素结合位点的大量丧失以及对胃饥饿素受体激动作用的行为不敏感。
这些研究在应激、一种新型代谢抵抗与过度恐惧记忆形成易感性之间建立了新的联系，并揭示胃饥饿素可以在不改变食欲的情况下调节未受应激动物的负面情绪。
