Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder
Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder
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DOI：
10.1038/s41398-020-0698-9
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发表时间：
2020-01-21
影响因子：
6.8
通讯作者：
Cohen, Hagit
中科院分区：
文献类型：
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作者：
Cohen, Shlomi;Matar, Michael A.;Cohen, Hagit
越来越多的证据表明，食欲素(orexins，ORX)是一种调节神经肽，通过调节神经内分泌、5-羟色胺能和去甲肾上腺素能系统，参与焦虑和抑郁相关的行为。这项研究在一个受控的前瞻性动物模型中评估了食欲素能系统在应激相关生理反应中的作用。以c-Fos作为神经元活性的标记物，研究了下丘脑ORX神经元对捕食气味应激(PSS)的激活模式和时程。评价暴露后7d的行为反应模式与ORX基因表达的关系。我们还观察了脑室微量注射ORX-A或ALMOXANT(ORX-A/B受体拮抗剂)对PSS暴露后7天大鼠行为反应的影响。测定下丘脑ORX-A、神经肽Y(NPY)和脑源性神经营养因子(BDNF)水平。与行为极度紊乱的大鼠(创伤后应激障碍[PTSD]表型)相比，行为轻度选择性紊乱的大鼠下丘脑核团中ORX-A和ORX-B的水平显著上调。在PSS前脑室微量注射ORX-A可降低PTSD表型的患病率，与人工脑脊液或almore xant组相比，almore xant组大鼠的PTSD表型患病率高于未治疗组。激活的ORX神经元导致BDNF和NPY表达上调，这可能为适应性应激反应的调节提供了额外的调节机制。研究表明，激活的ORX系统可能通过刺激BDNF和NPY的分泌来促进对PSS的适应性反应，而ORX-A的早期干预降低了PTSD表型的发生率，增加了适应性表型的发生率。这些发现为ORX系统参与应激相关障碍的潜在机制提供了一些见解。
Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.