Ministry of Health, Beer-Sheva Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer- Sheva, Israel.
Department of Psychology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Transl Psychiatry. 2020 Jan 21;10(1):10. doi: 10.1038/s41398-020-0698-9.
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.
越来越多的证据表明，食欲素（ORXs）作为调节神经肽，通过调节神经内分泌、5-羟色胺能和去甲肾上腺素能系统，与焦虑和抑郁相关行为有关。本研究在一个受控的前瞻性动物模型中评估了孤啡肽系统在应激相关生理反应中的作用。使用 c-Fos 作为神经元活性的标志物，检测了下丘脑 ORX 神经元对捕食者气味应激（PSS）的反应模式和时间进程。评估了暴露后 7 天的行为反应模式与 ORXs 表达之间的关系。我们还研究了脑室腔内微量注射 ORX-A 或阿莫雷克斯（ORX-A/B 受体拮抗剂）对 PSS 暴露后 7 天行为反应的影响。评估了下丘脑 ORX-A、神经肽 Y（NPY）和脑源性神经营养因子（BDNF）的水平。与行为严重中断的大鼠（创伤后应激障碍 [PTSD]-表型）相比，行为轻度选择性中断的大鼠下丘脑核中 ORX-A 和 ORX-B 水平显著上调。与人工脑脊液或阿莫雷克斯相比，PSS 前脑室腔内微量注射 ORX-A 可降低 PTSD 表型的发生率，而用阿莫雷克斯治疗的大鼠比未治疗的大鼠表现出更高的 PTSD 表型发生率。激活的 ORX 神经元导致 BDNF 和 NPY 的表达上调，这可能为调节适应性应激反应提供了另一种调节机制。该研究表明，激活的 ORX 系统可能通过刺激 BDNF 和 NPY 分泌促进对 PSS 的适应性反应，而早期干预 ORX-A 可降低 PTSD 表型的发生率，并增加适应性表型的发生率。这些发现为孤啡肽系统参与应激相关疾病的机制提供了一些见解。
