Roman Carolyn W, Lezak Kim R, Hartsock Matthew J, Falls William A, Braas Karen M, Howard Alan B, Hammack Sayamwong E, May Victor
Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Department of Psychological Science, University of Vermont, Burlington, VT 05405, USA.
Psychoneuroendocrinology. 2014 Sep;47:151-65. doi: 10.1016/j.psyneuen.2014.05.014. Epub 2014 May 27.
Chronic or repeated stressor exposure can induce a number of maladaptive behavioral and physiological consequences and among limbic structures, the bed nucleus of the stria terminalis (BNST) has been implicated in the integration and interpretation of stress responses. Previous work has demonstrated that chronic variate stress (CVS) exposure in rodents increases BNST pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) and PAC1 receptor (Adcyap1r1) transcript expression, and that acute BNST PACAP injections can stimulate anxiety-like behavior. Here we show that chronic stress increases PACAP expression selectively in the oval nucleus of the dorsolateral BNST in patterns distinct from those for corticotropin releasing hormone (CRH). Among receptor subtypes, BNST PACAP signaling through PAC1 receptors not only heightened anxiety responses as measured by different behavioral parameters but also induced anorexic-like behavior to mimic the consequences of stress. Conversely, chronic inhibition of BNST PACAP signaling by continuous infusion with the PAC1 receptor antagonist PACAP(6-38) during the week of CVS attenuated these stress-induced behavioral responses and changes in weight gain. BNST PACAP signaling stimulated the hypothalamic-pituitary-adrenal (HPA) axis and heightened corticosterone release; further, BNST PACAP(6-38) administration blocked corticosterone release in a sensitized stress model. In aggregate with recent associations of PACAP/PAC1 receptor dysregulation with altered stress responses including post-traumatic stress disorder, these data suggest that BNST PACAP/PAC1 receptor signaling mechanisms may coordinate the behavioral and endocrine consequences of stress.
长期或反复暴露于应激源会引发一系列适应不良的行为和生理后果，在边缘系统结构中，终纹床核（BNST）参与了应激反应的整合与解读。先前的研究表明，啮齿动物长期暴露于慢性可变应激（CVS）会增加BNST中垂体腺苷酸环化酶激活多肽（PACAP，Adcyap1）和PAC1受体（Adcyap1r1）的转录表达，并且急性注射BNST PACAP可刺激类似焦虑的行为。在此我们表明，慢性应激以不同于促肾上腺皮质激素释放激素（CRH）的模式选择性地增加背外侧BNST椭圆形核中的PACAP表达。在受体亚型中，BNST通过PAC1受体的PACAP信号传导不仅通过不同行为参数测量时增强了焦虑反应，还诱导了类似厌食的行为以模拟应激的后果。相反，在CVS期间连续一周通过持续输注PAC1受体拮抗剂PACAP(6 - 38)对BNST PACAP信号进行慢性抑制，减弱了这些应激诱导的行为反应和体重增加变化。BNST PACAP信号刺激下丘脑 - 垂体 - 肾上腺（HPA）轴并增强皮质酮释放；此外，在致敏应激模型中，给予BNST PACAP(6 - 38)可阻断皮质酮释放。综合近期PACAP/PAC1受体失调与包括创伤后应激障碍在内的应激反应改变之间的关联，这些数据表明BNST PACAP/PAC1受体信号传导机制可能协调应激的行为和内分泌后果。
