Sharko Amanda C, Fadel Jim R, Kaigler Kris F, Wilson Marlene A
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, School of Medicine, Columbia, SC, USA; WJB Dorn Veterans Affairs Medical Center, Columbia, SC, USA.
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, School of Medicine, Columbia, SC, USA; WJB Dorn Veterans Affairs Medical Center, Columbia, SC, USA.
Physiol Behav. 2017 Sep 1;178:93-102. doi: 10.1016/j.physbeh.2016.10.008. Epub 2016 Oct 13.
Identifying the neurobiological mechanisms that underlie differential sensitivity to stress is critical for understanding the development and expression of stress-induced disorders, such as post-traumatic stress disorder (PTSD). Preclinical studies have suggested that rodents display different phenotypes associated with extinction of Pavlovian conditioned fear responses, with some rodent populations being resistant to extinction. An emerging literature also suggests a role for orexins in the consolidation processes associated with fear learning and extinction. To examine the possibility that the orexin system might be involved in individual differences in fear extinction, we used a Pavlovian conditioning paradigm in outbred Long-Evans rats. Rats showed significant variability in the extinction of cue-conditioned freezing and extinction recall, and animals were divided into groups based on their extinction profiles based on a median split of percent freezing behavior during repeated exposure to the conditioned cue. Animals resistant to extinction (high freezers) showed more freezing during repeated cue presentations during the within trial and between trial extinction sessions compared with the group showing significant extinction (low freezers), although there were no differences between these groups in freezing upon return to the conditioned context or during the conditioning session. Following the extinction recall session, activation of orexin neurons was determined using dual label immunohistochemistry for cFos in orexin positive neurons in the hypothalamus. Individual differences in the extinction of cue conditioned fear were associated with differential activation of hypothalamic orexin neurons. Animals showing poor extinction of cue-induced freezing (high freezers) had significantly greater percentage of orexin neurons with Fos in the medial hypothalamus than animals displaying significant extinction and good extinction recall (low freezers). Further, the freezing during extinction learning was positively correlated with the percentage of activated orexin neurons in both the lateral and medial hypothalamic regions. No differences in the overall density of orexin neurons or Fos activation were seen between extinction phenotypes. Although correlative, our results support other studies implicating a role of the orexinergic system in regulating extinction of conditioned responses to threat.
确定应激差异敏感性背后的神经生物学机制对于理解应激诱导的疾病（如创伤后应激障碍，PTSD）的发生和表现至关重要。临床前研究表明，啮齿动物在巴甫洛夫条件性恐惧反应消退方面表现出不同的表型，一些啮齿动物群体对消退具有抗性。新兴文献还表明，食欲素在与恐惧学习和消退相关的巩固过程中发挥作用。为了研究食欲素系统可能参与恐惧消退个体差异的可能性，我们在远交系长 Evans 大鼠中使用了巴甫洛夫条件反射范式。大鼠在线索条件性僵立反应的消退和消退回忆方面表现出显著的变异性，根据重复暴露于条件线索期间僵立行为百分比的中位数分割，将动物分为不同的组。与显示出显著消退的组（低僵立组）相比，对消退有抗性的动物（高僵立组）在试验内和试验间消退阶段重复呈现线索期间表现出更多的僵立，尽管在回到条件环境或条件反射阶段时，这些组之间的僵立没有差异。在消退回忆阶段之后，使用双标记免疫组织化学法检测下丘脑食欲素阳性神经元中 cFos 的表达，以确定食欲素神经元的激活情况。线索条件性恐惧消退的个体差异与下丘脑食欲素神经元的不同激活有关。线索诱导的僵立消退较差的动物（高僵立组）在下丘脑内侧具有 Fos 的食欲素神经元百分比显著高于显示出显著消退和良好消退回忆的动物（低僵立组）。此外，消退学习期间的僵立与下丘脑外侧和内侧区域激活的食欲素神经元百分比呈正相关。在消退表型之间，食欲素神经元的总体密度或 Fos 激活没有差异。尽管是相关性的，但我们的结果支持其他研究，表明食欲素能系统在调节对威胁的条件性反应消退中发挥作用。
