Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction.
Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction.
复制标题
DOI：
10.1016/j.physbeh.2016.10.008
复制
发表时间：
2017-09-01
影响因子：
2.9
通讯作者：
Wilson MA
中科院分区：
文献类型：
--
作者：
Sharko AC;Fadel JR;Kaigler KF;Wilson MA
确定神经生物学机制，强调敏感性差异的理解是至关重要的发展和表达的压力引起的疾病，如创伤后应激障碍（PTSD）。临床前研究表明，啮齿类动物表现出与巴甫洛夫条件性恐惧反应消退相关的不同表型，其中一些啮齿类动物种群对灭绝具有抵抗力。一个新兴的文献也表明食欲素在与恐惧学习和灭绝相关的巩固过程中的作用。为了研究食欲素系统可能参与恐惧消退的个体差异的可能性，我们在远交的Long-Evans大鼠中使用了巴甫洛夫条件反射范式。大鼠表现出显着的变化，在灭绝的线索条件冻结和灭绝回忆，和动物被分成组的基础上，他们的灭绝配置文件的基础上的中位数分裂的百分比冻结行为在重复暴露于条件提示。动物抵抗灭绝（高冰柜）表现出更多的冻结在重复提示演示期间，在试验内和试验灭绝会议之间相比，组显着灭绝（低冰柜），虽然有没有这些组之间的差异，在冻结后返回到条件的上下文或在条件会话。在消退回忆阶段之后，使用下丘脑中食欲素阳性神经元中cFos的双标记免疫组织化学来确定食欲素神经元的激活。提示条件性恐惧消退的个体差异与下丘脑食欲素神经元的差异激活有关。动物表现出不良灭绝的线索诱导冻结（高冰柜）有显着更大的百分比食欲素神经元与Fos在内侧下丘脑比动物表现出显着的灭绝和良好的灭绝回忆（低冰柜）。此外，消退学习过程中的冻结与下丘脑外侧区和内侧区中激活的食欲素神经元的百分比呈正相关。在灭绝表型之间，食欲素神经元或Fos激活的总体密度没有差异。虽然相关，我们的研究结果支持其他研究暗示的orexinergic系统在调节灭绝的条件反应的威胁。
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.