CO2 reactivity and orexin activation as predictors of extinction phenotype to fear and reward cues

项目总结 非适应性联想学习是对先前中性刺激的持续条件性反应的基础 出现在创伤后应激障碍和成瘾中：在创伤事件中出现的暗示会导致创伤后应激障碍的恐惧反应，以及暗示 在奖赏刺激(如酒精或食物)之前的行为会导致上瘾时的奖赏行为。这些 反应可以通过消亡学习来减弱，在这种学习中，线索被重复呈现，而不是 以前学到的是令人恐惧或有益的结果。消亡记忆被认为是为了表达而竞争 具有对线索和随后的恐惧或奖励结果的原始联想记忆，这意味着 条件性反应可能会随着时间的推移、压力或语境的变化而回归(Bouton，2004)。 两个实验室都观察到了灭绝后条件性行为回归的个体差异。 和诊所(Bush等人，2007；Clapp等人，2016)，以及一些恐惧消退表型的预测因子 已经确定(Galatzer-Levy等人，2013年；Monfils等人，2019年；Shumake等人，2014,2018年)。然而， 预测个体在奖励灭绝中的差异的能力仍然是一个知识鸿沟。恐惧和恐惧的消失 奖赏记忆受制于相同的行为现象的返回，并且在神经回路中有重叠 这包括内侧前额叶皮质、杏仁核和海马体(Goode&Maren，2019；Peters等人， 2009年)。此外，起源于下丘脑外侧核的增食欲素神经元参与了 对恐惧、食物和酒精暗示的条件性反应消失。外侧型增食欲素受体的激活 下丘脑与对奖赏和恐惧线索的条件性反应的回归呈正相关 灭绝(Hamlin等人，2007；Monfils等人，2019；Moorman等人，2016；Sharko等人，2017)和对抗 食欲素受体可阻止这些行为的再次发生(Cason&Aston-Jones，2013；Flores等人，2014； Lawrence等人，2006年)。黄体中的增食欲素神经元也被二氧化碳(CO2)刺激激活(Johnson 等人，2012年；Monfils等人，2019年)。最近发现，行为二氧化碳的反应性与 与恐惧记忆消退后与促黄体生成素的激活呈正相关 在灭绝后的恐惧记忆和黄体生成素的食欲素激活之间(Monfils等人，2019年)。中心假说 提出的工作之一是，对二氧化碳挑战的行为反应和增食欲素的激活可以用来预测 灭绝表型对奖励和恐惧线索都有影响。这将通过确定二氧化碳的反应性 预测食物和酒精条件下大鼠的长期消退记忆以及二氧化碳反应和食欲素 黄体生成素的激活可以确定食物、酒精和恐惧的长期记忆消失的共同预测因素 暗示。二氧化碳反应性数据和脑组织将从两组接受过食物或酒精的大鼠中收集 条件反射、消退和长期记忆测试。这将与之前收集的数据结合在一起 恐惧条件下大鼠的二氧化碳反应性和增食欲素的激活。将使用统计建模来确定 行为二氧化碳反应性和食欲素激活的亚成分是最好的消退记忆预测因子。

PROJECT SUMMARY Maladaptive associative learning underlies the persistent conditioned responses to previously neutral stimuli seen in PTSD and addiction: cues present during the traumatic event result in fear responses in PTSD, and cues that precede rewarding stimuli (such as alcohol or food) lead to reward seeking behavior in addiction. These responses can be attenuated through extinction learning, where cues are repeatedly presented without the previously learned fearful or rewarding outcome. Extinction memories are thought to compete for expression with the original associative memory of the cue and subsequent fearful or rewarding outcome, meaning conditioned responses may return with the passage of time, stress, or change in context (Bouton, 2004). Individual differences in return of conditioned behavior after extinction have been observed in both the laboratory and the clinic (Bush et al., 2007; Clapp et al., 2016), and a number of predictors of fear extinction phenotype have been identified (Galatzer-Levy et al., 2013; Monfils et al., 2019; Shumake et al., 2014, 2018). However, the ability to predict individual differences in reward extinction remains a knowledge gap. Extinction of fear and reward memories are subject to the same return of behavior phenomena and have overlap in neural circuitry that includes the medial prefrontal cortex, amygdala, and hippocampus (Goode & Maren, 2019; Peters et al., 2009). In addition, orexin neurons, which originate in the lateral hypothalamus (LH), have been implicated in the extinction of conditioned responses to fear, food, and alcohol cues. Activation of orexin receptors in the lateral hypothalamus (LH) is positively correlated with the return of conditioned responses to reward and fear cues after extinction (Hamlin et al., 2007; Monfils et al., 2019; Moorman et al., 2016; Sharko et al., 2017) and antagonism of orexin receptors prevents the return of these behaviors (Cason & Aston-Jones, 2013; Flores et al., 2014; Lawrence et al., 2006). Orexin neurons in the LH are also activated by carbon dioxide (CO2) challenge (Johnson et al., 2012; Monfils et al., 2019). It was recently found that behavioral CO2 reactivity has a negative correlation with both fear memory after extinction and orexin activation in the LH and that there is a positive correlation between fear memory after extinction and orexin activation in the LH (Monfils et al., 2019). The central hypothesis of the proposed work is that behavioral reactivity and orexin activation to a CO2 challenge can be used to predict extinction phenotype to both reward and fear cues. This will be tested by determining whether CO2 reactivity predicts long-term extinction memory in food- and alcohol-conditioned rats and whether CO2 reactivity and orexin activation in the LH can identify common predictors of long-term extinction memory to food, alcohol, and fear cues. CO2 reactivity data and brain tissue will be collected from two sets rats that have undergone food or alcohol conditioning, extinction, and a long-term memory test. This will be combined with previously collected data on CO2 reactivity and orexin activation in fear conditioned rats. Statistical modeling will be used to determine which subcomponents of behavioral CO2 reactivity and orexin activation are the best predictors of extinction memory.