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

CO2 反应性和食欲素激活作为恐惧和奖励线索灭绝表型的预测因子

• 批准号: 10680220
• 负责人: Marissa Renee Raskin
• 金额: $ 4.45万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680220
• 关键词: Alcohols; Amygdaloid structure; Anxiety Disorders; Association Learning; Attenuated; Basic Science; Behavior; Behavior Therapy; Behavioral; Brain; Carbon Dioxide; Cells; Clinic; Conditioned Reflex; Cues; Data; Disease; Emotional; Exposure to; Extinction; FOS gene; Flushing; Food; Fright; Goals; Hippocampus; Human; Hypothalamic structure; Immunohistochemistry; Individual; Individual Differences; Knowledge; Label; Laboratories; Lateral; Lead; Learning; Medial; Memory; Mental disorders; Neurons; Outcome; Patients; Phase; Phenotype; Post-Traumatic Stress Disorders; Prefrontal Cortex; Rattus; Recording of previous events; Research; Rewards; Rodent; Sampling; Screening procedure; Statistical Models; Stimulus; Stress; System; Testing; Time; Training; Translating; Trauma; Work; addiction; alcohol cue; alcohol exposure; alcohol memory; alcohol use disorder; antagonist; brain tissue; career; conditioned fear; conditioning; diagnostic screening; fear memory; hypocretin; improved; large datasets; learning extinction; long term memory; neural circuit; patient subsets; predicting response; prevent; receptor; reduce symptoms; reinforcer; response; statistics; traumatic event; treatment strategy

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.

项目摘要 适应不良的联想学习是对先前中性刺激的持续性条件反应的基础 在创伤后应激障碍和成瘾中观察到：创伤事件中存在的线索导致创伤后应激障碍中的恐惧反应， 在奖赏刺激（如酒精或食物）之前的刺激导致成瘾中的奖赏寻求行为。这些 反应可以通过消退学习来减弱，在这种情况下，线索被反复呈现，而没有反应。 以前学习过的恐惧或奖励的结果。灭绝记忆被认为是竞争表达 与线索的原始联想记忆和随后的恐惧或奖励结果， 条件反射可能会随着时间的推移、压力或环境的变化而恢复（Bouton，2004）。 在两个实验室中都观察到了条件行为消退后恢复的个体差异。 和诊所（Bush等人，2007; Clapp等人，2016），以及一些恐惧灭绝表型的预测因子 已经被鉴定（Galatzer-Levy等人，2013; Monfils等人，2019; Shumake等人，2014年、2018年）的情况。但 预测奖励消退中个体差异的能力仍然是一个知识空白。消除恐惧， 奖赏记忆也同样受到行为现象的影响，并且在神经回路中有重叠 包括内侧前额叶皮层、杏仁核和海马体（Goode & Maren，2019; Peters等人， 2009年）。此外，起源于外侧下丘脑（LH）的食欲素神经元也参与了这一过程。 消除对恐惧、食物和酒精暗示的条件反应。外侧区食欲素受体的激活 下丘脑（LH）与奖励和恐惧线索的条件反应的回归呈正相关， 消光（Hamlin等人，2007; Monfils等人，2019; Moorman等人，2016; Sharko等人，（2017）对抗 食欲素受体的释放阻止了这些行为的恢复（Cason & Aston-Jones，2013;弗洛雷斯等人，二零一四年; 劳伦斯等人，2006年）。LH中的食欲素神经元也被二氧化碳（CO2）刺激激活（约翰逊 例如，2012; Monfils等人，2019年）。最近发现，行为CO2反应性具有负相关性 与消退后恐惧记忆和LH中食欲素的激活均呈正相关 消退后的恐惧记忆与LH中的食欲素激活之间的关系（Monfils等，2019年）。核心假设 提出的工作是，行为反应性和食欲素激活CO2的挑战，可用于预测 灭绝表型的奖励和恐惧线索。这将通过确定CO2反应性 预测食物和酒精条件大鼠的长期消退记忆，以及CO2反应性和食欲素 LH的激活可以识别对食物、酒精和恐惧的长期消退记忆的共同预测因子 线索将从两组接受食物或酒精的大鼠中收集CO2反应性数据和脑组织 条件反射消退和长期记忆测试这将与以前收集的数据相结合， 恐惧条件化大鼠的CO2反应性和食欲素激活。统计建模将用于确定 行为CO2反应性和食欲素激活的子成分是消退记忆的最佳预测因子。