Raskin Marissa, Keller Nicole E, Agee Laura A, Malone Cassidy A, Quevedo Silvia, Hilz Emily N, Roquet Rheall F, Shumake Jason, Smits Jasper A J, Telch Michael J, Otto Michael W, Lee Hongjoo J, Monfils M H
Interdisciplinary Neuroscience Program, The University of Texas at Austin, 1 University Station, Stop C7000, Austin, TX 78712.
Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712.
Physiol Behav. 2025 Sep 1;298:114949. doi: 10.1016/j.physbeh.2025.114949. Epub 2025 May 9.
Pavlovian conditioning can be used to model maladaptive associations seen in anxiety/trauma and substance use disorders. One approach to attenuate conditioned responses is extinction learning (which underlies exposure therapy), wherein cues are repeatedly presented without the expected fearful or rewarding outcome. Extinction is not effective for all; therefore, identifying biomarkers that can phenotype non-responders is necessary to optimize treatment. The orexin system is involved in fear and reward extinction and responses to CO exposure. We previously found that CO reactivity predicts fear extinction memory and CO-induced orexin activity, and orexin activity is associated with extinction memory. In a separate study, we replicated the finding that CO reactivity predicts fear extinction memory and extended this finding to appetitive extinction memory. Here, we combined behavioral and orexin activity data from these three studies in male rats to examine whether we might identify new or common associations of fear and reward extinction with CO reactivity and orexin in a larger combined sample. We found that neither CO reactivity nor CO-induced orexin activity associate with extinction memory in the combined fear and appetitive sample. We found common CO reactivity predictors in the combined fear sample, including a new predictor associated with orexin activity. In an expanded analysis, we found that prior CO exposure may affect subsequent CO reactivity and decrease orexin activity. Our findings support the potential of CO reactivity to serve as a screening tool for identifying likely responders to exposure-based therapy, though specific predictors may differ by reinforcer valence.
巴甫洛夫条件反射可用于模拟焦虑/创伤和物质使用障碍中出现的适应不良关联。一种减弱条件反应的方法是消退学习（这是暴露疗法的基础），即在没有预期的恐惧或奖励结果的情况下反复呈现线索。消退并非对所有人都有效；因此，识别可对无反应者进行表型分析的生物标志物对于优化治疗是必要的。食欲素系统参与恐惧和奖励消退以及对一氧化碳暴露的反应。我们之前发现一氧化碳反应性可预测恐惧消退记忆和一氧化碳诱导的食欲素活性，并且食欲素活性与消退记忆相关。在另一项研究中，我们重复了一氧化碳反应性可预测恐惧消退记忆这一发现，并将这一发现扩展到了食欲消退记忆。在此，我们结合了雄性大鼠这三项研究中的行为和食欲素活性数据，以检验在更大的合并样本中，我们是否能识别出恐惧和奖励消退与一氧化碳反应性及食欲素之间新的或常见的关联。我们发现，在合并的恐惧和食欲样本中，一氧化碳反应性和一氧化碳诱导的食欲素活性均与消退记忆无关。我们在合并的恐惧样本中发现了常见的一氧化碳反应性预测因子，包括一个与食欲素活性相关的新预测因子。在一项扩展分析中，我们发现先前的一氧化碳暴露可能会影响随后的一氧化碳反应性并降低食欲素活性。我们的研究结果支持一氧化碳反应性作为一种筛选工具的潜力，用于识别可能对基于暴露的疗法有反应的个体，尽管具体的预测因子可能因强化物效价而异。
