Smith K A, Raskin M R, Donovan M H, Raghunath V, Mansoorshahi S, Telch M J, Shumake J, Noble-Haeusslein L J, Monfils M H
Department of Psychology, The University of Texas at Austin, Austin, TX, United States.
Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, United States.
Front Behav Neurosci. 2023 Jun 16;17:1206073. doi: 10.3389/fnbeh.2023.1206073. eCollection 2023.
There is a strong association between traumatic brain injuries (TBIs) and the development of psychiatric disorders, including post-traumatic stress disorder (PTSD). Exposure-based therapy is a first-line intervention for individuals who suffer from PTSD and other anxiety-related disorders; however, up to 50% of individuals with PTSD do not respond well to this approach. Fear extinction, a core mechanism underlying exposure-based therapy, is a procedure in which a repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus leads to a decrease in fear expression, and is a useful tool to better understand exposure-based therapy. Identifying predictors of extinction would be useful in developing alternative treatments for the non-responders. We recently found that CO reactivity predicts extinction phenotypes in rats, likely through the activation of orexin receptors in the lateral hypothalamus. While studies have reported mixed results in extinction of fear after TBI, none have examined the long-term durability of this phenotype in the more chronically injured brain. Here we tested the hypothesis that TBI results in a long-term deficit in fear extinction, and that CO reactivity would be predictive of this extinction phenotype. Isoflurane-anesthetized adult male rats received TBI ( = 59) (produced by a controlled cortical impactor) or sham surgery ( = 29). One month post-injury or sham surgery, rats underwent a CO or air challenge, followed by fear conditioning, extinction, and fear expression testing. TBI rats exposed to CO (TBI-CO) showed no difference during extinction or fear expression relative to shams exposed to CO (sham-CO). However, TBI-CO rats, showed significantly better fear expression than TBI rats exposed to air (TBI-air). In contrast to previous findings, we observed no relationship between CO reactivity and post-extinction fear expression in either the sham or TBI rats. However, compared to the previously observed naïve sample, we observed more variability in post-extinction fear expression but a very similar distribution of CO reactivity in the current sample. Isoflurane anesthesia may lead to interoceptive threat habituation, possibly via action on orexin receptors in the lateral hypothalamus, and may interact with CO exposure, resulting in enhanced extinction. Future work will directly test this possibility.
创伤性脑损伤（TBI）与包括创伤后应激障碍（PTSD）在内的精神疾病的发生之间存在密切关联。基于暴露的疗法是患有PTSD和其他焦虑相关障碍的个体的一线干预措施；然而，高达50%的PTSD患者对这种方法反应不佳。恐惧消退是基于暴露的疗法的核心机制，是一种在没有无条件刺激的情况下重复呈现条件刺激会导致恐惧表达减少的过程，是更好地理解基于暴露的疗法的有用工具。识别消退的预测因素将有助于为无反应者开发替代治疗方法。我们最近发现，一氧化碳（CO）反应性可能通过激活下丘脑外侧的食欲素受体来预测大鼠的消退表型。虽然研究报告了TBI后恐惧消退的结果不一，但没有一项研究检查过这种表型在慢性损伤更严重的大脑中的长期持续性。在这里，我们测试了以下假设：TBI会导致恐惧消退的长期缺陷，并且CO反应性将预测这种消退表型。异氟烷麻醉的成年雄性大鼠接受TBI（n = 59）（由可控皮质撞击器产生）或假手术（n = 29）。损伤或假手术后一个月，大鼠接受CO或空气刺激，随后进行恐惧条件反射、消退和恐惧表达测试。暴露于CO的TBI大鼠（TBI-CO）在消退或恐惧表达方面与暴露于CO的假手术组（假手术-CO）相比没有差异。然而，TBI-CO大鼠的恐惧表达明显优于暴露于空气的TBI大鼠（TBI-空气）。与之前的研究结果相反，我们在假手术或TBI大鼠中均未观察到CO反应性与消退后恐惧表达之间的关系。然而，与之前观察的未处理样本相比，我们在当前样本中观察到消退后恐惧表达的变异性更大，但CO反应性的分布非常相似。异氟烷麻醉可能通过作用于下丘脑外侧的食欲素受体导致内感受威胁习惯化，并可能与CO暴露相互作用，从而增强消退。未来的工作将直接测试这种可能性。
