Brouns Elizabeth J, Ekins Tyler G, Ahmed Omar J
Department of Psychology, University of Michigan, Ann Arbor, MI 48109.
Michigan Psychedelic Center, University of Michigan, Ann Arbor, MI 48109.
Psychedelics (N Y). 2025 Apr 22. doi: 10.61373/pp025r.0002.
Psychedelic compounds have demonstrated remarkable therapeutic potential for treating neuropsychiatric disorders by promoting sustained neuroplasticity in the prefrontal cortex (PFC). Cognitive flexibility-the ability to adapt previously learned rules to novel situations-represents a critical PFC function that is frequently impaired in depression, PTSD, and neurodegenerative conditions. In this study, we demonstrate that a single administration of the selective serotonin 2A receptor agonist 25CN-NBOH produces significant, long-lasting improvements in cognitive flexibility in both male and female mice when measured 2-3 weeks posttreatment. Using a novel automated sequential learning paradigm, psychedelic-treated mice showed superior adaptability in rule reversal tasks compared to saline controls, as evidenced by enhanced poke efficiency, higher percentages of correct trials, and increased reward acquisition. These behavioral findings complement existing cellular research showing psychedelic-induced structural remodeling in the PFC and uniquely demonstrate sustained cognitive benefits persisting weeks after a single psychedelic dose. Our automated behavioral task provides a high-throughput method for evaluating cognitive flexibility effects of various psychedelic compounds, offering important implications for therapeutic applications in conditions characterized by cognitive rigidity, including depression, PTSD, and potentially Alzheimer's disease.
致幻化合物已显示出通过促进前额叶皮质（PFC）的持续神经可塑性来治疗神经精神疾病的显著治疗潜力。认知灵活性——即根据新情况调整先前所学规则的能力——是PFC的一项关键功能，在抑郁症、创伤后应激障碍（PTSD）和神经退行性疾病中经常受损。在本研究中，我们证明，在治疗后2至3周进行测量时，单次给予选择性5-羟色胺2A受体激动剂25CN-NBOH可使雄性和雌性小鼠的认知灵活性得到显著且持久的改善。使用一种新型的自动序列学习范式，与生理盐水对照组相比，接受致幻剂治疗的小鼠在规则反转任务中表现出更强的适应性，表现为戳击效率提高、正确试验的百分比更高以及奖励获取增加。这些行为学发现补充了现有的细胞研究，这些研究表明致幻剂可诱导PFC发生结构重塑，并独特地证明了单次致幻剂剂量后数周持续存在的认知益处。我们的自动行为任务提供了一种高通量方法，用于评估各种致幻化合物对认知灵活性的影响，这对于以认知僵化（包括抑郁症、PTSD以及可能的阿尔茨海默病）为特征的疾病的治疗应用具有重要意义。
