Two-step data: Experiment 1 VEH pre-drug

Manuscript abstract: Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2mgkg-1 (±)-DOI. We then demonstrate lasting effects of (±)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2mgkg-1 (±)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (±)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (±)-DOI’s effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (±)-DOI’s facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.研究手稿摘要：致幻剂可帮助多种神经精神疾病实现快速且持久的临床缓解，但其背后的作用机制仍不明确。临床前研究表明，5-羟色胺能致幻剂（serotonergic psychedelics）可增强神经元可塑性，但目前尚未探索认知与行为层面是否也能观察到此类神经可塑性变化。本研究显示，单次给药的致幻剂2,5-二甲氧基-4-碘安非他明((±)-DOI)可在急性药物作用消退后，对年轻成年小鼠的大脑结构可塑性与认知灵活性产生影响。通过离体磁共振成像（ex vivo magnetic resonance imaging），我们发现对小鼠以2 mg·kg⁻¹剂量全身给予(±)-DOI后1天，多个感觉皮层与联合皮层区域的体积显著增大。随后我们在两步式概率反转学习任务中证实了(±)-DOI对认知灵活性的持久影响：给药后1周进行任务结构的新型反转时，2 mg·kg⁻¹的(±)-DOI可提升小鼠对新反转的适应速率。值得注意的是，经(±)-DOI处理的小鼠会从奖励缺失中启动学习——这是该任务中小鼠通常不会采用的独特策略，表明其对此前被忽视的线索的敏感性显著提升。至关重要的是，进一步实验显示，(±)-DOI对认知灵活性的影响取决于药物给药与新型反转之间的时间间隔，以及干预性经历的性质。(±)-DOI对认知适应与新型思维策略的促进作用，或许可解释致幻辅助疗法的临床获益，尤其针对抑郁症、焦虑症或成瘾中常见的固着行为与抗拒改变的情况。此外，我们的研究结果强调了时间依赖性神经可塑性的关键作用，以及经验因素在塑造针对认知灵活性受损的致幻干预治疗潜力方面的重要影响。