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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.论文摘要：致幻剂可助力多种神经精神疾病实现快速且持久的缓解，但其背后的作用机制仍未阐明。临床前研究表明，血清素能致幻剂（serotonergic psychedelics）可增强神经元可塑性，但目前尚未明确认知与行为层面是否也会出现相应的神经可塑性变化。本研究显示，单次给予年轻成年小鼠致幻剂2,5-二甲氧基-4-碘安非他明（(±)-DOI），可在急性药物作用消退后，影响其大脑结构可塑性与认知灵活性。通过离体磁共振成像（ex vivo magnetic resonance imaging）技术，我们观察到，在全身给予2mg·kg⁻¹的(±)-DOI一天后，小鼠多个感觉皮层与联合皮层的脑体积出现增加。随后，我们通过两步式概率反转学习任务（probabilistic reversal learning task），证实了(±)-DOI对认知灵活性的持久影响：在给药一周后，2mg·kg⁻¹的(±)-DOI可提升小鼠对任务结构中新反转规则的适应速率。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有所提升。至关重要的是，后续实验表明，(±)-DOI对认知灵活性的影响取决于药物给药与新规则反转之间的时间间隔，同时也受干预期间实验经历的性质所调控。(±)-DOI对认知适应与新型思维策略的促进作用，或可解释致幻剂辅助疗法的临床获益，尤其针对抑郁、焦虑或成瘾患者中常见的固着行为与变革抵抗状态。此外，本研究结果凸显了时间依赖性神经可塑性的关键作用，以及经验因素在调控针对认知灵活性受损的致幻干预疗法潜力方面的影响。