Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration

Abstract

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.

Keywords: Cognitive flexibility; neuroplasticity; psychedelic therapy; reversal learning; serotonin 2a receptor.

Figure 1.

Experimental timeline and overview. (A) Experimental timeline (65). (B) Schematic of the SEQFR2-forward protocol. Mice have to sequentially poke left and then right within 30 s to earn a reward pellet. (C) Schematic of the SEQFR2-reversal protocol. Mice now are required to poke right and then left within 30 s to get a reward pellet.

Figure 2.

Single-dose psychedelic treatment induces a lasting reversal learning enhancement. (A) Group forward phase poke efficiency, with no significant effect of NBOH treatment. Each day has 4 points plotted corresponding to each hour of the 4-h per day sessions. (B) Group forward phase percentage of correct trials, indicating no significant effect of NBOH treatment. (C) NBOH treatment significantly increased the number of reward pellets dispensed during the forward phase. (D) NBOH treatment significantly increased poke efficiency during the reversal phase compared to saline injection, indicating enhanced cognitive flexibility. (E) NBOH increases the percentage of correct trials. (F) NBOH treatment significantly increased the number of reward pellets dispensed during the reversal phase. Shaded regions represent standard error of the mean (SEM), linear regressions shown in pink for NBOH and black for saline; ns, not significant; **p < 0.01; ****p < 0.0001.

Figure 3.

Lasting psychedelic enhancement of reversal learning ability in male and female mice. (Top) Forward and reversal phase changes to poke efficiency indicating NBOH treatment significantly improves reversal learning in female mice weeks after a single dose. (Bottom) Forward and reversal phase changes to poke efficiency in male mice indicating NBOH treatment significantly improves reversal learning weeks after a single dose. Shaded regions represent standard error of the mean (SEM), linear regressions shown in pink for NBOH and black for saline; ns, not significant; **p < 0.01; ****p < 0.0001.