Falkner, AnnegretWeber, Isla2022-07-152026-09-292022-07-152026-09-292022-04-222022-07-15http://arks.princeton.edu/ark:/88435/dsp016395wb274https://theses-dissertations.princeton.edu/handle/88435/dsp016395wb274Psychedelics, despite their complicated history and unconventional effects, are now being shown by medical and scientific practices to be helpful as a mental health therapy across many common diagnostic categories, including depression, PTSD, addiction, and more. Parallel to this medicalization, the movement towards legalization of psychedelic drugs in the United States and around the world suggests that psychedelics will soon be readily available for both recreational and clinical use. Importantly, systematic and controlled animal research could help to answer unknown interactions between psychedelics and various administration contexts, but this has not yet been done. Specifically, the context (whether positively or negatively valenced) in which these compounds are administered may enhance or limit their therapeutic potential. Using mice, we test the hypothesis that the psychedelic compound psilocybin alters acute activity within the hippocampus and has a greater anxiolytic effect in a follow-up behavioral battery when administered in a positive, enriched context as opposed to a negative, innately fearful context. We used inducible, genetically encoded fluorescent markers to label neuronal populations acutely activated by psilocybin and used behavioral tasks to assess anxiety-like behavior following treatment. We observed a significant reduction of the anxiety-like phenotype after psilocybin in the positive context but not after psilocybin in the negative context in the Open Field Task results from one of the experiments, providing some preliminary support for our hypothesis. Additionally, we observed a decrease in the number of hippocampal cells activated during psilocybin treatment (compared to treatment with saline) in both contexts, except that activation in sub areas of the ventral hippocampus, an emotional processing center, increased during psilocybin treatment in the positive context but not in the negative context. These results provide preliminary evidence that positive versus negative administration context may drive neural and behavioral signatures of psilocybin outcomes in mice and also suggests a greater anxiolytic effect on long-term behavior in female mice compared to males. This newly developed protocol can be used in future studies to further our understanding of the neural and behavioral effects of psychedelics in combination with varying external stimuli. This study and future research can clarify the importance of a controlled and intentional external environment for both therapeutic and recreational human psychedelic use.application/pdfenPrinceton University Senior Theses