Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Neuropsychopharmacology. 2023 Nov;48(12):1798-1807. doi: 10.1038/s41386-023-01613-4. Epub 2023 May 29.
The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2;Ai14 mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse.
在人类神经影像学研究中，环境背景对血清素能致幻剂主观体验的影响尚未得到充分研究，部分原因是成像环境的限制。在这里，我们在小鼠的笼内或丰富环境中给予生理盐水或裸盖菇素，用免疫荧光标记全脑 c-Fos，并使用光片荧光显微镜（LSFM）对 iDISCO+ 清除组织进行成像，以检查环境背景对裸盖菇素诱发的神经活动的影响。对 c-Fos 免疫荧光的体素分析揭示了与环境和裸盖菇素处理的主要影响相关的神经活动簇，这些簇通过 c-Fos 细胞密度测量得到了验证。裸盖菇素增加了新皮层、尾壳核、中央杏仁核和旁下丘脑核的亚区的 c-Fos 表达，而以主要不依赖于环境的方式降低了下丘脑、皮质杏仁核、纹状体和苍白球的 c-Fos 表达。为了评估未来对裸盖菇素激活的集合体进行机制研究的可行性，我们使用 TRAP2；Ai14 小鼠在这些神经元的一部分中证实了活性和 Cre 依赖性遗传标记。将每个裸盖菇素敏感簇作为节点进行网络分析表明，裸盖菇素破坏了高度相关区域之间的共同活动，降低了大脑模块性，并极大地减弱了模块间的共同活动。总的来说，我们的结果表明，环境和裸盖菇素的主要影响是强大的、广泛的和重新组织的网络架构，而环境×裸盖菇素的相互作用却出人意料地稀疏。
