UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.
UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.
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揭示裸盖菇素和环境对小鼠全脑即早期基因表达的协同作用。
DOI：
10.1101/2023.02.19.528997
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Heifets,BorisD
中科院分区：
文献类型：
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作者：
Rijsketic,DanielRyskamp;Casey,AustenB;Barbosa,DanielAN;Zhang,Xue;Hietamies,TuuliM;Ramirez-Ovalle,Grecia;Pomrenze,Matthew;Halpern,CaseyH;Williams,LeanneM;Malenka,RobertC;Heifets,BorisD
在人类神经成像研究中，背景对多巴胺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，我们将生理盐水或裸盖菇素给予在其家庭笼或富集环境中的小鼠，免疫荧光标记的全脑c-Fos，并用光片荧光显微镜（LSFM）对iDISCO+清除的组织进行成像，以检查环境背景对裸盖菇素引起的神经活动的影响。c-Fos-免疫荧光的体素分析揭示了与上下文和裸盖菇素治疗的主要影响相关的神经活性簇，这用c-Fos+细胞密度测量进行了验证。裸盖菇素增加c-Fos的表达在新皮质，尾壳核，中央杏仁核，丘脑底旁核的亚区，而它减少c-Fos在下丘脑，皮质杏仁核，纹状体，苍白球在一个主要的上下文无关的方式。为了评估未来对psilocybin激活的集合体进行机制研究的可行性，我们使用TRAP 2 +/−; Ai 14+小鼠在这些神经元的一个子集中确认了活性和Cre依赖性遗传标记。将每个裸盖菇素敏感簇作为一个节点处理的网络分析表明，裸盖菇素破坏了高度相关区域之间的协同活动，降低了大脑的模块性，并显着减弱了模块间的协同活动。总的来说，我们的研究结果表明，上下文和裸盖菇素的主要影响是强大的，广泛的，重组的网络架构，而上下文×裸盖菇素的相互作用是令人惊讶的稀疏。
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.