UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice

Abstract

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 cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus and decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum. Main effects of context and psilocybin-treatment were robust, widespread, and spatially distinct, whereas interactions were surprisingly sparse.

Psilocybin desynchronizes brain networks

“…The reduction of psilocybin-driven brain changes parallels the psychological principle of 'grounding' -directing one's attention on sensory perception as a means of alleviating intense or distressing thoughts or emotions -which is commonly employed in psychedelic-associated psychotherapy 35 . To our knowledge, this is the first evidence of context-dependent effects of psilocybin on functional connectivity and fills an important gap between preclinical studies of context dependence 36,37 and clinical observations 38 .…”

Co-administration of midazolam and psilocybin: Differential effects on subjective quality versus memory of the psychedelic experience

“…In preclinical models, serotonergic psychedelics modulate behavioral phenotypes and induce rapid (within hours) and long-lasting (weeks) neural plasticity 68,69,[86][87][88] , paralleling the time course of rapid symptomatic relief in patients 11,23,58,66 . Acutely induced changes in gene expression may alter circuits in prefrontal cortex and connected regions controlling emotional processing 89,90 . These changes may facilitate subsequent behavioral changes during the post-dosing psychotherapeutic "integration" sessions that are standard practice in clinical trials.…”

Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression

“…More recently, technological advances in tissue clearing, light sheet fluorescence microscopy, and automated detection of nuclei have enabled high-throughput mapping of c-Fos expression in the whole mouse brain 38,39 . We and others have applied this method to characterize the impact of psilocybin and ketamine 40,41,42 , joining a rapidly growing number of studies using brain-wide imaging of fluorescence signals to study drugs 43,44,45,46,47,48,49,50,51,52,53 . Although these early studies have provided valuable biological insights, only one or two drugs were typically included in each study thus far.…”