Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin

Abstract

Background: Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. Methods: Whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. Results: Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe, lateral habenula, and insular cortex for psilocybin and retrosplenial cortex for ketamine. Correlation of psilocybin's effects with gene expression highlighted potential roles of 5-HT2A and GluN2B subunit of NMDA receptors. Conclusions: The systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a valuable resource that highlights previously underappreciated regions for future investigations. By identifying regions with similar and disparate effects, the results provide insights into how psilocybin and ketamine may produce their rapid-acting and long-lasting therapeutic effects.

Towards an understanding of psychedelic-induced neuroplasticity

“…Other subcortical regions Some preliminary unpublished evidence suggests that psychedelics may enhance neuroplasticity in a few subcortical regions. In the aforementioned study of c-fos, psilocybin increased c-fos expression in the claustrum, locus ceruleus, lateral habenula and some areas of the thalamus, amygdala, and brainstem [107]. The pattern of expression changes correlated with 5-HT 2A receptor distribution [107].…”

“…In the aforementioned study of c-fos, psilocybin increased c-fos expression in the claustrum, locus ceruleus, lateral habenula and some areas of the thalamus, amygdala, and brainstem [107]. The pattern of expression changes correlated with 5-HT 2A receptor distribution [107]. Given that c-fos is a relatively unspecific marker, however, these results should be interpreted with caution, and more research is necessary to determine how psychedelics affect neuroplasticity in subcortical regions.…”

“…A recent unpublished study in mice examined expression of c-Fos, an early marker of neuroplastic processes, after treatment with psilocybin, revealing strong upregulation in most cortical regions. These included sensory visual, auditory, somatosensory, and gustatory areas, as well as motor and association areas, the anterior cingulate cortex (ACC), and the insula [107].…”

Neural Mechanisms and Psychology of Psychedelic Ego Dissolution

“…Preclinical evidence shows that psychedelics render the brain in a more malleable state. For example, C-Fos expression (a marker of neural activity) is identified across brain regions in mice under psilocybin (Davoudian et al, 2022), DMT developed new neurons in the hippocampus of mice (Morales-Garcia et al, 2020), and the development of dendritic spines in neurons and synaptic connectivity are observed in the prefrontal neurons of rats under DMT (Ly et al, 2018). Dendritic change can alter the enhancement and suppression of membrane excitability, which may create opposing actions on dendritic excitability that promote plasticity (Savalia et al, 2021).…”

“…Its connectivity with the prefrontal cortex is also important to extinction learning (Quirk and Mueller, 2008;Herry et al, 2010;Milad and Quirk, 2012;Baldi et al, 2021), and dysfunction of this connectivity marks fear disorders such as PTSD (Rauch et al, 2006;Shin et al, 2006). Under psilocybin, the basolateral AMG demonstrates an elevated expression level of c-Fos (a marker of neural activity) (Davoudian et al, 2022) and is implicated in mice under nonclassic psychedelics such as 3,4-methylenedioxymethamphetamine (Glavonic et al, 2022). However, destruction of the basolateral AMG had a negligible effect on prefrontal 5-HT cortical excitation in preclinical research.…”