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 brainwide 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.

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

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. In this study, 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. 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, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. 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. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects. 

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin

Crocin ameliorates depressive-like behaviors induced by chronic restraint stress via the NAMPT-NAD+-SIRT1 pathway in mice

Anatomical and functional evidence suggests that the PFC is fairly unique among all cortical regions, as it not only receives input from, but also robustly projects back to mesopontine monoaminergic and cholinergic cell groups. Thus the PFC is in a position to exert a powerful top-down control over several state setting modulatory transmitter systems that are critically involved in the domains of arousal, motivation, reward/aversion, working memory, mood regulation, and stress processing. Regarding this scenario, the origin of cortical afferents to the ventral tegmental area (VTA), laterodorsal tegmental nucleus (LDTg), and median raphe nucleus (MnR) was here compared, by using the retrograde tracer cholera toxin subunit b (CTb). CTb injections into VTA, LDTg, or MnR produced retrograde labeling in the cortical mantle, which was mostly confined to medial, orbital, and lateral PFC subdivisions, along with rostral and mid-cingulate areas. Remarkably, in all of the three groups, retrograde labeling was densest in layer V pyramidal neurons of the infralimbic, prelimbic, medial orbital and frontal polar cortex. Moreover, a conspicuous lambda-shaped region around the apex of the rostral pole of the nucleus accumbens stood consistently out as heavily labeled. At almost all rostrocaudal levels through the PFC analyzed, retrograde labeling was strongest following injections into MnR and weakest following injections into VTA. Altogether, our findings reveal a broadly similar set of prefrontal afferents to VTA, LDTg, and MnR, further supporting an eminent functional role of the PFC as a controller of all major state setting mesopontine modulatory transmitter systems.

Top-Down Projections of the Prefrontal Cortex to the Ventral Tegmental Area, Laterodorsal Tegmental Nucleus, and Median Raphe Nucleus

Top-down projections of the prefrontal cortex to the ventral tegmental area, laterodorsal tegmental nucleus, and median raphe nucleus

Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset

Mutilating palmoplantar keratoderma (PPK) is a heterogeneous genetic disease that poses enormous challenges to clinical diagnosis and genetic counselling. Lanosterol synthase (LSS) gene encodes LSS involved in the biosynthesis pathway of cholesterol. Biallelic mutations in LSS were found to be related to diseases such as cataracts, hypotrichosis and palmoplantar keratoderma‐congenital alopecia syndrome. The aim of this study was to investigate the contribution of the LSS mutation to mutilating PPK in a Chinese patient. The clinical and molecular characteristics of the patient were evaluated. A 38‐year‐old male patient with mutilating PPK was recruited in this study. We identified biallelic variants in the LSS gene (c.683C > T, p.Thr228Ile and c.779G > A, p.Arg260His). Immunoblotting revealed that the Arg260His mutant showed a significantly reduced expression level while Thr228Ile showed an expression level similar to that of the wild type. Thin layer chromatography revealed that mutant Thr228Ile retained partial enzymatic activity and mutant Arg260His did not show any catalytic activity. Our findings show the correlation between LSS mutations and mutilating PPK.

Biallelic mutations in LSS in autosomal‐recessive mutilating palmoplantar keratoderma

Lung adenocarcinoma (LUAD) is the main cause of death globally. The present study investigated the prognostic value and functional verification of nucleophosmin (NPM1) in LUAD. LUAD and normal samples from The Cancer Genome Atlas were analyzed to identify whether NPM1 is associated with LUAD prognosis. NPM1 protein expression level was verified by western blotting. Cell proliferation, migration and invasion were detected by Cell Counting Kit-8, wound healing and Transwell assays, respectively. EGFR/MAPK pathway-related proteins [phosphorylated (p)-EGFR/EGFR, p-MEK/MEK, and p-ERK/ERK] expression was measured through western blotting. A xenograft tumor mice model was constructed to perform the in vivo verification. NPM1 was upregulated in LUAD cells, and high-level NPM1 indicated poor prognosis in patients with LUAD. In vitro experiments revealed that NPM1 knockdown inhibited LUAD cell proliferation, migration and invasion. Moreover, protein expression of p-EGFR/EGFR, p-MEK/MEK and p-ERK/ERK was reduced with the NPM1 silencing. Furthermore, EGF, an activator of the EGFR/MAPK pathway, reversed the effects of NPM1. In vivo experiments showed that NPM1 knockdown inhibited tumor growth and protein levels of p-EGFR/EGFR, p-MEK/MEK and p-ERK/ERK. NPM1 is related to the poor prognosis of LUAD and promotes the malignant progression of LUAD by activating the EGFR/MAPK pathway. This discovery provides a new potential therapeutic target for the diagnosis and treatment of LUAD.

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Min Chen

Papers

Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset

Biallelic mutations in LSS in autosomal‐recessive mutilating palmoplantar keratoderma

Nucleophosmin promotes lung adenocarcinoma cell proliferation, migration and invasion by activating the EGFR/MAPK signaling pathway