Psychedelics, transcriptional rejuvenation, and heath/longevity thread

[Alex K Chen]

 

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https://www.hopkinsmedicine.org/news/newsroom/news-releases/2023/06/study-shows-psychedelic-drugs-reopen-critical-periods-for-social-learning
 

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Next, the scientists looked at psychedelic drugs’ impact on molecular mechanisms. First, in mouse brain cells, they examined a binding point, known as a receptor, for the neurotransmitter serotonin. The researchers found that while LSD and psilocybin use the serotonin receptor to open the critical period, MDMA, ibogaine and ketamine do not.

To explore other molecular mechanisms, the research team turned to ribonucleic acid (RNA), a cousin to DNA that represents which genes are being expressed (producing proteins) in the mice’s cells. The researchers found expression differences among 65 protein-producing genes during and after the critical period was opened.

About 20% of these genes regulate proteins involved in maintaining or repairing the extracellular matrix — a kind of scaffolding that encases brain cells located in the nucleus accumbens, an area associated with social learning behaviors that are responsive to rewards.

 

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Of note, many of the top scoring genes are components of the extracellular matrix (ECM) or have been implicated in its remodelling, including: Fn1(ref. ³⁷), Mmp16(ref. ³⁸), Trpv4(ref. ³⁹), Tinagl1(ref. ⁴⁰), Nostrin⁴¹, Cxcr4(ref. ⁴²), Adgre5(ref. ⁴³), Robo4(ref. ⁴⁴) and Sema3g⁴⁵

 

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Psychedelics induce remodelling of the ECM

Since psychedelics as a class all reopen the social reward learning critical period (Fig. 1) even though these drugs act on a diverse array of principal binding targets (Extended Data Fig. 7) and biochemical signalling pathways (Extended Data Fig. 9), we reasoned that the common mechanism that enables critical period reopening might be downstream of these cellular processes. Furthermore, given the durability of the response (Fig. 2), we hypothesized that psychedelics may modulate the expression of specific genes or pathways. To test this hypothesis, we carried out RNA sequencing of the microdissected NAc 48 h and 2 weeks after pretreatment with either saline, cocaine, ketamine, LSD or MDMA. We collected total mRNA from each sample and made strand-specific libraries for each of three replicates from each condition. Transcript-level abundances were collapsed to gene-level expression estimates for model fitting.

To directly compare treatment-related transcriptional changes specific to the shared ability of psychedelics to reopen the social reward learning critical period, we analysed the gene expression dataset between conditions in which the critical period is in the open state (48 h and 2 weeks after LSD treatment, 48 h after ketamine treatment, and 48 h after MDMA treatment) versus conditions where the critical period remains in or returns to the closed state (48 h and two weeks after saline treatment, 48 h and two weeks after cocaine treatment, and two weeks after ketamine treatment). Using this approach, we identified 65 genes that were significantly differentially expressed (likelihood ratio test; Benjamini–Hochberg-corrected q ≤ 0.1) (Fig. 5). Gene set enrichment analysis of this list identified significant enrichment of ontologies associated with endothelial development, regulation of angiogenesis, vascular development and tissue morphogenesis. Of note, many of the top scoring genes are components of the extracellular matrix (ECM) or have been implicated in its remodelling, including: Fn1(ref. ³⁷), Mmp16(ref. ³⁸), Trpv4(ref. ³⁹), Tinagl1(ref. ⁴⁰), Nostrin⁴¹, Cxcr4(ref. ⁴²), Adgre5(ref. ⁴³), Robo4(ref. ⁴⁴) and Sema3g⁴⁵. Additionally, the differentially expressed gene set includes the immediate early genes (IEGs) Fos, Junb, Arc and Dusp. When we did not control for the psychedelic-specific psychoactive response (saline versus all drug conditions, including cocaine), we identified 39 differentially expressed genes (Benjamini–Hochberg-corrected q ≤ 0.15) (Extended Data Fig. 10); however, enrichment analysis identified no significant ontologies associated with this gene set, and only 6 genes (Hspa12b, Sema3g, Eng, Flt4, Cavin1 and Ube4b) overlapped with the differentially expressed genes in the open state versus closed state dataset shown in Fig. 5. These results provide evidence that the shared ability of psychedelics to reopen the social reward learning critical period converges at transcriptional regulation of the ECM. On the basis of these findings, our working model (Fig. 6) posits that psychedelics act at a diverse array of binding targets (such as SERT, 5-HT_2AR, NMDA and KOR), to trigger a downstream signalling response that leads to activity-dependent (perhaps via IEG-mediated coincidence detection) degradation of the ECM, which in turn is the permissive event that enables metaplasticity. In this model, transcriptional upregulation of ECM components (for example, FN1) and downregulation of ECM proteolytic enzymes (for example, MMP-16), reflects the homeostatic response to these long-lasting cellular changes. Together, these results demonstrate novel biological effects (behavioural, temporal, electrophysiological and molecular) that—similar to therapeutic effects—are shared across psychedelics.

 

 

Edited January 4 by InquilineKea