Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice; de la Fuente et al 2021
Journal Club #10
Few things before we begin:
I apologize for my absence; life, research, and hobbies get heavy. I’m stoked to get this one out, and I have a lot of neat-o ideas and a large paper backlog as fodder for future issues.
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Let’s get to it…
Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice
Why They Did It
Mainstream medications available to afflictees of the global scourge of psychiatric disease stink on ice. For instance, they:
Take a while to work 🥱
Work poorly OR not at all 👎
Have lame side effects 🤮
As we all know, psychedelics tickle the brain in unique ways, which can help relieve some ailments.
Much focus lies on the acute action of psychedelics, i.e. what they are do while they are circulating through the brain. 🧠
Recent clinical trial work has shown that psychedelics may also have beneficial long-term effects, i.e. they leave behind changes that stave off psychiatric disease for days, months, even years after treatment.
The authors (oddly) claim "[psilocybin and other psychedelic’s] acute psychotic symptoms and drug abuse potential preclude [their] routine use in daily clinical practice.” 🤔
Although psychs can mimic an acute psychotic state, healing is attributed to this state. Further, classical psychedelics have weak reinforcing effects and have very minimal, if any, abuse potential (especially not psilocybin???). In fact the U.S. government itself is now funding research into the use of psilocybin to treat substance abuse.
Anyway, the primary aim of this research was to study the long-term behavioral impacts of the phenethylamine DOI, and the molecular mechanisms behind these effects. Specifically, they examine:
Behavior - related to depression, anxiety, and stress 🐁
Frontal cortex dendritic spine structure - Little branches on neurons that receive signals, specifically in the front region of the brain 🔬
Epigenetic alterations - Changes in how our bodies read DNA, rather than changes to the DNA 🧬
Gene expression - Which genes are turned on and off at a given moment in time 🎛
What They Did
Behavioral Tests
Rats received a dose of DOI and then tested for behaviors related to anxiety, passivity, cognition, and sensorimotor gating (the ability to filter out irrelevant information).
Researchers also wanted to understand how DOI interacts with 5HT2a serotonin receptor signaling activity in the context of fear and anxiety. So, a genetically modified strain of mice that lacked 5HT2a receptors (knockout mice) was bred for comparison with mice with 5HT2a receptors (wild-type mice).
Fear is induced in mice by associating an electric shock with an arbitrary context, such as a certain color cage wall. Fear is quantified by the amount of time mice spend immobile (“frozen from fear”). It is extinguished by putting the mice into the context in which it acquired the fear, but without shocks. ⚡️
Cortical Dendritic Density
Dendrites are the branches on neurons that receive messages from other neurons, and the cortex is the outer layer of the brain. 📩
To study dendritic density, researchers injected mice with a virus that contains a yellow fluorescent protein (YFP). The virus is designed to only activate in neurons with a certain gene sequence. In this case, the YFP was only expressed in an important population of neurons in the cortex called pyramidal neurons.
To count and characterize the dendrites of these cells, the mouse brain is dissected, sliced thinly, and imaged on a microscope that activates and images the fluorescent signal. 🔦
To understand what impact the 5HT2a receptor system has on dendritic density, the researchers compared the dendritic density of 5HT2aR -/- knockout mice with wild type mice.
To understand the impact of DOI on dendritic density, the researchers administered DOI and vehicle to knockout mice and wild-type mice, and compared dendritic density.
Frontal Cortex Transcriptome and Epigenome
A transcriptome is the set of mRNA present in a given cell at a given time. mRNA is the intermediate code between DNA and proteins, and so the mRNA present is indicative of which genes are expressed at that time. 🎛
An epigenome is a collection of changes to DNA structure which alter how it is read. A primary way DNA structure can be altered is by changing how it is packaged up in the cell nuclei, namely how it is wrapped around proteins called histones. Modifications to the histone proteins change the orientation by which DNA is packaged, exposing or hiding some genes from the transcription machinery. Here are some basics of epigenetics. 🧬
The researchers administered DOI to mice and profiled the transcriptome (mRNA present) and epigenome (histone modifications) of neurons sampled from the frontal cortex 24 hours, 48 hours, and 7 days after the DOI injection.
The findings are summarized in the figures below. The main takeaways are in the figure captions.
Figure 3A depicts the expression pattern of different enhancers in the epigenome at the time points measured and related gene functions. Enhancers are regions of DNA which, under certain histone packaging patterns, can increase the expression of certain genes.
Figure 3B depicts the expression pattern of different genes at the time points measured.
Figure 3C depicts the overlap between the epigenetic modification they measured and single nucleotide polymorphisms (SNPs) associated with common psychiatric disorders. An SNP is a variation in a single nucleotide in a gene sequence, which can cause a change in the protein produced. Certain SNPs are associated with diseases, and can thus be used to evaluate an individual predisposition for said diseases.
In the paper, Figure 4s depict gene expression networks over the time points measured, but is not included here for brevity.
My Take
What a doozy, I give you personal applause for making it all the way down here! There was a lot to unpack in this paper, and there is even more data both in the paper and in the supplementary material which I could not cover here. The most immediately rad aspect of this paper is the span of biological complexity it covers to answer the simple question of “What impacts does DOI have on behavior and physiology after it is gone?” The authors have demonstrated that DOI has a lasting impact on depressive- and anxiety-related behaviors, which likely occur due its role in altered 5HT2a receptor signaling. 5HT2a signaling networks increase the dendritic density in the cortex, and has a significant impact on epigenomic regulation in cortical neurons.
I wish I could discuss this paper with one million people more educated and skeptical than I, because although these findings are fairly concrete, there are always some background findings which make gray what seems black and white. One such finding is the fact that the knockout group (the mice which were bred to have no 5HT2a receptors) had a lower fear extinction and spine density than the wild-type. I think this is expected given the role of 5HT2a signaling in the fear response and the general involvement of receptors in receiving signals from dendrites. My friend Michael Haichin (and a good follow on Twitter @MichaelHaichin) pointed out that this might also make the observed increase in these values in the wild type more difficult to interpret. This is because as it could just be the receptors presence that caused the increase, rather than the DOI itself. I think we would both love further discussion on this thought, so hit us up if you have a piece to add.
Besides this, I enjoyed reading, cognizing, and interpreting this paper to the best of my ability. I think I need a break from behavior and molecular work…expect an ecology paper or something next. Cheers friends! 🥂🍻
I appreciate your feedback on how I did breaking down this science. Let me know in the comments:
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📃 Here’s the paper:
de la Fuente Revenga, M. et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 37, 109836 (2021).
From Around the Psychosphere
📝 Some related research: Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
🏝 Check out the lineup for the Wonderland: Miami, “The Largest Psychedelic Business Event Ever” and if you are going, let’s meet up! You can hear about it directly from Microdose CEO Patrick Moher on Psychedelics Today here. (Remember to use my code THETAB for 20% off your ticket price if you decide to join!!)
💃🦺🕺 If you are not following Dancesafe on socials, you need to. I absolutely love their Instagram, on which they post storied with the dopest and most informative information on all drugs with a strong eye on harm reduction. Give them a follow on Instagram and Twitter and test yo’ shit with their affordable and effective test kits.
Tunes for your next flow state
🍯 You must give My Morning Jacket’s new album a listen:
🔥 Cosmic Gate: Miami Open Skies March 2021
🤟🏽 Have a swell weekend friends 👽
This was awesome, thank you.
Always appreciate the tone these informative pieces are written in. Feels like I'm reminding myself rather than being lectured at. Big ups and many thanks