Learn Like Babies (Part 2): Psychedelics and Critical Periods

This is Part 2 of our discussion reviewing a 2023 study published in Nature which examines the ability for psychedelics to reopen social reward learning critical periods.

I highly suggest reading Part 1 if you haven’t done so already. Here’s a quick recap:

• Researchers tested whether psychedelics could re-open social reward learning critical periods in mice. Mice were housed together in a cage until a specified age for study.
• 48 hours prior to testing, mice received injections of a psychedelic (psilocybin, LSD, ketamine, or ibogaine) or placebo (saline). Researchers then exposed the mice to beddings within a cage and noted their preference for either bedding “pre-test”. The mice then underwent periods of “social conditioning”, where they interact with mice friends on one bedding, and then “isolation conditioning” where they hung out solo on the other bedding.
• After the end of the conditioning periods, researchers re-exposed the mice one-by-one to the cage and noted whether they showed a preference for the “social” bedding or “isolation” bedding. This was based on the amount of time spent exploring each bedding area.

We ended Part 1 after establishing that researchers found LSD, ketamine, ibogaine, and MDMA were effective in reopening social reward learning critical periods, while saline had no effect. This established that reopening this critical period is a shared property across psychedelics, and isn’t exclusive to MDMA (read Part 1 to learn why this was questioned). Next, researchers wanted to see if they could approximate how long psychedelics reopened this state.

Duration of Reopened Critical Periods

Across psychedelics, both acute subjective effects (the “trip”, hallucinations, stuff like that) and the duration of therapeutic response show considerable variation:

Duration of acute and therapeutic effects of psychedelics in humans

In previous research, this lab showed that MDMA reopens critical learning periods for ~two weeks, and returns to the closed state after about four weeks. In this study, they evaluated how long the critical learning period remained reopened in mice following psychedelic administration. This determination can help us understand whether the noted duration of therapeutic effect is similar to the duration for which the critical learning period remains reopened.

So, the researchers continued evaluating whether the mice remained in a state exhibiting significant social reward learning. They wanted to see how long this critical learning period remained open based on whether mice showed a preference for the “social” bedding or “isolation” bedding over time. The following table shows their results:

Length critical learning period remained reopened in mice following post-treatment

Now compare this back to the first table (“Duration of acute and therapeutic effects of psychedelics in humans”) above. I see patterns! The length of time the critical learning period remains re-opened is proportional to the noted length of acute effects when the psychedelics are administered to people.

Hyperplasticity & Metaplasticity

We’ve talked a lot about learning critical periods now. Are you curious about what causes them? Sames. I don’t miss being a kid (no shade, Mom, I just really like being an adult 🤷‍♂️), but I do miss going to school and learning as much as I could stuff inside my head every day. Which seemed way easier back then compared to now.

One mechanism thought to drive learning critical periods is metaplasticity. Metaplasticity describes the plasticity of synaptic plasticity. No, I’m not just spamming “plasticity”, these are real things. Let’s break that down into digestible chunks:

• Plasticity refers to your brain’s ability to rewire itself in response to stimuli
• A synapse is the place where neurons meet, greet, and communicate with one another. (Neurons are nerve cells that send messages throughout your body.)
• Synaptic plasticity, then, refers to the ability for synapses to rewire themselves in response to stimuli. Synapses can strengthen or weaken over time, depending on increases or decreases in activity.
• Metaplasticity refers to the fact that synaptic plasticity can be increased or decreased based on stimuli. The plasticity is plastic! Everything is plastic! I feel like every other word is “plastic” at this point and if I make a Mean Girls reference I’ll age myself so let’s move on.

In this study, researchers wanted to answer the question: do psychedelics induce hyperplasticity (a state of increased plasticity) or metaplasticity? (Turns out, plasticity can sit with us. I’ll see myself out.)

In this study, researchers wanted to answer the question: do psychedelics induce hyperplasticity (a state of increased plasticity) or metaplasticity? (Turns out, plasticity can sit with us. I’ll see myself out.)

Oxytocin depresses pre-synaptic signaling? Now why is that?

Sometimes, the brain needs to slow down a synapse short-term to allow for long-term growth. Without long-term depression (LTD), long-term potentiation (LTP) of the synapse wouldn’t be possible.

To test whether psychedelics induced metaplasticity or hyperplasticity, the team pre-treated mice with psychedelics (ibogaine, ketamine, MDMA, LSD, or psilocybin), cocaine, or saline. Then, either 48 hours or two weeks later, they bathed slices of the mice’s nucleus accumbens (NAc) in oxytocin and measured postsynaptical electrical currents. Pre-treatment with psychedelics caused a decrease in frequency (but not amplitude!) of excitatory post-synaptic currents. Pre-treatment with cocaine or saline, on the other hand, did not cause this effect. At 2 weeks, this effect still persisted in the NAc of mice pre-treated with LSD – but not ketamine.

Why cocaine? The NAc is a region of the brain implicated in reward-motivated learning. Cocaine can induce plasticity in the NAc, but it’s different from psychedelic-induced plasticity – including an inability to reopen social reward learning critical periods. (Turns out, not all plasticity is good!) Thus, we see that psychedelics induce metaplasticity – not hyperplasticity. This has important implications for further testing the therapeutic potential of psychedelic compounds.

Conclusion

In summary, this study sheds light on the fascinating effects of psychedelics on the brain’s ability to learn and adapt. By showing that psychedelics can reopen critical learning periods associated with social reward learning in mice, the research opens up exciting possibilities for understanding how these substances might be used therapeutically in humans. Moreover, the discovery that psychedelics induce metaplasticity, a unique form of synaptic plasticity, challenges our current understanding of how the brain responds to these compounds. This finding not only deepens our knowledge of psychedelics but also suggests potential new avenues for treating mental health conditions characterized by social difficulties. Moving forward, continued exploration of the mechanisms underlying psychedelic-induced metaplasticity could pave the way for innovative therapies aimed at enhancing social functioning and well-being.