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Breaking: Psychedelics reopen the social reward learning critical period

It's been a busy week in psychedelics, as researchers attempt to stay caught up on the latest research in the field. Last week, we broke down an article about a novel potential mechanism for psychedelic plasticity involving BDNF and modulation of receptors involved with developement. This week, we're highlighting a brand new paper which focuses on psychedelics increasing metaplasticity through reopening of the critical period of learning. This paper by Nardou et al. comes out of Dölen lab at Hopkins.

What is a "critical period" of learning?

Critical period refers to a fixed and crucial time during the early development of an organism when it can learn things that are essential to survival. Many animals and humans have critical periods that when missed, can have a pretty large impact. There are critical periods for several processes including: hearing and vision, social bonding, and language learning.

For example, children at two-years old are in a crucial developmental period where they begin to learn language. Fun fact, a two-year old has double the synapses of the average adult. Another example of a critical period is the early months in which birds must be exposed to the characteristic song of their species in order to learn it.

The authors have previously reported a critical period for social reward learning and shown that MDMA can reopen this period in adulthood. Building on that finding they wanted to assess whether classical psychedelics like LSD and psilocybin, as well as other psychedelics like ketamine and ibogaine, can produce similar results. Let's get into the findings.

Reopening of the critical period

The main method used throughout the paper and in the extended data is a social reward conditioned place preference (CPP). Like all conditioned place preference models, the idea is very basic classical conditioning. It begins with an unconditioned stimulus (social interaction) and an unconditioned response (place preference). The social interaction gets paired with the neutral stimulus (the bedding associated with social interaction) and becomes a conditioned stimulus. Then when the animal is tested again, they show a conditioned response (place preference) to the conditioned stimulus (the bedding).

The authors measure CPP at different age points and find increased preference for social interaction during the critical period of adolescence (about 3 to 7 weeks) and a downslope in adulthood (about 8-12 weeks). To test the psychedelics effects of CPP in later life (14 to 20 weeks) they administer the drug wait 48 hours, then condition the animals with social interaction or isolation, followed by a post-test where the animal is allowed to roam around and spend time wherever they like. The time they spend on the side paired with social interaction is considered "social reward seeking." See schematic from the extended figure 1 (above).

At 48 h post-adminstration PSI, LSD, ketamine and ibogaine all cause a significant shift in preference score to be similar to the open state whereas saline is no different from the closed state. To see how long this period lasts, they test the compounds multiple weeks following administration. At 2 weeks, LSD and psilocybin were similar to the open state which LSD lasting up to 3 weeks. At 4 weeks, ibogaine was similar to open state but not LSD. Interestingly, the shift followed by psilocybin at 1 week did not reach statistical significance but it did at 2 weeks, suggesting maybe a memory-related mechanism. See an example of the open/closed state curve with psilocybin from main text figure 1 (left).

The authors found that the ability of these compounds to return the animals to an open state was dependent on age and dose. For example, ketamine at anesthetic doses was not able to produce a reopening of the critical period and MDMA given in adolescence did not extend the existing critical period nor did it effect preference. The doses of psilocybin tested (0.1 and 0.2 mg/kg) are most likely sub-perceptual in mice, or only produce very few head twitches in other studies, suggesting that these doses may reopen the critical period without producing hallucination-like effects. It seems that while they did test other doses in the extended data, full dose responses were not conducted (which is most likely due to the large amount of mice and work it takes kudos to the experiments!) but that may be beneficial in the future.

The doses chosen and some of the extended data suggest variability with different doses of specific drugs (LSD or PSI) and this begs the question: would higher doses of psilocybin or lower doses of LSD be more or less effective in reopening this period? Would it last longer, shorter, not happen at all?

Interestingly, the main finding that ketamine, MDMA, LSD, psilocybin and ibogaine all produce a "reopening of the critical period" that extends to different time points seemingly correlates with the acute subjective effects in humans. The authors highlight that these data may support different integration periods following the use of the different psychedelics. This may be an over interpretation and it would be useful to see statistically correlative data in these regards. See main figure 3 (right).

Metaplasticity in the areas associated with reward learning

To understand long term changes occurring at the synaptic level, the authors employ ex vivo (tissue slices) electrophysiology to assess changes in metaplasticity. Electrophysiology exploits the electrical nature of cells to understand activation levels. Plasticity is a term that is tossed around quite a bit in psychedelics, and it refers to the brains ability to form and prune connections in a way that is optimally efficient. Metaplasticity, a less popular yet important term, refers to the extent in which plasticity can be modified. The process of increasing or decreasing the amount of plasticity occurring oer time is metaplasticity. In order to assess changes in this metaplasticity following psychedelic administration, animals were treated with either saline, cocaine, or the various psychedelics and sacrificed at 48 h or 2 weeks post-drug administration at which point brain tissue slices containing the nucleus accumbens (NAc) were obtained. They chose the NAc because its a brain region highly involved in reward learning.

In a previous study the authors show that oxytocin induced presynaptic long-term depression (LTD) in NAc in slices and that this was important in the encoding of social reward learning. LTD is a type of plasticity in which the synapse becomes depressed, less likely to form connections or grow. In the present study, they want to assess if psychedelics can alter this form of plasticity, if they can induce metaplasticity. To do so, they incubated the brain slices with oxytocin for 10 minutes induced LTD and then voltage clamp recordings were obtained. The dose of oxytocin and bath application time of 10 minutes seems like too long of a time period at that concentration and my confound result interpretation. Voltage clamp recordings refer to artificially holding the cell at a specific voltage, because again remember cells are electrical in nature, and by doing this it's possible to see the specific changes occurring in the electrical current.

They find that in the animals treated 48 h prior with MDMA, LSD, psilocybin, ibogaine, and ketamine there was a decreased in the frequency of miniature excitatory post-synaptic currents (mEPSC) induced by oxytocin, but not in the saline or cocaine pretreated slices. These mEPSCs represent how active the cells are and whether they are firing, so when there is a decrease in frequency, there is less firing overall. The measure of amplitude represent the changes in intensity, but in this study there were no changes in amplitude. In the two-week pretreated group, only LSD caused a decrease in oxytocin induced mEPSC frequency. No changes in baseline mEPSC frequency or amplitude was noted meaning there was no change without some form of induced plasticity such as the oxytocin-induced LTD. These data suggest that psychedelics produce metaplasiticty at 48 hours that may persist up to 2 weeks.

The authors only show ketamine and LSD at 2-weeks, did they also assess these other compounds at this time point? If not, why? Ibogaine was shown to persist in behavioral changes up to 4-weeks, so why not assess it here? If one of the goals of the study is to assess differences across drug classes- why not look at all of them? Further, oxytocin was used to induce long-term depression, but would these drugs modulate long-term potentiation as well? Bidirectional modulation is an important aspect of plasticity and metaplasticity, so it would be interesting to see if these changes are sustained in the other direction as well.

Receptor mechanisms behind the open state

To assess potential receptor mechanisms, they utilize 5-HT2A receptor antagonist ketanserin as well as beta-arrestin knock out mice (Barr2-KO). 5-HT2A is the receptor responsible for the subjective and perceptual effects of psychedelics but it is not known if its involved fully in the potential therapeutic effects. Prolonged binding at serotonin receptors can trigger beta-arrestin-induced signaling, which is different than classic G-coupled signaling. Evidence for biased signaling towards the Barr pathway is evidenced with some psychedelics like LSD.

The authors find that ketanserin (0.1 mg/kg) given 30 minutes before the test-drug and 48 h before CPP is able to block the effects of LSD, PSI and MDMA but not ketamine in the social reward test.

The authors do not state whether they tested ketanserin alone, which would have been a great addition to the experiment considering ketanserin has been shown to effect in vivo and in vitro measures on its own. The dose of ketanserin given is also relatively low compared to other studies where 1-5 mg/kg is given, which may have been done purposely to reduce the chance of antagonizing the 5-HT2C receptors. Further, a previous studies by others suggest that ketanserin at 1 mg/kg only occupies 70% of receptors in the rat brain, making it a weak antagonist.

In the Barr2-KO mice, social CPP was similar to the wildtype animals suggesting that no effects of genotype occurred to confound results. When testing LSD and MDMA, they found that both drugs reopened the critical period in wild-type animals but not in the Barr2-KO mice. Ketamine and ibogaine were able to reopen in both wild-type and KOs, suggesting a Barr2 mechanism involved in the effects of LSD and MDMA in the context of reopening the critical period associated with social reward learning. See panel from extended figure 8 (right).

The final hypothesis and conclusions

In addition to the findings on behavior and electrophysiology, they also sought to understand the potential changes in genomic landscape. They used RNA from brains treated with saline, cocaine, ketamine, LSD and MDMA to see what genes were altered in the NAc. They discover that many of the genes are involved with the remodeling of the extracellular matrix and some are immediate early genes. The psychedelic drugs tested had large up or down-regulations of these genes, whereas cocaine had some less robust modifications. While this part of the paper seemed generally exploratory, it would be interesting to see some epigenetic manipulation of candidate genes to further explore the mechanism.

A reminder: the extracellular matrix helps cells attach and communicate with, nearby cells, and plays an important role in cell growth, cell movement, and other cell functions.

The authors leave us with this hypothesis: psychedelics can open this critical period through a variety of binding targets that all trigger downstream signaling responses that potentially merge on activity-dependent (potentially through gene changes) alteration of the extracellular matrix which enables metaplasticity. See summary figure 6 (right).

This paper overall is an excellent body of work that not only highlights the differences in social reward learning across developmental stages and adulthood, it also shows that psychedelics are powerful agents to restore or mimic the social reward learning seen in adolescence in adult mice. It would be remiss not to note that any conditioned place preference is a culmination of classical conditioning, reinforcing effects of the reward, motivation to seek the reward as well as memory recall. The use of conditioned place preference to measure social reward is quite interesting and begs the question of how much of the effect of psychedelics has to do with strengthening the conditioning and reinforcing effects of social reward or restoring preference through mechanisms associated with memory recall. More work on this front should be done to better interpret the CPP results, such as social choice in animals where they can choose to be with their littermates versus another reward, or extend this idea to other behaviors found in the critical period.

In regards to the larger picture of metaplasticity and using electrophysiology to deepen our understanding, future directions can include assessing these compounds at additional time points and at additional locations such as the hippocampus. This brain region is vital for memory and consolidation and feedback from the NAc to the hippocampus and cortex makes up the pathway involved in reward. This work can also be conducted in vivo (alive behaving animals) to see how this modulation occurs in living systems, which could also be correlated with clinical work using EEG. Peep Zarmeen's dissertation project!

The work here can be used as a jumping off point for so much! Including potentially investigating learning and developmental disabilities, as well as neurodegenerative disorders. It also highlights that while classical and non-classical psychedelics may differ in their receptor targets, they are definitely converging on some of the same mechanisms.

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