Mouse study separates psilocybin's spine growth from its head-twitch response

Researchers at the University of California, Santa Cruz, gave mice a single dose of psilocybin and watched individual dendritic spines, the small bumps where one neuron receives signals from another, through the skull of a living animal. The same branches could be checked again days later.

The separation came from genetic work. Psilocybin acts on a serotonin receptor called 5-HT2A, thickest in one class of output cells in the cortex. When the receptor was restored only in those cells, psilocybin still drove new connections and made them stick, but the mice did not show the head-twitch response. When it was deleted from those cells and left everywhere else, the drug did nothing to the wiring while the twitching came through intact.

The authors found one limit on that split. In both engineered strains, psilocybin stopped accelerating the loss of old connections, so clearing out the old wiring appears to need other cell types too.

That twitch is a proxy, not a hallucination. Researchers cannot ask a mouse what it experienced, so head twitches stand in for hallucinogenic activity. The authors write that their results should not be read as directly addressing what causes hallucinations.

"These findings challenge the prevailing view that psilocybin simply increases neural connectivity and suggest that its effects depend on the brain's underlying condition," said Yi Zuo, a molecular biologist in the Department of Molecular, Cell and Developmental Biology at UC Santa Cruz and the study's senior author. Jacob Baker and Emily Kogan share first authorship. Zuo said treatments built on the split could deliver the fast and lasting antidepressant benefits of psychedelics while eliminating hallucinogenic side effects.

New connections stuck around

Within 24 hours, new spines appeared faster than in mice given saline. Of three doses tried, the middle and the high dose worked about equally.

The new connections were also sturdier. In untreated mice, most new bumps start out as short stubs that rarely last, and 40.6% survived a week; after psilocybin, 61.3% did. Three weeks out, 48.0% of the new spines in treated mice were still there, against 29.3% in controls. Shape tracked the same trend: 28.4% of new spines in treated animals grew the broad mushroom head that marks a mature, strong synapse, compared with 2.2% in controls.

In healthy mice the growth burst was brief. The drug also sped up removal of older connections, and net density drifted back toward where it started over three weeks.

Stress changed the response

The researchers then ran mice through 21 days of unpredictable mild stress, a standard rodent model used to mimic a depressive state, and dosed them the day after the stress stopped. New spine formation rose further, and the loss of existing connections, which kept running after stress ended in saline-treated mice, returned to the rate seen in unstressed animals.

In treated mice, 7.8% of connections lost during stress reappeared, against 4.8% in saline controls. That looked like a by-product of building spines everywhere, because new bumps were no likelier to appear where old ones had been lost.

What comes next

The authors suggest isolating the specific brain cells responsible for the hallucination-like responses, and charting spine production against changes in the animals' mood.

Nothing here changes what treatments are available today. The study did not test people, and the authors note that mouse findings need translating to humans.