Nature Neuroscience
June 1, 2023
Rafael Moliner, Mykhailo Girych, Vera Kovaleva et al.
439 citations
Psychedelics such as LSD and psilocin produce fast and lasting antidepressant effects by directly binding to the TrkB receptor, the receptor for brain-derived neurotrophic factor (BDNF). These compounds bind to TrkB with affinities 1,000 times higher than other antidepressants like fluoxetine and ketamine, and they interact with a distinct but partially overlapping site within the transmembrane domain of TrkB dimers. In mice, the neuroplasticity and antidepressant-like effects of psychedelics depend on TrkB binding and endogenous BDNF signaling, not on serotonin 2A receptor activation. However, LSD-induced head twitching requires serotonin 2A activation and is independent of TrkB binding. This suggests that high-affinity TrkB positive allosteric modulators without serotonin 2A activity could retain antidepressant benefits without hallucinogenic effects.
Nature Neuroscience
January 28, 2025
Casey Paquola, Margaret Garber, Stefan Frässle et al.
58 citations
The default mode network (DMN) is a set of brain regions important for complex thought and behavior. By combining postmortem tissue analysis and brain scans, researchers found that the DMN contains different types of cells, some specialized for processing single senses, others for combining information, and still others for memory. The DMN includes regions that receive input from sensory areas and a core that is relatively cut off from direct sensory information. Analysis of how signals flow through the DMN showed it uniquely balances output across different levels of sensory processing. These findings provide a structural basis for understanding the DMN's broad role in brain function and cognition.
Nature Neuroscience
October 2, 2025
Ahmad Hammo, Stephen Wisser, Joseph Cichon
20 citations
A single dose of psilocybin rapidly and sustainably reversed both mechanical allodynia and anxiety-depression-like behaviors in adult male and female mice with chronic pain. The effect depended on psilocin, the active metabolite, engaging prefrontal cortical circuits. Two-photon calcium imaging showed that psilocin quickly normalized hyperactivity in anterior cingulate cortex layer 2/3 pyramidal neurons, a hallmark of chronic pain. Full agonists of 5-HT2A and 5-HT1A receptors replicated some but not all of psilocin's cellular and behavioral effects, indicating that partial agonism at these receptors within shared pain-and-mood circuits underlies the dual therapeutic action.
Nature Neuroscience
July 1, 2025
Ya'El Courtney, Joshua P Head, Neil Dani et al.
10 citations
The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development. Apocrine secretion by embryonic ChP epithelial cells is a key regulator of the CSF proteome and neurodevelopment in male and female mice. Activation of serotonergic 5-HT2C receptors triggers sustained calcium signaling, driving high-volume apocrine secretion in mouse and human ChP. This secretion alters the CSF proteome, stimulating neural progenitors and shifting their developmental trajectory. Inducing ChP secretion in utero disrupts neural progenitor dynamics, cerebral cortical architecture, and offspring behavior. Illness or lysergic acid diethylamide exposure during pregnancy provokes coordinated ChP secretion in mouse embryos. The findings reveal a fundamental secretory pathway in the ChP that shapes brain development, and its disruption can have lasting consequences for brain health.
Nature Neuroscience
October 13, 2025
Jonah A. Padawer-Curry, Oliver J. Krentzman, Chao‐cheng Kuo et al.
9 citations
Psychedelics like psilocybin and DOI alter the brain's hemodynamic response, potentially disrupting the normal coupling between neuronal activity and blood flow. In human fMRI scans, psilocybin induced changes in hemodynamic response functions. In awake mice, DOI differentially affected the relationship between cortical excitatory neuronal activity and hemodynamic signals, both during whisker stimulation and at rest, leading to discordant changes in functional connectivity measures depending on whether they were based on neuronal or hemodynamic data. A selective serotonin-2A receptor antagonist reversed many of these effects. The findings indicate that the vasoactive effects of psychedelics must be considered when interpreting blood-based measures of brain function.
Nature Neuroscience
June 1, 2025
Sophie A. Rogers, Elizabeth A. Heller, Gregory Corder
8 citations
A single dose of psilocybin enhances behavioral flexibility by altering neural activity in the retrosplenial cortex. Using longitudinal single-cell calcium imaging in mice during a 5-day trace fear learning and extinction assay, the study found that psilocybin suppressed fear-active neurons and recruited extinction-active neurons, a pattern that predicted improved fear extinction. A computational model showed that inhibiting simulated fear-active units modulated the recruitment of extinction-active units and behavioral variability in freezing, consistent with the experimental findings. These results suggest psilocybin promotes behavioral flexibility by reorganizing cortical ensembles in the retrosplenial cortex.
Nature Neuroscience
December 24, 2025
Charles D. Nichols
The rapid expansion of psychedelic science risks overlooking past achievements and key pharmacological details, particularly regarding 5-HT_2A receptors. Recognizing and addressing these gaps is essential for responsible progress in the field.
Nature Neuroscience
September 1, 2025
Isak K Aarrestad, Lindsay P. Cameron, Ethan M Fenton et al.
Nonhallucinogenic psychoplastogens like tabernanthalog (TBG) promote cortical neuroplasticity through the same biochemical pathway as classic psychedelics—involving 5-HT2A, TrkB, mTOR, and AMPA receptor activation—but without inducing an immediate glutamate burst or immediate early gene activation. TBG-induced cortical spinogenesis is required for its sustained antidepressant-like behavioral effect in rodents. These findings clarify how certain psychoplastogens can produce neuroplasticity without hallucinogenic effects, challenging assumptions that glutamate burst and IEG activation are necessary for psychedelic-induced neuroplasticity.
Nature Neuroscience
September 11, 2019
R. Frau, Vivien Miczán, F. Traccis et al.
Prenatal cannabis exposure (PCE) in a rat model causes extensive molecular and synaptic changes in dopamine neurons of the ventral tegmental area, specifically in male offspring. These changes include altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity, leading to a hyperdopaminergic state and increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, an FDA-approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, suggesting a potential therapeutic approach for offspring exposed to cannabis during pregnancy.