bioRxiv : the preprint server for biology
March 27, 2026
James D. Johnson, Runyi Tian, Yasaman Etemadi et al.
Psilocybin preferentially dampens well-consolidated aversive sensory representations in the auditory cortex, rather than fresh associations, without broadly affecting auditory processing or new aversive learning. Using longitudinal two-photon calcium imaging in awake mice, psilocybin selectively reduced responses to aversive stimuli and earlier-established aversive-associated tones, while reward responses and responses to newly aversive-associated tones remained unaffected. At the population level, psilocybin acutely increased coordination across tone-responsive neurons, then later reduced it selectively among neurons encoding the aversive-associated tone. These results suggest psilocybin reshapes sensory representations of learned valence associations, potentially explaining its benefits in affective and trauma-related disorders.
bioRxiv : the preprint server for biology
January 24, 2026
Kwang-Hyun Hur, Lisa D Nickerson, Jack Bergman et al.
THC, the psychoactive compound in cannabis, selectively amplifies behavioral and brain responses to cues that predict rewards, without affecting responses to neutral cues or baseline reward consumption. In squirrel monkeys, a low dose of THC (3 μg/kg) increased conditioned approach behavior toward a visual stimulus associated with food delivery. Functional MRI showed that THC enhanced activity in reward-related brain regions—anterior cingulate cortex, striatum, hippocampus, and substantia nigra-ventral tegmental area (SN-VTA)—while leaving visual and motor cortices unaffected. Resting-state connectivity analyses revealed that THC strengthened communication within mesocorticolimbic networks, with the SN-VTA acting as a central hub. These findings indicate that THC boosts incentive salience and motivational drive toward reward-associated stimuli through selective modulation of this circuitry.
bioRxiv : the preprint server for biology
January 22, 2026
Margareth Nogueira, Giuseppe Giannotti, Carley N Miller et al.
Heroin self-administration increases the density of perineuronal nets (PNNs) in the ventral pallidum (VP) of mice. Depleting these PNNs with an enzyme prevents cue-induced reinstatement of heroin seeking, reduces the intrinsic excitability of parvalbumin-expressing VP neurons, strengthens inhibitory synaptic inputs onto them, and lowers Fos expression in those neurons after reinstatement. Chemogenetic activation of VP parvalbumin neurons rescues the suppressive effect of PNN depletion on heroin seeking, while chemogenetic inhibition mimics it. VP parvalbumin neurons and their PNNs are critical drivers of opioid seeking, and targeting PNNs in the VP may offer a novel therapeutic approach for relapse in opioid use disorder.
bioRxiv : the preprint server for biology
January 14, 2026
Teppei Matsubara, Abbas Sohrabpour, Seppo Ahlfors et al.
Cerebellar activity is hard to detect with standard magnetoencephalography (MEG) and electroencephalography (EEG) because of the cerebellum's depth, complex folding, and unfavorable source orientations. Analyzing clinical recordings from epilepsy patients, cerebellar signal-to-noise ratio (SNR) was consistently lower than superficial cortical reference levels. Reducing sensor-to-source distance alone, by placing on-scalp optically pumped magnetometers (OPMs) at standard sensor locations, did not improve cerebellar SNR. However, OPM layouts optimized for the posterior fossa produced substantial SNR gains in posterior cerebellar regions. Anatomical depth and geometry, not just sensor proximity, govern cerebellar detectability. This framework advances human brain mapping beyond the cerebrum.
bioRxiv : the preprint server for biology
November 13, 2025
Winson F Z Yang, Ruby Potash, Grace Mackin et al.
preprint
Advanced concentration absorption meditation (ACAM-J) produces a distinct, structured mode of awareness characterized by stable positive states and reduced narrative thought. In the first ultra-high-field (7T) fMRI study of jhana meditation, neural trajectories across eight successive states showed reorganization from anterior to posterior brain regions, flattening of cortical hierarchies, and nonlinear changes in global brain harmonics. These brain changes were tightly linked to equanimity, attentional stability, and behavior. Brain activity patterns associated with ACAM-J related more to attentional monitoring than to suffering-related processes. The findings suggest advanced meditation offers a framework for understanding psychological transformation and supporting human well-being.
bioRxiv : the preprint server for biology
November 8, 2025
Lucie Berkovitch, Alexandre Salvador, Thomas Andrillon et al.
preprint
Low doses of ketamine, an NMDA-receptor antagonist, disrupt the ability to consciously perceive visual information in healthy people. In a double-blind, placebo-controlled experiment with 21 volunteers, ketamine increased visual masking and reduced conscious perception of a digit. The N1 component of brain activity, an early marker of visual processing, was significantly reduced under ketamine and correlated with conscious access. Ketamine also induced psychotic-like and manic-like symptoms, but only the psychotic-like dimension was linked to impairments in conscious access. These findings suggest ketamine attenuates early visual brain responses, impairing conscious access, and that this mechanism differs in some ways from that seen in schizophrenia.
bioRxiv : the preprint server for biology
October 15, 2025
Rolf J Skyberg, Christopher W Fields, Dylan M Martins et al.
preprint
Psychedelics like DOI alter visual perception by increasing how often mice actively sample their visual environment during free movement, yet they reduce the neural responses in the primary visual cortex that these behaviors generate. The effects vary widely across individual neurons and depend on the type of visual input, with stronger suppression of responses to unpredictable stimuli than to predictable ones. This dissociation suggests that predictability of visual events influences how psychedelics disrupt sensory processing, offering insights into the neural basis of altered perceptual states.
bioRxiv : the preprint server for biology
October 7, 2025
Stefan Sumsky, Rory Ashmeade, Jiayang Liu et al.
preprint
Absence seizures cause sudden lapses in consciousness accompanied by spike-wave discharges, but how they impair sensory processing is unclear. In a rat model of absence epilepsy, behavioral performance on an auditory task collapsed during seizures, dropping from about 88% correct to less than 1%. However, electrical responses in the primary auditory cortex remained normal. Instead, a novel oscillatory signal in the anterior insular cortex was robust in healthy controls, reduced in epileptic rats between seizures, and nearly absent during seizures. This signal's reduction differed from that seen in satiated, unmotivated states, where waveform structure was preserved. The anterior insula appears to be a critical hub for gating auditory conscious awareness during seizures, offering a potential biomarker and intervention target.
bioRxiv : the preprint server for biology
September 30, 2025
Ya'El Courtney, Josephine M Anderson, Christian Lagares-Linares et al.
preprint
In mice, the psychedelic drug LSD crosses the placenta and enters embryonic cerebrospinal fluid within minutes. A single dose during pregnancy alters the organization of the cerebral cortex in the offspring, and repeated doses shift the balance of neuron types and increase microglia. Adult offspring, especially males, show reduced prepulse inhibition and rotational stereotypy. These findings identify a mechanism by which maternal psychedelic exposure can lead to lasting changes in brain development and behavior.
bioRxiv : the preprint server for biology
August 2, 2025
Belen Karakullukcu, Hamilton White, Christopher Connor et al.
preprint
Ketamine, a dissociative anesthetic with subanesthetic analgesic and antidepressant properties, alters neuronal signaling in ways not fully understood. Imaging the entire head of the nematode C. elegans during low-dose ketamine induction reveals two distinct phases: an early, low-dose state of hyperactive, synchronized neural activity, and a later, higher-dose state of system disorganization and spastic microscale motion. The NMDA-receptive interneuron AVA decouples from the system under low-dose ketamine. These findings support the hypothesis that ketamine causes neuronal disinhibition by suppressing key inhibitory interneurons, and identify functional differences between low- and high-dose dynamics in a complete nervous system.
bioRxiv : the preprint server for biology
June 15, 2025
Michael Von Gunten, Tenna Russell, Isaac Stirland et al.
preprint
A single high dose or four microdoses of LSD accelerated the extinction of morphine-induced conditioned place preference in both male and female mice. Whole-cell electrophysiology showed that excitatory synaptic plasticity in VTA GABA neurons, which was suppressed after morphine exposure, was restored 24 hours after a single high dose of LSD. Whole-brain DNA methylation analysis revealed significant differences in methylation profiles between morphine-treated mice that received LSD versus saline. These findings suggest that LSD may reverse or prevent morphine-induced changes in reward circuit plasticity and reduce measures of morphine preference.
bioRxiv : the preprint server for biology
May 23, 2025
Amanda M White, Adele D Bauer, Serge Faumont et al.
preprint
The psychedelic compound DOI strongly inhibits feeding in the roundworm C. elegans, even though effects on locomotion, swimming, and egg-laying were undetectable. This feeding suppression occurred independently of serotonin receptors, indicating that DOI may act through alternative molecular pathways. The findings suggest that C. elegans can serve as a cost-effective, genetically tractable model for studying psychedelic drug mechanisms, potentially revealing novel targets beyond the serotonergic system that could inform therapeutic applications for depression, PTSD, and substance use disorder.
bioRxiv : the preprint server for biology
March 17, 2025
Trevonn Gyles, Eric M Parise, Molly S Estill et al.
preprint
Treatment-resistant depression (TRD) affects about a third of patients who do not respond to standard antidepressants, yet its molecular basis is poorly understood. In a mouse model of TRD, where chronically stressed mice failed to respond to fluoxetine, subsequent ketamine treatment produced behavioral and transcriptional changes in the nucleus accumbens. Failed fluoxetine treatment primed the mice for a positive response to ketamine, and specific gene networks linked to stress susceptibility and antidepressant resistance were identified. These findings illuminate molecular mechanisms behind antidepressant resistance and address a gap in preclinical TRD models.
bioRxiv : the preprint server for biology
February 17, 2025
Rajiv S Rangan, R Max Petty, Suchismita Acharya et al.
preprint
Psychedelics can produce lasting changes in brain function beyond their immediate mind-altering effects, which is being explored for treating mental health disorders. The authors propose that psychedelics may modify proteins by covalently attaching to them through a process called transamidation, mediated by transglutaminase enzymes. They synthesized a modified version of mescaline, a psychedelic phenethylamine from cacti, and used click-chemistry in human astrocyte cell cultures to identify potential protein targets. Preliminary results suggest many glial proteins could be substrates for this modification, which they term phenethylaminylation. This speculative mechanism may help explain long-term cognitive changes from single psychedelic doses.
bioRxiv : the preprint server for biology
November 27, 2024
Nemanja Sarić, Zeynep Atak, Courtni Foster Sade et al.
preprint
Ketamine anesthesia given briefly to newborn mice with a genetic cilia defect causes lasting motor skill problems. These mice already have fewer spines on neurons in a key brain layer, and ketamine disrupts the spine changes normally seen during motor learning. The damage involves a non-lethal activation of caspase enzymes. Blocking caspase in newborns restored both spine density and motor performance, showing that this enzyme signaling is necessary for proper brain development. The findings suggest that children with cilia-related genetic conditions, such as those with congenital heart disease, may be especially vulnerable to anesthesia-induced developmental harm, and that targeting caspase could offer a protective strategy.
bioRxiv : the preprint server for biology
October 22, 2024
Kyle A Brown, Musa I Ajibola, Todd D Gould
preprint
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), rapidly potentiates synaptic transmission at the Schaffer collateral-CA1 synapse in mouse hippocampal slices, an effect that does not require N-methyl-D-aspartate receptor (NMDAR) activity. However, NMDAR activity is necessary to sustain a metaplastic state that lowers the threshold for long-term potentiation (LTP) hours after HNK exposure. The rapid potentiation depends on protein kinase A (PKA) and adenylyl cyclase 1 (AC1), but not AC5. These findings suggest that HNK's rapid synaptic actions initiate sustained priming mechanisms that favor antidepressant-relevant plasticity, offering a target for novel antidepressant strategies.
bioRxiv : the preprint server for biology
October 12, 2024
Mario de la Fuente Revenga, Javier González-Maeso
preprint
Psychedelics like LSD, psilocybin, and DOI produce their distinct effects by activating the serotonin 2A receptor (5-HT2AR). A new ex vivo method measures drug-induced activation of this receptor in mouse brain tissue by tracking changes in inositol monophosphate (IP1), a downstream signaling molecule. The method was specific to 5-HT2AR, as IP1 increases were absent in knockout mice. Head-twitch response counts, a behavioral correlate of psychedelic effects, correlated with IP1 levels in the frontal cortex. LSD increased IP1, while lisuride, a non-psychedelic 5-HT2AR agonist, did not. MDMA also raised IP1, likely by releasing serotonin, unlike 5-HTP or fluoxetine. This approach offers mechanistic insights into psychedelic and serotonergic drug action.
bioRxiv : the preprint server for biology
April 11, 2024
Ana Sofia Alberto-Silva, Selina Hemmer, Hailey A Bock et al.
preprint
Three new chemical variants of MDMA—ODMA, TDMA, and SeDMA—show similar activity at serotonin and dopamine transporters but reduced activity at serotonin 5-HT2A/2B/2C receptors, which may lower the risk of off-target side effects. They also differ from MDMA in how they are broken down by the liver, with fewer metabolic pathways and no phase II metabolites. The analogs interact more weakly with certain organic cation transporters. These findings suggest the new compounds could be promising therapeutic alternatives to MDMA for conditions like PTSD, though further research is needed to confirm whether they pose lower risks.
bioRxiv : the preprint server for biology
September 21, 2025
Johanna Rehn, Lucas Admeus, Bernat Kocsis
preprint
Adolescent exposure to a cannabis-like compound (CP-55940) in rats causes lasting abnormalities in brain theta oscillations during adulthood. Theta oscillations are crucial for memory and cognition, and their disruption is linked to psychiatric disorders. Rats given the compound during early adolescence (postnatal days 32-36) showed a significantly greater reduction in theta power in adulthood compared to those treated later (postnatal days 42-46). This suggests that early adolescence is a particularly vulnerable period for cannabis-induced changes in brain function, potentially increasing sensitivity to cannabinoids later in life.
bioRxiv : the preprint server for biology
August 22, 2025
Jose A Cortes-Briones, Juan Urrutia-Gandolfo, Pablo A Estevez et al.
preprint
The balance between excitatory and inhibitory (E/I) activity in the brain is important for normal function, and its disruption is linked to psychiatric disorders. In a randomized, double-blind, placebo-controlled study, healthy volunteers received low doses of ketamine (which shifts E/I balance toward excitation) and thiopental (which shifts it toward inhibition) while their brain activity was recorded with EEG. The drugs altered the aperiodic exponent of the power spectrum in opposite directions, matching computational predictions. Changes in the exponent correlated with subjective and cognitive effects, suggesting that this measure could serve as a noninvasive EEG biomarker for transient shifts in cortical E/I balance.
bioRxiv : the preprint server for biology
June 28, 2025
Jimmy Olusakin, Mahima Dewan, Atul Kashyap et al.
preprint
Prenatal exposure to THC (the psychoactive component of cannabis) and chronic psychosocial stress, alone or combined, impair maternal behavior in mice and produce lasting behavioral and molecular changes in adolescent offspring. All exposure groups showed disrupted caregiving, with additive effects when THC and stress were combined. Adolescent offspring displayed increased anxiety and reduced motivation, with THC alone affecting female social behavior. Gene expression changes in the prefrontal cortex and nucleus accumbens were sex- and region-specific, altering pathways related to mitochondria, synapses, and glial cells. THC and stress independently and additively impair maternal behaviors and leave lasting neurodevelopmental signatures.
bioRxiv : the preprint server for biology
March 28, 2025
Youngjai Park, Younghwa Cha, Hyoungkyu Kim et al.
preprint
The human brain shifts between two directional modes on a sub-second timescale: a top-down mode where anterior regions drive posterior activity and a bottom-up mode with reverse directionality. These shifts are most distinct during full consciousness and become less pronounced as awareness fades. Simultaneous EEG-fMRI recordings show the top-down mode coincides with higher-order cognitive network activity, while the bottom-up mode aligns with sensory system activity. An inattentive ADHD cohort exhibited imbalances in these transition dynamics compared to typically developing individuals. A coupled-oscillator model of the structural brain network reproduced these patterns, suggesting they arise naturally from inter-regional neural interactions.
bioRxiv : the preprint server for biology
January 16, 2025
Yungyi Hsiao, Marcos As Fonseca, Alina S Tiemroth et al.
preprint
A single dose of psychedelics causes lasting changes in alternative splicing in the mouse medial prefrontal cortex, particularly in parvalbumin interneurons, that persist for at least a month. While gene expression is only modestly altered, splicing patterns shift dramatically in a cell type-specific manner. These changes are linked to modifications in the extracellular matrix, synaptic physiology, and intrinsic physiology days to a week after treatment. The findings provide a resource for understanding the molecular and cellular basis of psychedelic-induced plasticity.