bioRxiv : the preprint server for biology
April 9, 2025
Kalman A Katlowitz, Shraddha Shah, Melissa C Franch et al.
11 citations
preprint
Learning, semantic processing, and online prediction persist in the human hippocampus during general anesthesia-induced loss of consciousness. Using high-density Neuropixels microelectrodes to record neural activity while playing tones to anesthetized patients, hippocampal neurons reliably detected oddball tones, and this effect grew over about ten minutes, consistent with learning. A recurrent neural network model showed that learning and oddball representation emerge from flexible tone discrimination. When language stimuli were played, single units and ensembles carried information about semantic and grammatical features of natural speech, even predicting semantic information about upcoming words. These results indicate that complex sensory processing occurs in the hippocampus even in the unconscious state.
bioRxiv : the preprint server for biology
February 15, 2025
Nicolas G Glynos, Emma R Huels, Amanda Nelson et al.
11 citations
preprint
Intravenous DMT in rats caused dose-dependent increases in serotonin and dopamine in the medial prefrontal and somatosensory cortices, along with changes in brain wave patterns: reduced theta and low gamma power, increased delta, medium gamma, and high gamma power, and altered functional connectivity. All doses produced head twitch responses, most after the low dose. For the first time, endogenous DMT was measured in these cortical sites at levels comparable to serotonin and dopamine, suggesting a physiological role for the compound. The findings point to shared mechanisms with other psychedelics and support DMT's potential for treating psychiatric disorders.
bioRxiv : the preprint server for biology
January 16, 2024
Ya'El Courtney, Joshua P Head, Elizabeth D Yimer et al.
9 citations
preprint
Apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. This process depends on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling, rapidly altering the CSF proteome and activating neural progenitors lining the brain's ventricles. Overactivation of this secretion—triggered by maternal administration of a serotonergic 5HT2C receptor agonist, maternal illness, or the psychedelic drug LSD during pregnancy—dysregulates cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and changes adult social behaviors. These findings demonstrate a mechanism by which diverse maternal stressors disrupt in utero brain development.
bioRxiv : the preprint server for biology
September 15, 2024
Isaac N Treves, Keara D Greene, Zia Bajwa et al.
7 citations
preprint
A systematic review of EEG and fMRI studies combining mindfulness meditation with neurofeedback found that fMRI studies primarily aimed to downregulate the default-mode network (DMN). Although decreases in DMN activations were observed during neurofeedback, there is a lack of evidence for transfer effects, and most studies lacked adequate controls such as sham neurofeedback, so DMN decreases may be confounded by general task-related deactivation. EEG studies most robustly supported modulation of theta band activity. Both EEG and fMRI mindfulness-based neurofeedback have been implemented with high fidelity in clinical populations, but mental health benefits have not been established. The review recommends sham-controlled RCTs and clear reporting using CRED-NF guidelines.
bioRxiv : the preprint server for biology
October 31, 2023
Charlotte Maschke, Jordan O'Byrne, Michele Angelo Colombo et al.
7 citations
preprint
Consciousness may depend on brain activity poised at criticality, a state with optimal computational properties. Electroencephalograms were recorded from healthy, unresponsive volunteers under propofol, xenon, or ketamine anesthesia. Ketamine spared consciousness (vivid dreams), allowing separation of unresponsiveness from unconsciousness. Unconscious states showed a departure from both the edge of activity propagation and the edge of chaos. The perturbational complexity index (PCI), a sensitive consciousness measure, was predicted from these dynamical properties with a mean absolute error below 7%. Results link PCI to criticality and support criticality's role in consciousness.
bioRxiv : the preprint server for biology
May 14, 2024
Run Zhang, Maribel Anguiano, Isak K Aarrestad et al.
5 citations
preprint
A new enzyme-based method called CaST (Ca2+-activated Split-TurboID) biochemically tags cells with elevated calcium levels in living animals within 10 minutes, without requiring implants or light delivery. The signal increases with calcium concentration and labeling time, acting as a time-gated integrator of calcium activity. Unlike transcriptional reporters that take hours, CaST allows immediate read-out after activity labeling. The approach was used to tag prefrontal cortex neurons activated by psilocybin in untethered mice, and the CaST signal correlated with psilocybin-induced head-twitch responses.
bioRxiv : the preprint server for biology
August 12, 2024
Lorenzo Pasquini, Alexander J Simon, Courtney L Gallen et al.
4 citations
preprint
The psychedelic DMT rapidly alters consciousness, producing physical transcendence, vivid auditory distortions, and visual imagery. Using simultaneous fMRI and EKG data from 14 healthy volunteers before, during, and after intravenous DMT (versus placebo), a brain substate emerged immediately after injection characterized by deactivations in the hippocampus and medial parietal cortex alongside increased superior temporal lobe activity. Hippocampal and medial parietal deactivations correlated with disruptions in the sense of time, space, and self-referential processes, reflecting a deconstruction of ordinary consciousness. Superior temporal lobe activations correlated with audio/visual hallucinations and the experience of "entities.
bioRxiv : the preprint server for biology
June 5, 2023
Vladimir M Pogorelov, Ramona M Rodriguiz, Bryan L Roth et al.
4 citations
preprint
Lisuride, a drug that activates the serotonin 2A receptor without causing hallucinations, reduced locomotion and rearing in mice but produced a U-shaped pattern of stereotypies. Head twitches and retrograde walking were rare. Grooming decreased in β-arrestin1 knockout mice but showed a biphasic response in β-arrestin2 knockouts. Prepulse inhibition was disrupted by lisuride only in β-arrestin1 knockouts, and this effect was not reversed by a serotonin 2A antagonist but was normalized by a dopamine D2/D3 antagonist in wild-type mice. Lisuride also reduced immobility in the tail suspension test and increased sucrose preference for up to two days, suggesting antidepressant-like effects without hallucinogenic activity.
bioRxiv : the preprint server for biology
November 23, 2024
Farid Aboharb, Pasha A Davoudian, Ling-Xiao Shao et al.
3 citations
preprint
A pipeline using light sheet fluorescence microscopy to measure immediate early gene expression in mouse brain tissues, combined with machine learning, can classify psychoactive drugs including psilocybin, ketamine, and MDMA. In one-versus-rest tests, the exact drug was identified with 67% accuracy, far above the 12.5% chance level. Psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with over 95% accuracy in pairwise comparisons. Shapley additive explanation identified brain regions driving the predictions. The approach offers a novel way to characterize and validate psychedelic and related compounds.
bioRxiv : the preprint server for biology
January 16, 2026
Fernanda Daher, Caio T Fukushima, Erik A Ingebretsen et al.
1 citation
A negative allosteric modulator of α5-GABA A receptors, Basmisanil (BSM), produces rapid and sustained improvements in motivation, pleasure-seeking, and active coping behaviors in mice, similar to ketamine but without its side effects. BSM activates specific cell types in the medial prefrontal cortex (mPFC) and engages signaling pathways (Erk, Akt-mTOR) that boost synaptic proteins for both glutamatergic and GABAergic function. It also reverses stress-induced impairments in memory and social interaction. Early activation of pyramidal neurons in the mPFC is necessary for BSM's rapid effects, while later GABAergic adaptations sustain long-term benefits, restoring excitation-inhibition balance and highlighting GABAergic targets for stress-related disorders.
bioRxiv : the preprint server for biology
July 6, 2025
Callum M White, Zohre Azimi, Robert Staadt et al.
1 citation
preprint
Theta waves (4-8 Hz) in the visual cortex are linked to cognitive states and perception, but their role in cortical activity and aberrant brain states is not fully understood. Using cortex-wide voltage imaging in awake mice, 5-Hz oscillations were found in both the visual and retrosplenial cortices, occurring spontaneously and when evoked by visual stimulation. Injection of a psychotropic 5-HT2AR agonist increased spontaneous 5-Hz oscillations and boosted the power, occurrence probability, and persistence of visually evoked 5-Hz oscillations. This modulation in both areas suggests strengthened top-down control of perception, supporting a mechanism underlying perceptual filling and visual hallucinations.
bioRxiv : the preprint server for biology
October 23, 2024
Rui Dai, Hyunwoo Jang, Anthony G Hudetz et al.
1 citation
preprint
Consciousness appears to depend on global interactions across multiple brain regions rather than on localized neural activity. Using fMRI data across psychedelic, sleep, and deep sedation states, the study found a mirror-image pattern: psychedelic states increased global functional connectivity and decreased local neural synchrony, while non-REM sleep and deep sedation showed the opposite pattern. This pattern was observed in anterior-posterior and posterior-posterior brain regions but not within the anterior brain alone. Anterior transmodal regions were key for anterior-posterior connectivity, while posterior transmodal and unimodal regions were critical for posterior-posterior connectivity. The findings support global theories of consciousness and bridge the Global Neuronal Workspace hypothesis and Integrated Information Theory by showing shared neural mechanisms.
bioRxiv : the preprint server for biology
October 22, 2024
Matthew B Pomrenze, Sam Vaillancourt, Juliana S Salgado et al.
1 citation
preprint
MDMA releases both dopamine and serotonin in the brain's reward center, the nucleus accumbens, but its strong serotonin release limits dopamine release and abuse potential. Using conditional knockout mice and direct brain infusions, the authors show that MDMA's serotonin release, acting through the serotonin transporter and 5-HT2C receptors, reduces the drug's reinforcing effects and conditioned place preference, while its prosocial effects are mediated by separate mechanisms. This platform predicts that (R)-MDMA, a novel entactogen, will have prosocial effects and low abuse potential.
bioRxiv : the preprint server for biology
May 14, 2024
Romain Durand-De Cuttoli, Brian M Sweis
1 citation
preprint
Depression alters how the brain balances attention to past losses versus future gains during decision-making, a phenomenon linked to the sunk cost bias—overvaluing irrecoverable past investments. In mice exposed to chronic social defeat stress (a depression model), sensitivity to sunk costs increased without changing overall willingness to wait. A single dose of ketamine (20 mg/kg) normalized this stress-induced hypersensitivity. In non-stressed mice, ketamine abolished sunk cost sensitivity entirely, causing decisions to rely solely on future investment. These results suggest ketamine's antidepressant effects may involve reducing the weight of past losses in ongoing decisions, promoting more future-oriented behavior.
bioRxiv : the preprint server for biology
May 14, 2024
Tobias Teichert, László Papp, Ferenc Vincze et al.
1 citation
preprint
A new recording method called MePhys uses 992 electrode contacts across 62 shafts implanted in a monkey hemisphere to measure brain activity at a mesoscopic scale, bridging the gap between fMRI, EEG, and microelectrode techniques. By analyzing over 300,000 simultaneously recorded electrode pairs, the method reveals that a subanesthetic dose of ketamine, which mimics aspects of psychosis, induces a pronounced state of functional disconnection and prevents the formation of stable large-scale intrinsic brain states. MePhys offers a complementary window into brain function with unique advantages and limitations.
bioRxiv : the preprint server for biology
March 6, 2024
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach et al.
1 citation
preprint
Ketamine's effects on movement in mice are blocked by the opioid receptor antagonist naltrexone, but its analgesic and antidepressant-like effects are not. Whole-brain imaging identified the central amygdala as the region most affected by naltrexone, where neurons expressing mu-opioid receptors and PKCδ were strongly activated by naltrexone but not by ketamine. Disrupting mu-opioid receptor function in the central amygdala, either with drugs or genetic techniques, blocked ketamine's locomotor effects. These results indicate that mu-opioid receptors in the central amygdala gate certain behavioral effects of ketamine without being direct targets of the drug.
bioRxiv : the preprint server for biology
June 18, 2026
Jacob J Baker, Emily Kogan, Shaorong Ma et al.
Psilocybin promotes the formation and maturation of synapses while accelerating the elimination of pre-existing synapses. Signaling through serotonin 2A receptors in cortical layer 5 pyramidal neurons is necessary and sufficient for this synaptic remodeling but is not required for the head-twitch response, a rodent proxy for hallucination.
bioRxiv : the preprint server for biology
June 12, 2026
Timothy Lawn, Johan Nakuci, Steve Cr Williams et al.
Spatial overlap among brain receptor maps derived from PET imaging can distort analyses that model multiple receptors together. Using test-retest fMRI data, the authors show that as more receptors are included in a multivariate model, the reliability of the resulting functional connectivity networks decreases, and this degradation is driven by collinearity among the receptor maps. A univariate approach, modeling each receptor independently, produces more reliable networks and, in a study comparing LSD to placebo, better captured the known role of the 5HT-2A receptor. Spatial collinearity is a fundamental constraint on multivariate molecular-enriched network estimation, and univariate modeling is recommended as a more robust default.
bioRxiv : the preprint server for biology
June 1, 2026
Panagiotis Fotiadis, Hyunwoo Jang, Rui Dai et al.
Brain waves coordinate neural communication and shape conscious perception. Analyzing blood oxygen level-dependent activity from the Human Connectome Project and other datasets across sleep, propofol anesthesia, and psychedelic states (LSD, DMT, psilocybin, nitrous oxide, ketamine), four dominant wave propagation motifs were identified: a global synchronized wave, an anti-correlated unimodal-transmodal wave, an anti-correlated task-positive/task-negative wave, and an anti-correlated visual-somatomotor wave.
bioRxiv : the preprint server for biology
May 11, 2026
Jared Plotkin, Elaine Zhu, Mélanie Druart et al.
A single dose of LSD in rats persistently reduces the emotional, or affective, component of pain, without altering basic sensation. This effect is produced by LSD acting directly in the anterior cingulate cortex (ACC), a brain region that assigns negative value to painful stimuli. Recordings of neural activity showed that LSD suppresses the ACC's responses to painful input, reducing how the brain encodes the unpleasantness of pain. Although LSD increased the intrinsic excitability of ACC neurons in isolated tissue, it paradoxically reduced their maximum firing in response to painful stimuli in living animals. These results suggest that psychedelics can disrupt the brain's transformation of a painful signal into an aversive experience.
bioRxiv : the preprint server for biology
April 22, 2026
Cory A Knox, Samuel C Woodburn, Amelia D Gilbert et al.
Psilocybin, a classic psychedelic, increases dendritic spine density in frontal cortical neurons and facilitates fear extinction after chronic restraint stress in mice, demonstrating its effects in a translationally relevant animal model. Prior studies had largely examined stress-naive animals, so these findings show that psilocybin can promote neural plasticity and behavioral recovery even after chronic stress.
bioRxiv : the preprint server for biology
April 21, 2026
Jeanine Yacoub, Elena Bray, Jude Bayyat et al.
Halogenating the 2-position of DMT and psilacetin reduces their activity at 5-HT2A and 5-HT2B receptors, which are linked to psychedelic effects and heart valve toxicity, while preserving activity at other therapeutic targets like 5-HT6. The 2-Br-psilacetin analogue did not cause head-twitch behavior in mice and reduced head-twitch caused by another psychedelic, indicating lower potential for psychedelic effects. Intermediate doses improved stress-related mood measures and cued learning. These findings suggest that 2-halogenated tryptamines could be developed as safer, non-psychedelic therapeutics for psychiatric and neurodegenerative disorders.
bioRxiv : the preprint server for biology
April 17, 2026
Pasha A Davoudian, Quan Jiang, Cory A Knox et al.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
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.