Cell Reports
June 1, 2018
Calvin Ly, Alexandra C. Greb, Lindsay P. Cameron et al.
1,158 citations
Serotonergic psychedelics, like ketamine, can robustly increase the growth of neurons and their connections (neuritogenesis and spinogenesis) in the prefrontal cortex, both in lab dishes and in living animals. These structural changes are accompanied by more synapses and enhanced function, as shown by microscopy and electrophysiology. The effects appear to arise from stimulation of TrkB, mTOR, and 5-HT2A signaling pathways, which may explain the clinical effectiveness of these compounds. The findings highlight the therapeutic potential of psychedelics and identify several chemical scaffolds for developing fast-acting, safe antidepressants that promote brain plasticity.
Cell Reports
March 28, 2023
Vern Lewis, Emma M. Bonniwell, Janelle K. Lanham et al.
129 citations
The non-hallucinogenic LSD analog 2-Br-LSD acts as a partial agonist at several aminergic G protein-coupled receptors, including 5-HT2A, but does not induce the head-twitch response in mice, indicating it lacks hallucinogenic effects. Unlike LSD, 2-Br-LSD does not activate 5-HT2B, avoiding a risk of cardiac valvulopathy. It produces weak 5-HT2A β-arrestin recruitment and internalization in vitro and does not cause tolerance after repeated dosing. In cultured rat cortical neurons, 2-Br-LSD promotes dendritogenesis and spinogenesis, and in mice it increases active coping behavior—an effect blocked by a 5-HT2A antagonist—and reverses behavioral effects of chronic stress. These findings suggest 2-Br-LSD has an improved pharmacological profile over LSD and potential therapeutic value for mood disorders.
Cell Reports
May 1, 2021
Zirui Huang, Vijay Tarnal, Phillip E. Vlisides et al.
119 citations
Conscious access to sensory information is likely gated at an intermediate site between primary sensory and transmodal association cortices, with the anterior insular cortex (AIC) playing a key role. Functional neuroimaging using a volitional mental imagery task in healthy volunteers, with propofol titrated to loss of behavioral responsiveness, showed that AIC dysfunction is associated with impaired transitions between default-mode and dorsal attention networks. Candidate subcortical regions such as the thalamus and basal forebrain did not show this association. In awake participants, pre-stimulus AIC activity near perceptual threshold predicted conscious access. These findings support the hypothesis that AIC regulates brain network transitions that gate conscious access.
Cell Reports
August 1, 2021
Pei-Yi Lin, Z. Z. Ma, Melissa Mahgoub et al.
97 citations
Ketamine rapidly relieves depression by activating BDNF-TrkB signaling specifically in CA1 neurons of the hippocampus. Deleting BDNF in either CA3 or CA1, or deleting its receptor TrkB only in postsynaptic CA1, blocks ketamine-induced synaptic strengthening. Ketamine triggers dynamin1-dependent TrkB activation and downstream signaling to produce these rapid synaptic effects. The findings pinpoint a precise synaptic location—CA1 neurons—where BDNF-TrkB signaling is required for ketamine's rapid antidepressant action.
Cell Reports
August 1, 2022
Ryan H. Gumpper, Jonathan F. Fay, Bryan L. Roth
49 citations
The serotonin 2C receptor, a G protein-coupled receptor (GPCR) targeted by drugs like the weight-loss medication lorcaserin and the psychedelic psilocin, exists in many protein isoforms due to RNA editing. This study presents the structures of three representative isoforms bound to each drug and analyzes agonist activation and constitutive activity across all 24 isoforms. A unique hydrogen-bonding network on intracellular loop 2, which is altered by RNA editing, differentially affects the receptor's constitutive and agonist signaling activities.
Cell Reports
April 23, 2024
Adeeti Aggarwal, Jennifer Luo, Helen Chung et al.
17 citations
Traveling cortical waves in the 3-6 Hz range coordinate neuronal activity across visual and parietal cortex only in brain states where perception is possible. In awake mice, visual stimuli reset spontaneous waves, producing stimulus-evoked feedback waves that entrain neurons. Under anesthesia, visual stimuli fail to disrupt spontaneous waves. During ketamine-induced dissociation, spontaneous waves themselves traverse the cortex caudally and entrain neurons, mimicking the stimulus-evoked pattern seen in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling waves emerge in states that allow perception, but only the awake state reliably links this coordination to external visual input.
Cell Reports
September 17, 2021
Carli Domenico, Daniel Haggerty, Xiang Mou et al.
16 citations
Lysergic acid diethylamide (LSD) reduces firing rates, directionality, and interaction with visual cortical neurons in hippocampal place cells of rats running along a familiar track. During head-twitching—a behavioral sign of a hallucination-like state—both hippocampal and visual cortical neurons temporarily increase firing rates. When rats are immobile, LSD enhances cortical firing synchrony similar to the wakefulness-to-sleep transition, while hippocampal-cortical interaction remains dampened but hippocampal awake reactivation persists. These findings suggest LSD suppresses hippocampal-cortical interactions during active behavior and immobility, degrading and isolating internal hippocampal representations from external sensory input, which may contribute to abnormal perceptions.
Cell Reports
March 25, 2025
Ulysse Klatzmann, Sean Froudist-Walsh, Daniel P Bliss et al.
14 citations
Conscious access involves 'ignition,' an all-or-none activation across cortical areas. Computer simulations of a detection task using a mesoscale connectome-based model of the macaque cortex reveal a dynamic bifurcation mechanism that produces ignition in a network of associative regions. A hierarchical NMDA/AMPA receptor gradient is critical: fast AMPA receptors drive feedforward signal propagation, while slow NMDA receptors in feedback pathways shape and sustain the ignited network. The model suggests higher NMDA-to-AMPA receptor ratios in sensory areas compared to association areas, a prediction supported by in vitro autoradiography data. The model accounts for diverse behavioral and physiological phenomena linked to consciousness.
Cell Reports
July 23, 2024
Kexin Jiang, You Zheng, Liting Zeng et al.
12 citations
The trace amine-associated receptor 1 (TAAR1) plays a key role in the signaling of the hallucinogen LSD and several antipsychotic drugs. This work presents the molecular structures of the TAAR1-Gs protein complex bound to LSD and to the partial agonist RO5263397, a drug candidate for schizophrenia and addiction. Through mutagenesis, functional studies, and molecular dynamics simulations, the authors describe a versatile binding pocket in TAAR1 that adapts to recognize different ligands, including in the ligand-free state. These results clarify cross-species recognition and partial activation of TAAR1, providing a structural basis for designing new antipsychotic medications.
Cell Reports
July 22, 2025
George Blackburne, Rosalind McAlpine, Marco S. Fabus et al.
10 citations
Inhaling a high dose of vaporized synthetic 5-MeO-DMT radically reorganizes low-frequency brain oscillations, making them heterogeneous, viscous, and nonrecurring, and halting their typical forward and backward travel across the cortex. This reorganization also causes broadband neural activity to become more stable and low-dimensional, with increased energy barriers for rapid global shifts. These findings, based on EEG data from 29 healthy individuals, provide a detailed account of how the drug sculpts human brain dynamics and reveal atypical cortical slow-wave behaviors relevant to neuroscientific models of serotonergic psychedelics.
Cell Reports
May 27, 2025
Alexandra G Bardon, Jesus J Ballesteros, Scott L Brincat et al.
8 citations
Two anesthetics with different molecular actions, ketamine and dexmedetomidine, both increase phase locking of neural oscillations in the prefrontal cortex of nonhuman primates during loss of responsiveness. Within a hemisphere, neighboring prefrontal subregions become less phase-aligned, possibly due to large traveling waves. However, homologous areas across hemispheres become more aligned in phase. These distinct patterns of cortical phase alignment, markedly different from waking states, may represent a common mechanism by which diverse anesthetics produce loss of responsiveness.
Cell Reports
December 24, 2024
Lim-Anna Sieu, Shobhit Singla, Jiayang Liu et al.
8 citations
Focal temporal lobe seizures in humans often cause loss of consciousness accompanied by cortical slow waves similar to deep sleep. Previous rat studies under anesthesia suggested that reduced subcortical arousal depresses cortical function, but could not link conscious behavior to physiology. In an awake mouse model, electrically induced hippocampal seizures impaired behavioral responses to sounds, triggered cortical slow waves, and reduced mean high-frequency cortical activity. Behavioral responses depended on cortical acetylcholine release at two timescales: slow state-related decreases correlated with overall impairment, while fast phasic release corresponded to variable spared or impaired responses per stimulus. These results establish a strong link between decreased cortical arousal and impaired consciousness during focal seizures.
Cell Reports
January 28, 2025
Yue Hu, Yifan Feng, Huoqing Luo et al.
6 citations
In mice, doses of ketamine that cause dissociation inhibit parvalbumin interneurons (PV-INs) in the retrosplenial cortex (RSC), increasing delta oscillations (1-3 Hz) and delta-gamma phase-amplitude coupling (δ-γ PAC) and producing dissociation-like behaviors. Directly inhibiting these neurons without ketamine also triggers delta oscillations, δ-γ PAC, and some dissociation-like behaviors. Activating RSC PV-INs or knocking down the NMDA receptor subunit NR1 and the HCN1 channel in these neurons reduces ketamine-induced delta oscillations, δ-γ PAC, and certain dissociation-like behaviors. The findings identify NR1 and HCN1 as ketamine targets in PV-INs that may cooperatively affect dissociation, suggesting potential therapeutic targets for dissociative symptoms.
Cell Reports
May 21, 2025
Lace M Riggs, Sage Aronson, Ta-Chung M Mou et al.
2 citations
A single dose of (2R,6R)-hydroxynorketamine (HNK), a metabolite of ketamine, rapidly strengthens weakened synapses in a rat model of treatment-resistant depression. In plasticity-deficient Wistar Kyoto rats, (2R,6R)-HNK boosted glutamatergic transmission, restored long-term potentiation (LTP), and reversed deficits in hippocampal-dependent memory. The drug selectively increased activity of CA1 pyramidal neurons during novelty exploration and restored spatial recognition memory reliant on Schaffer collateral pathways. Prior spatial learning partially blocked LTP in control rats, a pattern mirrored in LTP-impaired rats where spatial learning deficits were reversed by (2R,6R)-HNK. The findings indicate that (2R,6R)-HNK promotes adaptive synaptic changes at impaired synapses, improving cognitive function.
Cell Reports
July 22, 2025
Christof Koch
1 citation
Inhaling a high dose of the psychedelic 5-methoxy-N,N-dimethyltryptamine profoundly slows down brain activity, but unlike other psychedelics, it does not significantly reduce alpha band power in the electroencephalogram.
Cell Reports
April 7, 2026
Nicolas Decat, Arthur Le Coz, Jade Sénéchal et al.
Mental experiences during wakefulness and sleep are not as distinct as commonly thought. Analyzing electroencephalography (EEG) from 92 participants during daytime rest, researchers collected 375 reports of mental content scored on bizarreness, fluidity, spontaneity, and wake perception. Clustering these reports revealed four distinct types of mental states. Crucially, all four types occurred across wakefulness, N1 sleep, and N2 sleep. EEG measures of spectral power, complexity, and connectivity differentiated these mental states independently of whether participants were awake or asleep. The findings indicate that the waking and sleeping brain can produce the same mental state, and that fine-grained brain dynamics shape the content of mental experiences.
Cell Reports
August 29, 2023
Eli J Müller, Brandon R Munn, Michelle J. Redinbaugh et al.
A whole-brain computational model of the corticothalamic system, built from empirical data on targeted and diffusely projecting thalamocortical nuclei, reproduces key features of propofol anesthesia: reduced network integration, lower state diversity, impaired susceptibility to perturbation, and decreased corticocortical coherence. These signatures indicate suppressed information transfer across the cerebral cortex. Selectively stimulating the matrix thalamus in the model restores signatures of conscious arousal, matching empirical results in macaques, and produces wake-like information processing states. The findings suggest that matrix thalamocortical projections modulate large-scale cortical attractor dynamics to enable the complex communication states that support conscious awareness.
Cell Reports
July 25, 2023
Gal Vishne, Edden M Gerber, Robert T. Knight et al.
When people view a steady, unchanging image, the brain's sensory regions maintain a stable representation of what is being seen, even as overall neural activity changes over time. In contrast, frontal and parietal brain areas only represent the image's content briefly at the moment it first appears. These findings, based on intracranial recordings from ten people with epilepsy, suggest that sustained conscious perception may depend on sensory cortex, while discrete perceptual updates may rely on frontoparietal regions.
Cell Reports
March 16, 2021
Clément M. Garin, Y. Hori, S. Everling et al.
The default mode network (DMN) in humans is active during rest and self-directed thought. Comparing the DMN across humans and non-hominoid primates (macaques, marmosets, and mouse lemurs) reveals major differences in connectivity. In non-hominoid primates, the medial prefrontal cortex shows weak engagement with the posterior cingulate cortex, whereas strong correlated activity between these regions is a key human DMN feature. Instead, a fronto-temporal resting-state network involving the medial prefrontal cortex appears consistently across non-hominoid species. These shared features among non-hominoid primates, absent in humans, indicate a substantial gap in DMN organization and its associated cognitive functions.