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Neuron

ISSN 1097-4199

18 papers in the library · 2,645 citations · publishing 2010-2025

Papers

Ketamine: a paradigm shift for depression research and treatment

Neuron March 1, 2019 J. Krystal, C. Abdallah, G. Sanacora et al. 443 citations

Ketamine represents a new class of rapid-acting antidepressants effective for treatment-resistant mood disorders. Its development grew from a revised understanding of depression's biology. Research into how ketamine works is providing fresh insights into antidepressant mechanisms and challenging established views on the neurobiology of depression. The drug's fast, strong, and lasting effects on depressive symptoms appear ready to change how depression is treated.

DOI: 10.1016/j.neuron.2019.02.005 Full text Medicine Psychology

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

Neuron October 5, 2022 Can Cao, Ximena Barros-Álvarez, Shicheng Zhang et al. 158 citations

Lysergic acid diethylamide (LSD) acts through serotonin 5-HT2-family receptors, primarily 5-HT2A, but the closely related 5-HT2B receptor serves as a model due to its high expression. Cryo-electron microscopy structures of LSD-bound 5-HT2B in three states—transducer-free, coupled with Gq protein, and coupled with β-arrestin-1—reveal distinct signaling snapshots from a partially active to fully active states. These findings provide comprehensive molecular insights into LSD's signaling mechanisms and may accelerate the discovery of novel psychedelic drugs.

DOI: 10.1016/j.neuron.2022.08.006 Full text LSD Gq protein Htr2b Functional selectivity +10

An integrative, multiscale view on neural theories of consciousness.

Neuron May 15, 2024 Johan F Storm, P Christiaan Klink, Jaan Aru et al. 108 citations

Consciousness may be explained by multiple, partly compatible theories rather than a single winner. A group of scientists representing different theories argue that various accounts often address different aspects or mechanistic levels of conscious experience, so they do not necessarily contradict each other. Instead, several theories may converge on fundamental neuronal mechanisms and be complementary, allowing multiple perspectives to simultaneously advance understanding. The authors advocate for unifying, integration-oriented approaches that combine valuable elements from diverse theories, an approach that has so far been largely neglected.

DOI: 10.1016/j.neuron.2024.02.004 Full text

Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2.

Neuron May 1, 2022 J. Lopez, M. Lücken, E. Brivio et al. 78 citations

A single low dose of ketamine produces a rapid and lasting antidepressant effect in mice, but the molecular mechanisms are unclear. This work identifies Kcnq2 gene activity in glutamatergic neurons of the ventral hippocampus as a key regulator of ketamine's sustained action. Combining ketamine with retigabine, a KCNQ activator, enhanced antidepressant-like effects, an effect not seen with the classical antidepressant escitalopram. These findings advance understanding of ketamine's sustained antidepressant mechanisms and suggest potential clinical applications.

DOI: 10.1016/j.neuron.2022.05.001 Full text Medicine

The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.

Neuron July 15, 2025 Manish K Jain, Ryan H Gumpper, Samuel T Slocum et al. 42 citations

Classical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.

DOI: 10.1016/j.neuron.2025.06.012 Full text G-protein-coupled receptors Dopamine receptors Hallucinogen Psychedelics +3

Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells.

Neuron September 25, 2024 Ming Li, Xue-Ke Yang, Jian Yang et al. 30 citations

Traumatic memories from social defeat stress in mice are stored in engram cells of the basolateral amygdala (BLA). A single low dose of ketamine given during, but not after, a brief re-exposure to the trauma context reduces social avoidance behavior. This effect lowers both the activity and number of reactivated BLA engram cells. Dopamine projections from the ventral tegmental area to the BLA, acting through dopamine D2 receptors, can mimic or block the therapeutic effect. Single-cell RNA sequencing shows that re-exposure with ketamine alters memory-related pathways in the BLA. The findings suggest a mechanism for how ketamine may alleviate PTSD symptoms and point to potential treatments for trauma-related disorders.

DOI: 10.1016/j.neuron.2024.06.026 Full text Post-traumatic stress disorder Basolateral amygdala Dopamine d2 receptor Memory engram cells +8

Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance.

Neuron February 5, 2025 Marc Duque, Alex B Chen, Eric Hsu et al. 27 citations

A brief exposure to ketamine can produce lasting changes in behavior and mood. In larval zebrafish, a short ketamine treatment suppressed the passive "giving-up" response that normally occurs when swimming fails to produce forward movement. Whole-brain imaging showed that ketamine initially hyperactivates a circuit involving norepinephrine and astrocytes, which controls this passivity. After ketamine is removed, the same circuit becomes less sensitive to futility, resulting in long-term increased perseverance. Experiments using pharmacology, chemogenetics, and optogenetics confirmed that norepinephrine and astrocytes are both necessary and sufficient for this effect. In adult mice, astrocytes in the cortex were similarly activated during a futility test, and ketamine also caused astrocyte hyperactivation. The cross-species conservation of this mechanism suggests new strategies for treating affective disorders.

DOI: 10.1016/j.neuron.2024.11.011 Full text Ketamine Astrocytes Behavioral states Brain states +10

Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI.

Neuron November 20, 2024 Praachi Tiwari, Pasha A Davoudian, Darshana Kapri et al. 26 citations

The serotonergic psychedelic DOI reduces anxiety-like behavior by activating 5-HT2A receptors on fast-spiking parvalbumin (PV)-positive interneurons in the CA1/subiculum region of the ventral hippocampus. Experiments combining anatomical, pharmacological, and genetic methods showed that these receptors are necessary for the anxiolytic effect. In vivo recordings revealed that DOI increases the firing rate of PV-positive interneurons, most of which express 5-HT2A receptors. Restoring 5-HT2A receptors specifically in PV-positive cells in a loss-of-function background reinstated DOI's anxiety-relieving effects, identifying these interneurons as a cellular trigger for psychedelic-induced relief of anxiety-like behavior.

DOI: 10.1016/j.neuron.2024.08.016 Full text 5-ht2a receptor Anxiety 2,5-dimethoxy-4-iodoamphetamine Ca1 +2

Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens.

Neuron May 7, 2025 Federica Lucantonio, Jacob Roeglin, Shuwen Li et al. 24 citations

Ketamine rapidly and sustainably alleviates anhedonia, a core symptom of depression, by restoring weakened excitatory synapses onto D1-medium spiny neurons in the nucleus accumbens of chronically stressed mice. Artificially strengthening these synapses reproduces ketamine's behavioral benefits, while blocking the synaptic restoration prevents the therapeutic effect. The relevant synaptic inputs originate from the medial prefrontal cortex and ventral hippocampus.

DOI: 10.1016/j.neuron.2025.02.021 Full text Brain plasticity Synaptic plasticity Neuroscience research Reward circuits +10

Taking consciousness for real: Increasing the ecological validity of the study of conscious vs. unconscious processes.

Neuron May 15, 2024 Liad Mudrik, Rony Hirschhorn, Uri Korisky 15 citations

The field of consciousness research has developed rigorous experimental methods, but these often rely on artificial paradigms that differ from everyday conscious and unconscious processes, raising concerns about ecological validity. This review argues that adopting more naturalistic approaches, as other cognitive science fields have done, can challenge existing hypotheses, yield stronger effects, and enable new research questions. Three paths are identified: changing stimuli and experimental settings, changing measures, and changing research questions. The authors review studies that have begun implementing such approaches and, while acknowledging challenges, call for increasing ecological validity in consciousness studies.

DOI: 10.1016/j.neuron.2024.03.031 Full text Augmented reality Consciousness Ecological studies Naturalistic designs +2

Synaptic priming: A framework for pharmacotherapy in depression.

Neuron November 19, 2025 Kyle A Brown, Musa I Ajibola, Gustavo C Medeiros et al. 6 citations

Ketamine, a rapid-acting antidepressant, relieves depression symptoms for days after the drug leaves the body, and repeated doses produce longer-lasting effects. This review proposes that ketamine and similar drugs act as synaptic primers, making synapses more responsive to subsequent doses, a process derived from metaplasticity. The indirect relationship between ketamine's pharmacokinetics and sustained pharmacodynamics defines a dosing model called primer pharmacology, which can optimize therapeutic outcomes. The plasticity mechanisms engaged by antidepressants overlap with those triggered by stress and psychotherapy, suggesting combined treatment strategies. Emerging primers like psilocybin also fit this framework, offering a model to guide clinical and translational psychiatry.

DOI: 10.1016/j.neuron.2025.09.010 Full text Depression Ketamine Neuroplasticity Bcm +8

Structural basis of psychedelic LSD recognition at dopamine D1 receptor.

Neuron October 9, 2024 Luyu Fan, Youwen Zhuang, Hongyu Wu et al. 6 citations

LSD dissociates extremely rapidly from the dopamine D1 receptor, driven by the flexibility of extracellular loop 2. Cryo-electron microscopy structures reveal a distinctive binding mode with the ergoline moiety oriented toward transmembrane helix 4. G protein binding stabilizes the extracellular loop 2 conformation, which markedly slows LSD's dissociation rate. These kinetic and structural insights clarify how LSD engages dopamine receptors and how G protein coupling versus β-arrestin coupling is determined, advancing understanding of GPCR dynamics and signal transduction.

DOI: 10.1016/j.neuron.2024.07.003 Full text Lysergic acid diethylamide Psychedelics LSD Dopamine receptors drd1 Gpcrs +6