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
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
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.