Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors – Nature

Goodwin, G. M. et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N. Engl. J. Med. 387, 1637–1648 (2022).
Google Scholar
Davis, A. K. et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry 78, 481–489 (2021).
Google Scholar
Carhart-Harris, R. et al. Trial of psilocybin versus escitalopram for depression. N. Engl. J. Med. 384, 1402–1411 (2021).
Google Scholar
Bogenschutz, M. P. et al. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry 79, 953–962 (2022).
Google Scholar
Ly, C. et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 23, 3170–3182 (2018).
Google Scholar
Jones, K. A. et al. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc. Natl Acad. Sci. USA 106, 19575–19580 (2009).
Google Scholar
Shao, L. X. et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 109, 2535–2544 (2021).
Google Scholar
de la Fuente Revenga, M. et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 37, 109836 (2021).
Google Scholar
Jefferson, S. J. et al. 5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice. Neuropsychopharmacology 48, 1257–1266 (2023).
Google Scholar
Kwan, A. C., Olson, D. E., Preller, K. H. & Roth, B. L. The neural basis of psychedelic action. Nat. Neurosci. 25, 1407–1419 (2022).
Google Scholar
Duman, R. S. & Aghajanian, G. K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012).
Google Scholar
Cameron, L. P. et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 589, 474–479 (2021).
Google Scholar
Lu, J. et al. An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress. Mol. Psychiatry 26, 6237–6252 (2021).
Google Scholar
Anastasiades, P. G. & Carter, A. G. Circuit organization of the rodent medial prefrontal cortex. Trends Neurosci. 44, 550–563 (2021).
Google Scholar
Baker, A. et al. Specialized subpopulations of deep-layer pyramidal neurons in the neocortex: bridging cellular properties to functional consequences. J. Neurosci. 38, 5441–5455 (2018).
Google Scholar
Shepherd, G. M. Corticostriatal connectivity and its role in disease. Nat. Rev. Neurosci. 14, 278–291 (2013).
Google Scholar
Li, N., Chen, T. W., Guo, Z. V., Gerfen, C. R. & Svoboda, K. A motor cortex circuit for motor planning and movement. Nature 519, 51–56 (2015).
Google Scholar
Musall, S. et al. Pyramidal cell types drive functionally distinct cortical activity patterns during decision-making. Nat. Neurosci. 26, 495–505 (2023).
Google Scholar
Tang, L. & Higley, M. J. Layer 5 circuits in V1 differentially control visuomotor behavior. Neuron 105, 346–354 (2020).
Google Scholar
Garcia, A. F., Crummy, E. A., Webb, I. G., Nooney, M. N. & Ferguson, S. M. Distinct populations of cortical pyramidal neurons mediate drug reward and aversion. Nat. Commun. 12, 182 (2021).
Google Scholar
Davies, M. F., Deisz, R. A., Prince, D. A. & Peroutka, S. J. Two distinct effects of 5-hydroxytryptamine on single cortical neurons. Brain Res. 423, 347–352 (1987).
Google Scholar
Araneda, R. & Andrade, R. 5-Hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40, 199–412 (1991).
Avesar, D. & Gulledge, A. T. Selective serotonergic excitation of callosal projection neurons. Front. Neural Circuits 6, 12 (2012).
Google Scholar
Elliott, M. C., Tanaka, P. M., Schwark, R. W. & Andrade, R. Serotonin differentially regulates L5 pyramidal cell classes of the medial prefrontal cortex in rats and mice. eNeuro https://doi.org/10.1523/ENEURO.0305-17.2018 (2018).
Amargos-Bosch, M. et al. Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. Cereb. Cortex 14, 281–299 (2004).
Google Scholar
Savalia, N. K., Shao, L. X. & Kwan, A. C. A dendrite-focused framework for understanding the actions of ketamine and psychedelics. Trends Neurosci. 44, 260–275 (2021).
Google Scholar
Puig, M. V., Celada, P., Diaz-Mataix, L. & Artigas, F. In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents. Cereb. Cortex 13, 870–882 (2003).
Google Scholar
Kim, Y. et al. Whole-brain mapping of neuronal activity in the learned helplessness model of depression. Front. Neural Circuits 10, 3 (2016).
Google Scholar
Davoudian, P. A., Shao, L. X. & Kwan, A. C. Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin. ACS Chem. Neurosci. 14, 468–480 (2023).
Google Scholar
Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007).
Google Scholar
Matho, K. S. et al. Genetic dissection of the glutamatergic neuron system in cerebral cortex. Nature 598, 182–187 (2021).
Google Scholar
Nagai, Y. et al. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat. Neurosci. 23, 1157–1167 (2020).
Google Scholar
Halberstadt, A. L., Chatha, M., Klein, A. K., Wallach, J. & Brandt, S. D. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology 167, 107933 (2020).
Google Scholar
Malenka, R. C., Lancaster, B. & Zucker, R. S. Temporal limits on the rise in postsynaptic calcium required for the induction of long-term potentiation. Neuron 9, 121–128 (1992).
Google Scholar
Bittner, K. C., Milstein, A. D., Grienberger, C., Romani, S. & Magee, J. C. Behavioral time scale synaptic plasticity underlies CA1 place fields. Science 357, 1033–1036 (2017).
Google Scholar
Lee, S. J., Escobedo-Lozoya, Y., Szatmari, E. M. & Yasuda, R. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458, 299–304 (2009).
Google Scholar
Friedrich, J., Zhou, P. & Paninski, L. Fast online deconvolution of calcium imaging data. PLoS Comput. Biol. 13, e1005423 (2017).
Google Scholar
Ali, F. et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat. Commun. 11, 72 (2020).
Google Scholar
Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).
Google Scholar
DeFelipe, J., Arellano, J. I., Gomez, A., Azmitia, E. C. & Munoz, A. Pyramidal cell axons show a local specialization for GABA and 5-HT inputs in monkey and human cerebral cortex. J. Comp. Neurol. 433, 148–155 (2001).
Google Scholar
Jun, J. J. et al. Fully integrated silicon probes for high-density recording of neural activity. Nature 551, 232–236 (2017).
Google Scholar
Cameron, L. P. et al. 5-HT2ARs mediate therapeutic behavioral effects of psychedelic tryptamines. ACS Chem. Neurosci. 14, 351–358 (2023).
Google Scholar
Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B. & Thompson, S. M. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc. Natl Acad. Sci. USA 118, e2022489118 (2021).
Google Scholar
Sekssaoui, M., Bockaert, J., Marin, P. & Bécamel, C. Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player? Neuropsychopharmacology 49, 747–756 (2024).
Google Scholar
Choi, W. et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nat. Commun. 9, 4824 (2018).
Google Scholar
Yao, Z. et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell 184, 3222–3241 (2021).
Google Scholar
Aghajanian, G. K. & Marek, G. J. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36, 589–599 (1997).
Google Scholar
Kaplan, A. L. et al. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature 610, 582–591 (2022).
Google Scholar
Cao, D. et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science 375, 403–411 (2022).
Google Scholar
Dembrow, N. C., Zemelman, B. V. & Johnston, D. Temporal dynamics of L5 dendrites in medial prefrontal cortex regulate integration versus coincidence detection of afferent inputs. J. Neurosci. 35, 4501–4514 (2015).
Google Scholar
Anastasiades, P. G., Collins, D. P. & Carter, A. G. Mediodorsal and ventromedial thalamus engage distinct L1 circuits in the prefrontal cortex. Neuron 109, 314–330 (2021).
Google Scholar
Silberberg, G. & Markram, H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron 53, 735–746 (2007).
Google Scholar
Wu, S. J. et al. Cortical somatostatin interneuron subtypes form cell-type-specific circuits. Neuron 111, 2675–2692 (2023).
Google Scholar
Suzuki, M. & Larkum, M. E. General anesthesia decouples cortical pyramidal neurons. Cell 180, 666–676 (2020).
Google Scholar
Bharioke, A. et al. General anesthesia globally synchronizes activity selectively in layer 5 cortical pyramidal neurons. Neuron 110, 2024–2040 (2022).
Google Scholar
Wilkinson, S. T., Holtzheimer, P. E., Gao, S., Kirwin, D. S. & Price, R. B. Leveraging neuroplasticity to enhance adaptive learning: the potential for synergistic somatic-behavioral treatment combinations to improve clinical outcomes in depression. Biol. Psychiatry 85, 454–465 (2019).
Google Scholar
Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).
Google Scholar
Tervo, D. G. et al. A designer AAV variant permits efficient retrograde access to projection. Neuron 92, 372–382 (2016).
Google Scholar
Shamash, P., Carandini, M., Harris, K. D. & Steinmetz, N. A. A tool for analyzing electrode tracks from slice histology. Preprint at bioRxiv https://doi.org/10.1101/447995 (2018).
Wang, Q. et al. The Allen Mouse Brain Common Coordinate Framework: a 3D reference atlas. Cell 181, 936–953 (2020).
Google Scholar
Claudi, F. et al. Visualizing anatomically registered data with brainrender. eLife 10, e65751 (2021).
Google Scholar
Pologruto, T. A., Sabatini, B. L. & Svoboda, K. ScanImage: flexible software for operating laser scanning microscopes. Biomed. Eng. Online 2, 13 (2003).
Google Scholar
Thevenaz, P., Ruttimann, U. E. & Unser, M. A pyramid approach to subpixel registration based on intensity. IEEE Trans. Image Process. 7, 27–41 (1998).
Google Scholar
Holtmaat, A. et al. Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat. Protoc. 4, 1128–1144 (2009).
Google Scholar
Mitrić, M. et al. Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain. Sci. Rep. 9, 9479 (2019).
Google Scholar
Radnikow, G. & Feldmeyer, D. Layer- and cell type-specific modulation of excitatory neuronal activity in the neocortex. Front. Neuroanat. 12, 1 (2018).
Google Scholar
Pnevmatikakis, E. A. & Giovannucci, A. NoRMCorre: an online algorithm for piecewise rigid motion correction of calcium imaging data. J. Neurosci. Methods 291, 83–94 (2017).
Google Scholar
Ali, F. et al. Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation. Mol. Psychiatry 26, 1945–1966 (2021).
Google Scholar
Lutcke, H., Gerhard, F., Zenke, F., Gerstner, W. & Helmchen, F. Inference of neuronal network spike dynamics and topology from calcium imaging data. Front. Neural Circuits 7, 201 (2013).
Google Scholar
Friedman, A. et al. A corticostriatal path targeting striosomes controls decision-making under conflict. Cell 161, 1320–1333 (2015).
Google Scholar
Boudreau, E. et al. Intraperitoneal catheter placement for pharmacological imaging studies in conscious mice. Lab. Anim. 39, 23–25 (2010).
Google Scholar
Siegle, J. H. et al. Open Ephys: an open-source, plugin-based platform for multichannel electrophysiology. J. Neural Eng. 14, 045003 (2017).
Google Scholar
Buccino, A. P. et al. SpikeInterface, a unified framework for spike sorting. eLife 9, e61834 (2020).
Google Scholar
Pachitariu, M. et al. Kilosort: realtime spike-sorting for extracellular electrophysiology with hundreds of channels. Preprint at bioRxiv https://doi.org/10.1101/061481 (2016).
Liu, R. J. & Aghajanian, G. K. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc. Natl Acad. Sci. USA 105, 359–364 (2008).
Google Scholar