Previews the Cranial Windows of Perception

Previews The cranial windows of perception

Jeffrey F. DiBerto1 and Bryan L. Roth1,* 1Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2021.07.017

Psilocybin has emerged as a potentially rapidly acting antidepressant with enduring actions. In this issue of Neuron, Shao et al. (2021) show that psilocybin quickly induces dendritic spine formation in cortical layer V pyramidal neurons. These results provide a potential cellular substrate for psilocybin’s therapeutic actions.

If the doors of perception were enduring therapeutic effects remain The authors began their study by cleansed, every thing would unknown. establishing a behaviorally relevant appear to man as it is, Infinite. Many prior studies have demonstrated dose of PSI to use for their experiments. For man has closed himself up, that antidepressant drugs, including the First, they administered mice PSI or till he sees all things thro’ narrow rapidly acting antidepressant ketamine (Li saline to determine what doses produce chinks of his cavern. ÀWilliam et al., 2010) as well as conventional antide- a head-twitch response, a behavioral Blake (The Marriage of Heaven pressants (Benes and Vincent, 1991), can phenotype in rodents evoked by psy- and Hell) induce dendritic spine formation. Among chedelics that is characterized by rapid many other compensatory alterations in side-to-side head movements. Finding Psychedelic drugs such as lysergic neuronal function induced by antidepres- that a 1 mg/kg dose of PSI robustly in- acid diethylamide (LSD), psilocybin, sants, spine formation has emerged as a creases head twitches relative to saline mescaline, and N,N’-dimethyltryptamine potential final pathway (Moda-Sava et al., or lower drug doses, the authors next induce profound alterations in percep- 2019). Some years ago, Jones et al. show that this dose also ameliorates tion and have been used ritualistically (2009) reported that the psychedelic drug escape avoidance behavior in mice by indigenous peoples for millennia 2,5-dimethoxy-4-iodoamphetamine subjected to a learned helplessness (Nichols, 2016). Although psychedelic rapidly induced spine formation in cortical paradigm. drugs were actively studied for their ther- pyramidal neurons. More recently, others Having established a dose of PSI that apeutic potential in the 1950s and 1960s have reported rapid spine formation of produces psychedelic drug-like actions (Nichols, 2016), widespread recreational cortical neurons in vitro to be a common and ameliorates a model stress-coping use of psychedelics in the 1960s led to feature of psychedelic, but not of non-psy- behavior, the authors next investigated their eventual criminalization. Psyche- chedelic, 5-HT2AR agonists (Ly et al., how PSI might alter dendritic spine delics are experiencing a renaissance in 2018). Collectively these findings have morphology in vivo. Shao et al. installed psychiatry due to several clinical trials raised the intriguing possibility that psy- cranial windows above the cingulate/ demonstrating the potential of one or chedelic-drug-induced spine formation premotor cortex of Thy1GFP mice, in two doses of psilocybin to cause rapid and synaptic plasticity might represent which cortical layer V and VI pyramidal and enduring improvements in depres- one way in which psychedelic drugs exert neurons were fluorescently labeled. sion and anxiety (Reiff et al., 2020). Psilo- their therapeutic potential. Following a single administration of PSI, cybin, found in mushrooms of the genus A key distinguishing feature of the puta- the authors quantified thousands of den-

Psilocybe and prodrug of the 5-HT2A re- tive therapeutic action of PSI is its dritic spines at various time points over ceptor (5-HT2AR) agonist psilocin, has enduring action after one dose. In this the course of about 1 month. They found gained particular clinical traction after issue of Neuron, Shao et al. (2021) used that PSI modestly, but signiﬁcantly, in- being designated a ‘‘breakthrough ther- two-photon microscopy to show, remark- creases spine morphological parameters apy’’ for treatment-resistant depression ably, that a single dose of PSI induced including spine density, head width, and by the United States Food and Drug sustained alterations in cortical neuron protrusion length. Notably, the formation Administration (hereafter, PSI will inter- spine formation and plasticity. For these of new spines occurred rapidly after drug changeably refer to psilocybin and psilo- studies, the authors chronically monitored treatment, with the rates of spine protru- cin). Despite an atomic-level under- cortical layer V pyramidal neuron apical sion and retraction returning to baseline standing of psychedelic drug actions dendrites, where 5-HT2AR expression is levels after several days. Of the new (Kim et al., 2020) and a mushrooming enriched, and quantiﬁed spine dynamics spines that form in cingulate/premotor body of literature maintaining psyche- as well as the functional consequences cortex dendrites, about half remained delics’ therapeutic potential (Reiff et al., of behaviorally relevant doses of PSI on morphologically stable after 1 week, 2020), the neurobiological mechanisms spine structural remodeling in mice and about one-third remained so after by which psychedelic drugs exert their (Figure 1). 1 month.

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serotonin receptors (Kim et al., 2020, Nichols, 2016), these ‘‘off-target’’ actions of PSI might be therapeutically impor- tant. As suggested by Hesselgrave et al. (2021), PSI and other psychedelics may exert their therapeutic actions by virtue of their robust polypharmacology. This study by Shao et al. is the first to demonstrate an enduring action of a psychedelic drug on spine morphology in vivo. Indeed, a similar phenomenon has been observed in response to another rapid-acting antidepressant, the dissocia- tive drug ketamine (Li et al., 2010). These convergent biological consequences to drugs diverging in their pharmacological sites of action merit further investigation, as the signaling pathways responsible for them may elucidate alternative drug targets with more direct action and Figure 1. Figure 1. Psilocybin alters behavior and neuronal properties after a single greater clinical efficacy. While the behav- administration Psilocybin, found in mushrooms of the genus Psilocybe, is dephosphorylated in vivo into the 5-HT2AR ioral consequences of psychedelic spine agonist psilocin (center). At sufficient doses, systemic administration of psilocybin produces a halluci- remodeling were not directly assessed nogenic-like head-twitch response (top left) and promotes stress-related escape avoidance behaviors by Shao et al., Moda-Sava et al. used a (top right) in mice. Additionally, psilocybin treatment remodels apical dendrite spines in cortical layer V pyramidal neurons, which can be monitored in vivo by two-photon microscopy (bottom right), and re- photoactivable, synapse-targeted Rac1 sults in elevated glutamatergic synaptic function (bottom left). This figure was created with BioRender. to optogenetically reverse ketamine- com. Protein Data Bank entry 6WHA was used to create the 5-HT2AR icon. induced spine remodeling, blocking its lasting but not initial antidepressant-like effects (Moda-Sava et al., 2019). A similar Shao et al. next demonstrated that the concluded that PSI broadly alters spines approach may be useful for future studies morphological changes in these regions in cortical layer V pyramidal neurons. If to understand the necessity of psyche- were correlated with elevated synaptic spine remodeling is related to PSI’s thera- delic-induced spine remodeling to elicit function. Since cortical layer V neurons peutic effects, the heterogeneity across and maintain a therapeutic response. receive dense glutamatergic innervation, cortical areas observed in this study could the authors used whole-cell electrophysi- provide clues to the locus or loci for PSI’s ACKNOWLEDGMENTS ology to record miniature excitatory post- potential therapeutic actions. We thank Gavin P. Schmitz for providing sample synaptic currents (mEPSCs) in these cells. A particularly intriguing finding from electrophysiology tracings. Work was supported At 24 h after drug administration, they this study is that pretreatment of mice in the Roth lab by R37DA04567. observed a significant increase in mEPSC with 1 mg/kg ketanserin, a 5-HT2A/CR frequency and a moderate increase in antagonist, completely blocks PSI- REFERENCES mEPSC amplitude in neurons from PSI- evoked head twitches without signifi- versus saline-treated mice. Given that cantly affecting spine remodeling in Benes, F.M., and Vincent, S.L. (1991). Changes in dendritic spine morphology in response to many PSI-induced dendrites persist the cingulate/premotor cortex. A recent increased availability of monoamines in rat medial 1 month following treatment, it would be study by Hesselgrave et al. conducted prefrontal cortex. Synapse 9, 235–237. of interest to determine the extent to in rats similarly found that 2 mg/kg ketan- Hesselgrave, N., Troppoli, T.A., Wulff, A.B., which this increased excitability is main- serin reduces PSI’s ability to evoke head Cole, A.B., and Thompson, S.M. (2021). tained over a longer period of time. twitches but not its antidepressant-like Harnessing psilocybin: antidepressant-like Shao et al. also examined infralimbic/ behavioral effects in the forced-swim behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in prelimbic and motor cortex to determine test (Hesselgrave et al., 2021). Shao mice. Proc. Natl. Acad. Sci. USA 118, if PSI’s effects generalize across cortical et al. note, however, that ketanserin has e2022489118. areas. Using confocal microscopy, they poor brain penetration and that results Jones, K.A., Srivastava, D.P., Allen, J.A., again compared spine characteristics be- could be different with more potent and Strachan, R.T., Roth, B.L., and Penzes, P. tween PSI- versus saline-treated mice selective 5-HT2AR antagonists. An alter- (2009). Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through ka- 24 h after drug administration. Although native is that although 5-HT2ARs are lirin-7 signaling. Proc. Natl. Acad. Sci. USA the changes they observed in these regions necessary for psychedelics’ hallucino- 106, 19575–19580. were less pronounced and inconsistent in genic and hallucinogenic-like effects in Kim, K., Che, T., Panova, O., DiBerto, J.F., Lyu, the morphological parameters effected humans and rodents, because PSI and J., Krumm, B., Wacker, D., Robertson, M.J., (e.g., protrusion length), the authors other psychedelics activate many other Seven, A.B., Nichols David, E., et al. 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Data-driven computational modeling predicts ‘‘superhubs’’ play key role in epileptic dynamics

Sarah F. Muldoon1,* 1Department of Mathematics, CDSE Program, and Neuroscience Program, University at Buffalo, SUNY, Buffalo, NY 14260, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2021.07.024

How individual neurons inﬂuence epileptic networks remains an open question. In this issue of Neuron, Had- jiabadi et al. (2021) use data-driven, computational models to predict the presence of ‘‘superhubs’’: highly connected neurons that drive network activity through feedforward motifs.

Computational models have become controlled environment, which also tiform dynamics. Importantly, the structure increasingly prominent in neuroscience makes them particularly appealing to of these networks is constructed from and research because of their ability to simu- study the role of network structure in constrained by experimental data from late highly complex interactions between pathological conditions such as epilepsy. two-photon imaging of neuronal activity, elements of brain networks, provide a Epilepsy is one of the most common providing a further link between experi- platform to make predictions about neurological disorders and is character- mental and computational work. experimental outcomes, and perform ized by recurrent seizures that represent Hadjiabadi et al. (2021) first study a computational experiments that might the abnormal activity of neurons. Seizures model of acute seizures in zebrafish. not be possible in vivo (Bansal et al., are generally observed at the macroscopic Neuronal activity from both baseline and 2018). With the availability of experimental scale through electroencephalogram preseizure states is used to fit models of data that probe brain networks at high (EEG) or local field potential (LFP) signals effective connectivity (directed network levels of spatial and temporal resolution, and have been traditionally described as structure) between neurons for each state. researchers can now incorporate these ‘‘hypersynchronous’’ activity of neurons. Importantly, during the fitting process, the data into models to build increasingly However, in the past decade as it has known regional connectivity of zebrafish is specialized and/or personalized models become possible to record the activity of used as a constraint in order to encourage of brain structure and function. While individual neurons, it has become increas- models that reflect the actual anatomy of much work has focused on building brain ingly clear that neurons play a heteroge- the system. The authors then study the to- network models at the macroscopic level nous role in seizure dynamics (Truccolo pology of the connectivity of the models, and studying regional brain dynamics et al., 2011), and current research now specifically looking for the presence of (Sanz-Leon et al., 2015), other recent strives to understand how the activity of in- hub neurons—neurons with an unusually work has involved microscopic models dividual neurons combines to give rise to high number of connections. studying networks of neurons to probe seizure states (Wenzel et al., 2019). In Hub neurons have previously been how individual neurons impact network this issue of Neuron, Hadjiabadi et al. shown to play a driving role in healthy syn- dynamics (Sadeh and Clopath, 2020). A (2021) take a data-driven, computational chronous brain activity in developing net- key benefit of these brain network models approach to this question and build works (Bonifazi et al., 2009), and computa- is their ability to explore the link between models of epileptic circuits to explore the tional modeling work has also predicted brain structure and function in a role of individual neurons in driving epilep- that the presence of hub neurons would

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