Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

Shao, Ling-Xiao; Liao, Clara; Gregg, Ian; Davoudian, Pasha A; Savalia, Neil K.; Delagarza, Kristina; Kwan, Alex C.

doi:10.1016/j.neuron.2021.06.008

Cited by 331 publications

(310 citation statements)

References 54 publications

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“…Notably, the 5-HT1b receptor resulted in the second largest energy reduction in our model. This is of particular interest as recent animal models have implicated this receptor as the the potential site of antidepressant action of selective serotonin reuptake inhibitors (SSRIs) 51 as well as a potential route through which serotonergic psychedelics like psilocybin enact their synaptogenesis and antidepressant effects 52,53 .…”

Section: Network Control Theory Reveals Psychedelic-induced Flattening Of the Brain's Energy Landscapementioning

confidence: 99%

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

Singleton

Luppi

Carhart-Harris

et al. 2021

Preprint

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Psychedelics like lysergic acid diethylamide (LSD) offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. The RElaxed Beliefs Under Psychedelics (REBUS) model postulates that 5-HT2a receptor agonism allows the brain to explore its dynamic landscape more readily, as suggested by more diverse (entropic) brain activity. Formally, this effect is theorized to correspond to a reduction in the energy required to transition between different brain-states, i.e. a ″flattening of the energy landscape.″ However, this hypothesis remains thus far untested. Here, we leverage network control theory to map the brain′s energy landscape, by quantifying the energy required to transition between recurrent brain states. In accordance with the REBUS model, we show that LSD reduces the energy required for brain-state transitions, and, furthermore, that this reduction in energy correlates with more frequent state transitions and increased entropy of brain-state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors, we demonstrate the specific role of this receptor in flattening the brain′s energy landscape. Also, in accordance with REBUS, we show that the occupancy of bottom-up states is increased by LSD. In addition to validating fundamental predictions of the REBUS model of psychedelic action, this work highlights the potential of receptor-informed network control theory to provide mechanistic insights into pharmacological modulation of brain dynamics.

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Section: Network Control Theory Reveals Psychedelic-induced Flattening Of the Brain's Energy Landscapementioning

confidence: 99%

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

Singleton

Luppi

Carhart-Harris

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Likewise, a single dose of psilocybin promotes the formation of dendritic spines on layer 5 pyramidal neurons in the mouse medial frontal cortex in vivo , significantly increasing spine density; the psilocybin-induced new spines are no less stable than those formed under control conditions. In addition, psilocybin increases spine head size, which represents a strengthening of synapses (Shao et al, 2021 ). In the hippocampus and the PFC of pigs, a single dose of psilocybin also promotes synaptogenesis, as evidenced by a persistent increase in the presynaptic density of synaptic vesicle protein 2 (SV2A), a presynaptic integral glycoprotein that regulates neurotransmitter release (Raval et al, 2021 ).…”

Section: Classical Psychedelics and Their Effects On Neuroplasticity And Neural Circuitsmentioning

confidence: 99%

Serotonergic Psychedelics in Neural Plasticity

Łukasiewicz

Baker

Zuo

et al. 2021

Front. Mol. Neurosci.

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Psychedelics, compounds that can induce dramatic changes in conscious experience, have been used by humans for centuries. Recent studies have shown that certain psychedelics can induce neural plasticity by promoting neurite growth and synapse formation. In this review, we focus on the role of classical serotonergic psychedelics in neural plasticity and discuss its implication for their therapeutic potentials.

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“…Ketamine increases BDNF protein translation ( 135 , 145 ) and its antidepressant effects are absent when administered to inducible BDNF knockout mice ( 135 ) or homozygous mice harboring the BDNF Val66Met mutation ( 136 ). Ketamine and psychedelics modulate cortical neuron function by increasing dendritic spine and synapse density in the PFC ( 129 , 146 – 149 ); however, ketamine's effects on structural plasticity appear to last for approximately a week ( 150 ) while psilocybin's effects seem to be more durable lasting for at least a month ( 151 , 152 ). Though the primary molecular targets of ketamine and serotonergic psychedelics are distinct, their downstream pharmacology overlaps, requiring AMPA receptor, TrkB, and mTOR activation to elicit changes in neuronal structure and function ( 135 – 137 , 148 , 153 , 154 ).…”

Section: Introductionmentioning

confidence: 99%

“…This correlates well with the effects of the drug on dendritic spine density ( 129 , 150 ). In contrast, the mood-elevating properties of psilocybin seem to last significantly longer ( 40 – 42 , 151 ), as do its effects on neuronal structure ( 152 ). Currently, it is unclear exactly how long the effects of non-hallucinogenic psychoplastogens will last following a single administration, and head-to-head comparisons with ketamine and psilocybin are warranted to help establish optimal dosing frequency.…”

Section: Introductionmentioning

confidence: 99%

Psychedelics and Other Psychoplastogens for Treating Mental Illness

et al. 2021

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Psychedelics have inspired new hope for treating brain disorders, as they seem to be unlike any treatments currently available. Not only do they produce sustained therapeutic effects following a single administration, they also appear to have broad therapeutic potential, demonstrating efficacy for treating depression, post-traumatic stress disorder (PTSD), anxiety disorders, substance abuse disorder, and alcohol use disorder, among others. Psychedelics belong to a more general class of compounds known as psychoplastogens, which robustly promote structural and functional neural plasticity in key circuits relevant to brain health. Here we discuss the importance of structural plasticity in the treatment of neuropsychiatric diseases, as well as the evidence demonstrating that psychedelics are among the most effective chemical modulators of neural plasticity studied to date. Furthermore, we provide a theoretical framework with the potential to explain why psychedelic compounds produce long-lasting therapeutic effects across a wide range of brain disorders. Despite their promise as broadly efficacious neurotherapeutics, there are several issues associated with psychedelic-based medicines that drastically limit their clinical scalability. We discuss these challenges and how they might be overcome through the development of non-hallucinogenic psychoplastogens. The clinical use of psychedelics and other psychoplastogenic compounds marks a paradigm shift in neuropsychiatry toward therapeutic approaches relying on the selective modulation of neural circuits with small molecule drugs. Psychoplastogen research brings us one step closer to actually curing mental illness by rectifying the underlying pathophysiology of disorders like depression, moving beyond simply treating disease symptoms. However, determining how to most effectively deploy psychoplastogenic medicines at scale will be an important consideration as the field moves forward.

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Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

Cited by 331 publications

References 54 publications

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

Serotonergic Psychedelics in Neural Plasticity

Psychedelics and Other Psychoplastogens for Treating Mental Illness

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