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Cited by 84Psychedelics and Drug StudiesNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress

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Lu, Ju, Tjia, Michelle, Mullen, Brian, Cao, Bing, Lukasiewicz, Kacper, Shah-Morales, Sajita, Weiser, Sydney, Cameron, Lindsay P. +3 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-021-01159-1PMC PMC8613316
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Abstract

Psychological stress affects a wide spectrum of brain functions and poses risks for many mental disorders. However, effective therapeutics to alleviate or revert its deleterious effects are lacking. A recently synthesized psychedelic analog tabernanthalog (TBG) has demonstrated anti-addictive and antidepressant potential. Whether TBG can rescue stress-induced affective, sensory, and cognitive deficits, and how it may achieve such effects by modulating neural circuits, remain unknown. Here we show that in mice exposed to unpredictable mild stress (UMS), administration of a single dose of TBG decreases their anxiety level and rescues deficits in sensory processing as well as in cognitive flexibility. Post-stress TBG treatment promotes the regrowth of excitatory neuron dendritic spines lost during UMS, decreases the baseline neuronal activity, and enhances whisking-modulation of neuronal activity in the somatosensory cortex. Moreover, calcium imaging in head-fixed mice performing a whisker-dependent texture discrimination task shows that novel textures elicit responses from a greater proportion of neurons in the somatosensory cortex than do familiar textures. Such differential response is diminished by UMS and is restored by TBG. Together, our study reveals the effects of UMS on cortical neuronal circuit activity patterns and demonstrate that TBG combats the detrimental effects of stress by modulating basal and stimulus-dependent neural activity in cortical networks.

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Crossref · 10.1038/s41380-021-01159-1

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  • A single dose of TBG completely rescued circuit-level dysfunction induced by chronic stress, including deficits in dendritic spine density, calcium dynamics, and interneuron function.

    “a single dose of TBG was able to completely rescue circuit-level dysfunction induced by chronic stress, which included deficits in dendritic spine density, calcium dynamics, and interneuron function”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [255]

    The Results sections report that a single post-stress dose of TBG restored several calcium-activity measures and PV+ interneuron excitability to control levels. But the dendritic-spine Results say new spine formation compensated for only about 20% of spines lost during stress; the Discussion likewise calls this partial compensation. Thus “completely rescued” overstates the circuit-level findings. Page numbers are not available in our copy. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • AAZ and TBG produce sustained (>1 week) antidepressant-like effects following a single administration in both environmental (chronic unpredictable stress) and genetic (VMAT2 heterozygous mice) models of depression as measured via behavioral tests relevant to motivation, anhedonia, anxiety, and cognitive flexibility.

    “produce sustained (>1 week) antidepressant-like effects following a single administration in both environmental (chronic unpredictable stress) and genetic (VMAT2 heterozygous mice) models of depression as measured via behavioral tests relevant to motivation, anhedonia, anxiety, and cognitive flexibility”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [255]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • AAZ and TBG have demonstrated robust plasticity-promoting properties.

    “Our two most advanced compounds—AAZ and TBG—have demonstrated robust plasticity-promoting properties”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [255]

    The Results section on post-stress dendritic spine regrowth reports that TBG nearly doubled spine formation within a day in stressed mice, supporting its plasticity-promoting properties. The passages address TBG, but our copy provides no evidence for AAZ (searched: AAZ, AAZ plasticity). No page numbers were provided. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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References 99 · Cited by 84

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Authors
Lu, J., Tjia, M., Mullen, B., Cao, B., Lukasiewicz, K., Shah-Morales, S., Weiser, S., Cameron, L. P., Olson, D. E., Chen, L., & Zuo, Y.
Affiliations
  • University of California, Santa Cruz (US)
  • Stanford Medicine (US)
  • University of California, Davis (US)
Corresponding author
  • Lu, Ju
  • Zuo, Yi
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-05-25
Volume
26
Issue
11
Pages
6237-6252
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-021-01159-1
PMC
PMC8613316
OpenAlex
W3164900028
Cited by
84
References
99
Citations by year
2026: 16 · 2025: 22 · 2024: 12 · 2023: 13 · 2022: 14 · 2021: 7
FWCI
7.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH109475, R01MH104227, T32MH112507, R01MH091193)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS104950, R01NS115660)
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD101266, R01HD084215)
  • Max-Planck-Gesellschaft (Max Planck Fellowship)
  • SU | School of Medicine, Stanford University (Stanford Dean’s Postdoctoral Fellowship)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01GM128997)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
psychological stress, anxiety, somatosensory cortex, neuronal activity, cognitive flexibility, sensory processing deficits, neural circuit modulation
MeSH terms
Animals, Hallucinogens, Neurons, Somatosensory Cortex, Vibrissae, Mice

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