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

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

Lu, J., Tjia, M., Mullen, B. et al. An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01159-1

 

Link to Journal Article – https://www.nature.com/articles/s41380-021-01159-1

 

 

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.

 

Aim:

To assess the potential mechanisms by which the psychedelic analogue ‘Tabernanthalog’ (TBG) may work to alleviate stress-induced cognitive deficits.

 

Key Points:

Stress Induction

  • This is an in vivo study utilising murine (mouse) models of unpredictable mild stress, all mice were randomly assigned to experimental groups.

 

  • 7-day unpredictable mild stress was used as the stress protocol in experimental group, to mimic a variability in daily stress as with ‘real-life’

 

  • Elevated plus maze test, four-choice odour discrimination and reversal test and whisker-dependent texture discrimination test were used to assess stress/anxiety levels in all mice 24h following the stress protocol. Mice subjected to the stress protocol performed worse than the control group in all tests, indicating higher baseline anxiety/stress.

 

TBG Administration/Clinical Effects

  • Single-dose administered to experimental group intraperitoneally at 10mg/kg bodyweight, in line with previous pharmacokinetic studies determining this as the lowest dose associated with activation of the 5-HT2 neuroreceptors.

 

  •  TBG administration was shown to reduce levels of anxiety/stress in the experimental group within 24h, characterised by a normalisation of stress-test performance.

 

  • It was also shown to significantly promote the formation of new dendritic spines in the cortex following elimination induced by stress exposure (c.20% compensation)

 

Concluding Remarks: This research highlights the potential of utilising analogues of classic psychedelics as a therapeutic tool. Results have shown that TBG administration significantly promotes dendritic spine formation and restoration of the neuronal population lost due to induced stress. Further studies are needed to confirm its safety profile in humans, as well as develop a therapeutic target based on further research into the pharmacological profile.

 

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