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Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

Catarina Albergaria, N. Tatiana Silva, Dana Darmohray, View ORCID ProfileMegan R. Carey
doi: https://doi.org/10.1101/511113
Catarina Albergaria
Champalimaud Neuroscience Program, Champalimaud Center for the Unknown, Lisbon, Portugal
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N. Tatiana Silva
Champalimaud Neuroscience Program, Champalimaud Center for the Unknown, Lisbon, Portugal
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Dana Darmohray
Champalimaud Neuroscience Program, Champalimaud Center for the Unknown, Lisbon, Portugal
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Megan R. Carey
Champalimaud Neuroscience Program, Champalimaud Center for the Unknown, Lisbon, Portugal
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  • ORCID record for Megan R. Carey
  • For correspondence: megan.carey@neuro.fchampalimaud.org
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Abstract

Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellumdependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • New experiments using CB1 antagonist AM251; Additional analysis of locomotor phenotype of CB1KO mice; Additional analyses of behavioral state for all genotypes and conditions; Substantive textual revisions

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted September 27, 2020.
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Cannabinoids modulate associative cerebellar learning via alterations in behavioral state
Catarina Albergaria, N. Tatiana Silva, Dana Darmohray, Megan R. Carey
bioRxiv 511113; doi: https://doi.org/10.1101/511113
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Cannabinoids modulate associative cerebellar learning via alterations in behavioral state
Catarina Albergaria, N. Tatiana Silva, Dana Darmohray, Megan R. Carey
bioRxiv 511113; doi: https://doi.org/10.1101/511113

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