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Neuronal and astrocytic CB1R signaling differentially modulates goal-directed behavior and working memory by distinct temporal mechanisms

Neuropsychopharmacology (2023)Cite this article

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Abstract

Several cognitive processes, including instrumental behavior and working memory, are controlled by endocannabinoids acting on cannabinoid receptor 1 (CB1R) in the brain through retrograde and presynaptic inhibition of GABA or glutamate release. However, the temporal mechanisms underlying the control of these cognitive processes by CB1Rs remain largely unknown. Here, we have developed a light-sensitive CB1R chimera (optoCB1R) by replacing the intracellular domains of bovine rhodopsin with those of human CB1R. We demonstrated that light stimulation of optoCB1R triggered canonical CB1R signaling by inhibiting cAMP (but not cGMP or IP1) signaling and activating the MAPK pathway in vitro or in vivo. Moreover, light stimulation of optoCB1R in corticostriatal glutamatergic neurons could temporally inhibit excitatory postsynaptic currents (EPSCs) at the level of seconds. Importantly, transient (3 s) and “time-locked”, but not random, activation of optoCB1R signaling in corticostriatal neurons at the time of reward affected animal sensitivity to outcome devaluation and inhibited goal-directed behavior. However, prolonged (~30 min) but not transient (10 or 30 s) activation of astrocytic CB1R signaling in the hippocampus impaired working memory. Consequently, neuronal and astrocytic CB1R signaling differentially regulate working memory and goal-directed behavior through distinct temporal and cellular mechanisms. Ultimately, the pharmacological blockade of adenosine A2AR improved the neuronal and astrocytic CB1R-induced impairments in goal-directed behavior and working memory, possibly through modulation of EPSCs and c-Fos, respectively. Therefore, A2AR may represent a promising target for managing cognitive dysfunction resulting from the use of CB1R drugs.

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Fig. 1: Light activation of OptoCB1R effectively mimics endogenous CB1R intracellular signaling.
Fig. 2: Optogenetic corticostriatal glutamatergic optoCB1R at the time of reward changes the animal’s sensitivity to outcome devaluation and inhibits EPSC in brain slices.
Fig. 3: Treatment with KW6002 restored the sensitivity to outcome devaluation after the overactivation of CB1R signaling.
Fig. 4: Long-term stimulation of astrocyte CB1R signaling impaired working memory.
Fig. 5: KW6002 treatment improved working memory damaged by astrocyte CB1R overactivation.

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Funding

This research was supported by a National Natural Science Foundation of China grant (No. 81901082, No. 81871035, and No.82071378) and the Zhejiang Provincial Natural Science Foundation (LZ19H090001).

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  1. These authors contributed equally: Huiping Shang, Peijun Li.

Authors and Affiliations

  1. Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China

    Huiping Shang, Xiangxiang Lin, Qionghui Cai, Zhihui Li, Yue Song, Jiang-fan Chen & Jianhong Zhou

  2. Key Laboratory of Structural Malformations in Children of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China

    Peijun Li & Lu Deng

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  1. Huiping Shang
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Contributions

JZ and JC conceived and designed the study. JZ and JC wrote the manuscript. HS performed the experiments. HS, PL, and LD performed electrophysiological experiments. HS, XL, QC, and YS conducted behavioral experiments. ZL and JC designed optoCB1R. HS, PL, XL, QC, and YS analyzed the data.

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Correspondence to Jiang-fan Chen or Jianhong Zhou.

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Shang, H., Li, P., Lin, X. et al. Neuronal and astrocytic CB1R signaling differentially modulates goal-directed behavior and working memory by distinct temporal mechanisms. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01533-3

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