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Theranostics 2024; 14(3):1126-1146. doi:10.7150/thno.90792 This issue Cite

Research Paper

Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway

Fan Wang1, Chao-bao Liu1, Yi Wang1, Xi-xi Wang1, Yuan-yao Yang1, Chang-you Jiang1,2, Qiu-min Le1,2, Xing Liu1,2, Lan Ma1,2, Fei-fei Wang1,2✉

1. School of Basic Medical Sciences, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Pharmacology Research Center, Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200032, China.
2. Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai 200032, China.

✉ Corresponding author: Fei-fei Wang, PhD, School of Basic Medical Sciences, Fudan University (ffwangedu.cn); Address: 138 Yixueyuan Road, Shanghai, 200032, China. Tel.: +86-21-54237680; Fax: +86-21-54237621.

Citation:
Wang F, Liu Cb, Wang Y, Wang Xx, Yang Yy, Jiang Cy, Le Qm, Liu X, Ma L, Wang Ff. Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway. Theranostics 2024; 14(3):1126-1146. doi:10.7150/thno.90792. https://www.thno.org/v14p1126.htm
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Abstract

Graphic abstract

Background: Neurons in the ventral tegmental area (VTA) are sensitive to stress and their maladaptation have been implicated in the psychiatric disorders such as anxiety and addiction, etc. The cellular properties of the VTA neurons in response to different stressors related to different emotional processing remain to be investigated.

Methods: By combining immediate early gene (IEG)-dependent labeling, rabies virus tracing, ensemble-specific transcriptomic analysis and fiber photometry recording in the VTA of male mice, the spatial distribution, brain-wide connectivity and cellular signaling pathways in the VTA neuronal ensembles in response to morphine (Mor-Ens) or foot shock (Shock-Ens) stimuli were investigated.

Results: Optogenetic activation of the Mor-Ens drove approach behavior, whereas chemogenetic activation of the Shock-Ens increased the anxiety level in mice. Mor-Ens were clustered and enriched in the ventral VTA, contained a higher proportion of dopaminergic neurons, received more inputs from the dorsal medial striatum and the medial hypothalamic zone, and exhibited greater axonal arborization in the zona incerta and ventral pallidum. Whereas Shock-Ens were more dispersed, contained a higher proportion of GABAergic neurons, and received more inputs from the ventral pallidum and the lateral hypothalamic area. The downstream targets of the G protein and β-arrestin pathways, PLCβ3 and phosphorylated AKT1Thr308, were relatively enriched in the Mor-Ens and Shock-Ens, respectively. Cariprazine, the G-protein-biased agonist for the dopamine D2 receptor, increased the response of Mor-Ens to sucrose water and decreased the anxiety-like behavior during morphine withdrawal, whereas the β-arrestin-biased agonist UNC9994 decreased the response of Shock-Ens to tail suspension.

Conclusions: Taken together, these findings reveal the heterogeneous connectivity and signaling pathways of the VTA neurons in response to morphine and foot shock, providing new insights for development of specific interventions for psychiatric disorders caused by various stressors associated with different VTA neuronal functions.

Keywords: Ventral tegmental area, Morphine, Foot shock, Ensemble, GPCR

Citation styles

APA
Wang, F., Liu, C.b., Wang, Y., Wang, X.x., Yang, Y.y., Jiang, C.y., Le, Q.m., Liu, X., Ma, L., Wang, F.f. (2024). Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway. Theranostics, 14(3), 1126-1146. https://doi.org/10.7150/thno.90792.

ACS
Wang, F.; Liu, C.b.; Wang, Y.; Wang, X.x.; Yang, Y.y.; Jiang, C.y.; Le, Q.m.; Liu, X.; Ma, L.; Wang, F.f. Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway. Theranostics 2024, 14 (3), 1126-1146. DOI: 10.7150/thno.90792.

NLM
Wang F, Liu Cb, Wang Y, Wang Xx, Yang Yy, Jiang Cy, Le Qm, Liu X, Ma L, Wang Ff. Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway. Theranostics 2024; 14(3):1126-1146. doi:10.7150/thno.90792. https://www.thno.org/v14p1126.htm

CSE
Wang F, Liu Cb, Wang Y, Wang Xx, Yang Yy, Jiang Cy, Le Qm, Liu X, Ma L, Wang Ff. 2024. Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway. Theranostics. 14(3):1126-1146.

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