Metabolic Brain Disease

, Volume 34, Issue 5, pp 1421–1430 | Cite as

Re-examining the role of ventral tegmental area dopaminergic neurons in motor activity and reinforcement by chemogenetic and optogenetic manipulation in mice

  • Man-Yi Jing
  • Xiao Han
  • Tai-Yun Zhao
  • Zhi-Yuan Wang
  • Guan-Yi Lu
  • Ning Wu
  • Rui SongEmail author
  • Jin LiEmail author
Original Article


The precise contributions of ventral tegmental area (VTA) dopaminergic (DAergic) neurons to reward-related behaviors are a longstanding hot topic of debate. Whether the activity of VTA DAergic neurons directly modulates rewarding behaviors remains uncertain. In the present study, we investigated the fundamental role of VTA DAergic neurons in reward-related movement and reinforcement by employing dopamine transporter (DAT)-Cre transgenic mice expressing hM3Dq, hM4Di or channelrhodopsin 2 (ChR2) in VTA DAergic neurons through Cre-inducible adeno-associated viral vector transfection. On the one hand, locomotion was tested in an open field to examine motor activity when VTA DAergic neurons were stimulated or inhibited by injection of the hM3Dq or hM4Di ligand clozapine-N-oxide (CNO), respectively. CNO injection to selectively activate or inhibit VTA DAergic neurons significantly increased or decreased locomotor activity, respectively, compared with vehicle injection, indicating that VTA DAergic neuron stimulation is directly involved in the regulation of motor activity. On the other hand, we used the optical intracranial self-stimulation (oICSS) model to investigate the causal link between reinforcement and VTA DAergic neurons. Active poking behavior but not inactive poking behavior was significantly escalated in a frequency- and pulse duration-dependent manner. In addition, microdialysis revealed that the concentration of dopamine (DA) in the nucleus accumbens (NAc) was enhanced by selective optogenetic activation of VTA DAergic neurons. Furthermore, systemic administration of a DA D1 receptor antagonist significantly decreased oICSS reinforcement. Our research profoundly demonstrates a direct regulatory role of VTA DAergic neurons in movement and reinforcement and provides meaningful guidance for the development of novel treatment strategies for neuropsychiatric diseases related to the malfunction of the reward system.


Ventral tegmental area Dopamine Chemogenetic Optogenetic Motor activity Reinforcement 



This work was supported by the National Key R&D Program of China (2017YFC131040), National Natural Science Foundation of China (No. U1502225), National Key R&D Program of China (2016YFC0800907), National Natural Science Foundation of China (81573405), Medical Innovation Program (16CXZ033) and Beijing Nova Program (xx2014A014).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of NeuropsychopharmacologyBeijing Institute of Pharmacology and ToxicologyBeijingChina

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