State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
Metab Brain Dis. 2019 Oct;34(5):1421-1430. doi: 10.1007/s11011-019-00442-z. Epub 2019 Jul 16.
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.
腹侧被盖区 (VTA) 多巴胺能 (DAergic) 神经元对奖赏相关行为的确切贡献是一个长期存在的热门话题。VTA DAergic 神经元的活动是否直接调节奖赏行为仍不确定。在本研究中，我们通过 Cre 诱导的腺相关病毒载体转染，在 VTA DAergic 神经元中表达 hM3Dq、hM4Di 或通道视紫红质 2 (ChR2) 的多巴胺转运体 (DAT)-Cre 转基因小鼠，研究了 VTA DAergic 神经元在奖赏相关运动和强化中的基本作用。一方面，通过注射 hM3Dq 或 hM4Di 配体氯氮平-N-氧化物 (CNO)，分别刺激或抑制 VTA DAergic 神经元，在旷场中测试运动，以检查 VTA DAergic 神经元被刺激或抑制时的运动活性。与载体注射相比，CNO 注射选择性地激活或抑制 VTA DAergic 神经元，分别显著增加或减少运动活性，表明 VTA DAergic 神经元的刺激直接参与了运动活性的调节。另一方面，我们使用光颅内自我刺激 (oICSS) 模型来研究强化与 VTA DAergic 神经元之间的因果关系。主动戳行为而非非活动戳行为以频率和脉冲持续时间依赖的方式显著增加。此外，微透析显示，VTA DAergic 神经元的选择性光遗传学激活增强了伏隔核 (NAc) 中多巴胺 (DA) 的浓度。此外，系统给予 DA D1 受体拮抗剂显著降低了 oICSS 强化。我们的研究深刻地证明了 VTA DAergic 神经元在运动和强化中的直接调节作用，并为开发与奖励系统功能障碍相关的神经精神疾病的新型治疗策略提供了有意义的指导。
