Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), Sorbonne Université, INSERM, CNRS, Paris, France.
Unité de Neurobiologie Intégrative des Systèmes Cholinergiques, Department of Neuroscience, Institut Pasteur, Paris, France.
Elife. 2018 Sep 4;7:e37487. doi: 10.7554/eLife.37487.
Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through β2-containing (β2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.
腹侧被盖区（VTA）的多巴胺（DA）神经元整合胆碱能输入，以调节关键功能，如动机和目标导向行为。然而，乙酰胆碱（ACh）对 VTA 回路和与奖励相关的行为的调制的时间动态范围和作用机制尚不清楚。在这里，我们使用了一种化学遗传学方法，用于在活体小鼠中快速和精确地用光操纵 VTA 神经元中的烟碱型神经递质传递。我们提供了直接的证据，表明 ACh 音调通过包含β2 亚基的（β2*）烟碱型 ACh 受体（nAChRs）精细调节 VTA DA 神经元的发放特性。此外，在 VTA 局部光拮抗这些受体足以可逆地开启和关闭尼古丁强化作用。通过使靶向脑回路中的烟碱型传递得到控制，这项技术将有助于揭示 nAChRs 的各种生理功能，并可能有助于设计与神经精神疾病相关的新型治疗方法。
