Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Cell Rep. 2018 May 22;23(8):2236-2244. doi: 10.1016/j.celrep.2018.04.062.
Ventral tegmental area (VTA) glutamate neurons are important components of reward circuitry, but whether they are subject to cholinergic modulation is unknown. To study this, we used molecular, physiological, and photostimulation techniques to examine nicotinic acetylcholine receptors (nAChRs) in VTA glutamate neurons. Cells in the medial VTA, where glutamate neurons are enriched, are responsive to acetylcholine (ACh) released from cholinergic axons. VTA VGLUT2 neurons express mRNA and protein subunits known to comprise heteromeric nAChRs. Electrophysiology, coupled with two-photon microscopy and laser flash photolysis of photoactivatable nicotine, was used to demonstrate nAChR functional activity in the somatodendritic subcellular compartment of VTA VGLUT2 neurons. Finally, optogenetic isolation of intrinsic VTA glutamatergic microcircuits along with gene-editing techniques demonstrated that nicotine potently modulates excitatory transmission within the VTA via heteromeric nAChRs. These results indicate that VTA glutamate neurons are modulated by cholinergic mechanisms and participate in the cascade of physiological responses to nicotine exposure.
腹侧被盖区 (VTA) 谷氨酸能神经元是奖励回路的重要组成部分，但它们是否受到胆碱能调制尚不清楚。为了研究这一点，我们使用分子、生理和光刺激技术来检查 VTA 谷氨酸能神经元中的烟碱型乙酰胆碱受体 (nAChR)。富含谷氨酸能神经元的中 VTA 细胞对来自胆碱能轴突释放的乙酰胆碱 (ACh) 有反应。VTA VGLUT2 神经元表达已知构成异源 nAChR 的 mRNA 和蛋白亚基。电生理学结合双光子显微镜和光活化烟碱的激光闪光光解用于证明 VTA VGLUT2 神经元的体细胞树突亚细胞区室中的 nAChR 功能活性。最后，通过基因编辑技术对内在 VTA 谷氨酸能微电路进行光遗传学分离，证明尼古丁通过异源 nAChR 强烈调节 VTA 内的兴奋性传递。这些结果表明，VTA 谷氨酸能神经元受到胆碱能机制的调节，并参与尼古丁暴露引起的生理反应级联。
