Chen Gaowei, Lai Shishi, Jiang Shaolei, Li Fengling, Sun Kaige, Wu Xiaocong, Zhou Kuikui, Liu Yutong, Deng Xiaofei, Chen Zijun, Xu Fang, Xu Yu, Wang Kunhua, Cao Gang, Xu Fuqiang, Bi Guo-Qiang, Zhu Yingjie
Shenzhen Key Laboratory of Drug Addiction, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shenzhen Neher Neural Plasticity Laboratory, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Yunnan University School of Medicine, Yunnan University, Kunming 650091, China; Southwest United Graduate School, Kunming 650092, China.
Neuron. 2024 Aug 21;112(16):2783-2798.e9. doi: 10.1016/j.neuron.2024.06.004. Epub 2024 Jul 2.
The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LS) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LS neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.
外侧隔区（LS）由多种对各种动机行为至关重要的细胞类型组成。然而，这些细胞类型的转录谱、空间排列、功能和连接性尚未得到系统研究。利用单核RNA测序，我们描绘了LS中多种基因定义的细胞类型，它们在奖赏处理中发挥着不同作用。值得注意的是，我们发现腹侧LS中表达雌激素受体1（Esr1）的神经元通过投射到腹侧被盖区是奖赏寻求的关键驱动因素，并且这些神经元在甲基苯丙胺（METH）奖赏和觅药行为中起重要作用。长期暴露于METH通过上调超极化激活的环核苷酸门控（HCN）通道增加LS神经元的兴奋性，从而导致METH诱导的运动敏化。这些见解不仅阐明了奖赏处理中隔区复杂的分子、回路和功能结构，还揭示了一条对METH奖赏和行为敏化至关重要的神经通路。
