Cellular and circuit architecture of the lateral septum for reward processing

• DOI: 10.1016/j.neuron.2024.06.004
• Publication Date: 2024-07-02T15:35:47Z
• Authors: Gaowei Chen; Shishi Lai; Shaolei Jiang; Fengling Li; Kaige Sun; Xiaocong Wu; Kuikui Zhou; Yutong Liu; Xiaofei Deng; Zijun Chen; Fang Xu; Yu Xu; Kunhua Wang; Gang Cao; Fuqiang Xu; Guo-Qiang Bi; Yingjie Zhu
• Keywords: Neurons; Male; Mice, Inbred C57BL; Mice; Reward; Ventral Tegmental Area; Neural Pathways; Drug-Seeking Behavior; Estrogen Receptor alpha; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Animals; Septal Nuclei; Methamphetamine

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 (LSEsr1) 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 LSEsr1 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.