Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Brain Research Institute, University of Zurich, Zürich 8057, Switzerland.
Neuron. 2019 Dec 4;104(5):899-915.e8. doi: 10.1016/j.neuron.2019.09.005. Epub 2019 Oct 28.
Chronic stress (CS) is a major risk factor for the development of depression. Here, we demonstrate that CS-induced hyperactivity in ventral tegmental area (VTA)-projecting lateral habenula (LHb) neurons is associated with increased passive coping (PC), but not anxiety or anhedonia. LHb→VTA neurons in mice with increased PC show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons selectively alter PC and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show CS-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics, we reveal a set of genes that can collectively serve as biomarkers to identify mice with increased PC and differentiate LHb→VTA from LHb→DR neurons. Together, we provide a set of biological markers at the level of genes, synapses, cells, and circuits that define a distinctive CS-induced behavioral phenotype.
慢性应激（CS）是抑郁发生的一个主要危险因素。在这里，我们证明 VTA 投射外侧缰核（LHb）神经元的 CS 诱导的过度活跃与增加的被动应对（PC）有关，但与焦虑或快感缺失无关。在 PC 增加的小鼠中，LHb→VTA 神经元表现出增加的爆发和紧张性放电，以及来自被盖外侧核（EP）的兴奋性输入的突触适应。EP→LHb 或 LHb→VTA 神经元的体内操纵选择性地改变 PC 和与努力相关的动机。相反，中缝背核（DR）投射的 LHb 神经元不会表现出 CS 诱导的过度活跃，并且由 EP 间接靶向。通过单细胞转录组学，我们发现了一组基因，可以作为生物标志物来识别 PC 增加的小鼠，并将 LHb→VTA 与 LHb→DR 神经元区分开来。总之，我们提供了一组基因、突触、细胞和回路水平的生物学标记物，定义了一种独特的 CS 诱导的行为表型。
