Chronic stress induces activity, synaptic and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors

Chronic stress (CMS) affects many brain functions and is a major risk factor for the development of depression. Here, we demonstrate that CMS-induced hyperactivity in 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 CMS-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 CMS-induced behavioral phenotype. 20 mice were analyzed for a total of 73 LHb cells. 6 mice (27 cells) were stressed, and 14 mice (46 cells) were not stressed. 19 cells were projecting to the Dorsol Raphe, and 54 cells were projecting to the VTA