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. Overall design: 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