UC Berkeley

Chronic stress is a major risk factor for the development of depression. In recent years, the lateral habenula (LHb) has emerged as a potential key structure in depression. LHb is connected with dopaminergic neurons in the ventral tegmental area (VTA) and serotoninergic neurons in the dorsal raphe nucleus (DR), and changes in these monoaminergic systems have been associated with depression-related behaviors. In my dissertation, I demonstrate that chronic stress-induced hyperactivity in LHb neurons projecting to VTA is associated with increased passive coping but not anxiety or anhedonia. Moreover, LHb→VTA neurons in mice with increased passive coping 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 also selectively alter passive coping and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show chronic stress-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics I reveal a set of genes that can collectively serve as biomarkers to identify mice with increased passive coping phenotype and differentiate LHb→VTA from LHb→DR neurons. Together, I provide a set of biological markers at the level of genes, synapses, cells and circuits that define a distinctive chronic stress-induced behavioral phenotype.