Journal
NEURON
Volume 104, Issue 5, Pages 899-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2019.09.005
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Funding
- NIMH [R01MH112721, R01MH107742]
- Hellman Foundation
- Whitehall Foundation [2015-12-69]
- Shurl and Kay Curci Foundation
- Rita Allen Foundation
- Wayne and Gladys Valley Foundation
- UC Berkeley Regents' Junior Faculty Fellowship
- Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [CRETP3_166815]
- Anandamahidol Foundation
- Boehringer Ingelheim Foundation
- Swiss National Science Foundation (SNF) [CRETP3_166815] Funding Source: Swiss National Science Foundation (SNF)
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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.
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