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Proc Natl Acad Sci U S A. 2018 May 29;115(22):5792-5797. doi: 10.1073/pnas.1801837115. Epub 2018 May 11.

A neural pathway controlling motivation to exert effort.

Proulx CD1,2,3, Aronson S4,2,3, Milivojevic D4,2,3, Molina C4,2,3, Loi A4,2,3, Monk B4,2,3, Shabel SJ4,2,3, Malinow R1,2,3.

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Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093;
Department of Neurosciences, University of California, San Diego School of Medicine, La Jolla, CA 92093.
Section of Neurobiology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093.
Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093.


The neural mechanisms conferring reduced motivation, as observed in depressed individuals, is poorly understood. Here, we examine in rodents if reduced motivation to exert effort is controlled by transmission from the lateral habenula (LHb), a nucleus overactive in depressed-like states, to the rostromedial tegmental nucleus (RMTg), a nucleus that inhibits dopaminergic neurons. In an aversive test wherein immobility indicates loss of effort, LHb→RMTg transmission increased during transitions into immobility, driving LHb→RMTg increased immobility, and inhibiting LHb→RMTg produced the opposite effects. In an appetitive test, driving LHb→RMTg reduced the effort exerted to receive a reward, without affecting the reward's hedonic property. Notably, LHb→RMTg stimulation only affected specific aspects of these motor tasks, did not affect all motor tasks, and promoted avoidance, indicating that LHb→RMTg activity does not generally reduce movement but appears to carry a negative valence that reduces effort. These results indicate that LHb→RMTg activity controls the motivation to exert effort and may contribute to the reduced motivation in depression.


fiber photometry; lateral habenula; motivation; optogenetics; rostromedial tegmental nucleus

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