Stress transforms lateral habenula reward responses into punishment signals

Neuronal activity in the lateral habenula (LHb), a brain region implicated in depression [C. D. Proulx, O. Hikosaka, R. Malinow, Nat. Neurosci. 17, 1146–1152 (2014)], decreases during reward and increases during punishment or reward omission [M. Matsumoto, O. Hikosaka, Nature 447, 1111–1115 (2007)]. While stress is a major risk factor for depression and strongly impacts the LHb, its effect on LHb reward signals is unknown. Here we image LHb neuronal activity in behaving mice and find that acute stress transforms LHb reward responses into punishment-like neural signals; punishment-like responses to reward omission also increase. These neural changes matched the onset of anhedonic behavior and were specific to LHb neurons that distinguished reward and its omission. Thus, stress distorts LHb responsivity to positive and negative feedback, which could bias individuals toward negative expectations, a key aspect of the proposed pathogenesis of depression [A. T. Beck, Depression: Clinical, Experimental, and Theoretical Aspects, sixth Ed (1967)].