The Lateral Habenula to Ventral Tegmental Area Pathway is Required for Aversive Learning and Defensive Behaviors

The lateral habenula (LHb) provides aversive signals to the ventral tegmental area (VTA), but its contribution to learning and behavior remains poorly understood. Using a retrograde viral strategy, we targeted VTA-projecting LHb neurons and monitored calcium activity during active avoidance training. These neurons were activated by aversive stimuli and predictive cues as animals acquired avoidance responses and showed increased activity at movement onset during the tail suspension test (TST). Silencing LHb[->]VTA transmission impaired avoidance learning, prolonged escape latency, and reduced the persistence and vigor of active coping in the TST, without affecting baseline locomotion. Anatomical and ex vivo electrophysiology revealed that LHb terminals innervate both dopaminergic (TH) and non-dopaminergic (TH-) VTA neurons, exhibiting session-specific synaptic adaptations during avoidance learning. Together, these findings identify the LHb[->]VTA pathway as a source of aversive predicting signals required for the acquisition of avoidance behavior and the persistence of active coping in aversive context. HighlightsO_LILHb[->]VTA neurons are required for aversive learning and adaptive avoidance C_LIO_LIThese neurons respond to aversive stimuli, predictive cues, and movement onset C_LIO_LISilencing the pathway impairs avoidance learning and reduces active coping in aversive contexts C_LIO_LILHb[->]VTA inputs innervate DA and non-DA neurons and undergo learning-related plasticity C_LI