The lateral habenula as a link between negative outcomes and adaptive strategy switching

Abstract

Flexible strategy use relies on the concerted effort of multiple cognitive processes. Originally appreciated for its role in aversive conditioning (for review, see Mondoloni et al., Transl Psychiatry 12: 86 [2022]), the lateral habenula (LHb) has recently been linked to flexible behavior more broadly (Baker et al., Front Behav Neurosci 9: 1–22 [2015]; Baker et al., Front Mol Neurosci 12: 1–15 [2019]; Mizumori and Baker, Trends Neurosci 40: 481–493 [2017]; Hones and Mizumori, Front Behav Neurosci 16: 852235 [2022]; Ahmadlou et al., Nature 641: 151–161 [2025]), prompting the question as to whether its encoding of negative outcomes contributes specifically to adaptive strategy switching. To address this gap in knowledge, the present study investigated how LHb inactivation with muscimol affects distinct aspects of flexible decision-making that depend on an understanding of negative outcomes when using a spatial set-shifting task. LHb inactivation resulted in a decreased ability to efficiently acquire new strategies after changes in reward contingencies but did not affect the exploitation of adopted strategies. A measure of choice flexibility confirmed that, without an intact LHb, rats fail to appropriately adapt to new strategies following errors. This effect suggests that the LHb contributes to the appropriate use of negative choice outcomes to inform future decisions. Therefore, aversive signaling in the LHb may play a broad role beyond purely aversive contexts, such as in guiding behavioral adaptation.