Abstract
Animals can readily learn that stimuli predict the absence of specific appetitive outcomes; however, the neural substrates underlying such outcome-specific conditioned inhibition remain largely unexplored. Here, we examined the involvement of the lateral habenula (LHb) and of its inputs onto the rostromedial tegmental nucleus (RMTg) in inhibitory learning using female and male rats as subjects. In these experiments, we used backward conditioning and contingency reversal to establish outcome-specific conditioned inhibitors for two distinct appetitive outcomes, and then assessed the effects of manipulations of the LHb and the LHb-RMTg pathway on that inhibitory encoding using the Pavlovian-instrumental transfer paradigm. In control animals, we found that an outcome specific conditioned inhibitor biased choice away from actions delivering that outcome and towards actions earning other outcomes. Importantly, both electrolytic lesions of the LHb and selective ablation of LHb neurons using Cre-dependent Caspase3 expression in Cre-expressing neurons projecting to the RMTg, abolished this bias. This deficit was specific to conditioned inhibition; an excitatory predictor of a specific outcome biased choice towards actions delivering the same outcome to a similar degree whether the LHb or the LHb-RMTg network was intact or not. LHb lesions also disrupted the ability of animals to inhibit previously encoded stimulus-outcome contingencies after their reversal, pointing to a critical role of the LHb and of its inputs onto the RMTg in outcome-specific conditioned inhibition in appetitive settings. These findings are consistent with the developing view that the LHb promotes a negative reward prediction error in Pavlovian conditioning.
SIGNIFICANCE STATEMENT
Stimuli that positively or negatively predict rewarding outcomes influence choice between actions that deliver those outcomes. Previous studies have found that a positive predictor of a specific outcome biases choice towards actions delivering that outcome. In contrast, a negative predictor of an outcome biases choice away from actions earning that outcome and towards other actions. Here we reveal that the lateral habenula is critical for negative predictors, but not positive predictors, to affect choice. Furthermore, these effects were found to require activation of lateral habenula inputs to the rostromedial tegmental nucleus. These results are consistent with the view that the lateral habenula establishes inhibitory relationships between stimuli and food outcomes and computes a negative prediction error in Pavlovian conditioning.
Footnotes
The authors declare no competing financial interests.
This research was supported by funding from the Australian Research Council in the form of an Early Career Fellowship to VL (DE140100868), a Laureate Fellowship to BWB (FL0992409) and a Discovery Project to both VL and BWB (DP130103965). BWB is supported by a Senior Principal Research Fellowship from the NHMRC of Australia (GNT1079561)
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