Lateral Hypothalamic GABAergic Neurons Encode Reward Predictions that Are Relayed to the Ventral Tegmental Area to Regulate Learning

Eating is a learned process. Our desires for specific foods arise through experience. Both electrical stimulation and optogenetic studies have shown that increased activity in the lateral hypothalamus (LH) promotes feeding. Current dogma is that these effects reflect a role for LH neurons in the control of the core motivation to feed, and their activity comes under control of forebrain regions to elicit learned food-motivated behaviors. However, these effects could also reflect the storage of associative information about the cues leading to food in LH itself. Here, we present data from several studies that are consistent with a role for LH in learning. In the first experiment, we use a novel GAD-Cre rat to show that optogenetic inhibition of LH γ-aminobutyric acid (GABA) neurons restricted to cue presentation disrupts the rats’ ability to learn that a cue predicts food without affecting subsequent food consumption. In the second experiment, we show that this manipulation also disrupts the ability of a cue to promote food seeking after learning. Finally, we show that inhibition of the terminals of the LH GABA neurons in ventral-tegmental area (VTA) facilitates learning about reward-paired cues. These results suggest that the LH GABA neurons are critical for storing and later disseminating information about reward-predictive cues. •We characterize a GAD-Cre rat, allowing for manipulation of GABAergic neurons•Optogenetic inhibition of LH GABA prevents learning about reward-predictive cues•LH GABA inhibition after learning prevents a cue from eliciting motivated behavior•LH GABA sends cue-elicited expectancy signals to VTA to regulate future learning Sharpe et al. show that LH GABA neurons are critical for acquisition and storage of cue-reward associations. Furthermore, LH GABA neurons relay cue-elicited expectancies to VTA to regulate future learning. This challenges current dogma, which argues that LH produces motivated output as dictated by forebrain regions or hormonal imbalance.