Feeding satisfies metabolic need but is also controlled by external stimuli, like palatability or predator threat. Nucleus accumbens shell (NAcSh) projections to the lateral hypothalamus (LH) are implicated in mediating such feeding control, but the neurons involved and their mechanism of action remain elusive. We show that dopamine D1R-expressing NAcSh neurons (D1R-MSNs) provide the dominant source of accumbal inhibition to LH and provide rapid control over feeding via LH GABA neurons. In freely feeding mice, D1R-MSN activity reduced during consumption, while their optogenetic inhibition prolonged feeding, even in the face of distracting stimuli. Conversely, activation of D1R-MSN terminals in LH was sufficient to abruptly stop ongoing consumption, even during hunger. Direct inhibition of LH GABA neurons, which received input from D1R-MSNs, fully recapitulated these findings. Together, our study resolves a feeding circuit that overrides immediate metabolic need to allow rapid consumption control in response to changing external stimuli. VIDEO ABSTRACT.

Dopamine (DA) neurons of the VTA track cues and rewards to generate a reward prediction error signal during Pavlovian conditioning. Here we explored how these neurons respond to a self-paced, operant task in freely moving mice. The animal could trigger a reward-predicting cue by remaining in a specific location of an operant box for a brief time before moving to a spout for reward collection. VTA DA neurons were identified using DAT-Cre male mice that carried an optrode with minimal impact on the behavioral task. In vivo single-unit recordings revealed transient fast spiking responses to the cue and reward in correct trials, while for incorrect ones the activity paused, reflecting positive and negative error signals of a reward prediction. In parallel, a majority of VTA DA neurons simultaneously encoded multiple actions (e.g., movement velocity, acceleration, distance to goal, and licking) in sustained slow firing modulation. Applying a GLM, we show that such multiplexed encoding of rewarding and motor variables by individual DA neurons was only apparent while the mouse was engaged in the task. Downstream targets may exploit such goal-directed multiplexing of VTA DA neurons to adjust actions to optimize the task's outcome.

52Dopamine (DA) neurons of the ventral tegmental area (VTA) track external cues and 53 rewards to generate a reward prediction error (RPE) signal during Pavlovian conditioning. Here 54 we explored how RPE is implemented for a self-paced, operant task in freely moving mice. The 55 animal could trigger a reward-predicting cue by remaining in a specific location of an operant 56 box for a brief time before moving to a spout for reward collection. In vivo single-unit recordings 57 revealed phasic responses to the cue and reward in correct trials, while with failures the activity 58 paused, reflecting positive and negative error signals of a reward prediction. In addition, a 59 majority of VTA DA neurons also encoded parameters of the goal-directed action (e.g. 60 movement velocity, acceleration, distance to goal and licking) by changes in tonic firing rate. 61 Such multiplexing of individual neurons was only apparent while the mouse was engaged in 62 the task. We conclude that a multiplexed internal representation during the task modulates VTA 63 DA neuron activity, indicating a multimodal prediction error that shapes behavioral adaptation 64 of a self-paced goal-directed action. 65 66 93 19 . In brief, mice had to find an unmarked "trigger zone" in the operant box and remain there 94 two seconds, which would activate a light cue. Once the cue was presented, the animal had 95 four seconds to collect the reward by licking for a drop of fat solution at a spout located at the 96 other side of the box. The animal could engage in the next trial at its own pace. We performed 97 single-unit recordings of the VTA and video recorded the movement of the mouse. We found 98 that VTA DA neurons multiplexed phasic responses to salient events with tonic activity 99 reflecting parameters of the motor output. 100 101 102 4 Results 103Operant spatial task and behavioral performance. We injected a virus expressing cre-104 dependent channelrhodopsin (ChR2) and implanted a 16-channel optrode mounted into a 105 microdrive into the VTA of DAT-Cre mice (Fig. 1a). After recovery, we started the pre-training 106 phase that lasted five to ten days where the mice were conditioned in a cue-reward paradigm 107 (Fig.1b,c). The mice learned to associate a randomly occurring 4s light stimulus (cue) with the 108 availability of a drop of a fat solution (5% of lipofundin, BBraun, Sempach, Switzerland). We 109 then switched to the cue-guided spatial navigational task for five to twenty days ( Fig. 1c bottom 110 timeline), where the cue was triggered once the mouse had spent 2s in a small (4x4cm), 111 unmarked trigger zone (TZ) of the operant chamber (grey dotted square in Fig.1b). To collect 112 the reward the mouse had to move to the other end of the box. 113 Within a few sessions, all mice found the TZ and the reward rate increased whereas 114 the median inter-reward interval decreased in the first days ( Fig. 1f and Fig. S1). Since the 115 median inter-reward interval was insensitive to slow initiation or occasional breaks, we chose i...

No abstract