What drives sugar addiction

NATURE | RESEARCH HIGHLIGHTS

• Prin

NEUROSCIENCE

Kay Tye of the Massachusetts Institute of Technology in Cambridge and her colleagues genetically engineered mice so that the neurons in a brain circuit involved in reward processing would fire when exposed to light. When the researchers activated these neurons, the animals sought sugar more frequently through a port in their cage, even when they received a mild electric shock to their feet in the process. Switching the neurons off stopped the sugar-seeking behaviour, but did not prevent the mouse from eating its normal food.

The researchers propose that targeting this pathway could be a possible therapy for compulsive overeating.

Original Article:

Decoding Neural Circuits that Control Compulsive Sucrose Seeking

Highlights

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LH-VTA neurons encode reward-seeking actions after they transition to habits

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A subset of LH neurons downstream of VTA encode reward expectation

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LH-VTA projections provide bidirectional control over compulsive sucrose seeking

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Activating LH-VTA GABAergic projections increases maladaptive gnawing behavior

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Summary

The lateral hypothalamic (LH) projection to the ventral tegmental area (VTA) has been linked to reward processing, but the computations within the LH-VTA loop that give rise to specific aspects of behavior have been difficult to isolate. We show that LH-VTA neurons encode the learned action of seeking a reward, independent of reward availability. In contrast, LH neurons downstream of VTA encode reward-predictive cues and unexpected reward omission. We show that inhibiting the LH-VTA pathway reduces “compulsive” sucrose seeking but not food consumption in hungry mice. We reveal that the LH sends excitatory and inhibitory input onto VTA dopamine (DA) and GABA neurons, and that the GABAergic projection drives feeding-related behavior. Our study overlays information about the type, function, and connectivity of LH neurons and identifies a neural circuit that selectively controls compulsive sugar consumption, without preventing feeding necessary for survival, providing a potential target for therapeutic interventions for compulsive-overeating disorder.

We designed a Pavlovian conditioning task in which food-deprived mice had to cross a shock grid to retrieve a sucrose reward (Figure 5B). In the first “baseline” epoch (with the shock grid off), we verified that each mouse had acquired the Pavlovian conditioned approach task. In the second (“Shock”) epoch, the shock grid delivered mild foot shocks every second. Finally, in the third epoch (“Shock+Light”), we continued to deliver foot shocks but also illuminated LH terminals in the VTA with blue light (10 Hz) in mice expressing ChR2 and matched eYFP controls and yellow light (constant) for mice expressing NpHR and their eYFP controls (Figure 5B).

We observed a significantly higher number of port entries per cue during the Shock+Light epoch and a significantly higher difference score (Shock+Light epoch − Shock-only epoch) in ChR2 mice relative to eYFP mice (Figure 5C and Movie S1). In contrast, photoinhibition of the LH-VTA pathway resulted in a significant reduction in port entries per cue and difference scores in the NpHR mice relative to eYFP mice (Figure 5D and Movie S2). Within-session extinction experiments during which cue presentations were not followed by sucrose deliveries showed similar trends in effect (Figure S4).