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. 2016 Mar 1;113(9):2520-5.
doi: 10.1073/pnas.1515724113. Epub 2016 Feb 16.

Consumption of Palatable Food Primes Food Approach Behavior by Rapidly Increasing Synaptic Density in the VTA

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Free PMC article

Consumption of Palatable Food Primes Food Approach Behavior by Rapidly Increasing Synaptic Density in the VTA

Shuai Liu et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

In an environment with easy access to highly palatable and energy-dense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.

Keywords: VTA; dopamine; excitatory synaptic transmission; palatable food; synaptic density.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The 24-h SHF exposure primes future food approach behaviors and consumption. (A) Mice were preexposed to a pellet of SHF (1–5 g) to prevent food neophobia, and 3 d later were given 24- or 1-h unlimited SHF in their home cages and then returned to chow (RF). (B) Two days after access to SHF, mice were placed in a light/dark conflict box containing a pellet of SHF in the center of the “food zone” for 10 min. (CE) Mice with 24-h SHF exposure traveled more in the food zone (C), had decreased latency to the first exit from the dark box compared with mice with 1-h SHF exposure (D), and had increased food zone entries (E). (F) Entries to the food zone were significantly increased 2 d after mice had access to 24-h SHF compared with 1-h SHF only when the food was present. (G) Mice with 24-h access to SHF consumed more food after the test than mice with 1-h SHF. n, number of mice. Bars represent mean ± SEM. *P < 0.05; **P < 0.01.
Fig. 2.
Fig. 2.
Intra-VTA insulin suppresses enhanced food approach behaviors and food consumption days after access to 24-h SHF. Mice were fed 1- or 24-h SHF. Two days later, insulin or vehicle was microinjected in the VTA 15 min before placing animals in the light/dark conflict box. (A) A Sidak’s multiple comparison test revealed a significant increase in distance traveled in the food zone 2 d after 24-h SHF in intra-VTA vehicle-treated mice (P < 0.001), but no significant effect when insulin was delivered intra-VTA (P > 0.05). (B) Latency to exit the dark box was significantly shorter in vehicle-injected mice given 24-h SHF (P < 0.01), but not significantly different in insulin-injected mice given 24-h SHF (P > 0.05). (C) Entries to the food zone were significantly greater in vehicle-injected mice given 24-h SHF (P < 0.01), but not significantly different in insulin-injected mice given 24-h SHF (P > 0.05). (D) SHF consumed after the test was significantly greater in vehicle-injected mice previously given 24-h SHF (P < 0.001), but not significantly different in insulin-injected mice previously given 24-h SHF (P > 0.05). n, number of mice. Bars represent mean ± SEM. ***P < 0.001; **P < 0.01; *P < 0.05.
Fig. 3.
Fig. 3.
Insulin suppresses excitatory synaptic transmission onto VTA dopamine neurons from mice exposed to RF or 24-h SHF. Two days after 24-h SHF, mice were decapitated, and midbrain slices were prepared for whole-cell patch-clamp electrophysiology. mEPSCs were recorded 10 min before and 20 min after insulin (500 nM) application. (A) Example recordings of mEPSCs in the presence (Lower) or absence (Upper) of insulin from dopamine neurons of mice with access to 24-h SHF (Right) or RF (Left). (B) Insulin significantly suppressed mEPSCs in mice with access to 24-h SHF or RF. A Sidak’s multiple comparison test revealed a significant effect of insulin on mEPSC frequency on mice exposed to 24-h SHF (P < 0.001) or RF (P < 0.05). (C) Insulin did not significantly modulate AMPAR mEPSC amplitudes recorded from dopamine neurons of mice exposed to 24-h SHF or RF. (D) The effect size was significantly greater in mice exposed to 24-h SHF compared with RF (P < 0.05). Bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 4.
Fig. 4.
The 24-h access to SHF induces a long-lasting increase in glutamate release onto VTA dopamine neurons. (A) AMPAR mEPSCs were recorded from VTA dopamine neurons 2 or 7 d after 24-h SHF or RF exposure. A Sidak’s multiple comparison test revealed a significant effect of SHF on mEPSC frequency at 2 (P < 0.05) and 7 (P < 0.05) d after the initial 24-h SHF exposure. (Upper) Example recordings of mEPSC events from dopamine neurons recorded 2 d after RF or SHF. (B) mEPSC amplitude was not significantly different 2 or 7 d after the initial 24-h SHF exposure. (Upper) Example recordings of mEPSC events from dopamine neurons recorded 7 d after RF or SHF exposure. (C) The paired pulse ratio was not significantly different between RF and SHF mice at 2 or 7 d after 24-h SHF exposure. (D) Sample paired pulse ratio recordings from dopamine neurons of RF (Left) or SHF (Right) mice 2 d (Upper) or 7 d (Lower) after access to SHF or RF. Bars or symbols represent mean ± SEM. *P < 0.05.
Fig. 5.
Fig. 5.
After 24-h SHF, increased endocannabinoid tone offsets increased glutamate release. Immediately after 24-h access to SHF, mice were decapitated, and midbrain slices were prepared for whole-cell patch-clamp electrophysiology. (A) Application of AM251 (2 µM) significantly increased AMPAR EPSCs in mice exposed to 24-h SHF (filled circles) compared with RF (open circles). (Upper) example traces of evoked AMPAR EPSCs onto VTA neurons from mice with 24-h access to SHF (filled circle) or RF (open circle). (B) Paired pulses were evoked with a 50-ms interstimulus interval (ISI). The paired pulse ratio was significantly greater in VTA neurons from mice with 24-h SHF compared with neurons from RF mice or VTA neurons treated with AM251 (2 µM) from SHF mice. (Upper) Example traces of AMPA EPSCs from VTA dopamine neurons from mice with 24-h access to RF (Left), SHF (Center), or SHF + AM251 (Right). (C) A Sidak’s multiple comparison test revealed mEPSC frequency was not significantly different between vehicle-treated slices of RF or SHF mice (P > 0.05). However, in AM251, mEPSC frequency was significantly greater in VTA neurons from SHF mice (P < 0.05). (Upper) Example traces of mEPSCs from VTA neurons from RF or SHF mice. (D) There was no significant effect of diet on mEPSC amplitude in the presence or absence of AM251 (P > 0.05). (Upper) Example traces of mEPSCs from VTA neurons treated with AM251 (2 µM) from RF or SHF mice. n/N, number of cells/number of mice. Bars or symbols represent mean ± SEM. *P < 0.05.
Fig. 6.
Fig. 6.
The 24-h SHF induces increased excitatory synapses onto dopamine neurons. Electron micrographs were prepared from the VTA of RF and SHF mice (n = 4 mice per group, 1,250- to 1,400-µm2 area per mouse). (A) The 24-h SHF induced a significant increase in excitatory synapses onto VTA dopamine neurons (P < 0.001), but it did not change excitatory inputs to nondopaminergic neurons (P > 0.05). (B) There was no significant effect of diet on symmetrical synapse number. (C) A representative electron micrograph demonstrating excitatory (immunogold-labeled PSD-95; open arrow) and inhibitory (filled arrow) synapses onto a dopaminergic neuron (immunogold-labeled DAT; blue/asterisks). Shaded arrow represents inhibitory synapse onto a nondopaminergic neuron. (Scale bar, 500 nm.) (D) Percent GluA1 at active zone. (E) The 24-h SHF did not alter GluA1 at the membrane (filled bars) and in recycling pools (open bars) of excitatory synapses onto dopamine neurons from RF (Upper) and SHF (Lower) mice (n = 3 mice per group, >100 synapses per condition). (F) Representative electron micrograph of VTA synapse from a RF (Upper) or SHF (Lower) mouse showing immunogold-labeled DAT (asterisks) and GluA1 (arrows). (Scale bar, 70 nm.) Bars or symbols represent mean ± SEM. ****P < 0.001.
Fig. 7.
Fig. 7.
After 24-h SHF, inhibition of insulin signaling enabled food approach behaviors and plasticity. Mice were fed 1- or 24-h SHF. Immediately after, S961 or vehicle was microinjected in the VTA 15 min before placing animals in the light/dark conflict box. (A) A Sidak’s multiple comparison test revealed a significant increase in distance traveled in the food zone immediately after 24-h SHF in intra-VTA S961-treated mice (P < 0.05), but no significant effect with vehicle (P > 0.05). (B) Latency to exit the dark box was significantly shorter in S961-injected mice given 24-h SHF (P < 0.01), but not vehicle (P > 0.05). (C) Entries to the food zone were significantly greater in S961-injected mice given 24-h SHF (P < 0.05), but not vehicle-injected mice given 24-h SHF (P > 0.05). (D) SHF consumed after the test was significantly less in vehicle- or S961-injected mice previously given 24-h SHF (P < 0.001). n, number of mice. (E) Immediately after SHF exposure in streptozotocin (STZ)-treated mice, mEPSC frequency was significantly greater (P < 0.05). (F) mEPSC amplitude was significantly different between RF and SHF mice (P < 0.05). n/N, number of cells/number of mice. (G) Example traces of mEPSCs from VTA neurons of STZ-treated mice exposed to RF or SHF. Bars represent mean ± SEM. ***P < 0.001; **P < 0.01; *P < 0.05.

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