Sales of full-sugar fizzy drinks are almost triple those of diet versions, providing real-world confirmation of the laboratory finding that humans, as well as animals, prefer sugar to artificial sweeteners. However, it is not simply that sugary things taste better. Mice with a mutation that prevents them from perceiving sweet tastes still prefer the natural sugar sucrose over the artificial sweetener sucralose.

This is because sugar, unlike artificial sweeteners, has nutritional value, and both humans and animals find it rewarding to consume foods with a high caloric content. Consuming sugar has been known to cause certain parts of the brain to release more of the chemical transmitter dopamine, which is used to signal reward, but exactly how this process produces a preference for sugar has been unclear.

Now, Domingos et al. have revealed that a brain region called the lateral hypothalamus is responsible for this effect. This region of the brain—which helps to control appetite and which is also connected to the brain’s reward system—normally contains cells called MCH neurons. Domingos et al. show that the natural preference for sucrose over sucralose can be reversed by stimulating the MCH neurons with light, which in turn stimulates dopamine release in reward centers in the brain. Moreover, mutant mice that do not have any MCH neurons in the lateral hypothalamus show a reduced preference for sucrose over sucralose, compared to normal mice, and they release less dopamine than normal mice when they consume sucrose.

By demonstrating that MCH neurons are both necessary and sufficient for sensing the nutritional value of sugar, these results provide new insights into the biological basis of sugar cravings. However, given the health implications of excessive sugar consumption, they may ultimately be used to find ways to make sugar less desirable, or to make artificial sweeteners more closely mimic the real thing.

Animals and humans generally prefer sugars containing glucose, such as sucrose, compared to non-nutritive sweeteners such as sucralose (Smiciklas-Wright et al., 2002; Jacobson, 2005; Domingos et al., 2011; Sicher, 2011) as a result of the post-ingestive rewarding effect of sucrose (Domingos et al., 2011). This post-ingestive rewarding effect of sucrose was first described by showing that non-nutritive liquids that are paired to glucose administration either in the intra-gastric tract or in plasma, are greatly preferred over liquids that are not paired with nutrients (de Araujo et al., 2008; Ren et al., 2010; de Araujo et al., 2010; Oliveira-Maia et al., 2011; Sclafani et al., 2011; Fernstrom et al., 2012; de Araujo et al., 2013). In addition, sweet-blind Trpm5 knockout mice can still sense the nutrient value of sucrose (de Araujo et al., 2008). These studies have indicated that the nutrient value of sucrose is sensed and in turn establishes a preference for nutritive sugars (Ren et al., 2010; de Araujo et al., 2010; Sclafani et al., 2011; Fernstrom et al., 2012). These data further indicate that the post-ingestive rewarding effect plays an important role in driving nutrient choice (in addition to sweet taste). However, despite the substantial evidence that they play a major, perhaps dominant, role in driving food intake and sweetener preference, the neural pathways that sense glucose and mediate the post-ingestive rewarding effect of sucrose have not been identified.

Rodent studies have further shown that sucrose but not artificial sweeteners such as sucralose can drive dopamine (DA) release in the midbrain even in the absence of taste (de Araujo et al., 2008; Ren et al., 2010; de Araujo et al., 2010; Oliveira-Maia et al., 2011; Sclafani et al., 2011; Fernstrom et al., 2012; de Araujo et al., 2013). The combination of sweet taste plus an increase of dopamine accounts for the preference for natural vs artificial sweeteners (Domingos et al., 2011). We previously reported that the artificial sweetener sucralose is preferred to sucrose only if supplemented by a proxy for this post-ingestive reward in the form of optogenetic activation of DA neurons (Domingos et al., 2011). However, the elements of the neural circuit that convey the post-ingestive rewarding effect of sucrose and activate DA neurons are unknown.

Melanin-concentrating hormone-expressing neurons (Pmch or, MCH neurons; in accordance with previous literature [Shimada et al., 1998; Alon and Friedman, 2006; Kong et al., 2010], we adopt the later nomenclature throughout this report) in the lateral hypothalamus (LH) are glucose sensitive, and show increased activity when extracellular glucose levels increase (Burdakov et al., 2005; Kong et al., 2010). Pmch knockout and MCH neuronal ablation lead to reduced body weight, indicating a critical role of these neurons in the regulation of energy balance (Shimada et al., 1998; Whiddon and Palmiter, 2013). In addition, MCH neurons send dense projections to reward centers in the striatum and midbrain where dopaminergic neurons are located (current report). This strong anatomical connection between MCH neurons and reward nuclei, as well as the fact that MCH neurons sense glucose levels, led us to hypothesize that these hypothalamic neurons could play a role in conveying the reward value of sucrose.

We first tested whether optogenetic activation of MCH neurons could alter an animal’s preference for sucrose vs sucralose using a BAC transgenic Pmch-CRE mouse line that we generated (see ‘Materials and methods’). Pmch-CRE mice were crossed to the channelrhodopsin-2 (ChR2) reporter mouse line B6;129S-Gt(ROSA)26Sortm32(CAG-COP4*H134R/EYFP)Hze/J (Madisen et al., 2012), herein abbreviated Rosa26-LSL-ChR2-YFP, to generate Pmch-ChR2 mice. We characterized Pmch-CRE mice and thus confirmed tissue- and cell-specific expression of ChR2-YFP in MCH neurons as shown (Figure 1A). The YFP signal was seen in the LH with the characteristic appearance of MCH neurons (Figure 1A), and there was a 92 ± 8% overlap of YFP and MCH. In addition, 97 ± 3% of MCH neurons expressed ChR2-YFP (Figure 1B). Whole-cell patch-clamp recordings in slice preparations confirmed light-evoked spiking at 5, 10, and 20 Hz (Figure 1C), as well as during continuous light pulses of one second (Figure 1D). The spike rate of MCH neurons was higher with light pulses of 20 Hz vs 5 Hz. Note, glucose has been shown to evoke similar high-frequency bursting of MCH neurons (see inset, Figure 1D) (Burdakov et al., 2005). We also recorded voltage responses to consecutive pulses of continuous light in order to test the capacity of these cells to resist repeated trains of light stimulation (Figure 1D). Spike attenuation (Figure 1D, inset) during optogenetic stimulation was similar to what has been previously reported for glucose-triggered responses (Burdakov et al., 2005; Kong et al., 2010) in MCH neurons, and changes in membrane potential were resilient to optical stimulation (Figure 1—figure supplement 1B).

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We implanted optical fibers into the LH of Pmch-ChR2 and Pmch-CRE control mice (respectively, ChR2[+] and ChR2[–]) and assayed their preferences in a series of two-bottle choice tests (Figure 2, Figure 2—figure supplement 1 and ‘Materials and methods’). After five licks at a designated sipper, laser pulses of 5 Hz, 20 Hz, were delivered for 1 s, followed by a refractory period of another second (‘Materials and methods’ and Figure 2—figure supplement 1). ChR2(+) and ChR2(–) mice had equal preference for water+laser vs water alone at all stimulation frequencies tested (Figure 2A). We next compared an animal’s preference for sucrose vs sucralose plus optogenetic activation of MCH neurons (see ‘Materials and methods’ for the rationale of concentrations chosen). In the absence of ChR2 (gray bars in Figure 2) or at a low stimulation frequency of 5 Hz (Figure 2A), animals still preferred sucrose to sucralose. However, consistent with the greater effect of 20 Hz on spiking of MCH neurons in slice preparation, a light frequency of 20 Hz, as well as continuous light, inverted an animal’s preference with a strong preference for sucralose plus MCH activation relative to sucrose (Figure 2B, Figure 2—figure supplement 2). At 20 Hz, ChR2(–) mice (Figure 2B, middle panel, gray bars) displayed a preference ratio for sucrose of 82.2 ± 3%, whereas ChR2(+) mice had a sucrose preference ratio of 20.0 ± 4% (Figure 2B, middle panel, blue bars). This preference ratio for sucrose is significantly lower than isopreference (p<0.0001 one sample T-test against 50%). Under continuous light, ChR2(–) mice displayed a preference ratio for sucrose of 76.7 ± 3% (Figure 2B, right panel, gray bars), whereas ChR2(+) mice displayed a preference ratio for sucrose of 26.8 ± 5% (Figure 2B, right panel, blue bars). This preference ratio for sucrose is significantly lower than isopreference (p<0.0007 one sample T-test against 50%).

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The post-ingestive rewarding effect of glucose is associated with an increase of DA release in the striatum (de Araujo et al., 2013; de Araujo et al., 2008; de Araujo et al., 2010; Ren et al., 2010), and we confirmed that MCH neurons densely innervate the striatum and the ventral midbrain, making synapses onto DA neurons (Figure 3—figure supplement 1, ‘Materials and methods’). We thus tested whether the inversion of preference to sucralose by activating MCH neurons was correlated with increases in striatal DA release as measured by microdialysis in ChR2(+) mice (de Araujo et al., 2008; de Araujo et al., 2013) (Figure 3A). After signal stabilization, samples were collected during a 30-min period when the animals had access to sucralose (Figure 3A,B). As previously reported, animals drinking sucralose (without light stimulation) displayed negligible changes in striatal DA levels (Figure 3B). Animals drinking sucralose when the laser was set to OFF displayed an overall 8.2 ± 2.6% change from baseline DA (average across all S1–S5 samples); this change was not significantly different from baseline (gray bars in Figure 3E p>0.05, one sample T-test against 100% baseline). However, when sucralose ingestion was coupled to laser stimulation of MCH neurons, DA release significantly increased in the striatum (**p<0.008; Figure 3C–G, blue bars). When laser was set to ON during ingestion of sucralose, DA levels increased 68.7 ± 9% vs baseline DA (average across all S1–S5 samples, blue bars in Figure 3E). This increase is not only significantly different from baseline and the OFF condition, but is also significantly different from DA release after experimenter-controlled (i.e., direct) delivery of laser pulses, in the absence of sucralose ingestion (light blue bar in Figure 2E, ****p<5.7e10⁻⁷, t-test, with Bonferroni correction for multiple comparisons). Each animal received the same number of pulses as the number of laser pulses during ingestion of sucralose in the ON condition (Figure 3E). Mice used in condition laser-ON were the same as in condition laser-OFF. Optogenetic activation of MCH neurons markedly increased sucralose ingestion during the laser ON condition (*p<0.05; Figure 3F) while activation of MCH neurons did not change intake of water (Figure 2—figure supplement 2). As mentioned above, optogenetic stimulation of MCH neurons paired to water was not preferred to water alone, showing that activation of MCH neurons is not rewarding in the absence of sucralose. Thus, both MCH activation and the presence of sucralose were required to establish a change of preference.

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We next tested whether a loss of MCH neurons decreased DA release during sucrose intake. We crossed Pmch-CRE mice to C57BL/6-Gt(ROSA)26Sortm1(HBEGF)Awai/J, (Buch et al., 2005) herein abbreviated Rosa26-LSL-DTR, to generate Pmch-CRE;LSL-DTR mice that specifically express the diphtheria toxin receptor (DTR) in MCH neurons (Figure 4). We injected Pmch-CRE;LSL-DTR mice with diphtheria toxin (+DT) or vehicle (+veh) intracranially (1 ng/g of body weight). This dose led to a complete loss of MCH neurons (Figure 4A, see Figure 4—figure supplement 1 for other doses). MCH-ablated (Pmch-CRE-LSL-DTR+DT) and control mice (Pmch-CRE-LSL-DTR+veh, and LSL-DTR+DT) were subjected to microdialysis sampling of striatal DA during sucrose ingestion (Figure 4B). Control mice drinking sucrose displayed significantly higher dopamine levels compared to MCH-ablated mice (Figure 4C–F; **p<0.008 ANOVA in Figure 4E). Control mice showed an overall 118.3 ± 0.3% increase in striatal DA levels while drinking sucrose (average across all S1–5 samples, Figure 4F, ***p<1.98e10⁻⁹ T-test). The increase of DA levels was significantly above those at baseline (p<0.0018, one sample T-test compared to 100% baseline). In contrast to animals without DT injection, MCH-ablated mice showed a negligible DA efflux during sucrose intake, and the levels after sucrose exposure did not differ from baseline levels (p>0.4, one sample T-test compared to 100% baseline). Baseline DA levels were similar in both groups (Figure 4, Figure 4—figure supplement 2A). Consistent with a lower reward value of sucrose, when given free access to sucrose or water, MCH-ablated mice consumed significantly less sucrose than control mice (Figure 4G, *p<0.05 ANOVA), while water intake was equivalent between the groups (Figure 4, Figure 4—figure supplement 2B).

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MCH-ablated and control mice were also given a series of choices sequentially with studies of (A) sucrose vs sucralose, (B) sucrose vs water, (C) sucralose vs water (Figure 5A–C), and preference ratios for each comparison were computed. Preference ratios for sucrose in Pmch-CRE;LSL-DTR(+veh), LSL-DTR(+DT) and Pmch-CRE;LSL-DTR(+DT) mice were, respectively, 77.1 ± 7%, 82.0 ± 4%, and 39.9 ± 5%. While control mice preferred sucrose to sucralose, MCH-ablated mice no longer had a preference for sucrose. This reduction in sucrose preference is statistically significant (Figure 5A, *p<0.0012, ^¥p<0.009, T-test with Bonferroni correction for multiple comparisons, same-symbol pairs indicate statistically significant differences; see also Figure 5—figure supplement 1 for total licks in each). However, MCH neuronal ablation did not alter an animal’s preference for either sucrose or sucralose vs water indicating that, in contrast to their requirement for establishing the post-ingestive effect of sucrose, MCH neurons are not required for establishing a preference for sweet taste (Figure 5B,C and Figure 5—figure supplement 1). The postprandial increase in blood glucose after sucrose ingestion was normal in MCH-ablated animals (Figure 5 and Figure 5—figure supplement 2), demonstrating that the changes in sucrose preference were not a result of any differences in blood glucose levels (Kong et al., 2010). Altogether, these data indicate that activation of MCH neurons are necessary and sufficient for establishing the preference of animals for sucrose compared to artificial sweeteners.

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Finally, to confirm that MCH neurons are required for the post-ingestive rewarding effect of sugar even in the absence of sweet taste, we tested whether sucrose could condition preference in sweet-blind Trpm5^–/– mice lacking MCH neurons (Figure 5D, de Araujo et al., 2008). Sweet-blind control mice showed a significant side bias towards the side where sucrose was placed during the conditioning sessions, in which sucrose or sucralose are delivered at opposite sides on alternate days, (Figure 5D). In contrast, sweet-blind MCH-ablated mice did not show a preference in this conditioning protocol, indicating that the post-ingestive rewarding effect of sucrose had been lost. Trpm5^–/– Pmch-CRE;LSL-DTR+veh and Trpm5^–/–LSL-DTR+DT control mice showed conditioned side preferences of 70 ± 3% and 79 ± 5% respectively, towards the side where sucrose was placed. Trpm5^–/– Pmch-CRE;-LSL-DTR(+DT) mice had 50 ± 7% conditioned side preference towards the side where sucrose was placed. This reduction in sucrose conditioning was statistically significant from that of controls (Figure 5D, *p<0.045, ^¥p<0.099, T-test with Bonferroni correction for multiple comparisons, same-symbol pairs indicate statistically significant differences). Finally, the behavioral conditioning by the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5^–/– mice positively correlates with the extent of DA neuron activation, as assayed by staining for cFos in DA neurons in the ventral tegmental area (VTA) (Figure 5, Figure 5—figure supplement 2). These data confirm that MCH neurons are required for sensing the nutrient value of sucrose in the absence of taste.

In this manuscript, we report that MCH neurons are necessary and sufficient for establishing a preference for sucrose vs sucralose, an artificial sweetener. MCH neurons serve as an essential link between glucose sensing and sugar reward, and these data thus identify a key component of the neural circuit that establishes the preference for natural vs artificial sweeteners (Smiciklas-Wright et al., 2002; Jacobson, 2005; Domingos et al., 2011; Sicher, 2011).

MCH neurons have previously been shown to be excited by glucose (Burdakov et al., 2005; Kong et al., 2010), suggesting that direct glucose sensing by these neurons regulates reward. However, it is also possible that glucose is sensed elsewhere, such as by putative gastric/intestinal sensors or other nutrient sensors, which inform the brain and MCH neurons about the nutrient content of ingested food (Sclafani et al., 2011). Glucose sensing in MCH neurons or elsewhere would explain why, even in the absence of taste (such as in Trpm5^–/– mice), sucrose is able to drive significant increase of striatal DA. This increase, in turn, conveys reward and conditions behavior (de Araujo et al., 2008). We note, however, that optogenetic stimulation of MCH neurons alone is not sufficient to alter behavior in the absence of taste. The data thus suggest that MCH neurons are components of a reward-encoding network that integrates information from multiple sources, including the nutrients themselves, lingual taste buds and, possibly, other sites of glucose sensing like the gut. Consistent with this possibility, viral tracing from lingual taste buds shows that MCH neurons are part of a circuit processing gustatory information (Pérez et al., 2011). This finding is also consistent with the optogenetic data reported here, showing a requirement for both sweet taste and activation of MCH neurons to drive reward. The role of MCH neurons uncovered here contrasts with that of DA neurons, which upon optogenetic stimulation have been shown to be rewarding when paired to water (Domingos et al., 2011).

A synergy between taste and the post-ingestive rewarding effect would explain why sucrose and other fructose/glucose disaccharides, which are more potent stimulators of sweet-taste receptors than glucose alone, are generally preferred to glucose alone (Sclafani and Mann, 1987; Nelson et al., 2001). This synergy would also explain why our optogenetic gain of function experiments lead to an inversion of preference, rather than an isopreference, which could perhaps have been achieved by decreasing the concentration of sucralose. Likewise, the loss of function of MCH neurons leads to isopreference, but this could perhaps be biased toward sucralose by increasing its concentration. Further studies will be necessary to establish the relevant sites of glucose sensing, identify additional elements of the neural circuit integrating gustatory perception with nutrient sensing and reward, as well as elucidating the neural mechanisms by which MCH neurons regulate striatal DA release. Several methods including viral tracing can be used to identify monosynaptic or polysynaptic inputs onto MCH and DA neurons.

As mentioned, the activity of MCH neurons is increased by glucose (Burdakov et al., 2005). Glucose-activated MCH neurons and pancreatic β cells share signal transduction components necessary for glucose sensing, and both Kir6.2 and UCP2 regulate glucose excitability of MCH neurons (Kong et al., 2010). Moreover, a loss of function of Kir6.1 in MCH neurons leads to alterations in results of a glucose tolerance test with increased plasma glucose at later times, establishing a role for these neurons in glucose homeostasis (Kong et al., 2010). Further studies are required to establish whether these or other components of glucose sensing pathways are also required for the ability of MCH neurons to influence sucrose preference. It is possible, however, that additional neural populations are components of this nutrient sensing circuit. For example, orexin/hypocretin-containing neurons can also sense glucose and it is thus possible that these or other neural populations in the mesolimbic system, or higher order centers can also influence the reward value of sugar (Burdakov et al., 2005; Karnani and Burdakov, 2011).

Previous reports have also explored the relationship between MCH neurons and reward: both MCH knockout and MCH ablated mice show augmented locomotor responses to psychostimulant drugs (Pissios et al., 2008; Whiddon and Palmiter, 2013). These augmented locomotor phenotypes contrast with the behavioral effect we see with a loss of sucrose preference in MCH ablated mice. It is possible that the locomotor phenotypes in response to stimulants result from actions in the ventral striatum, where the MCH receptor (MCHR-1) is expressed, and that sucrose preference relies on other brain areas. Further experiments will be required to ascertain which brain areas and MCH projections are relevant for sucrose preference. Loss of function of MCHR-1 recreates the locomotor phenotypes seen in Pmch^−/− mice: Mchr1^−/− mice are super-sensitive to the locomotor activating effects of d-amphetamine (Smith et al., 2005). These studies do not establish whether it is MCH or another neurotransmitter expressed in these neurons that is responsible for the observed phenotypes, and further experiments will also be required to ascertain whether the MCH neuropeptide itself is relevant for sucrose preference.

We assayed dopamine release using microdialysis to show that MCH neural activation increases dopamine release in the striatum and that the increase of dopamine in response to sucrose is lost after ablation of MCH neurons. Consistent with this, the levels of cFos in dopaminergic neurons of the VTA are reduced in MCH-ablated, sweet-blind Trpm5 KO mice given sucrose. These assays of taste-blind mice confirm that MCH neurons regulate the activity of dopaminergic neurons, though the data do not establish whether this effect of dopaminergic neural activity and dopamine release is direct and/or indirect. Further studies will be necessary to establish how MCH neurons regulate dopaminergic signaling. The delineation of this neural circuit may also provide a basis for understanding how leptin modulates reward (Domingos et al., 2011). The effects of leptin on reward are unlikely to be a result of a direct effect on MCH neurons as they do not appear to express the leptin receptor (Leinninger et al., 2011). However, a distinct neural population in the LH expressing neurotensin respond to leptin, and further studies may reveal whether or not leptin reduces MCH activity indirectly by activating these cells (Leinninger et al., 2011). Ablation of MCH neurons attenuates the obese phenotype of leptin deficient ob/ob mice indicating that MCH neurons are downstream of leptin action (Alon and Friedman, 2006).

Ablation of MCH neurons causes hypophagia and leanness, and it is possible that the reduced food intake is a result of a loss of the reward value of nutrient in these animals (Alon and Friedman, 2006). The reward value of sugar is also regulated by leptin, which has been recently reported to have a presynaptic action to suppress excitatory synaptic input onto VTA DA neurons (Domingos et al., 2011; Thompson and Borgland, 2013). Further studies will reveal whether leptin modulates excitatory output to the VTA via MCH neurons or influences nutrient preference by a direct effect on DA neurons in the VTA. The importance of brain nutrient sensing for behavior has also been studied in Drosophila (Dus et al., 2011, 2013; Miyamoto et al., 2012, 2013). Future studies will likely elucidate the extent to which the cellular mechanisms and neural pathways that regulate nutrient preference are shared between invertebrates and mammals. Brain nutrient sensing may represent an evolutionary adaptation to avoid starvation, by expediting decisions about which foods to consume.

In summary, these results confirm that MCH neurons are both necessary and sufficient for sensing the nutrient value of sucrose and suggest that these neurons play a critical role in establishing nutrient preference. The market share of sugared soda is nearly triple that of diet soda (Smiciklas-Wright et al., 2002; Jacobson, 2005; Sicher, 2011), and our data suggest a biological approach to potentially regulate sugar consumption. This could be achieved via the development of means for suppressing the activity MCH neurons, or via the development of new artificial sweeteners with neuroexcitatory activity specific to MCH neurons.

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Author details

1. Ana I Domingos

   Laboratory of Molecular Genetics, The Rockefeller University, New York, United States

   Present address

   Obesity Laboratory, The Gulbenkian Science Institute, Oeiras, Portugal

   Contribution

   AID, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   For correspondence

   dominan@igc.gulbenkian.pt

   Competing interests

   The authors declare that no competing interests exist.

2. Aylesse Sordillo

   Laboratory of Molecular Genetics, The Rockefeller University, New York, United States

   Contribution

   AS, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Marcelo O Dietrich

   1. Section of Comparative Medicine, Yale University, New Haven, United States
   2. Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

   Contribution

   MOD, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Zhong-Wu Liu

   Section of Comparative Medicine, Yale University, New Haven, United States

   Contribution

   Z-WL, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Luis A Tellez

   1. Feeding Laboratory, The JB Pierce Laboratory, New Haven, United States
   2. Department of Psychiatry, Yale University School of Medicine, New Haven, United States

   Contribution

   LAT, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Jake Vaynshteyn

   Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

   Contribution

   JV, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

7. Jozelia G Ferreira

   1. Feeding Laboratory, The JB Pierce Laboratory, New Haven, United States
   2. Department of Psychiatry, Yale University School of Medicine, New Haven, United States

   Contribution

   JGF, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

8. Mats I Ekstrand

   Laboratory of Molecular Genetics, The Rockefeller University, New York, United States

   Contribution

   MIE, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

9. Tamas L Horvath

   Section of Comparative Medicine, Yale University, New Haven, United States

   Contribution

   TLH, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

10. Ivan E de Araujo

    1. Feeding Laboratory, The JB Pierce Laboratory, New Haven, United States
    2. Department of Psychiatry, Yale University School of Medicine, New Haven, United States

    Contribution

    IEA, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

11. Jeffrey M Friedman

    1. Laboratory of Molecular Genetics, The Rockefeller University, New York, United States
    2. Howard Hughes Medical Institute, The Rockefeller University, New York, United States

    Contribution

    JMF, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    friedj@rockefeller.edu

    Competing interests

    The authors declare that no competing interests exist.

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