Zhongyan Gong ’18 and Yexin Yang ’18

What makes you crave food, your hunger? Imagine you woke up with not enough sleep and drove to your office; coincidently, a colleague brought a Starbucks vanilla latte to let you try; unexpectedly, you felt energetic and performed well at your work that day. Then, you start to buy Starbucks coffee every workday. When you go out on weekends, you see a Starbucks and cannot help getting a cup of drink even though you don’t need coffee. It is similar when we encounter food: for example, sometimes when we see a yellow M of McDonald and get some food even if we are not hungry. We are born to have the innate physiological response to food: once we smell or sees a delicious food, our internal digestive organs will secrete in response to the food. This response is heightened or taken advantage of by food company through well-shaped advertisement. It is because our appetite-drives are more complicated than simple physical responses that they can be shaped by even more abstract things in the environment, for example, the logo of a food brand alone can elicit our motivation to eat. A sign of Starbucks itself can motivate us to buy a drink even not necessarily have a drink present. That’s because we have unconsciously learned to associate the symbolic sign with food and make ‘good’ use of this association in daily life. Today we are going to introduce what does Neuroepigentics tell us about reward association formation and the cue-driven motivated behavior, and understanding the neuroscience will partially help us control our behavior.


Studies in Neuroepigenetics focus on how gene expression changes in the brain in response to the environment. The neuroepigenetic regulation has two candidates: DNA and histones (the proteins where the DNA strings wrap on). Both candidates can be labeled by two markers: “acetyl” tag or “methyl” tag, which are embedded with instructions. Using an analogy from the previous podcast (Mark and Aditya), the acetyl- and methyl-tags are like the traffic lights, where acetyl-tags are green lights and methyl-tags are red lights, respectively, turn on or off DNA expression in specified time and place (Figure 1). Thus, the amount of tags could reveal the expression level of the target gene. If one gene is modified with more methyl-tags, meaning it has a low expression level.

Methyl-tags and acetyl-tags
Figure 1 Methyl-tags and acetyl-tags help in dynamically controlling gene expression.

Pavlov’s Dog

Before going further to introduce the exact changes in the brain, let’s have a glance at how scientists started to explore the associative learning by the classic Pavlovian Dog experiment to understand the meaning of this association in terms of the feeding behavior. As in common, when a dog sees the food (reward), the reward elicits a natural biological response – salivation. But when a dog hears a bell sound (cue), the unpaired cue will not generate any behavioral response. In the experiment, the Russian physiologist Ivan Pavlov trained his dog by repeatedly presenting a bell sound (cue) with food serving, and he unexpectedly found that, by the end of training, ringing the bell alone can trigger the dog to salivate. Pavlov concluded that his dog learned to associate the bell cue with the food reward. In fact, this learning process occurs subconsciously, and it’s evolutionary beneficial because it prepares our internal organs for the coming food by the time the cue appears, which can facilitate the feeding process. Similarly, we always subconsciously associate the brand, either the word or the picture of a brand, with their products through continuous experiencing and pairing. Therefore, a “two-tailed mermaid” (Starbucks) becomes such a strong conditioned cue which triggers our appetite and then makes us motivated to get coffee. With this background, would there be something change in the brain during this kind of cue-induced reward craving after associative learning process?

Neuroepigenetics in Reward Pathway

Though human behaviors are complicated, by studying rats, we could dissect the motivated behavior elicited after associative-learning using different methods. From the brain’s point of view, one of the pathways involved in mediating reward-learning and eliciting motivation to crave reward is the meso-cortico-limbic dopamine system. We are interested in the neurons in the Ventral Tegmental Area (VTA) releasing dopamine to the neurons in the Nucleus Accumbens (NAc), because these two parts mediating your subconscious motivated behavior for reward. One study by Jeremy J. Day et. al. (2013) found the DNA methyl-tag in the brain region sending out dopamine (the VTA) is required for forming the association between reward and cues. However, the precise meaning of these methyl-tag changes needs further exploration. Studies in other brain regions of the reward pathway provide more spotlights on craving in addition to just learning the association: while everyone learn the association between the reward and cues, why a portion of individuals are more compulsive to get rewards when seeing cues?

Dopamine is the key neural currency mediating food craving. For dopamine to effectively signal to another brain cell, it needs to bind to its receptor. Imagine that one lives in the Ventral Tegmental Area, and the receptor is the telephone at the other end of the line in the Nucleus Accumbens, calling transmits dopamine signal. Without the dopamine receptor, the call cannot be answered. Scientists also interested in the changes in expression of the Dopamine Receptors because its amount contributes to the motivation when seeing the reward cue. Particularly, scientists have focused on how different amounts of the Dopamine 2 receptor, one of the molecules that receive the reward signal, change in different people how that, in turn, affect reward (e.g., food and drug) seeking.

Food and drugs are both powerful and rewarding, and that is because similar parts of the brain, those involved in reward and motivation – including the dopamine signaling I wrote about earlier- respond to food and drugs in a similar way (Volkow, Wang, Tomasi, & Baler, 2012). One study by Flagel et al. (2016) added more neuroepigenetic evidence using drug study in cue-induced cocaine-seeking. They found rats with more methyl-tag – the red light – in the region controlling Dopamine 2 receptor gene expression (promoter region) in the reward pathway (Nucleus Accumbens) showed more robust cue-induced drug-seeking behavior. This reveals that the genetic predisposition matters. Another study (Johnson & Kenny, 2010) showed that the food environment could change the levels of Dopamine 2 receptor in the brain. This study showed that the low levels of Dopamine 2 receptor could induce compulsive food seeking and that remarkable levels of this molecule were reduced by chronic access to palatable food.

neuroepigentics pathway
Figure 2 A brief illustration of neuroepigentics in the reward dopamine pathway in response to the food and paired cue.


Putting the previously discussed studies into a common situation, one possible reason for gaining weight is that I have unlimited access to fat-rich food, for example, French fries and latte. If I regularly eat them for a long period, my Dopamine 2 receptor level might be reduced. Then, I will seek more palatable food. In addition, the associated cues facilitate the food seeking. As a result, I eat more food not only because I compulsively seek food, but also because associated cues motivate me to get more food. This might be a possible situation we would experience when we respond to our diet environment. But it is not the only situation. Individuals might start with different rewarding dopamine pathways which are inherited prior to the exposure to the diet environment. There is no doubt that both genetic predisposition and diet environment contribute to our cue-induced reward-seeking.

Although the cues are emphasized in shaping behaviors, there are other factors also contribute to cue-induced motivation in reward learning, factors such as the emotional states (e.g., stress) and the knowledge of upcoming events (no eating in the bus). Is disappointing when your caffeine-control plan may be disrupted by seeing the sign of Starbucks, and this cue secretly motivates you to get a cup of coffee. However, with the knowledge of this phenomenon, it is possible that we could change the compulsive seeking by disassociating the cues or controlling ourselves. When you see a food sign, you could use your powerful mind with higher cognitive instruction signaling to the reward pathway that “do not eat extra food” and resist the desire.

1. Flagel, S. B., Chaudhury, S., Waselus, M., Kelly, R., Sewani, S., Clinton, S. M., . . . Akil, H. (2016). Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model. Proceedings of the National Academy of Sciences, 113(20), E2861.
2. Day, J. J., Childs, D., Guzman-Karlsson, M. C., Kibe, M., Moulden, J., Song, E., . . . Sweatt, J. D. (2013). DNA methylation regulates associative reward learning. Nat Neurosci, 16, 1445. doi:10.1038/nn.3504
3. Johnson, P. M., & Kenny, P. J. (2010). Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci, 13, 635+.
4. Volkow, N. D., Wang, G. J., Tomasi, D., & Baler, R. D. (2012). Obesity and addiction: neurobiological overlaps. Obesity Reviews, 14(1), 2-18. doi:10.1111/j.1467-789X.2012.01031.x
5. Vollbrecht Peter, J., Mabrouk Omar, S., Nelson Andrew, D., Kennedy Robert, T., & Ferrario Carrie, R. (2016). Pre‐existing differences and diet‐induced alterations in striatal dopamine systems of obesity‐prone rats. Obesity, 24(3), 670-677. doi:10.1002/oby.21411

Music in the show:
1. Java Jive-The Ink Spots 1999
2. Dinner Bell-They Might Be Giants 1992
3. I Can’t Help Myself (Sugar Pie, Honey Bunch)-Four Tops 1965
4. Java Jive-The Puppini Sisters 2006

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