Updated: Jul 26, 2018
Good news: the upswinging trend of obesity in the past 50 years may not be entirely our fault. It turns out that our brain may very well have multiple types of hunger, and as the world gets quicker, flashier, and more stressful around us, our brains may be stimulated in ways that make us want to eat more. Ryan Cassidy is an Md/PhD candidate in the lab of Qingchun Tong, PhD who is housed at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, and he studies the physical circuitry of the hypothalamus as it relates to what we eat. Ryan thinks that there are clearly defined connections in this small, ancient part of the brain that connect hunger to how we feel emotionally, and he uses mice as model to discover them.
When we talk about the hypothalamus, we’re really getting into the most basic parts of the brain. Together with the brain stem, the hypothalamus is commonly called the ‘lizard brain’, which is meant to insinuate that the functions of it are basic and primal, and not that lizards are lesser animals (it’s not personal, lizard lovers). This brain section responds directly to stimulation. See food, eat food. There are no conversations about whether the food may want to be eaten, or whether we’re watching our weight, or whether it’s really the right season for melon. This almond-sized part of our brain only cares about survival.
Let’s focus on two small parts of the hypothalamus, the arcuate nucleus and the lateral hypothalamic area. When mice are stimulated in the arcuate nucleus they have an aggressive hunger. This hunger is the kind that animals who are at the brink of starvation have, where everything around you looks like a turkey dinner, and you’re willing to put your life on the line and fight for some scraps. As you can imagine, these are not happy mice. On the other end, when the lateral hypothalamus is stimulated, these mice are the giggly teenagers who come home suspiciously extra-hungry in the middle of the day. The anxiety and manic eating is gone, the mice seek out this stimulation, and they seem to actually enjoy it. One big difference between these two is that the lateral hypothalamus is not accessible by the blood, but the arcuate nucleus is. This means that the arcuate nucleus can be signaled directly by things like low glucose, which cause the stomach to create a messenger molecule called ghrelin, which stimulates hunger. However, hunger is a really complicated sensation, because lots of things can cause us to feel hungry. Things like nausea, smells, visuals, and even our own stomach twisting around in our bellies. The Tong lab is trying to figure out all the roads that the signal of hunger may take and what each path means as to how we feel.
To really see what’s happening in the brain, the researchers use an amazing technique called optogenetics. We’ve all heard the phrase ‘the brain lit up’ before, right? Optogenetics is a roundabout way of externally causing this ‘lighting up’, by using genetic tools to manually control brain sections . To start, scientists identify and select the neurons in the brain that they want to study. Surprisingly, the tool of the trade for optogeneticists is viruses. Viruses are actually similar to your favorite juice-filled gummy candy. Harder outer shell, delicious goodness inside. Only here, the innards are something called channelrhodopsin, and the viruses are squirting it into the cells that the scientists want to look at. Channelrhodopsin is sensitive to certain laser light, and when it’s in a neuron cell that is shot by the laser, channelrhodopsin acts like a switch that turns that specific neuron ‘on’. Since researchers can now activate the specific section of interest at will, it is super easy to use light to study the effects that that section has on the whole body. Remember when we said earlier that the mice seemed to enjoy lateral stimulation over arcuate? You probably thought to yourself “Well gee, I wonder how they knew what the mice were thinking. Did they ask them? Maybe there were tiny mouse score cards they could use to rate it?” Not in this study, but as mice get smarter maybe there will be in the future. What the researchers did use was pretty simple, though. They rigged up a box so that on one side, the lasers would activate the brain sections with channelrhodopsin, and on the other side they would not. Then the mice were free to do as they please. Dr. Tong was kind enough to supply a video of what this experiment looks like:
[video coming soon]
In the video, we see a selective activation of the lateral hypothalamus projections into the forebrain. The basal forebrain normally increases alertness and anxiety, but when the lateral hypothalamus is activated and sends signals, it inhibits the anxiety and causes feeding. A normal mouse is very skittish in a new environment, sticking close to the safety of the walls. In this video, we can see how relaxed and open the mouse seems to be, and how he can’t seem to get the food in his face fast enough. This is indicative of lateral area stimulation.
Ryan hopes that mapping hunger centers in the brain will drive the development of drugs and behavioral therapies specifically targeting those areas. If we learn the brains coding, we can hijack and rewrite it to control the emotions and sensations that we feel. In the past, there were cases of medicines brought to trial testing that tried to target the brain to combat obesity and anxiety. A drug called rimonabant works by interacting with the same brain receptors that marijuana does, cannabinoid receptor 1, but with the opposite mechanism. Rimonabant was incredibly effective at reducing appetite, but also induced depression and a significant increase in suicide in its users and was pulled off the market by the FDA. On the opposite end of the spectrum is a drug called olanzapine. Olanzapine users saw great efficacy in treating their depression and psychosis, but with the drawback of being reliably upgraded from normal to overweight in 12 weeks time. Hunger and mood seem to have this complex connection that sits at the heart of the Tong lab’s studies. By fleshing out this relationship, Ryan envisions discovering a medicinal therapy that specifically targets the hypothalamus sections of interest without the broad range of negative side effects that we see from so many modern prescriptions.
One benefit about working with the lizard brain is that it is far more ancient and hence different than our higher order, more advanced brain parts, the parts that separate us from the iguanas-this makes it easy to target specifically without affecting mental function. This difference reduces what is called pleiotropic effects, which are the proverbial dominoes falling in every direction when you alter the one in the middle. Pleiotropic effects are what happens when you tinker with a small part of a complex system and other parts are affected, such as the cases of the drugs above. With hypothalamic targeting, we shouldn’t have to worry about weight loss medications that somehow cause depression or vice-versa. These medications will be a much safer, cleaner alternative to the common methods used today to combat obesity, which are things like cutting people open to suck out their fat and chopping up their stomachs into smaller parts. Compared to that, viruses and lasers in the brain sounds pretty good now, huh.