Insatiable

A glimpse into the neural circuitry of hunger and feeding.

Imagine your favourite food. Think about its texture, how it looks on a plate, its colour. Is it warm or cold? Does the smell and taste of it conjure memories of places or people you love?

None of these qualities have anything to do with the most basic and essential function of food, which is to give us the nutrients our bodies can’t make along with enough energy to get through a day. But the sensory components of a meal are arguably just as essential.

There’s a reason food is front and centre at holiday gatherings, birthday parties, weddings, and wakes. Feeding each other makes us feel good, and it brings us closer to each other. And I know that at my saddest or most stressed, I don’t reach for celery sticks or kale salad. I usually want what I know is “bad” for me — chocolate and French fries are special weaknesses — because it makes me feel better, even if I’m not especially hungry.

Mice are go-to model animals for neuroscience because they share so many things with people. The structure of their brains and the way their nerve cells fire, their genetics, and even some of their behaviours are similar enough that we can study them and make meaningful inferences about how our own brains work. But I was surprised to learn that mice also have odd little quirks that I’d always thought of as uniquely human. They stress-eat. They midnight-snack. And they love to binge on chocolate.

When our brains tell us we’re hungry, they’re ultimately seeking to restore metabolic imbalances they’ve sensed in the rest of our bodies. Typically, calorie-dense foods like fats and sugars that give us an instant energy boost are assigned a high reward value by our brains, and so we’re more motivated to seek them out.

There are dozens of factors that might cause human beings not to do this when they feel the urge to eat but since mice, (at least as far as we know) are unburdened by the social and cultural pressures that might lead to disordered eating, it’s easier to unravel the neural circuits that drive them to eat.

Most of this circuitry is thought to live in the hypothalamus, a region responsible for maintaining many of our other most essential functions like heart rate, blood pressure, and body temperature. Feeding circuits also communicate extensively with the same reward and pleasure circuits that are associated with learning and addiction.

Many different kinds of neurons and chemical messengers work together to orchestrate the complex and delicate symphony of energy homeostasis. In simple terms, homeostasis simply means balance. You can think of homeostasis among the systems of your body a little bit like a thermostat in your house. In the winter, you might set the temperature a little warmer to keep the house cosy and in the hotter summer months, you might set the thermostat a little lower to keep you cool. When you pick a “set point” for the thermostat, it senses when the temperature in the house strays too far below or above this point and switches on the heater or the air conditioning to maintain the temperature you chose. Our bodies have “set points” too — when your nutrient reserves are depleted, for example, or your body temperature spikes or drops, different groups of neurons fire off signals to encourage you to eat, sweat, or otherwise change your behaviour to keep your energy levels within a set range. AGRP neurons are just one group of nerve cells that help defend homeostasis within our bodies.

The star of the show in recent decades, however, has been the AGRP neuron. A decade ago, a group of researchers at Harvard found that turning these specific neurons on could drive a mouse to eat voraciously and to gain weight over the course of just a few days, even if he was already well-fed. The opposite was also true — turning these neurons off right around a mouse’s typical breakfast time caused them to lose interest in food entirely.

Based on these behaviours, AGRP neurons were understood as drivers of hunger and feeding. Intuitively, we think of the activation of a neuron or group of neurons as an on-switch to drive a certain behaviour, like foraging or feeding.

Since the urge to feed is so foundational for our survival, the circuits that control hunger have received a lot of attention. It is more subtle and difficult to pin down how we know when to stop eating, once we start.

It was assumed that since it was possible to manipulate hunger and feeding in such a straightforward way — it was just a matter of activating or inactivating AGRP neurons —  the animal’s activity states would also correlate in an easy-to-interpret way with how much they ate and how hard they worked to forage for food.

The results found by the researchers, however, were actually counter-intuitive.

When a mouse senses that food is nearby — either by smell or by sight — the activity of the hunger-sensitive AGRP neurons drops dramatically, and almost instantaneously. Even more interesting was that the degree to which this activity was dampened depended on how delicious the food seemed to the mouse. For things like peanut butter or chocolate, the drop in activity was even more severe than for the mouse’s standard fare.

What this was all interpreted to mean was that while these neurons sense nutritional imbalance within the body and try to drive behaviour to remedy that imbalance (say, convincing a mouse to run to the opposite side of its cage for a Hershey’s kiss), their almost immediate silencing as soon as food is located seems to be a mechanism whereby the brain tells the mouse that it can stop expending energy trying to find food, especially if it’s plentiful and highly palatable.

Essentially our brains tell us to stop feeding before we even start.

These signals don’t necessarily come solely from the environment. They also reach our brains directly from our guts. In fact, many of the chemicals responsible for telling us when it’s time to push away our plates are generated in our guts and intestines, and signal to our brains via the vagus nerve, a sort of high-speed brain-body railway that allows cues from our bodies to reach the deeper regions of our brains without a need for centralized processing in complex sensory or decision-making centers higher up.

Some of the chemicals, collectively known as “satiation factors,” such as serotonin or a protein called CCK, are released when nutrients are detected in the stomach. Others respond to mechanical forces in the stomach and small intestine. Even in a hungry mouse, for example, artificially stretching the stomach or intestine without providing food or nutrients has the same effect on a mouse’s AGRP neurons as a stockpile of chocolate would. These chemicals don’t just control whether or not we look for food. They’re capable of controlling more subtle things like the frequency of meals and portion size — the difference between snacking multiple times a day or eating a couple of large meals.

Emotions and memories play a big role in how and when we eat too, though. Mood disorders like seasonal affective disorder and major depression usually disrupt appetite, and when we’re anxious or stressed some of us snack compulsively while others feel too ill to eat at all. Perhaps because it is so essential to our survival, the proteins and neural circuits that control hunger are also powerful emotional regulators.

Serotonin is best known for its mood-elevating effects and is a common target for antidepressants — and it also helps signal to the brain that we’re full and it’s time to stop feeding. Another satiety factor, CCK, has been linked to panic attacks and anxiety.

It makes sense that our brains would feed us unpleasant emotions at times when we desperately need to remedy an energy imbalance — but unless that imbalance is life-or-death it can be difficult to identify the source of that discomfort when we’re busy or stressed or surrounded by dozens of other potential factors that could nudge us over the edge of a bad mood.

My last year of graduate school was an emotional roller coaster but I had a friend who used to stop me before I’d start sizing up the impossible enormity of my problems over coffee and ask me if I’d eaten anything that day. At first, I was a little incredulous at the question but I started to appreciate these daily check-ins when I realized how frequently the answer was “no”.

While my problems were still there and still difficult, they were easier to manage when I wasn’t constantly running on an empty stomach. I also realized that when I started to work longer hours the first thing I stopped doing to free up more time was food preparation. I’d end up snacking on whatever I could find in the cafeteria at random intervals throughout the day, but I’d taken for granted what a major mood lift it was to take an hour out of a day and cook something with people I cared about once my schedule slowed down again.

Feeding ourselves can sometimes feel like an afterthought or a chore, but hunger is one of the most powerful reminders of how impossible it is to disentangle our brains from our bodies — things we think of more as “physical” phenomena from emotional ones. As tempting as it is to think in terms of dualities, our minds and bodies both run on the same fuel.