Long Periods of Calorie Shortage Send the Mouse Brain Into “Low-Power Mode”

A new study published in the journal Neuron suggests that long-term reductions in caloric intake send the brain into a “power-saving” mode that cuts the amount of information it transmits to consume less energy. The findings, published by researchers from the University of Edinburgh, reveal how the fuel-guzzling human brain, which is responsible for up to 20% of our body’s energy consumption despite making up only 3% of its mass, tunes itself down in energy-scarce scenarios.

This change to the brain’s activity comes at a cost. “Basically, we have found the mechanisms that explain how the brain can enter low-battery mode. You need less energy, but you also function less well,” said Prof. Nathalie Rochefort, a fellow at the University of Edinburgh’s Centre for Discovery Brain Sciences and co-author of the paper, in an interview with Technology Networks.

Visual cortex provides perfect model

 
Rochefort’s team, including first author and postdoctoral research fellow Zahid Padamsey, used the mouse visual cortex as a model to study “low-battery mode”. This area was chosen, said Rochefort, because it has been extremely well characterized in previous studies, is easy to access for imaging studies and because the input to the area – essentially whatever the mouse was viewing at any given time – could easily be controlled.

Cells across the body and brain run on a kind of energy currency called adenosine triphosphate (ATP), which can be chemically broken down or synthesized during chemical reactions in the cell. ATP’s breakdown is crucial for supplying energy to cell processes like muscle contraction. It also plays an essential role in brain communication, said Padamsey, “Whenever you're signaling or transmitting a synaptic potential, you need to restore ion gradients. That's where ATP comes in; you're constantly moving sodium and potassium ions against their electrochemical equilibrium. This is what's causing your ATP utilization. The easiest way for a neuron to save energy is to just reduce the amount of ion fluxes it experiences during synaptic signaling.”

Calorie crackdown comes at a cost

Padamsey carefully measured the electrical activity coming from the visual cortex after periods of lower calorie intake, which caused the mice to lose 15% of their baseline bodyweight. The recordings showed that, to lower the amount of ATP being used, visual neurons made changes to their electrochemical properties that had the net effect of reducing the number of ions moving in and out of the cell.

But there’s a chemical catch to this increased efficiency.

To maintain the frequency of signals coming from neurons with a lower ion count, the brain essentially amplifies the signal contributed by each ion molecule. This, however, makes the system much more sensitive, and  caused the mice’s visual neurons to signal in response to even the slightest electrical impulses. “The consequence that we see is that the cells become noisier and more variable in their ability to transmit information,” said Padamsey.

What’s the knock-on effect of this change?

The team took electrophysiological readings from visual cortex neurons that they knew should only respond when certain orientations of shapes are shown to the mice. After calorie restriction, these neurons became less focused, reacting to other shape orientations. Essentially, this change was like switching from a high-pixel density camera to a low-pixel density camera – still useful for taking pictures, but at an impaired performance level, said Rochefort.

Satiety hormone plays a role

The next question for the team was how the mice were able to respond to reduced body weight by reducing brain performance. The key, Rochefort explained, was a hormone called leptin; the body’s chief signal for “feeling full” after a meal.

“It’s secreted by fat stores in the periphery,” said Rochefort. “It’s actually amazing to see that it not only affects cortical function but also that we can trick the cortex by supplementing leptin artificially in food-restricted mice.”

When mice were supplemented with leptin, their brains switched back to regular power mode. The exact biochemical pathway that allows leptin to fire the sleepy brain back up is currently unclear. Rochefort suggests that signaling through the blood-brain barrier, leptin-sensitive neurons in the hypothalamus or regulation of other hormones produced in the thyroid could be potential routes.

If a hormone stored in fat can speed up the brain, shouldn’t the post-Christmas period be a time of immense scientific and social advancement? Not quite. “If you have too much leptin for a prolonged period of time, or you eat too many chocolate bars and increase your fat mass too much, the elevated leptin signaling triggers leptin resistance in the brain,” said Padamsey. “We don't exactly know what mechanistically happens, but we do know that the brain responds less and less to leptin input. The brain in essence thinks it's starving.”

In deducing not only the changes that occur to visual signaling in response to chronic food shortage, but also the mechanistic reasons why it happens, the team’s paper has taken significant strides in understanding how the brain performs in lean periods. But there’s far further to go.

The researchers conducted this study in male mice, but Padamsey has good reason to believe that the effect will be less impactful in females and subject to different hormonal regulations. “Females across several species are very reluctant to lose fat mass when you reduce calorie intake. With males, you adjust calorie intake, their fat mass drops, their leptin levels drop and we see all these effects. You do the same calorie restriction in the female, and they hold on to their fat mass; they tend to lose lean mass instead.” This could be due to the influence of hormones like estrogen, said Rochefort.

The team are also keen to see how other brain systems are affected by sustained calorie shortage and how leptin might affect the brain when excess eating leads to obesity.

Reference:

Padamsey Z, Katsanevaki D, Dupuy N, Rochefort NL. Neocortex saves energy by reducing coding precision during food scarcity. Neuron. 2021;0(0). doi:10.1016/j.neuron.2021.10.024