How the Brain Balances Excitation and Inhibition

Neuroscientists are working to uncover how these two classes of cells work — and specifically, how they interact with a rarer third category of cells that influence their behavior. These insights could eventually help reveal how to restabilize networks that get out of balance, which can even occur as a result of normal aging. 

Balance Is Key

Excitatory and inhibitory neurons work in similar ways. Most release chemical messengers known as neurotransmitters, which travel across the tiny gaps known as synapses and dock onto cuplike proteins called receptors on the next neuron. What distinguishes excitatory and inhibitory neurons is the type of neurotransmitters they release.

Excitatory neurons in the brain almost exclusively release glutamate when they activate, or fire. Glutamate triggers a bunch of positive ions to flood into a neuron, increasing its internal voltage and spurring it to fire an action potential, a strong burst of electricity that travels down a nerve fiber and makes the neuron release its own set of molecules to communicate with others, and so on.

In contrast, when inhibitory neurons fire, they release a neurotransmitter known as GABA that triggers negatively charged ions to flood into the neighboring neuron or positively charged ions to flood out. With a lower internal voltage, the next neuron won’t fire. Inhibitory neurons “function as sort of a breaker,” said Tomasz Nowakowski, a neuroscientist at the University of California, San Francisco.

These stops and gos enable a highway system in the brain, ensuring that the signals end up in the correct places at the correct times, so that you can grab the apple on your desk, hum your favorite tune or remember where you left your phone.

In the mammalian cortex, excitatory neurons vastly outnumber inhibitory ones. But throughout mammalian brain evolution, inhibitory neurons have diversified and increased in quantity, suggesting that they play critical roles in higher-order functioning.

Inhibitory neurons have “often been ascribed support roles,” said Annabelle Singer, a neuroscientist and neuroengineer at the Georgia Institute of Technology and Emory University. That’s likely because it’s simply easier to study excitatory neurons. For example, an excitatory place cell in the hippocampus can fire when an animal is in a particular location. When this happens, its excitation of other cells can be observed. “It’s very clear-cut,” she said. But an inhibitory neuron “fires a lot everywhere, and it’s much harder to say what is it responding to,” she said. We don’t know what signal it is inhibiting, and the cells connected to it don’t respond with firing of their own.

Still, studies are starting to illuminate how and when inhibitory neurons fire. In a recent study published in Nature, Singer and her colleagues found that inhibitory neurons help mice learn rapidly and remember where to find food by selectively decreasing how much they fire when the animal is near a location where food can be found. By firing less frequently as the mouse approaches the location, inhibitory neurons enhance the desired signals, thereby “enabling this learning about the important location,” Singer said. This suggests that they play a much more active role in memory than previously thought.

What’s more, the prevalent view of inhibitory neurons once cast them as more generalist in their activity, doing this kind of “blanket-y inhibition, inhibiting everything that is around their axons,” said Nuno Maçarico da Costa, a neuroscientist at the Allen Institute. But da Costa and his team, as part of the Microns project, a large-scale effort to fully map out a 1-cubic-millimeter portion of a mouse’s visual cortex, discovered that inhibitory neurons are very specific in choosing what cells to inhibit.

The brain’s circuits are all built from a mixture of inhibitory and excitatory cells conversing in diverse ways. For example, some inhibitory cells prefer to send signals to another neuron’s little branches called dendrites, while others send signals to a neuron’s cell body. Others tag team to inhibit certain other cells. These different moving parts weave together, through mechanisms not entirely understood, to create our reactions, thoughts, memories and consciousness.

But neurons communicate thousands of times faster than the cognitive effects they generate, transmitting signals in tens of milliseconds or less. “Neurotransmitters work really fast, but a lot of the behavioral and cognitive components that we need are really slow,” Cembrowski said. This apparent mismatch is “one of the central and great mysteries of the brain.”

A Third Category

Another category of cells might help to resolve this timing issue.

Neuromodulatory neurons, which are much rarer in the brain, work on slower timescales, but their effects last much longer and are much more widespread. Rather than sending molecules across a synapse exclusively to the next neuron, they can spill their molecules — a subset of neurotransmitters called neuromodulators — into an entire area, where they interact with many different synapses. The molecules they release, such as dopamine or serotonin, lead to changes within excitatory or inhibitory neurons, making them more or less likely to fire. They create “a slow undercurrent of signaling that imparts important changes in the fast dynamics of the brain,” Cembrowski said.

For example, the neuromodulator norepinephrine plays a strong role in emotionally charged memory. When released, it helps strengthen connections between neurons that form and reinforce memory, so that they fire more often and thus “guide particularly emotional experiences into memory,” he said.

These basic identities — excitatory, inhibitory, neuromodulatory — bring some structure to the way that our various types of neurons operate, but their roles can blur. For example, some excitatory and inhibitory neurons also seem to have a neuromodulatory function built into them. A small number of neurons, especially ones related to emotion, can fire GABA and glutamate packaged together, giving them both excitatory and inhibitory properties. Some neurons can switch identities, say, from an excitatory to an inhibitory neuron, under chronic stress and other conditions.

Though much diversity exists within broad categories of neurons — as one brain cell atlas after another is showing — they all enable the rhythm of excitation and inhibition. Neuroscientists are only scratching the surface of what happens when the networks are thrown off balance, but the work could lead to more treatments to fix them, Cembrowski said. “This can make a huge difference, both in individuals’ quality of life and society as a whole.”