Neuroscientist to explore how diversity of neurons supports learning and memory in mammals

Scientists have known for more than 100 years that the brain possesses many different kinds of neurons, or nerve cells. Neuroscientists like Camillo Golgi and Santiago Ramón y Cajal stained the cells with silver solution to reconstruct the shape of individual neurons, for which the pair received a Nobel Prize in 1906.

Since then, scientists have identified scores of neuron types across a wide range of animal species, said Virginia Tech neuroscientist Daniel English. Once scientists recognized these anatomical differences, they began hypothesizing about functional differences.

“For 20 years, people have tried to figure out, what does each type of neuron do based on its anatomy and its activity?” said English, assistant professor in the School of Neuroscience, part of the Virginia Tech College of Science. “How much does cell diversity really matter?”

The hypotheses that have since arisen point to the possibility that each of the brain’s 100-plus nerve cells, with its own shapes, gene expression, and connections with partner neurons, may uniquely contribute to complex mammalian behaviors like learning and memory.

Over the next decade, English aims to be the first to test those hypotheses, among inhibitory neurons of the hippocampus. With support from the Whitehall Foundation, he will explore how anatomical differences among neurons translate to differences in how they support behaviors like episodic memory — the brain’s ability to hold onto sequences of experienced events.

To do so, English’s research team will use a technology known as optogenetics to control and monitor the activity of one type of neuron at a time. Optogenetics involves manipulating neuron activity using light, to either activate or silence specific neurons. “By controlling the activity of one type of cell, which we know is different anatomically from the rest, we can see if it does or does not have a unique role in circuit activity known to support memory behaviors,” English said.

It’s the beginning of English’s broader endeavor of working his way through a group of neurons known as interneurons, or inhibitory cells, for a deeper understanding of their roles in memory.

The first cell type on English’s list: axo-axonic cells. Axo-axonic cells can be found all over the brain. Those found in the motor cortex are called chandelier cells because their axon branches resemble strings of crystal chandelier beads, while those found in the hippocampus — a key structure for memory — look more like a tangled web. They’re the ones of interest to English.

In the hippocampus, there are somewhere between 20 and 50 types of interneurons, including axo-axonic cells. Interneurons turn other cells off, English said, while excitatory cells, also known as pyramidal cells, turn other cells on. The roles of these two cell types are interconnected: Pyramidal cells are responsible for telling each part of the brain what another part is doing, English added, while the pattern and level of their activity is controlled by the inhibitory cells that are intertwined with them in the same circuit. Much of mammalian behavior relies on this dynamic of bidirectional communication between the two types of neurons.

As inhibitory cells, axo-axonic cells are thought to be important for daily function and consciousness, specifically episodic memory, which allows us to remember sequences of places we’ve been and things we’ve done. It allows you, for instance, to make a cognitive map of the buildings you remember to have passed on your way to work. “Those neurons are also supporting the fact that I remembered that I walked my dog this morning, then I left the house, and then I dropped my son at school,” English said. “It’s sequences of places or experiences.”

English is particularly interested in axo-axonic cells’ role as the “final arbiter of the output of pyramidal cells.” This cell type may have the strongest effect on excitatory cell activity. “They’re the only neuron that has veto power,” English said. “All the other interneurons inhibit different parts of the cell and influence the probability of the cell firing, but don’t make a final decision.”

For English, axo-axonic cells are just the first in a long list of neurons to study. “We’re starting with one type of neuron that we know has a lot of roles in both pathological and normal brain states,” he said. “The goal is to ultimately understand what the job is for all 20 neurons.”