40 THE SCIENTIST | the-scientist.com

I

n the spring of 2019, neuroscientist Heather Cameron set

up a simple experiment. She and her colleagues put an

adult rat in the middle of a plastic box with a water bottle

at one end. They waited until the rat started drinking and

then made a startling noise to see how the animal would

respond. The team did this repeatedly with regular rats and with

animals that were genetically altered so that they couldn’t make

new neurons in their hippocampuses, a brain region involved

in learning and memory. When the animals heard the noise,

those that could make new hippocampal neurons immediately

stopped slurping water and looked around, but the animals lack-

ing hippocampal neurogenesis kept drinking. When the team

ran the experiment without the water bottle, both sets of rats

looked around right away to figure out where the sound was

coming from. Rats that couldn’t make new neurons seemed to

have trouble shifting their attention from one task to another,

the researchers concluded.^1

“It’s a very surprising result,” says Cameron, who works at

the National Institute of Mental Health (NIMH) in Bethesda,

Maryland. Researchers studying neurogenesis in the adult

hippocampus typically conduct experiments in which animals

have had extensive training in a task, such as in a water maze,

or have experienced repetitive foot shocks, she explains. In her

experiments, the rats were just drinking water. “It seemed like

there would be no reason that the hippocampus should have

any role,” she says. Ye t in animals engineered to lack hippocam-

pal neurogenesis, “the effects are pretty big.”

The study joins a growing body of work that challenges

the decades-old notion that the primary role of new neurons

within the adult hippocampus is in learning and memory. More

recently, experiments have tied neurogenesis to forgetting, one

possible way to ensure the brain doesn’t become overloaded

with information it doesn’t need, and to anxiety, depression,

stress, and, as Cameron’s work suggests, attention. Now, neuro-

scientists are rethinking the role that new neurons, and the

hippocampus as a whole, play in the brain.

The memory link

The first hint that adult animal brains may make new neurons

appeared in the early 1960s, when MIT neurobiologist Joseph

Altman used radioactive labeling to track the proliferation of nerve

cells in adult rats brains.^2 Other data published in the 1970s and

1980s supported the conclusion, and in the 1990s, Fred “Rusty” Gage

and his colleagues at the Salk Institute in La Jolla, California, used

an artificial nucleotide called bromodeoxyuridine (BrdU) to tag new

neurons born in the brains of adult rats and humans.^3 Around the

same time, Elizabeth Gould of Princeton University and her collabo-

rators showed that adult marmoset monkeys made new neurons in

their hippocampuses, specifically in an area called the dentate gyrus.^4

While some researchers questioned the strength of the evidence sup-

porting the existence of adult neurogenesis, most of the field began

to shift from studying whether adult animal brains make new neu-

rons to what role those cells might play.

In 2011, René Hen at Columbia University and colleagues creat-

ed a line of transgenic mice in which neurons generated by neuro-

genesis survived longer than in wildtype mice. This boosted the

overall numbers of new neurons in the animals’ brains. The team

then tested the modified mice’s cognitive abilities. Boosting

numbers of newly born neurons didn’t improve the mice’s perfor-

mances in water mazes or avoidance tasks compared with control

mice. But it did seem to help them distinguish between two events

that were extremely similar. Mice with more new neurons didn’t

freeze as long as normal mice when put into a box that was simi-

lar to but not exactly the same as one in which they’d experienced

a foot shock in earlier training runs.^5

These results dovetailed with others coming out at the time,

particularly those showing that aging humans, in whom neuro-

genesis is thought to decline, often have trouble remembering

details that distinguish similar experiences, what researchers call

pattern separation.6,7 “The line of thinking is that the memories

that are most likely to be impacted by neurogenesis are memories

that are really similar to each other,” says Sarah Parylak, a staff

scientist in Gage’s lab at the Salk Institute.

As insights into pattern separation emerged, scientists were

beginning to track the integration of new rodent neurons into

existing neural networks. This research showed that new neurons

born in the dentate gyrus had to compete with mature neurons

for connections to neurons in the entorhinal cortex (EC), a region

of the brain with widespread neural networks that play roles in

memory, navigation, and the perception of time.^8 (See “Memories

of Time” on page 32.) Based on detailed anatomical images, new

dentate gyrus neurons in rodents appeared to tap into preexisting

synapses between dentate gyrus neurons and EC neurons before

creating their own links to EC neurons.

To continue exploring the relationship between old and new

neurons, a group led by the Harvard Stem Cell Institute’s Amar

Sahay, who had worked with Hen on the team’s 2011 study, wiped

out synapses in the dentate gyruses of mice. The researchers over-

expressed the cell death–inducing protein Krüppel-like factor 9

in young adult, middle-aged, and old mice to destroy neuronal

dendritic spines, tiny protrusions that link up to protrusions of

other neurons, in the brain region. Those lost connections led to

increased integration of newly made neurons, especially in the

two older groups, which outperformed age-matched, untreated

mice in pattern-separation tasks.^9 Adult-born dentate gyrus neu-

rons decrease the likelihood of reactivation of those old neurons,

Sahay and colleagues concluded, preventing the memories from

being confused.

Neurogenesis appears to play a role

in both remembering and forgetting.