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What Do New Neurons in the Brains of Adults Actually Do?

Adult neurogenesis, already appreciated for its role in learning and memory, also participates in
mental health and possibly even attention, new research suggests.

Ashley Yeager
May 1, 2020

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 ABOVE: © ISTOCK.COM, KTSIMAGE
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 lacking hippocampal neurogenesis kept drinking. When the team ran the experiment without the
water bottle, both sets of rats looked around right away to gure out where the sound was coming from. Rats that
couldn’t make new neurons seemed to have trouble shi ing their attention from one task to another, the
researchers concluded.

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

at the National Institute of Mental Health (NIMH) in
Bethesda, Maryland. Researchers studying neurogenesis
Aging humans, in whom
in the adult hippocampus typically conduct experiments neurogenesis is thought to
in which animals have had extensive training in a task,
decline, often have trouble
such as in a water maze, or have experienced repetitive
foot shocks, she explains. In her experiments, the rats
remembering details that
were just drinking water. “It seemed like there would be distinguish similar experiences.
no reason that the hippocampus should have any role,”
she says. Yet in animals engineered to lack hippocampal
neurogenesis, “the e ects 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.
 E ect Evidence Related health conditions

Memory Most of the research into neurogenesis involves

boosting or inhibiting animals’ generation of new
neurons, then training animals on a complex
Alzheimer’s disease, Parkinson’s
memory task such as nding a treat in a maze, and
disease
later retesting the animals. Decreasing
neurogenesis tends to hamper the animals’ ability
to remember.

Forgetting Training mice or rats on a memory task before

manipulating neurogenesis has also been found to
a ect the strength of the trained memory.
Alzheimer’s disease and other
Boosting neurogenesis reduced the memory’s
forms of dementia
strength, perhaps an extreme form of forgetting
that at normal levels avoids the remembering of
unnecessary details.

Emotion
Research has linked decreased neurogenesis with
more anxious and depressive behaviors in mice.
Stress can reduce neurogenesis, ultimately leading PTSD, anxiety, depression
mice to be more anxious in future stressful
situations.

Attention

Research has linked decreased neurogenesis with

Autism
trouble switching focus.

The memory link

The rst 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. 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 arti cial nucleotide called
bromodeoxyuridine (BrdU) to tag new neurons born in the brains of adult rats and humans. Around the same
time, Elizabeth Gould of Princeton University and her collaborators showed that adult marmoset monkeys made
new neurons in their hippocampuses, speci cally in an area called the dentate gyrus. While some researchers
questioned the strength of the evidence supporting the existence of adult neurogenesis, most of the eld began to
shi from studying whether adult animal brains make new neurons to what role those cells might play.

See “Brain Gain”

In 2011, René Hen at Columbia University and colleagues created 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 modi ed mice’s cognitive abilities. Boosting
numbers of newly born neurons didn’t improve the mice’s performances 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 similar to
but not exactly the same as one in which they’d experienced a foot shock in earlier training runs.

These results dovetailed with others coming out at the time, particularly those showing that aging humans, in
whom neurogenesis is thought to decline, o en have trouble remembering details that distinguish similar
experiences, what researchers call pattern separation. “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
sta 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. (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 overexpressed 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.
Adult-born dentate gyrus neurons decrease the likelihood of reactivation of those old neurons, Sahay and
colleagues concluded, preventing the memories from being confused. 

Parylak compares this situation to going to the same restaurant a er it has changed ownership. In her
neighborhood in San Diego, there’s one location where she’s dined a few times when the restaurant was serving
di erent cuisine. It’s the same location, and the building retains many of the same features, “so the experiences
would be easy to mix up,” she says, but she can tell them apart, possibly because of neurogenesis’s role in pattern
separation. This might even hold true for going to the same restaurant on di erent occasions, even if it served the
same food.

That’s still speculative at this point. Researchers haven’t been able to watch neurogenesis in action in a living
human brain, and it’s not at all clear if the same thing is going on there as in the mouse brains they have observed.
While many scientists now agree that neurogenesis does occur in adult human brains, there is little consensus
about what it actually does. In addition to the work supporting a role for new neurons in pattern separation,
researchers have accumulated evidence that it may be more important for forgetting than it is for remembering.

How Adult-Born Neurons Integrate into the Brain

In recent years, images and videos taken with state-of-the-art microscopy techniques have shown that new
neurons in the dentate gyrus of the hippocampus go through a series of changes as they link up to existing
networks in the brain.
 A neural stem cell divides to generate a new
neuron (green).

© LISA CLARK

As the new neuron grows, it rotates from a

horizontal to a vertical position and connects
to an interneuron (yellow) in a space called
the hilus that sits within the curve of the
dentate gyrus. The young neuron also starts
making connections with well-established
dentate gyrus neurons (blue) as well as
neurons in the hippocampus (red).

© LISA CLARK

Once connections are formed, mature

neurons send signals into the new neuron,
and the cell starts ring o more of its own
signals. At around four weeks of age, the
adult-born neuron gets hyperexcited,
sending electrical signals much more o en
than its well-established neuronal neighbors
do.

© LISA CLARK
 © LISA CLARK

As the new neuron connects with still more

neurons, interneurons in the hilus start to
send it signals to tamp down its activity.

© LISA CLARK

See full infographic: WEB | PDF

The importance of forgetting

It seems counterintuitive for neurogenesis to play a role in both remembering and forgetting, but work by Paul
Frankland of the Hospital for Sick Children Research Institute in Toronto suggests it is possible. In 2014, his team
showed that when mice made more new neurons than normal, they were more forgetful. He and his colleagues
had mice run on wheels to boost levels of neurogenesis, then trained the animals on a learning task. As expected,
they did better than control mice who hadn’t exercised. (See “How Exercise Reprograms the Brain,” The Scientist,
October 2018.) In other animals, the researchers boosted neurogenesis a er the mice learned information thought
to be stored, at least in the short term, in the hippocampus. “When we did that, what we found was quite
surprising,” Frankland says. “We found a big reduction in memory strength.”

His team was puzzled by the result. Adding to the confusion, the researchers had observed a larger e ect in
memory impairment with mice that learned, then exercised, than they had seen in memory improvement when
the mice ran rst and then learned. As he dug into the literature, Frankland realized the e ect was what other
neuroscientists had called forgetting. He found many theoretical papers based on computational modeling that
argued that as new neurons integrate into a circuit, the patterns of connections in the circuit change, and if
information is stored in those patterns of connections, that information may be lost. (See “Memory Munchers” on
page 21.)

The notion surprised other neuroscientists, mainly because up to that point they’d had two assumptions related to
neurogenesis and forgetting. The rst was that generating new neurons in a normal animal should be good for
memory. The second was that forgetting was bad. The rst assumption is still true, Frankland says, but the second
is not. “Many people think of forgetting as some sort of failure in our memory systems,” he explains. Yet in healthy
brains there’s tons of forgetting happening all of the time. “And, in fact, it’s important for memory function,”
Frankland says. “It would actually be disadvantageous to remember everything we do.” 

Parylak says this idea of forgetting “certainly has

provoked a lot of discussion.” It’s unclear, for example,
whether the mice in Frankland’s experiments are
Experiments have tied
forgetting, or if they are identifying a repeat event as neurogenesis to forgetting,
something novel. This is the point, she explains, where
doing neurogenesis research in humans would be
anxiety, depression, stress, and
bene cial. “You could ask a person if they’d actually
forgotten or if they are making some kind of extreme attention.
discrimination.”

Despite the questions regarding the results, Frankland and his colleagues continued their work, testing mice’s
forgetfulness with all types of memories, and more recently they asked whether the forgetting e ect jeopardized
old and new memories alike. In experiments, his team gave mice a foot shock, then boosted hippocampal
neurogenesis (with exercise or a genetic tweak to neural progenitor cells), and put the mice in the same container
they’d been shocked in. With another group of mice, the researchers waited nearly a month a er the foot shock
before boosting neurogenesis and putting the mice back in the container. Boosting the number of new neurons,
the team found, only weakened the newly made memory, but not one that had been around for a while. “This
makes a lot of sense,” Frankland says. “As our memories of everyday events gradually get consolidated, they
become less and less dependent on the hippocampus,” and more dependent on another brain region: the cortex.
This suggests that remote memories are less sensitive to changes in hippocampal neurogenesis levels.

The hippocampus tracks what’s happened to you, Frankland says. “Much of that’s forgotten because much of it is
inconsequential. But every now and then something interesting seems to happen,” and it’s these eventful
memories that seem to get “backed up” in other areas of the brain.

How adult-born neurons function in a circuit

Researchers think neurogenesis helps the brain distinguish between two very similar objects or events, a
phenomenon called pattern separation. According to one hypothesis, new neurons’ excitability in response to
novel objects diminishes the response of established neurons in the dentate gyrus to incoming stimuli, helping
to create a separate circuit for the new, but similar, memory.

© LISA CLARK
See full infographic: WEB | PDF

Beyond memory

At NIMH, one of Cameron’s rst studies looking at the e ects of neurogenesis tested the relationship between new
neuronal growth and stress. She uncovered the connection studying mice that couldn’t make new neurons and
recording how they behaved in an open environment with food at the center. Just like mice that could still make
new neurons, the neuro-genesis-de cient mice were hesitant to go get the food in the open space, but eventually
they did. However, when the animals that couldn’t make new neurons were stressed before being put into the open
space, they were extremely cautious and anxious, whereas normal mice didn’t behave any di erently when
stressed.

Cameron realized that the generation of new neurons also plays a role in the brain separate from the learning and
memory functions for which there was growing evidence. In her experiments, “we were looking for memory
e ects and looked for quite a while without nding anything and then stumbled onto this stress e ect,” she says. 

The cells in the hippocampus are densely packed with receptors for stress hormones. One type of hormone in
particular, glucocorticoids, is thought to inhibit neurogenesis, and decreased neurogenesis has been associated
with depression and anxiety behaviors in rodents. But there wasn’t a direct link between the experience of stress
and the development of these behaviors. So Cameron and her colleagues set up an experiment to test the
connection.

When the team blocked neurogenesis in adult mice and then restrained the animals to moderately stress them,
their elevated glucocorticoid levels were slow to recover compared with mice that had normal neurogenesis. The
stressed mice that could not generate new neurons also acted oddly in behavioral tests: they avoided food when
put in a new environment, became immobile and increasingly distressed when forced to swim, and drank less
sugary water than normal mice when it was o ered to them, suggesting they don’t work as hard as normal mice to
experience pleasure. Impaired adult neurogenesis, the experiments showed, played a direct role in developing
symptoms of depression, Cameron says.

The notion that neurogenesis and stress might be tied directly to our mental states led Cameron to look back into
the literature, where she found many suggestions that the hippocampus plays a role in emotion, in addition to
learning and memory. Even Altman, who unexpectedly identi ed neurogenesis in adult rodents in the 1960s, and
colleagues suggested as much in the 1970s. Yet the argument has only appeared sporadically in the literature since
then. “Stress is complicated,” Cameron says; it’s hard to know exactly how stressful experiences a ect neurogenesis
or how the generation of new neurons will in uence an animal’s response to stress. Some types of stress can
decrease neurogenesis while others, such as certain forms of intermittent stress, can increase new neuronal
growth. Last year, Cameron and colleagues found that generating new neurons helps rats used to model post-
traumatic stress disorder recover from acute and prolonged periods of stress.

Her work has also linked neurogenesis to other

characteristics of rodent behavior, including attention
and sociability. In 2016, with Gould at Princeton and a
Neurogenesis appears to play a
few other collaborators, she published work suggesting role in both remembering and
that new neurons are indeed tied to social behavior. The
forgetting.
team created a hierarchy among rats, and then
deconstructed those social ranks by removing the
dominant male. When the researchers sacri ced the animals and counted new neurons in their brains, the rats
from deconstructed hierarchies had fewer new neurons than those from control cages with stable ranks. Rats with
uncertain hierarchies and fewer new neurons didn’t show any signs of anxiety or reduced cognition, but they
weren’t as inclined as control animals to spend time with new rats put into their quarters, preferring to stick with
the animals they knew. When given a drug—oxytocin—to boost neurogenesis, they once again began exploring
and spending time with new rats that entered their cages.

The study from Cameron’s lab on rats’ ability to shi their attention grew out of the researchers’ work on stress, in
which they observed that rodents sometimes couldn’t switch from one task to the next. Turning again to the
literature, Cameron found a study from 1969 that seemed to suggest that neurogenesis might a ect this task-
switching behavior. Her team set up the water bottle experiments to see how well rats shi ed attention. Inhibiting
neurogenesis in the adult mice led to a 50 percent decrease in their ability to switch their focus from drinking to
searching for the source of the sound.

“This paper is very interesting,” says J. Tiago Gonçalves, a neuroscientist at Albert Einstein College of Medicine in
New York who studies neurogenesis but was not involved in the study. It could explain the ndings seen in some
behavioral tasks and the incongruences between ndings from di erent behavioral tasks, he writes in an email to
The Scientist. Of course, follow-up work is needed, he adds.

Cameron argues that shi ing attention may be yet another behavior in which the hippocampus plays an essential
role but that researchers have been overlooking. And there may be an unexplored link between making new
neurons and autism or other attention disorders, she says. Children with autism o en have trouble shi ing their
attention from one image to the next in behavioral tests unless the original image is removed. 

It’s becoming clear, Cameron continues, that neurogenesis has many functions in the adult brain, some that are
very distinct from learning and memory. In tasks requiring attention, though, there is a tie to memory, she notes.
“If you’re not paying attention to things, you will not remember them.”

Do new neurons appear anywhere else in the brain?

Many, though not all, neuroscientists agree that there’s ongoing neurogenesis in the hippocampus of most
mammals, including humans. In rodents and many other animals, neurogenesis has also been observed in the
olfactory bulbs. Whether newly generated neurons show up anywhere else in the brain is more controversial. 

There had been hints of new neurons showing up in the striatum of primates in the early 2000s. In
2005, Heather Cameron of the National Institute of Mental Health and colleagues corroborated those ndings,
showing evidence of newly made neurons in the rat neocortex, a region of the brain involved in spatial
reasoning, language, movement, and cognition, and in the striatum, a region of the brain involved in planning
movements and reacting to rewards, as well as self-control and exible thinking (J Cell Biol, 168:415–27). Nearly
a decade later, using nuclear-bomb-test-derived carbon-14 isotopes to identify when nerve cells were
born, Jonas Frisén of the Karolinska Institute in Stockholm and colleagues examined the brains of postmortem
adult humans and con rmed that new neurons existed in the striatum (Cell, 156:1072–83, 2014). 

See “Isotopic Bomb Traces Are a Boon to Biological Dating”

“Those results are great,” Cameron says. They support her idea that there are di erent types of neurons being
born in the brain throughout life. “The problem is they’re very small cells, they’re very scattered, and there’re
very few of them. So they’re very tough to see and very tough to study.”

Keywords:
cell & molecular biology, forgetting, human adult neurogenesis, learning, learning and memory, memory, mouse brain, neural circuit,
neurogenesis, neuroscience, pattern separation, rodent