Every science writer loves a good challenge to dogma. I wish I had been in the working world in the spring of 1992, when one such intellectual overhaul happened in neuroscience. The dogma: Neurons, unlike most of the body’s cells, can’t be replenished. You’re born with just 100 billion of them and you better use them wisely. The challenge: Samuel Weiss and Brent Reynolds reported in Science that brain tissue taken from adult mice could be chemically coaxed into making new neurons.

“It left us speechless,” Weiss told the New York Times. Everybody else was pretty stunned, too. Over the next six years, other researchers confirmed that this so-called neurogenesis happens in the adult hippocampus of many animals, including tree shrews, marmosets, Old World monkeys and people. Today, more than two decades since the splashy Science report, adult neurogenesis is a bona fide subfield, with hundreds of labs studying it around the world.

But after all this time, researchers still don’t really know what it’s for. Studies have uncovered a wide variety of environmental stimuli — what you might think of as inputs — that affect neurogenesis in the dentate gyrus, a part of the hippocampus. Running and antidepressants can ramp up neurogenesis, for example, while stress, social isolation, sleep deprivation and aging can shut it down. Scientists have also looked at the outputs of neurogenesis, showing that a boost of new neurons may be important for exploratory behavior and certain kinds of learning, such as navigating a new space. But how do the inputs lead to the outputs?

“I like to think of the dentate as an association machine,” says Sam Pleasure, a neuroscientist at the University of California, San Francisco. All day long, he says, we’re walking around the world trying to associate various sensations and emotions — big dog with fangs, small screaming toddler, perilous traffic intersection — so that we can remember them later. “All these stimuli are happening and converge on this circuit, and they somehow affect how new neurons are recruited into the circuit, and that ends up coming out as the ability to form new memories.” But how it all works on the molecular level is a black box.

Two papers published in Cell Stem Cell [1 , 2]open that box a little bit. They identify molecular inhibitors — what Pleasure calls “wet blankets” — that turn off neurogenesis in certain contexts.

Opening the Black Box of Neurogenesis by Virginia Hughes

Homer prevents stress-induced cognitive deficits

Before examinations and in critical situations, we need to be particularly receptive and capable of learning. However, acute exam stress and stage fright causes learning blockades and reduced memory function. Scientists from the Max Planck Institute of Psychiatry in Munich have now discovered a mechanism responsible for these cognitive deficits, which functions independently of stress hormones. In animal studies, the researchers show that social stress reduces the volume of Homer-1 in the hippocampus – a region of the brain that plays a central role in learning. This specific protein deficiency leads to altered neuronal activity followed by deterioration in the animals’ learning performance. In the experiments, it was possible to prevent the cognitive deficit by administering additional volumes of the protein to the mice. This suggests that Homer-1 could provide a key molecule for the development of drugs for the treatment of stress-induced cognitive deficits.

Klaus Wagner, a scientist at the Max Planck Institute of Psychiatry, studied the learning behaviour of mice that had been subjected to severe stress. He exposed the animals to social stress – a pressure also frequently experienced by humans today. A male mouse was placed in the cage of an aggressive member of the same species for five minutes. The latter tried to banish the “intruder” by attacking it. Unlike in nature, the test mouse was unable to flee from the cage and was under severe stress, as substantiated by measurements of the stress hormones in its blood.

Following a period of eight hours in which the animal was able to recover in its own cage, its behaviour was examined. While the mouse’s motivation, activity and sensory functions were not impaired at this time, it displayed clear deficits in its learning behaviour. A single five-minute situation of social stress was sufficient, therefore, to impair the animal’s learning performance hours later.

The researchers at the Max Planck Institute then tried to establish which mechanisms were responsible for these cognitive deficits. They identified the protein Homer-1, the concentration of which declines specifically in the hippocampus after exposure to stress. Through its interaction with the neuronal messenger substance glutamate and its receptors, Homer-1 modulates the communication in the neuronal synapses. When the volume of Homer-1 in the hippocampus falls after exposure to stress, the natural receptor activity is severely disrupted and learning capacity declines. The researchers were able to prevent this effect by increasing the Homer-1 concentration again.

Mathias Schmidt, Research Group Leader at the Max Planck Institute of Psychiatry interprets the results as follows: “With our study, we demonstrated the regulation of glutamate-mediated communication in the hippocampus, which directly controls learning behaviour. This mechanism functions independently of stress hormones for the most part. The molecule Homer-1 assumes a key role in this process and will hopefully provide new possibilities in future for targeted pharmaceutical intervention for the avoidance of cognitive deficits.”

Preventing chronic pain with stress management

For chronic pain sufferers, such as people who develop back pain after a car accident, avoiding the harmful effects of stress may be key to managing their condition. This is particularly important for people with a smaller-than-average hippocampus, as these individuals seem to be particularly vulnerable to stress. These are the findings of a study by Dr. Pierre Rainville, PhD in Neuropsychology, Researcher at the Research Centre of the Institut universitaire de gériatrie de Montréal (IUGM) and Professor in the Faculty of Dentistry at Université de Montréal, along with Étienne Vachon-Presseau, a PhD student in Neuropsychology. The study appeared in Brain, a journal published by Oxford University Press.

“Cortisol, a hormone produced by the adrenal glands, is sometimes called the ‘stress hormone’ as it is activated in reaction to stress. Our study shows that a small hippocampal volume is associated with higher cortisol levels, which lead to increased vulnerability to pain and could increase the risk of developing pain chronicity,” explained Étienne Vachon-Presseau.

As Dr. Pierre Rainville described, “Our research sheds more light on the neurobiological mechanisms of this important relationship between stress and pain. Whether the result of an accident, illness or surgery, pain is often associated with high levels of stress Our findings are useful in that they open up avenues for people who suffer from pain to find treatments that may decrease its impact and perhaps even prevent chronicity. To complement their medical treatment, pain sufferers can also work on their stress management and fear of pain by getting help from a psychologist and trying relaxation or meditation techniques.” 

Research summary

This study included 16 patients with chronic back pain and a control group of 18 healthy subjects. The goal was to analyze the relationships between four factors: 1) cortisol levels, which were determined with saliva samples; 2) the assessment of clinical pain reported by patients prior to their brain scan (self-perception of pain); 3) hippocampal volumes measured with anatomical magnetic resonance imaging (MRI); and 4) brain activations assessed with functional MRI (fMRI) following thermal pain stimulations. The results showed that patients with chronic pain generally have higher cortisol levels than healthy individuals. 

Data analysis revealed that patients with a smaller hippocampus have higher cortisol levels and stronger responses to acute pain in a brain region involved in anticipatory anxiety in relation to pain. The response of the brain to the painful procedure during the scan partly reflected the intensity of the patient’s current clinical pain condition. These findings support the chronic pain vulnerability model in which people with a smaller hippocampus develop a stronger stress response, which in turn increases their pain and perhaps their risk of suffering from chronic pain. This study also supports stress management interventions as a treatment option for chronic pain sufferers.

(Image: iStock)

Small groups of brain cells store concepts for memory formation– from Luke Skywalker to your grandmother

Concepts in our minds – from Luke Skywalker to our grandmother - are represented by their own distinct group of neurons, according to new research involving a University of Leicester neuroscientist.

The research, by neuroscientist Professor Rodrigo Quian Quiroga from the University of Leicester Centre for Systems Neuroscience together with Professor Itzhak Fried, of the UCLA David Geffen School of Medicine, Tel Aviv Sourasky Medical Center and Tel Aviv University, and Professor Christof Koch, of the California Institute of Technology and Allen Institute for Brain Science, Seattle, is featured in a recent article of the prestigious Scientific American magazine.

Recent experiments during brain surgeries have shown that small groups of brain cells are responsible for encoding memories of specific people or objects.

These neurons may also represent different variations of one thing – from the name of a person to their appearance from many different viewpoints.

The researchers believe that single concepts may be held in as little as thousands of neurons or less – a tiny fraction of the billion or so neurons contained in the medial temporal lobe, which is a memory related structure within the brain.

The group were able to monitor the brain activity of consenting patients undergoing surgery to treat epilepsy. This allowed the team to monitor the activity of single neurons in conscious patients while they looked at images on laptop screens, creating and recalling memories.

In previous experiments, they had found that single neurons would ‘fire’ for specific concepts – such as Luke Skywalker – even when they were viewing images of him from different angles or simply hearing or reading his name.

They have also found that single neurons can also fire to related people and objects – for instance, the neuron that responded to Luke Skywalker also fired to Yoda, another Jedi from Star Wars.

They argue that relatively small groups of neurons hold concepts like Luke Skywalker and that related concepts such as Yoda are held by some but not all of the same neurons. At the same time, a completely separate set of neurons would hold an unrelated concept like Jennifer Aniston.

The group believes this partially overlapping representation of related concepts are the neural underpinnings of encoding associations, a key memory function.

Professor Quian Quiroga said: “After the first thrill when finding neurons in the human hippocampus with such remarkable firing characteristics, converging evidence from experiments we have been carrying out in the last years suggests that we may be hitting one of the key mechanisms of memory formation and recall.

“The abstract representation of concepts provided by these neurons is indeed ideal for representing the meaning of the sensory stimuli around us, the internal representation we use to form and retrieve memories. These concepts cells, we believe, are the building blocks of memory functions.”

Researchers develop tool for reading the minds of mice

If you want to read a mouse’s mind, it takes some fluorescent protein and a tiny microscope implanted in the rodent’s head.

Stanford scientists have demonstrated a technique for observing hundreds of neurons firing in the brain of a live mouse, in real time, and have linked that activity to long-term information storage. The unprecedented work could provide a useful tool for studying new therapies for neurodegenerative diseases such as Alzheimer’s.

The researchers first used a gene therapy approach to cause the mouse’s neurons to express a green fluorescent protein that was engineered to be sensitive to the presence of calcium ions. When a neuron fires, the cell naturally floods with calcium ions. Calcium stimulates the protein, causing the entire cell to fluoresce bright green.

A tiny microscope implanted just above the mouse’s hippocampus – a part of the brain that is critical for spatial and episodic memory – captures the light of roughly 700 neurons. The microscope is connected to a camera chip, which sends a digital version of the image to a computer screen.

The computer then displays near real-time video of the mouse’s brain activity as a mouse runs around a small enclosure, which the researchers call an arena.

The neuronal firings look like tiny green fireworks, randomly bursting against a black background, but the scientists have deciphered clear patterns in the chaos.

"We can literally figure out where the mouse is in the arena by looking at these lights," said Mark Schnitzer, an associate professor of biology and of applied physics and the senior author on the paper, recently published in the journal Nature Neuroscience.

When a mouse is scratching at the wall in a certain area of the arena, a specific neuron will fire and flash green. When the mouse scampers to a different area, the light from the first neuron fades and a new cell sparks up.

"The hippocampus is very sensitive to where the animal is in its environment, and different cells respond to different parts of the arena," Schnitzer said. "Imagine walking around your office. Some of the neurons in your hippocampus light up when you’re near your desk, and others fire when you’re near your chair. This is how your brain makes a representative map of a space."

The group has found that a mouse’s neurons fire in the same patterns even when a month has passed between experiments. “The ability to come back and observe the same cells is very important for studying progressive brain diseases,” Schnitzer said.

How chronic pain disrupts short term memory

A group of Portuguese researchers from IBMC and FMUP at the University of Porto has found the reason why patients with chronic pain often suffer from impaired short –term memory. The study, to be published in the Journal of Neuroscience, shows how persistent pain disrupts the flow of information between two brain regions crucial to retain temporary memories.

Chronic pain suffers often complain of short term memory’s problems. The neural mechanisms why this occurs are however not understood. Recent studies in animals showed that pain can disturb several cognitive processes as well as change the brain pathways for how we think and feel. Of the many cognitive disturbances observed the most important include problems in spatial memory, recognition memory, attention and even emotional and non-emotional decisions.

In the new article the team of researchers from the University of Porto led by Vasco Gallardo describes in a rat model of neuropathic pain how a neuronal circuit crucial for the processing of short-term memory is affected by pain. The circuit, established between the prefrontal cortex and the hippocampus, is essential for encoding and retaining temporary memories on spatial information. The researchers used multi-electrodes implanted in the brain to record neuronal activity during a behaviour dependent of spatial memory - the animals were trained in a maze where they had to choose between two alternative paths and then asked to recall their chosen path.

The results show that after a painful injury there is a significant reduction in the amount of information that passes through the circuit. This could mean a loss of ability to process information on spatial localization memory, or that those regions critical to memory are now “overwhelmed” by the painful stimuli disrupting the flow of information for memory.

According to Vasco Gallardo, the team ” has already demonstrated that peripheral nerve injury induces an instability in the spatial coding capacity of hippocampus neurons “, where is seen “a clear reduction in their capacity to encode information on the location of the animal.”

So to the author “this new work contributes to the demonstration that chronic pain induces alterations in the function of brain circuits that are not directly connected to tactile or painful processes”. So as a result of chronic pain it is seen that “are also affected neuronal circuits linked to the processing of memories and emotions, what might mean a need for larger and more integrative strategies in the treatment of painful pathologies”, says the researcher.

Researchers identify potential target for age-related cognitive decline

Cognitive decline in old age is linked to decreasing production of new neurons. Scientists from the German Cancer Research Center have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.

The hippocampus – a structure of the brain whose shape resembles that of a seahorse – is also called the “gateway” to memory. This is where information is stored and retrieved. Its performance relies on new neurons being continually formed in the hippocampus over the entire lifetime. “However, in old age, production of new neurons dramatically decreases. This is considered to be among the causes of declining memory and learning ability”, Prof. Dr. Ana Martin-Villalba, a neuroscientist, explains.

Martin-Villalba, who heads a research department at the German Cancer Research Center (DKFZ), and her team are trying to find the molecular causes for this decrease in new neuron production (neurogenesis). Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.

"We find considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. We therefore suspected this signaling molecule to be responsible for the fact that hardly any young neurons are generated any more in old age." The scientists tested their assumption in mice whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs had developed these animals at DKFZ. The term "Dickkopf" (from German "dick" = thick, "Kopf" = head) also goes back to Niehrs, who had found in 1998 that this signaling molecule regulates head development during embryogenesis.

Human memory study adds to global debate

An international study involving researchers from the University of Adelaide has made a major contribution to the ongoing scientific debate about how processes in the human brain support memory and recognition.

The study used a rare technique in which data was obtained from within the brain itself, using electrodes placed inside the brains of surgery patients.

Obtained in Germany, the data was sent to the University of Adelaide’s School of Psychology for further analysis using new techniques developed there. The results are published today in the Proceedings of the National Academy of Sciences (PNAS).

"Being able to understand how human memory works is important because there is a range of conditions that affect memory, such as Alzheimer’s disease, head injury, and ageing," says Professor John Dunn, Head of the School of Psychology at the University of Adelaide and a co-author of the study, which was led by researchers at the universities of Cambridge, UK, and Bonn, Germany.

"Scientists know a lot about memory from years of study, but there is an ongoing debate about how certain mechanisms in the brain process memory, and how those mechanisms work together.

"What we’re looking at is how the human brain processes ‘recognition memory’, which is our ability to recognise people, objects or events that we’ve encountered in the past."

The debate has centered on two key regions in the brain:

• the hippocampus, which is very important to memory and is one of the first regions of the brain to suffer damage from Alzheimer’s disease; and
• the perirhinal cortex, which receives sensory information from all of the body’s sensory regions.

"The debate is whether or not these two regions work in the same or different ways to support memory and recognition Studies over the years have led to both conclusions," Professor Dunn says.

He says this new study, which uses data from inside the brain instead of from electrodes on the scalp, far from the critical regions, revealed that different processes are at work in the hippocampus and the perirhinal cortex.

"Our analysis shows that these regions are responding to and processing memory in two very different ways. The activity levels in those regions changed in different ways according to the amount of information that could be remembered," Professor Dunn says.

"This study won’t settle the debate once and for all, but it does add weight to those scientists who believe that these two distinct parts of the brain respond to memory in different ways," he says.