The discovery that the human brain continues to produce new neurons in adulthood challenged a major dogma in the field of neuroscience, but the role of these neurons in behavior and cognition is still not clear. In a review article published by Cell Press February 21st in Trends in Cognitive Sciences, Maya Opendak and Elizabeth Gould of Princeton University synthesize the vast literature on this topic, reviewing environmental factors that influence the birth of new neurons in the adult hippocampus, a region of the brain that plays an important role in memory and learning.
The authors discuss how the birth of such neurons may help animals and humans adapt to their current environment and circumstances in a complex and changing world. They advocate for testing these ideas using naturalistic designs, such as allowing laboratory rodents to live in more natural social burrow settings and observing how circumstances such as social status influence the rate at which new neurons are born.
“New neurons may serve as a means to fine-tune the hippocampus to the predicted environment,” Opendak says. “In particular, seeking out rewarding experiences or avoiding stressful experiences may help each individual optimize his or her own brain. However, more naturalistic experimental conditions may be a necessary step toward understanding the adaptive significance of neurons born in the adult brain.”
In recent years, it has become increasingly clear that environmental influences have a profound effect on the adult brain in a wide range of mammalian species. Stressful experiences, such as restraint, social defeat, exposure to predator odors, inescapable foot shock, and sleep deprivation, have been shown to decrease the number of new neurons in the hippocampus. By contrast, more rewarding experiences, such as physical exercise and mating, tend to increase the production of new neurons in the hippocampus.
The birth of new neurons in adulthood may have important behavioral and cognitive consequences. Stress-induced suppression of adult neurogenesis has been associated with impaired performance on hippocampus-dependent cognitive tasks, such as spatial navigation learning and object memory. Stressful experiences have also been shown to increase anxiety-like behaviors that are associated with the hippocampus. In contrast, rewarding experiences are associated with reduced anxiety-like behavior and improved performance on cognitive tasks involving the hippocampus.
Although scientists generally agree that our day-to-day actions change our brains even in adulthood, there is some disagreement on the adaptive significance of new neurons. For instance, the literature presents mixed findings on whether new neurons generated under a specific experimental condition are geared toward the recognition of that particular experience or if they provide a more naive pool of new neurons that enable environmental adaptation in the future.
Gould and her collaborators recently proposed that stress-induced decreases in new neuron formation might improve the chances of survival by increasing anxiety and inhibiting exploration, thereby prioritizing safety and avoidant behavior at the expense of performing optimally on cognitive tasks. On the other hand, reward-induced increases in new neuron number may reduce anxiety and facilitate exploration and learning, leading to greater reproductive success.
“Because the past is often the best predictor of the future, a stress-modeled brain may facilitate adaptive responses to life in a stressful environment, whereas a reward-modeled brain may do the same but for life in a low-stress, high-reward environment,” says Gould, a professor of psychology and neuroscience at Princeton University.
However, when aversive experiences far outnumber rewarding ones in both quantity and intensity, the system may reach a breaking point and produce a maladaptive outcome. For example, repeated stress produces continued reduction in the birth of new neurons, and ultimately the emergence of heightened anxiety and depressive-like symptoms.
“Such a scenario could represent processes that are engaged under pathological conditions and may be somewhat akin to what humans experience when exposed to repeated traumatic stress,” Opendak says.
Because many studies that investigate adult neurogenesis use controlled laboratory conditions, the relevance of the findings to real-world circumstances remains unclear. The use of a visible burrow system–a structure consisting of tubes, chambers, and an open field–has allowed researchers to recreate the conditions that allow for the production of dominance hierarchies that rats naturally form in the wild, replicating the stressors, rewards, and cognitive processes that accompany this social lifestyle.
“This more realistic setting has revealed individual differences in adult neurogenesis, with more new neurons produced in dominant versus subordinate male rats,” Gould says. “Taking findings from laboratory animals to the next level by exploring complex social interactions in settings that maximize individual variability, a hallmark of the human experience, is likely to be especially illuminating.”
The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.
In brain cancer cells, the protein PARC plays a key role in long-term cell survival. In both images, the red represents the protein cytochrome c, which is released when mitochondria are damaged and trigger apoptosis — cell suicide. At left, injured brain cancer cells exhibit little cytochrome c; they use the protein PARC to degrade the released cytochrome c, allowing the cancer cells to survive. At right, when researchers reduced PARC, cytochrome c accumulated, allowing apoptosis to carry on.
Credit: Vivian Gama, PhD, UNC School of Medicine
Researchers at the UNC School of Medicine have discovered that the protein PARC/CUL9 helps neurons and brain cancer cells override the biochemical mechanisms that lead to cell death in most other cells. In neurons, long-term survival allows for proper brain function as we age. In brain cancer cells, though, long-term survival contributes to tumor growth and the spread of the disease.
These results, published in the journal Science Signaling, not only identify a previously unknown mechanism used by neurons for their much-needed survival, but show that brain cancer cells hijack the same mechanism for their own survival.
The discovery will lead to new investigations of brain cancer treatments and provides insight into Parkinson’s disease, including a potential new research tool for scientists.
“PARC is very similar to Parkin, a protein that’s mutated in Parkinson’s disease,” said Mohanish Deshmukh, PhD, a professor of cell biology and physiology and senior author of the Science Signaling paper. “We think they might work in tandem to protect neurons.”
If so, researchers can investigate the interplay between these proteins to create better drugs to treat the second-most prevalent neurodegenerative disease after Alzheimer’s disease.
Vivian Gama, PhD, a postdoctoral fellow in Deshmukh’s lab, led the experiments in cell cultures and animal models. First, she used external stimuli to promote the damage of mitochondria – the energy sources for cells. In most cell types, when mitochondria are damaged, they release a protein called cytochrome c, which triggers a cascade of biochemical steps that end in cell death – a process known as apoptosis.
PARC/CUL9 blocked this process; it degraded cytochrome c, halted apoptosis, and allowed for long-term cell survival. “In this setting, we want PARC to do that because we want neurons to survive as long as possible,” said Gama, first author of the Science Signalingpaper.
Deshmukh, a member of the UNC Neuroscience Center and the UNC Lineberger Comprehensive Cancer Center, said, “In Parkinson’s disease, we know that Parkin targets damaged mitochondria for degradation. However, exactly what happens to the proteins, such as cytochrome c, that are released from the damaged mitochondria has been unknown. Now, we think PARC plays a role in this process.”
Deshmukh and Gama’s work could lead to an alternative way to study Parkinson’s disease. Other researchers have created mouse models that lack the Parkin gene, but Gama said these models don’t have many of the hallmark symptoms that human patients have, making the model less than desirable for researchers. “Our hypothesis is that in the absence of Parkin, PARC still does the job,” Gama said, “as it may allow cells to survive.”
Gama and Deshmukh are now creating a model that lacks both the Parkin and PARC genes.
They will also investigate PARC as a target for cancer treatment.
“We tested several cancer cell lines and found that PARC degrades cytochrome c in medulloblastoma, a cancer of the central nervous system and in neuroblastoma, a cancer of the peripheral nervous system,” Gama said. “Not all cytochrome c is degraded; there are likely other factors involved. But PARC is an important player.”
When Gama and colleagues triggered the apoptotic process in brain cancer cells, they found that PARC allowed the cells to survive. When PARC was inhibited, the cells were more vulnerable to stress and damage, which means they could be more vulnerable to compounds aimed at destroying them.
Deshmukh said, “We show that brain cancer cells co-opt PARC to bypass apoptosis in the same way that neurons do and for the exact same purpose.”
The above story is based on materials provided by University of North Carolina School of Medicine. Note: Materials may be edited for content and length.
New light-sensitive proteins allow scientists to study how multiple sets of neurons interact with each other.
MIT-led researchers engineered neurons so they can be activated with either blue or red light, allowing each population to be controlled separately.
IMAGE: YASUNOBU MURATA/MCGOVERN INSTITUTE
Optogenetics is a technique that allows scientists to control neurons’ electrical activity with light by engineering them to express light-sensitive proteins. Within the past decade, it has become a very powerful tool for discovering the functions of different types of cells in the brain.
Most of these light-sensitive proteins, known as opsins, respond to light in the blue-green range. Now, a team led by MIT has discovered an opsin that is sensitive to red light, which allows researchers to independently control the activity of two populations of neurons at once, enabling much more complex studies of brain function.
“If you want to see how two different sets of cells interact, or how two populations of the same cell compete against each other, you need to be able to activate those populations independently,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and a senior author of the new study.
The new opsin is one of about 60 light-sensitive proteins found in a screen of 120 species of algae. The study, which appears in the Feb. 9 online edition of Nature Methods, also yielded the fastest opsin, enabling researchers to study neuron activity patterns with millisecond timescale precision.
Boyden and Gane Ka-Shu Wong, a professor of medicine and biological sciences at the University of Alberta, are the paper’s senior authors, and the lead author is MIT postdoc Nathan Klapoetke. Researchers from the Howard Hughes Medical Institute’s Janelia Farm Research Campus, the University of Pennsylvania, the University of Cologne, and the Beijing Genomics Institute also contributed to the study.
In living color
Opsins occur naturally in many algae and bacteria, which use the light-sensitive proteins to help them respond to their environment and generate energy.
To achieve optical control of neurons, scientists engineer brain cells to express the gene for an opsin, which transports ions across the cell’s membrane to alter its voltage. Depending on the opsin used, shining light on the cell either lowers the voltage and silences neuron firing, or boosts voltage and provokes the cell to generate an electrical impulse. This effect is nearly instantaneous and easily reversible.
Using this approach, researchers can selectively turn a population of cells on or off and observe what happens in the brain. However, until now, they could activate only one population at a time, because the only opsins that responded to red light also responded to blue light, so they couldn’t be paired with other opsins to control two different cell populations.
To seek additional useful opsins, the MIT researchers worked with Wong’s team at the University of Alberta, which is sequencing the transcriptomes of 1,000 plants, including some algae. (The transcriptome is similar to the genome but includes only the genes that are expressed by a cell, not the entirety of its genetic material.)
Once the team obtained genetic sequences that appeared to code for opsins, Klapoetke tested their light-responsiveness in mammalian brain tissue, working with Martha Constantine-Paton, an MIT professor of brain and cognitive sciences and of biology, a member of the McGovern Institute, and an author of the paper. The red-light-sensitive opsin, which the researchers named Chrimson, can mediate neural activity in response to light with a 735-nanometer wavelength.
The researchers also discovered a blue-light-driven opsin that has two highly desirable traits: It operates at high speed, and it is sensitive to very dim light. This opsin, called Chronos, can be stimulated with levels of blue light that are too weak to activate Chrimson.
“You can use short pulses of dim blue light to drive the blue one, and you can use strong red light to drive Chrimson, and that allows you to do true two-color, zero-cross-talk activation in intact brain tissue,” says Boyden, who is a member of MIT’s Media Lab and the McGovern Institute for Brain Research.
Researchers had previously tried to modify naturally occurring opsins to make them respond faster and react to dimmer light, but trying to optimize one feature often made other features worse.
“It was apparent that when trying to engineer traits like color, light sensitivity, and kinetics, there are always tradeoffs,” Klapoetke says. “We’re very lucky that something natural actually was more than several times faster and also five or six times more light-sensitive than anything else.”
These new opsins lend themselves to several types of studies that were not possible before, Boyden says. For one, scientists could not only manipulate activity of a cell population of interest, but also control upstream cells that influence the target population by secreting neurotransmitters.
Pairing Chrimson and Chronos could also allow scientists to study the functions of different types of cells in the same microcircuit within the brain. Such cells are usually located very close together, but with the new opsins they can be controlled independently with two different colors of light.
“I think the tools described in this excellent paper represent a major advance for both basic and translational neuroscience,” says Roska Botond, a senior group leader at the Friedrich Miescher Institute for Biomedical Research in Switzerland, who was not part of the research team. “Optogenetic tools that are shifted towards the infrared range, such as Chrimson described in this paper, are much better than the more blue-shifted variants since these are less toxic, activate less the pupillary reflex, and activate less the remaining photoreceptors of patients.”
Most optogenetic studies thus far have been done in mice, but Chrimson could be used for optogenetic studies of fruit flies, a commonly used experimental organism. Researchers have had trouble using blue-light-sensitive opsins in fruit flies because the light can get into the flies’ eyes and startle them, interfering with the behavior being studied.
Vivek Jayaraman, a research group leader at Janelia Farms and an author of the paper, was able to show that this startle response does not occur when red light is used to stimulate Chrimson in fruit flies.
Because red light is less damaging to tissue than blue light, Chrimson also holds potential for eventual therapeutic use in humans, Boyden says. Animal studies with other opsins have shown promise in helping to restore vision after the loss of photoreceptor cells in the retina.
The researchers are now trying to modify Chrimson to respond to light in the infrared range. They are also working on making both Chrimson and Chronos faster and more light sensitive.
MIT’s portion of the project was funded by the National Institutes of Health, the MIT Media Lab, the National Science Foundation, the Wallace H. Coulter Foundation, the Alfred P. Sloan Foundation, a NARSAD Young Investigator Grant, the Human Frontiers Science Program, an NYSCF Robertson Neuroscience Investigator Award, the IET A.F. Harvey Prize, the Skolkovo Institute of Science and Technology, and Janet and Sheldon Razin ’59.
Editors note: Original publication can be found here.
Editors note: Original publication can be found here.
This image shows a vertical projection of a stack of confocal images taken from a transgenic mouse, in which green fluorescent protein (GFP) is expressed in all ciliated olfactory sensory neurons. GFP brightly labels the olfactory neuronal cell bodies (OCB), their apical dendrites (AD), and terminal knobs (TK). Staining does not extend into the sensory cilia, which remain invisible in this preparation. Basally to the olfactory neuronal cell bodies is the unstained layer of basal stem cells (LBC), from which degenerating neurons are constantly regenerated. The olfactory axons grow in bundles (AB) through the basal lamina (BL), and then fasciculate to form the tracts of the olfactory nerve, which projects into the brain.
“An ailment not to be treated,” read the prescription for a spinal cord injury on an Egyptian papyrus in 1,700 B.C. Not much has changed in the intervening millennia. Despite decades of research, modern medicine has made little headway in its quest to reverse damage to the central nervous system.
That is not to say, however, that there isn’t a glimmer of hope. Laura Wong, an M.D./Ph.D. student in Professor Eric Frank’s molecular physiology lab at the Sackler School, has been able to coax damaged nerve cells known as sensory neurons to regenerate, growing as much as 10 times longer than previously documented. What’s more, the new neurons make organized connections with their counterparts inside the spinal cord and brain stem, ensuring information from the outside world paints an accurate picture inside the brain.
“All the regeneration in the world isn’t going to make any difference if they don’t reconnect. You’re still not going to get any function,” says Wong, who has worked since 2010 in Frank’s lab, which is trying to develop therapies for spinal cord injuries.
Her findings, which she presented at the annual meeting of the Society for Neuroscience in 2011 and 2012, shed light on the complex processes behind nerve cell growth and regeneration. If those results can be replicated in patients, it could prevent certain types of nerve damage and improve quality of life for some.
Going the Distance
Unlike tissues such as skin and bone, the cells of the central nervous system in an adult are notoriously resistant to healing. Not only does the supply of natural growth stimulants decline as we age, but the body also produces chemicals that discourage nerve cells from regenerating. Worse, the scar tissue that starts to form immediately after a spinal cord injury also contains compounds that hinder nerve cell growth.
Researchers in Frank’s lab have been seeking ways to either stimulate growth or block the mechanisms that inhibit nerve cell growth—or both—since 2005. Wong’s predecessor in the lab, Pamela Harvey, a 2009 graduate of the Sackler School, tested a synthetic version of a nerve cell growth factor, called artemin, on crushed sensory neurons that relay information from the hands, arms and shoulders to the brain.
“With some other growth-promoting compounds you get regeneration, but you see those axons growing kind of willy-nilly,” says Laura Wong. Photo: Alonso Nichols
The damage mimics a common injury called Erb’s palsy, which can occur when a baby’s shoulder gets caught behind the mother’s pelvis during labor and delivery, creating undue strain on nerves in the newborn’s neck. Riders thrown head first off a motorcycle or snowmobile can suffer similar injuries.
“Anytime the shoulder goes one way and the head and neck go the other, that’s when you see these injuries,” Wong says.
In earlier experiments, Harvey and Frank found that treating with artemin did indeed stimulate the sensory nerve fibers to regenerate and grow back into the spinal cord over the course of about six weeks. In her follow-up experiments, Wong showed that artemin could induce those nerve fibers to grow the 3- to 4-centimeter distance from there up to the brainstem, where the brain and the spinal cord meet. That’s a little more than an inch—or roughly 10 times longer than any other researchers have been able to demonstrate with artemin or any other growth factor.
“A lot of other researchers just haven’t seen this length,” notes Wong, who saw the artemin-induced growth occur over a period of three to six months.
That’s important, because while axons only have to grow across microscopic distances in a developing embryo, they would have to bridge much wider gaps—depending on the site of the injury—to heal a neural injury in an adult, Wong says. Nerves that extend from the spine to the foot or toe can reach lengths of about 60 centimeters, she adds.
But Wong’s artemin-treated nerve fibers achieved more than unprecedented growth. They also reestablished connections with correct regions in the brain stem, just as Harvey had seen the nerve cells do in the spinal cord. That is, the axons essentially plugged themselves back in just as they were prior to the injury, and, like an old-fashioned telephone switchboard, they sent the right messages to the right parts of the brain.
That’s crucial because should the sensory nerves that relay pain signals become crossed, for example, it could result in a patient feeling phantom pain or the sensation of pain from something that shouldn’t cause discomfort at all.
“With some other growth-promoting compounds you get regeneration, but you see those axons growing kind of willy-nilly,” says Wong. “You can see where it would be just as detrimental to have things wired incorrectly as it would be to have things not wired at all.”
Just a Start
Artemin isn’t a panacea for spinal cord injuries, Wong and Frank stress. To work its cellular magic, the compound must be administered within a day or two, and the sooner the better. Also, artemin promotes growth only in sensory neurons—and so far, only in rats—which means such growth wouldn’t improve motor function for someone who had been paralyzed by a spinal cord injury, for example.
But if the findings, which Wong presented at the Society for Neuroscience meetings in 2011 and 2012, prove applicable to humans, restoring sensation alone could still improve quality of life, even for those living with paralysis. Giving these people the ability to sense heat, cold and pain could help them avoid other accidental injuries, says Frank.
Wong hopes her work with sensory neurons will help unlock the secrets to promoting regeneration of other, more obstinate types of neurons in the brainstem and spinal cord. While she demonstrated that the sensory nerves plugged themselves back into the spinal cord precisely where they should have, it’s not clear how they did that.
Frank speculates that chemical cues guided the cells back into place. Should researchers be able to identify those cues, they potentially could use that knowledge to spark regeneration of other classes of neurons, such as motor neurons.
“There is hope—not proof—that even in humans these guidance molecules will persist into adulthood,” says Frank. “That means if we are able to get neurons to regenerate in patients, we might be able to make them go back to the right place. These experiments suggest we have some reason to believe it may work.”
Editors note: Original article can be found here.