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In addition to the featured articles posted in the blog, links to other research news articles are posted on the Brain Science News page.

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New type of neuron discovered in rat brain – rosehip neuron

From Allen Institute for Brain Science:

Scientists identify a new kind of human brain cell

August 27, 2018

One of the most intriguing questions about the human brain is also one of the most difficult for neuroscientists to answer: What sets our brains apart from those of other animals?

“We really don’t understand what makes the human brain special,” said Ed Lein, Ph.D., Investigator at the Allen Institute for Brain Science. “Studying the differences at the level of cells and circuits is a good place to start, and now we have new tools to do just that.”

undefinedA reconstruction of a newly discovered type of human neuron. The researchers who identified the new cell type dubbed it a ‘rosehip neuron’ for its compact, budlike shape. Image courtesy of Boldog, et al.; Nature Neuroscience.

In a new study published today in the journal Nature Neuroscience, Lein and his colleagues reveal one possible answer to that difficult question. The research team, co-led by Lein and Gábor Tamás, Ph.D., a neuroscientist at the University of Szeged in Szeged, Hungary, has uncovered a new type of human brain cell that has never been seen in mice and other well-studied laboratory animals.

undefinedTamás and University of Szeged doctoral student Eszter Boldog dubbed these new cells “rosehip neurons” — to them, the dense bundle each brain cell’s axon forms around the cell’s center looks just like a rose after it has shed its petals, he said. The newly discovered cells belong to a class of neurons known as inhibitory neurons, which put the brakes on the activity of other neurons in the brain.

The study hasn’t proven that this special brain cell is unique to humans. But the fact that the special neuron doesn’t exist in rodents is intriguing, adding these cells to a very short list of specialized neurons that may exist only in humans or only in primate brains.

The researchers don’t yet understand what these cells might be doing in the human brain, but their absence in the mouse points to how difficult it is to model human brain diseases in laboratory animals, Tamás said. One of his laboratory team’s immediate next steps is to look for rosehip neurons in postmortem brain samples from people with neuropsychiatric disorders to see if these specialized cells might be altered in human disease.

When different techniques converge

In their study, the researchers used tissue samples from postmortem brains of two men in their 50s who had died and donated their bodies to research. They took sections of the top layer of the cortex, the outermost region of the brain that is responsible for human consciousness and many other functions that we think of as unique to our species. It’s much larger, compared to our body size, than in other animals.

undefined“It’s the most complex part of the brain, and generally accepted to be the most complex structure in nature,” Lein said.

Tamás’ research lab in Hungary studies the human brain using a classical approach to neuroscience, conducting detailed examinations of cells’ shapes and electrical properties. At the Allen Institute, Lein leads a team working to uncover the suite of genes that make human brain cells unique from each other and from the brain cells of mice.

Several years ago, Tamás visited the Allen Institute to present his latest research on specialized human brain cell types, and the two research groups quickly saw that they’d hit on the same cell using very different techniques.

“We realized that we were converging on the same cell type from absolutely different points of view,” Tamás said. So they decided to collaborate.

The Allen Institute group, in collaboration with researchers from the J. Craig Venter Institute, found that the rosehip cells turn on a unique set of genes, a genetic signature not seen in any of the mouse brain cell types they’ve studied. The University of Szeged researchers found that the rosehip neurons form synapses with another type of neuron in a different part of the human cortex, known as pyramidal neurons.

undefinedThis is one of the first studies of the human cortex to combine these different techniques to study cell types, said Rebecca Hodge, Ph.D., Senior Scientist at the Allen Institute for Brain Science and an author on the study.

“Alone, these techniques are all powerful, but they give you an incomplete picture of what the cell might be doing,” Hodge said. “Together, they tell you complementary things about a cell that can potentially tell you how it functions in the brain.”

How do you study humanity?

What appears to be unique about rosehip neurons is that they only attach to one specific part of their cellular partner, indicating that they might be controlling information flow in a very specialized way.

If you think of all inhibitory neurons like brakes on a car, the rosehip neurons would let your car stop in very particular spots on your drive, Tamás said. They’d be like brakes that only work at the grocery store, for example, and not all cars (or animal brains) have them.

“This particular cell type — or car type — can stop at places other cell types cannot stop,” Tamás said. “The car or cell types participating in the traffic of a rodent brain cannot stop in these places.”

The researchers’ next step is to look for rosehip neurons in other parts of the brain, and to explore their potential role in brain disorders. Although scientists don’t yet know whether rosehip neurons are truly unique to humans, the fact that they don’t appear to exist in rodents is another strike against the laboratory mouse as a perfect model of human disease — especially for neurological diseases, the researchers said.

undefined“Our brains are not just enlarged mouse brains,” said Trygve Bakken, M.D., Ph.D., Senior Scientist at the Allen Institute for Brain Science and an author on the study. “People have commented on this for many years, but this study gets at the issue from several angles.”

“Many of our organs can be reasonably modeled in an animal model,” Tamás said. “But what sets us apart from the rest of the animal kingdom is the capacity and the output of our brain. That makes us human. So it turns out humanity is very difficult to model in an animal system.”

Other co-authors on the study include Jennie Close, Zoe Maltzer, Song-Lin Ding, Jeremy Miller, Soraya Shehata, Kimberly Smith, Susan Sunkin and Abby Wall of the Allen Institute for Brain Science; Judith Baka, Sándor Bordé, Nóra Faragó, Ágnes K. Kocsis, Balázs Kovács, Gábor Molnár, Gáspár Oláh, Attila Ozsvár, Márton Rózsa and Pál Barzó of the University of Szeged; Mark Novotny, Brian Aevermann, Francisco Diez-Fuertes, Jamison McCorrison, Danny Tran, Pratap Venepally, Roger Lasken, Nicholas Schork and Richard Scheuermann of the J. Craig Venter Institute; László Puskás of the Hungarian Academy of Sciences; and Frank Steemers of Illumina, Inc.

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Single neurons switch firing rates between different stimuli

FROM DUKETODAY:

Neurons Can Carry More Than One Signal at a Time

Study sheds light on how the brain encodes complex information

A cartoon illustration of two white neurons with wavy lines in the background
A Duke team found that individual neurons can encode information about multiple stimuli simultaneously, much the same way electronics like cell phones sort signals by frequency. Credit: Cruger Creations

Back in the early days of telecommunications, engineers devised a clever way to send multiple telephone calls through a single wire at the same time. Called time-division multiplexing, this technique rapidly switches between sending pieces of each message.

New research from Duke University shows that neurons in the brain may be capable of a similar strategy.

In an experiment examining how monkeys respond to sound, a team of neuroscientists and statisticians found that a single neuron can encode information from two different sounds by switching between the signal associated with one sound and the signal associated with the other sound.

“The question we asked is, how do neurons preserve information about two different stimuli in the world at one time?” said Jennifer Groh, professor in the department of psychology and neuroscience, and in the department of neurobiology at Duke.

“We found that there are periods of time when a given neuron responds to one stimulus, and other periods of time where it responds to the other,” Groh said. “They seem to be able to alternate between each one.”

The results may explain how the brain processes complex information from the world around us, and may also provide insight into some of our perceptual and cognitive limitations. The results appeared July 13 in Nature Communications.

To make the discovery, Groh and her team collaborated with Surya Tokdar, associate professor of statistical science at Duke, to develop and apply several new methods of analysis to their experimental data.

Most studies of single neuron behavior investigate only one stimulus at a time, looking at how an individual neuron responds when the subject is played a single note or shown a single image.

But reality is rarely so simple. Our brains are capable of processing multiple stimuli at once — such as listening to a friend at a party with music playing in the background, or picking out the buzz of a cicada from a symphony of trilling insects.

“It is not obvious how you go from single neurons encoding single objects, to neurons encoding multiple objects,” said Valeria Caruso, a research scientist in Duke’s department of psychology and neuroscience. “We wanted to provide an intermediate step, looking at how neurons encode small groups of objects.”

To complicate matters, single-neuron studies have shown that many sensory neurons are broadly tuned, meaning each is capable of responding to sounds at a range of different frequencies. For example, the same neurons triggered by your friend’s voice may also be triggered by the notes of your favorite tunes.

“If I am a neuron and I’m able to respond to both an image of a pillow and the couch it is resting on, how does the brain infer that both the pillow and the couch are present?” Groh said.

In the experiment, the researchers sat monkeys in a darkened room and trained them to look in the direction of sounds that they heard. The researchers played either one sound or two sounds, with each sound at a different frequency and coming from different locations.

When the researchers played two sounds together, the monkeys looked first in the direction of one sound, and then in the direction of the other sound, indicating that the monkeys recognized the existence of two distinct sounds.

To find out how the monkeys’ brains encoded both sounds simultaneously, the team used electrodes in the inferior colliculus, a key point in the brain’s auditory pathway, to measure the small spikes in the local electric field caused by neurons firing.

The researchers investigated the response of single neurons to both individual sounds and to combined sounds. The standard practice in the field is to count how many spikes occur over a period of time and compute the average of a number of trials, Groh said. But this method obscures any fluctuations in activity that might indicate the neurons are switching back and forth between different stimuli.

The team applied a combination of advanced statistical methods, including a new method called a Dynamic Admixture Point Process model developed by Tokdar and his team, to extract more detailed patterns from the data.

They found that a single neuron could respond to one sound with one firing rate, and a second sound with a different firing rate. When both sounds were played simultaneously, it appeared to fluctuate between the two firing rates. Sometimes the fluctuations were fast enough that the neurons switched within a half second of the presentation of the sound, and in other cases the switching was slower.

The team repeated the statistical analysis on data from experiments conducted by Winrich Freiwald, a professor of neurosciences and behavior at The Rockefeller University. In these experiments, Freiwald investigated the firing rates of single neurons in a visual area of the cortex in response to images of one face or two faces. The analysis revealed the same switching pattern when two faces were present.

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Combination of B vitamins and omega-3 fatty acids slows cognitive decline in MCI

From University of Oxford News and Events:

Omega 3 capsules

Omega-3 levels affect whether B vitamins can slow brain’s decline

While research has already established that B vitamin supplements can help slow mental decline in older people with memory problems, an international team have now found that having higher levels of Omega-3 fatty acids in your body could boost the B vitamins’ effect.

The team, from the Universities of Cape Town, Oslo, Oxford and the UAE, studied more than 250 people with mild cognitive impairment (MCI) in Oxford. MCI is when brain function is below what is normally expected for a person’s age but is not significant enough to interfere with daily life. While it is not as serious as dementia, if untreated it often progresses to become dementia.

Dr Celeste de Jager said: ‘We previously found that B vitamins are able to slow or prevent the atrophy of the brain and memory decline in people with MCI. This was most effective in those who had above average blood levels of homocysteine, a factor related to B vitamin status that may be toxic to the brain.  Scientists in our team initially found that there was a link between Omega-3 levels, homocysteine, and brain atrophy rates. We wanted to find out whether Omega-3 and B vitamins might interact to prevent cognitive decline.’

At the start of the study, each person was given a set of tests to measure their cognition, and had a blood test to determine the levels of two Omega-3 fatty acids commonly found in oily fish: docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

The participants were split into two randomly-selected groups, who received either a B-vitamin supplement or a placebo pill over two years. Their cognitive performance was also measured and the results compared with the baseline results from the start of the study.

Dr Abderrahim Oulhaj said: ‘We found that for people with low levels of Omega-3, the vitamin supplements had little to no effect. But for those with high baseline Omega-3 levels, the B vitamins were very effective in preventing cognitive decline compared to the placebo. This result complements our previous finding that B vitamins slow the rate of brain atrophy in MCI only in those with a good Omega-3 level to start with.’

The team also found that levels of DHA might be more important than levels of EPA, although they caution that more research must be done to establish whether this is true.

Professor David Smith said: ‘The next stage will be to see whether providing a combination of B vitamins and Omega-3 supplements can slow the conversion from MCI to Alzheimer’s disease. This would be an important step in the prevention of Alzheimer’s disease. We have high hopes that this trial would work but funding is not easy to obtain for such studies.’

 Read more.

Alpha-beta rhythms in deeper layers of prefrontal cortex regulate gamma rhythms in superficial layers during working memory tasks

From MIT News:

 

 

Study: Rhythmic interactions between cortical layers underlie working memory

MIT neuroscientists suggest a model for how we gain volitional control of what we hold in our mind

David Orenstein | Picower Institute for Learning and Memory
January 15, 2018

Working memory is a sort of “mental sketchpad” that allows you to accomplish everyday tasks such as calling in your hungry family’s takeout order and finding the bathroom you were just told “will be the third door on the right after you walk straight down that hallway and make your first left.” It also allows your mind to go from merely responding to your environment to consciously asserting your agenda.

“Working memory allows you to choose what to pay attention to, choose what you hold in mind, and choose when to make decisions and take action,” says Earl K. Miller, the Picower Professor in MIT’s Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences. “It’s all about wresting control from the environment to your own self. Once you have something like working memory, you go from being a simple creature that’s buffeted by the environment to a creature that can control the environment.”

For years Miller has been curious about how working memory — particularly the volitional control of it — actually works. In a new study in the Proceedings of the National Academy of Sciences led by Picower Institute postdoc Andre Bastos, Miller’s lab shows that the underlying mechanism depends on different frequencies of brain rhythms synchronizing neurons in distinct layers of the prefrontal cortex (PFC), the area of the brain associated with higher cognitive function. As animals performed a variety of working memory tasks, higher-frequency gamma rhythms in superficial layers of the PFC were regulated by lower-frequency alpha/beta frequency rhythms in deeper cortical layers.

The findings suggest not only a general model of working memory, and the volition that makes it special, but also new ways that clinicians might investigate conditions such as schizophrenia where working memory function appears compromised.

Layers of waves

To conduct the study, Bastos worked from several lines of evidence and with some relatively new technology. Last year, for example, co-author and Picower Institute postdoc Mikael Lundqvist led a study showing that gamma waves perked up in power when sensory (neuroscientists call it “bottom-up”) information was loaded into and read out from working memory. In previous work, Miller, Bastos, and their colleagues had found that alpha/beta rhythms appeared to carry “top-down” information about goals and plans within the cortex. Top-down information is what we use to make volitional decisions about what to think about or how to act, Miller says.

The current study benefitted from newly improved multilayer electrode brain sensors that few groups have applied in cognitive, rather than sensory, areas of the cortex. Bastos realized that if he made those measurements, he and Miller could determine whether deep alpha/beta and superficial gamma might interact for volitional control of working memory.

In the lab Bastos and his co-authors, including graduate students Roman Loonis and Simon Kornblith, made multilayer measurements in six areas of the PFC as animals performed three different working memory tasks.

In different tasks, animals had to hold a picture in working memory to subsequently choose a picture that matched it. In another type of task, the animals had to remember the screen location of a briefly flashed dot. Overall, the tasks asked the subjects to store, process, and then discard from working memory the appearance or the position of visual stimuli.

“Combining data across the tasks and the areas does lead to additional weight for the evidence,” Bastos says.

A mechanism for working memory

Across all the PFC areas and all tasks, the data showed the same thing: When sensory information was loaded into working memory, the gamma rhythms in superficial layers increased and the alpha/beta rhythms in deep layers that carried the top-down information decreased. Conversely, when deep-layer alpha/beta rhythms increased, superficial layer gamma waned. Subsequent statistical analysis suggested that gamma was being controlled by alpha and beta rhythms, rather than the other way around.

“This suggests mechanisms by which the top-down information needed for volitional control, carried by alpha/beta rhythms, can turn on and off the faucet of bottom-up sensory information, carried by gamma, that reaches working memory and is held in mind,” Miller says.

With these insights, the team has since worked to directly test this multilayer, multifrequency model of working memory dynamics more explicitly, with results in press but not yet published.

Charles Schroeder, research scientist and section head in the Center for Biomedical Imaging and Neuromodulation at the Nathan S. Kline Institute for Psychiatric Research, describes two contributions of the study as empirically important.

“First, the paper clearly shows that critical cognitive operations (in this case working memory) are underlain by periodic (oscillatory) network activity patterns in the brain, and that these must be addressed by single trial analysis,” Schroeder says. “This provides an important conceptual alternative to the idea that working memory must involve continuous neural activation. Secondly, the findings strongly reinforce the notion that dynamic coupling across high- and low-frequency ranges performs a clear mechanistic function: Lower frequency activity dominant in the lower layers of the prefrontal area network controls the temporal patterning of higher frequency information representation in the superficial layers of the same network of areas. The important conceptual innovation in this case lies in allowing lower frequency control operations to act directly on higher frequency information representation within each cortical area.”

Read more.

Sleep boosts communication between hippocampus and sensory neocortex involved in memory formation

From NINDS Press Releases:

Study shows how memories ripple through the brain

Monday, October 30, 2017

NIH-funded study suggests increased communication between key brain areas during sleep

 

Neuronal cross-talk in the sleeping brain

Neuronal cross-talk in the sleeping brain:  NIH-funded research suggests that increased communication between two brain areas during sleep may play a role in memory formation. Image courtesy of György Buzsáki, M.D., Ph.D., NYU School of Medicine.

Using an innovative “NeuroGrid” technology, scientists showed that sleep boosts communication between two brain regions whose connection is critical for the formation of memories. The work, published in Science, was partially funded by the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a project of the National Institutes of Health devoted to accelerating the development of new approaches to probing the workings of the brain.

“Using new technologies advanced by the BRAIN Initiative, these researchers made a fundamental discovery about how the brain creates and stores new memories,” said Nick Langhals, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke.

A brain structure called the hippocampus is widely thought to turn new information into permanent memories while we sleep. Previous work by the new study’s senior author, NYU School of Medicine professor György Buzsáki, M.D., Ph.D., revealed high-frequency bursts of neural firing called ripples in the hippocampus during sleep and suggested they play a role in memory storage. The current study confirmed the presence of ripples in the hippocampus during sleep and found them in certain parts of association neocortex, an area on the brain’s surface involved in processing complex sensory information.

“When we first observed this, we thought it was incorrect because it had never been observed before,” said Dion Khodagholy, Ph.D., the study’s co-first author and assistant professor at Columbia University in New York.

Using a cutting-edge NeuroGrid system they invented, along with recording electrodes placed deeper into the brain, the researchers examined activity in several parts of rats’ brains during non-rapid eye movement (NREM) sleep, the longest stage of sleep. Their NeuroGrid consists of a collection of tiny electrodes linked together like the threads of a blanket, which is then laid across an area of the brain so that each electrode can continuously monitor the activity of a different set of neurons.

“This particular device allows us to look at multiple areas of the brain at the same time,” said Jennifer Gelinas, M.D., Ph.D., the study’s co-first author and assistant professor at Columbia University.

The team was also surprised to find that the ripples in the association neocortex and hippocampus occurred at the same time, suggesting the two regions were communicating as the rats slept. Because the association neocortex is thought to be a storage location for memories, the researchers theorized that this neural dialogue could help the brain retain information.

To test that idea, they examined brain activity during NREM sleep in rats trained to locate rewards in a maze and in rats that explored the maze in a random fashion. In the latter group of animals, the ripples in the hippocampus and cortex were no more synchronized before exploring the maze than afterwards. In the trained rats, the learning task increased the cross-talk between those areas, and a second training session boosted it even more, further suggesting that such communication is important for the creation and storage of memories.

The group hopes to use the NeuroGrid in people undergoing brain surgery for other reasons to determine if the same ripples occur in the human brain. The researchers also plan to investigate if manipulating that neural firing in animals can boost or suppress memory formation in order to confirm that ripples are important for that process.

“Identifying the specific neural patterns that go along with memory formation provides a way to better understand memory and potentially even address disorders of memory,” said Dr. Gelinas.

Read more.

Female axons are smaller and microtubules more likely to break during head trauma

From Penn State News:

PHILADELPHIA – Women have smaller, more breakable nerve fibers in the brain compared to men that may make them more susceptible to concussions, suggests a new study from Penn Medicine neuroscientists published online today in the journal Experimental Neurology.
press

In a series of laboratory tests using rat and human neuronal cells, the research team, led by Douglas H. Smith, MD, director of the Penn Center for Brain Injury and Repair and the Robert A. Groff Professor of Neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, found that female axons were smaller and had fewer microtubules – “train tracks” that transport molecules up and down the axons – that were more likely to break after applying the same amount of force from a simulated traumatic brain injury.

That breaking is what researchers believe may lead to symptoms associated with concussions, such as dizziness or loss of consciousness. The susceptibility may also help explain why female athletes have an increased risk of concussions and worse outcomes than male athletes, as previous studies have shown.

“The paper shows us that there is a fundamental, anatomical difference between male and female axons,” Smith said. “In the male axon, there are a great number of microtubules, which make the entire structure stronger, whereas in female axons, it’s more of a leaner type of architecture, so it’s not as strong.”

Considered the “electric grid” of the brain, axons are long, slender parts of the neuron that communicate messages from one cell to another. When someone suffers a traumatic blow to the head, the axons are stretched at a very rapid rate. While the axons typically stay intact, their microtubules can break under the strain. The faster they stretch, the stiffer the crosslinking proteins known as tau become. This transfers high stress onto the microtubule that can result in them rupturing, setting off a molecular imbalance.

“You can imagine that if something goes wrong with that transport system, the cargos get dumped out and start to pile up and that will create a huge problem,” Smith said.

This buildup causes abnormal inflows of sodium and calcium ions. Researchers believe that levels of calcium become high enough to trigger a self-destruct process, in which protein-breaking enzymes are unleashed, begin to degrade the axonal structure, and ultimately compromise the nerve fiber. The researchers found that 24 hours after trauma, female axons had significantly more swellings and a greater loss of calcium signaling function than male axons.

“When axons function normally, they let sodium pass through the membrane, and it creates a spark that can be transferred as ‘electricity’ down the axon,” Smith said. “In concussion, you can have immediate loss of that ability to transfer that ‘electricity.’ That’s why the characteristic, behavioral changes occur.”

People who suffer from concussions – about two million sports-related concussions occur in the United State every year – can experience confusion, headaches, dizziness, and temporary loss of consciousness, which typically disappear after a few hours or days. Recent Penn studies have also suggested that concussions can lead to long-term cognitive impairments.

The researchers, which included first author, Jean-Pierre Dollé, PhD, of the Penn Center for Brain Injury and Repair, used transmission electron microscopy to study the structural differences between female and male axons from both rat and human neurons. Next, they evaluated the axons’ response to dynamic stretch injury, to mimic a traumatic axonal injury, using computational and in vitro models.

Past studies have shown that female athletes have a higher rate of concussion and appear to have worse outcomes than their male counterparts participating in the same sport, the researchers noted in the current study. Also, results from a 2017 study, presented at this year’s American Academy of Neurology’s annual meeting, found that women athletes are 50 percent more likely than male athletes to have a sports-related concussion.

The in vitro findings, researchers said, may have implications for concussion, where axonal injury is the most commonly described pathological feature. “It is conceivable that under the same level of mechanical loading during head impact, axons in female brains may be more susceptible to damage than axons in male brains due to fundamental differences in axon ultrastructure,” they wrote.

Further in vivo studies are needed to support these findings, Smith said. One next step would be to compare blood biomarkers. For instance, do concussed females have more axon proteins, which rise in the blood after a concussion, than males? SNTF (alpha II-spectrin N-terminal fragment), and APP (amyloid precursor protein) are two examples of biomarkers of axonal injury, Penn researchers reported in previous studies. Investigating white matter changes in male and female athletes playing the same sport with advanced neuroimaging is another avenue to explore, Smith said.

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Optogenetics in Monkeys and Other Primates

From The Scientist:

Lighting Up Monkey Brains

Optogenetic and chemogenetic tools illuminate brain and behavior connections in nonhuman primates.

By Jyoti Madhusoodanan | November 1, 2017

TYPECASTING: Immunohistochemical staining shows selective labeling of Purkinje cells (green) and their axons (red) in the granular layer of the cerebellar cortex. (Scale bar = 200 microns) NEURON, 95:51-62, 2017

Since optogenetics burst onto the scene in the early 2000s, brain researchers have embraced the technique to study functions ranging from sleep and hunger to voluntary movements and sensory input. The vast majority of these studies have been conducted in rodents, and much has been learned, but extrapolating to humans from a species so different from us poses a challenge.

Brain research in nonhuman primates precedes optogenetics by decades. Attempts to understand the links between brain function and behavior have relied on techniques such as inserting an electrode into the brain to activate or interrupt neural signals, and creating lesions to disrupt pathways. But these approaches only reveal whether the altered brain regions are involved in the functions being studied, with little detail about the types of cells or networks involved.

Controlling neurons with light (optogenetics) or chemicals (chemogenetics) offers researchers a much more precise way to study brain function. Optogenetics utilizes a microbial protein known as channelrhodopsin (ChR), a light-activated ion channel. When inserted into animal cells under the control of a cell type–specific promoter, the protein is expressed in subsets of neurons, and a beam of light can be used to trigger its activity, spurring those neurons to action. Chemogenetics deploys chemicals rather than light. Cells are engineered to carry DREADD (designer receptors exclusively activated by designer drugs) pro­teins, which are then activated by a drug that doesn’t otherwise affect animal metabolism.

Rodents are often genetically engineered to encode ChR, DREADDs, or other controlling elements. But so far, genetically modifying primates has proven more difficult and expensive, limiting researchers to using viral vectors for delivering genes for these proteins to the brain. These vectors are generally derived from adenoviruses, says Jessica Raper of the Yerkes National Primate Research Center. “Just like humans, nonhuman primates can have neutralizing antibodies for these viruses, so any method must prescreen for antibodies specific to the serotype being used,” she explains.

The larger primate brain also requires larger amounts of vector to be injected directly into the brain, sometimes in multiple doses that may damage tissue. Furthermore, delivering light deep into the brain requires inserting an optical fiber, and chemicals designed to activate inserted genetic sequences must be able to cross the blood-brain barrier. (See “Getting Drugs Past the Blood-Brain Barrier”) That means much more trial and error than in mouse studies. “There’s no universal solution for primates as there is with the host of genetically modified rodents,” says William Stauffer of the University of Pittsburgh.

Nonetheless, several recent studies have managed to probe the function of specific brain regions or cell types in rhesus monkeys, marmosets, and other primates using optogenetic and chemogenetic tools. Here, The Scientist profiles some of these recent efforts.

 

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