In addition to the featured articles posted in the blog, links to other research news articles are posted on the Brain Science News page.
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: 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.
From Penn State News:
Women May be More Vulnerable to Concussions Because of “Leaner” Nerve Fibers, Penn Study Suggests
“Train tracks” of female axons were more likely to break from a simulated brain injury than male axons
November 27, 2017
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.
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.
From The Scientist:
Lighting Up Monkey Brains
Optogenetic and chemogenetic tools illuminate brain and behavior connections in nonhuman primates.
November 1, 2017|
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.
From Illinois News Bureau:
Ringing in ears keeps brain more at attention, less at rest, study finds
From Salk News Releases:
New kinds of brain cells revealed
Salk and UC San Diego scientists analyzed methylation patterns of neurons to find new subtypes
LA JOLLA—Under a microscope, it can be hard to tell the difference between any two neurons, the brain cells that store and process information. So scientists have turned to molecular methods to try to identify groups of neurons with different functions.
Now, Salk Institute and University of California San Diego scientists have, for the first time, profiled chemical modifications of DNA molecules in individual neurons, giving the most detailed information yet on what makes one brain cell different from its neighbor. This is a critical step in beginning to identify how many types of neurons exist, which has eluded neuroscientists but could lead to a dramatically better understanding about brain development and dysfunction. Each cell’s methylome—the pattern of chemical markers made up of methyl groups that stud its DNA—gave a distinct readout that helped the Salk team sort neurons into subtypes. The work appears in the journal Science on August 10, 2017.
“We think it’s pretty striking that we can tease apart a brain into individual cells, sequence their methylomes, and identify many new cell types along with their gene regulatory elements, the genetic switches that make these neurons distinct from each other,” says co-senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and an investigator of the Howard Hughes Medical Institute.
In the past, to identify what sets different types of neurons apart from each other, researchers have studied levels of RNA molecules inside individual brain cells. But levels of RNA can rapidly change when a cell is exposed to new conditions, or even throughout the day. So the Salk team turned instead to the cells’ methylomes, which are generally stable throughout adulthood.
“Our research shows that we can clearly define neuronal types based on their methylomes,” says Margarita Behrens, a Salk senior staff-scientist and co-senior author of the new paper. “This opens up the possibility of understanding what makes two neurons—that sit in the same brain region and otherwise look similar—behave differently.”
The team began their work on both mouse and human brains by focusing on the frontal cortex, the area of the brain responsible for complex thinking, personality, social behaviors and decision making, among other things. They isolated 3,377 neurons from the frontal cortex of mice and 2,784 neurons from the frontal cortex of a deceased 25-year-old human.
The researchers then used a new method they recently developed called snmC-seq to sequence the methylomes of each cell. Unlike other cells in the body, neurons have two types of methylation, so the approach mapped both types—called CG methylation (for DNA sequence containing the nucleotides cytosine and guanine) and non-CG methylation.
Neurons from the mouse frontal cortex, they found, clustered into 16 subtypes based on methylation patterns, while neurons from the human frontal cortex were more diverse and formed 21 subtypes. Inhibitory neurons—those that provide stop signals for messages in the brain—showed more conserved methylation patterns between mice and humans compared to excitatory neurons. The study also identified unique human neuron subtypes that had never been defined before. These results open the door to a deeper understanding of what sets human brains apart from those of other animals.
“This study opens a new window into the incredible diversity of brain cells,” says Eran Mukamel of the UC San Diego Department of Cognitive Science, a co-senior author of the work.
Next, the researchers plan to expand their methylome study to look at more parts of the brain, and more brains.
From NINDS Press Release:
Brain “relay” also key to holding thoughts in the mind
Wednesday, May 3, 2017
Thalamus eyed as potential treatment target for schizophrenia’s working memory deficits
Long assumed to be a mere “relay,” an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health revealed that the thalamus sustains the ability to distinguish categories and hold thoughts in mind.
By manipulating activity of thalamus neurons, scientists were able to control an animal’s ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say.
“If the brain works like an orchestra, our results suggest the thalamus may be its conductor,” explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH’s National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). “It helps ensembles play in-sync by boosting their functional connectivity.”
Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia, and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience.
The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers.
Two of the groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain’s thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems.
Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward.
Optogenetically suppressing neuronal activity in the thalamus blocked the mice’s ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals’ performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory.
What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons.
“Our study may have uncovered the key circuit elements underlying how the brain represents categories,” suggested Halassa.
Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse’s ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay – and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain’s memory hub, the hippocampus.
Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. “Top-down” signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus were required to encode in PFC neurons the location of the reward – analogous to the correct door in the Halassa experiment.
“Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input,” noted Gordon. “Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.”
In their study, the Janelia team and Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held in the cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa.
“Our results show that cortex circuits alone can’t sustain the neural activity required to prepare for movement,” explained Gerfen. “It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit.”
From NINDS Press Release:
NIH scientists try to crack the brain’s memory codes
Thursday, June 1, 2017
Studies of epilepsy patients uncover clues to how the brain remembers
The studies were led by Kareem Zaghloul, M.D., Ph.D., a neurosurgeon-researcher at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Persons with drug resistant epilepsy in protocols studying surgical resection of their seizure focus at the NIH’s Clinical Center enrolled in this study. To help locate the source of the seizures, Dr. Zaghloul’s team surgically implanted a grid of electrodes into the patients’ brains and monitored electrical activity for several days.
“The primary goal of these recordings is to understand how to stop the seizures. However, it’s also a powerful opportunity to learn how the brain works,” said Dr. Zaghloul.
For both studies, the researchers monitored brain electrical activity while testing the patients’ memories. The patients were shown hundreds of pairs of words, like “pencil and bishop” or “orange and navy,” and later were shown one of the words and asked to remember its pair.
In one study, published in the Journal of Neuroscience, the patients correctly remembered 38 percent of the word pairs they were shown. Electrical recordings showed that the brain waves the patients experienced when they correctly stored and remembered a word pair often occurred in the temporal lobe and prefrontal cortex regions. Nevertheless, the researchers showed that the waves that appeared when recalling the words happened faster than the waves that were present when they initially stored them as memories.
“Our results suggest the brain replays memories on fast forward,” said Dr. Zaghloul.
In the second study, published in Current Biology, the researchers used a new type of grid, called a high density microelectrode array, to monitor the activity of dozens of individual neurons during the memory tests. The arrays were implanted into the middle temporal gyrus, a part of the brain thought to control word, face and distance recognition.
In this study, the patients correctly remembered 23 percent of the word pairs. When the researchers looked at the electrical recordings, they found that the pattern of neurons that fired when the patients correctly recalled a word pair appeared to be similar to the pattern of neurons that fired when they first learned the pair. Moreover, the results showed that the overall activity of the neurons was specific to each individual word pair and was quietest when the patients correctly remembered a pair, suggesting that the brain only uses a small proportion of neurons to represent each memory.
“These results support the idea that each memory is encoded by a unique firing pattern of individual neurons in the brain,” concluded Dr. Zaghloul.