Cannabis use is associated with disturbances in concentration and memory. New research by neuroscientists at the University of Bristol, published in the Journal of Neuroscience, has found that brain activity becomes uncoordinated and inaccurate during these altered states of mind, leading to neurophysiological and behavioural impairments reminiscent of those seen in schizophrenia.
The collaborative study, led by Dr Matt Jones from the University's School of Physiology and Pharmacology, tested whether the detrimental effects of cannabis on memory and cognition could be the result of 'disorchestrated' brain networks.
Brain activity can be compared to performance of a philharmonic orchestra in which string, brass, woodwind and percussion sections are coupled together in rhythms dictated by the conductor. Similarly, specific structures in the brain tune in to one another at defined frequencies: their rhythmic activity gives rise to brain waves, and the tuning of these brain waves normally allows processing of information used to guide our behaviour.
Using state-of-the-art technology, the researchers measured electrical activity from hundreds of neurons in rats that were given a drug that mimics the psychoactive ingredient of marijuana. While the effects of the drug on individual brain regions were subtle, the drug completely disrupted co-ordinated brain waves across the hippocampus and prefrontal cortex, as though two sections of the orchestra were playing out of synch.
Both these brain structures are essential for memory and decision-making and heavily implicated in the pathology of schizophrenia.
The results from the study show that as a consequence of this decoupling of hippocampus and prefrontal cortex, the rats became unable to make accurate decisions when navigating around a maze.
Dr Jones, lead author and MRC Senior Non-clinical Fellow at the University, said: "Marijuana abuse is common among sufferers of schizophrenia and recent studies have shown that the psychoactive ingredient of marijuana can induce some symptoms of schizophrenia in healthy volunteers. These findings are therefore important for our understanding of psychiatric diseases, which may arise as a consequence of 'disorchestrated brains' and could be treated by re-tuning brain activity."
Michal Kucewicz, first author on the study, added: "These results are an important step forward in our understanding of how rhythmic activity in the brain underlies thought processes in health and disease."
A tiny difference in the coding pattern of a single gene significantly affects the rate at which men's intellectual function drops with advancing age, investigators at the Stanford University School of Medicine and the Veterans Affairs Palo Alto Health Care System have learned.
In a study to be published online Oct. 25 in Translational Psychiatry, the researchers tested the skills of experienced airplane pilots and found that having one version of the gene versus the other version doubled the rate at which the participants' performance declined over time.
The particular genetic variation, or polymorphism, implicated in the study has been linked in previous studies to several psychiatric disorders. But this is the first demonstration of its impact on skilled task performance in the healthy, aging brain, said the study's senior author, Ahmad Salehi, MD, PhD, clinical associate professor of psychiatry and behavioral sciences at Stanford.
The study also showed a significant age-related decline in the size of a key brain region called the hippocampus, which is crucial to memory and spatial reasoning, in pilots carrying this polymorphism.
"This gene-associated difference may apply not only to pilots but also to the general public, for example in the ability to operate complex machinery," said Salehi, who is also a health-science specialist at the VA-Palo Alto.
The gene in question codes for a well-studied protein called brain-derived neurotropic factor, or BDNF, which is critical to the development and maintenance of the central nervous system. BDNF levels decline gradually with age even in healthy individuals; researchers such as Salehi have suspected that this decline may be linked with age-related losses of mental function.
Genes, which are blueprints for proteins, are linear sequences of DNA composed of four different chemical units all connected like beads on a string. The most common version of the BDNF gene dictates that a particular building block for proteins, called valine, be present at a particular place on the protein. A less common - though far from rare - variation of the BDNF gene results in the substitution of another building block, methionine, in that same spot on the protein. That so-called "val/met" substitution occurs in about one in three Asians, roughly one in four Europeans and Americans, and about one in 200 sub-Saharan Africans. Such a change can affect a protein's shape, activity, level of production, or distribution within or secretion by cells in which it is made.
It appears that the alternative "met" version of BDNF doesn't work as well as the "val" version. This variant has been linked to higher likelihood of depression, stroke, anorexia nervosa, anxiety-related disorders, suicidal behavior and schizophrenia.
So Salehi and his colleagues decided to look at whether this polymorphism actually affected human cognitive function. To do this, they turned to an ongoing Stanford study of airplane pilots being conducted by two of the paper's co-authors - Joy Taylor, PhD, clinical associate professor of psychiatry and behavioral sciences, and Jerome Yesavage, MD, professor of psychiatry and behavioral sciences -examining a wide array of neurological and psychiatric questions.
For this new research, Salehi and his colleagues followed 144 pilots, all healthy Caucasian males over the age of 40, who showed up for three visits, spaced a year apart, spanning a two-year period. During each visit, participants - recreational pilots, certified flight instructors or civilian air-transport pilots - underwent an exam called the Standard Flight Simulator Score, a Federal Aviation Administration-approved flight simulator for pilots.
This test session employs a setup that simulates flying a small, single-engine aircraft. Each participant went through a half-dozen practice sessions and a three-week break before his first visit. Each annual visit consisted of morning and afternoon 75-minute "flights," during which pilots confronted flight scenarios with emergency situations, such as engine malfunctions and/or incoming air traffic. Resulting test scores pooled several variables, such as pilots' reaction times and their virtual planes' deviations from ideal altitudes, directions and speed. A pilot's score represented the overall skill with which he executed air-traffic control commands, avoided airborne traffic, detected engine emergencies and approached landing strips.
Blood and saliva samples collected on the pilots' first visits allowed the Stanford investigators to genotype all 144 pilots, of whom 55 (38.2 percent) turned out to have at least one copy of a BDNF gene that contained the "met" variant. In their analysis, the researchers also corrected for pilots' degree of experience and the presence of certain other confounding genetic influences.
Inevitably, performance dropped in both groups. But the rate of decline in the "met" group was much steeper.
"We saw a doubling of the rate of decline in performance on the exam among met carriers during the first two years of follow-up," said Salehi.
About one-third of the pilots also underwent at least one round of magnetic resonance imaging over the course of a few years, allowing the scientists to measure the size of their hippocampi. "Although we found no significant correlation between age and hippocampal size in the non-met carriers, we did detect a significant inverse relationship between age and hippocampal size in the met carriers," Salehi said.
Salehi cautioned that the research covered only two years and that the findings need to be confirmed by following participants over a multiyear period. This is now being done, he added.
No known drugs exist that mimic BDNF's action in the brain, but there is one well-established way to get around that: Stay active. "The one clearly established way to ensure increased BDNF levels in your brain is physical activity," Salehi said.
Washington State University researchers have taken a promising step toward creating an animal model for decoding the specific brain circuits involved in depression. By electrically stimulating a brain region central to an animal’s primary emotions, graduate student Jason Wright and his advisor Jaak Panksepp saw rats exhibit various behaviours associated with a depressed, negative mood or affect.
“We might now have a model that allows us to actually know where to look in the brain for changes relevant to depression, and we can monitor how activity in these regions change during states of negative affect and the restoration of positive affect,” says Wright. “There are no other models out there like this.”
The researchers caution that their work comes with various caveats and that many factors still need to be evaluated.
But while rats aren’t humans and can’t talk about their emotions, researchers like Panksepp have demonstrated that their emotions can be valid indicators of their moods. The researchers also believe a focus on specific emotional circuits, shared by all mammals, improves less specific stressors.
“No one has previously stimulated a specific brain system and produced a depressive cascade,” says Panksepp, who has pioneered work in how core emotions stem from deep, ancient parts of the brain. “That is what this paper does.”
Their research, published in this month’s issue of the journal Neuroscience & Biobehavioral Reviews, opens up new avenues of experimentation and treatments by offering a model in which scientists can directly create positive and negative effects with the dependent and independent variables that science relies on.
And with the pandemic of depression in Western society, researchers say there is a real need for more specific tests focusing on depression-linked emotion networks in a highly controlled fashion.
For now, they say, the lack of animal models aimed at the core emotional issues of depression might be why little progress has been made in antidepressant medicinal development. They note that no conceptually novel drug treatments of depression have emerged since the accidental discovery in the 1960s that increasing brain neurotransmitters like norepinephrine and serotonin can alleviate some depressive symptoms.
Wright and Panksepp focused on the dorsal periaqueductal grey, an area of grey matter in the midbrain that controls perceptions of pain, the fight-or-flight response and emotions of grief, panic and social loss. For 15 days, the researchers administered brief electrical stimuli to the region for 30 seconds over 10 minutes each day.
For up to a month afterwards, they documented dramatic reductions in ultrasonic sounds that indicated a positive affective state. Earlier work by Panksepp’s group has demonstrated that the squeal-like ultrasonic sounds reflect a primordial form of social joy comparable—and perhaps evolutionarily linked—to human laughter.
The rats also exhibited higher levels of agitation, drank less sugar water and explored their surroundings less—further indications of a depressed state.
Wright and Panksepp hope this kind of controlled, network-focused work opens a potential new era in developing psychiatric models.
“In this way,” they write, “we may be able to more precisely identify the types of brain systems that lead to various forms of depressive despair and sift through their neurochemical underpinnings for the most promising brain chemicals and vectors for new medicinal development.”
New research suggests that some patients develop a potentially deadly blood infection from their implanted cardiac devices because bacterial cells in their bodies have gene mutations that allow them to stick to the devices.
Geoscientists were the major contributors to the finding.
Proceedings of the National Academy of Sciences published the study results online this week.
“Geobiologists, key to these results, use atomic force microscopy to study the forces with which bacteria adhere to mineral surfaces,” said Enriqueta Barrera, program director in the National Science Foundation’s Division of Earth Sciences, which funded the research.
“These scientists have adapted this approach, along with molecular dynamics simulations, to gain a better understanding of the strength with which the proteins of infectious bacteria adhere to cardiac implants,” said Barrera. “Such results might have implications for the development of medication to treat this type of infection.”
Patients with implants can develop infections because of a biofilm of persistent bacteria on the surfaces of their devices.
A biofilm is a community of bacterial cells that lives on the surface of a solid substrate. Biofilms are the most common mode of life for all bacteria, whether they reside in the environment or in the human body.
The scientific principles governing the formation of bacterial biofilms on cardiac devices are strongly linked with those of biofilm formation on mineral surfaces, hence the connection with geobiology.
Scientists found that some strains of the bacteria, Staphylococcus aureus, have just a few genetic variants in the proteins on their surfaces that make them more likely to form these biofilms.
The research seeks to get to the heart of a medical paradox: devices such as pacemakers, defibrillators and prosthetic cardiac valves save lives, but they cause infections in about 4 percent of the estimated 1 million patients receiving implants each year in the United States.
Because biofilms resist antibiotics, the only treatment is surgery to remove the contaminated device and implant a new one. This adds up to thousands of surgeries and more than $1 billion in health care costs every year.
A team led by scientists at Ohio State University and Duke University Medical Center used atomic force microscopy and powerful computer simulations to determine how Staph bacteria bond to the devices in the process of forming these biofilms.
The findings offer clues about potential techniques that could be employed to prevent infections in patients who need these devices to stay alive.
“We’re probing the initial step to that biofilm formation,” said Steven Lower, scientist at Ohio State and lead author of the paper reporting the study’s results.
“Can you shut that down somehow? If that bacterium never sticks, there’s no biofilm. It’s that simple. But it’s not quite that simple in practice.”
Using Staph cells collected from patients–some with cardiac device-related infections–the researchers examined how these bacteria adhere to implants to create a biofilm.
The bond forms when a protein on the bacterial cell surface connects with a common human blood protein coating an implanted device.
But an estimated half of all Americans have Staph bacteria living in their noses, and not every cardiac implant patient develops an infection.
So why do some strains of these bacteria cause infection while others remain dormant?
The researchers discovered that Staph surface proteins containing three genetic variants, or single-nucleotide polymorphisms, formed stronger bonds with the human proteins than did Staph proteins without those variants.
The presence of these genetic variants was associated with the strains of bacteria that had infected implanted cardiac devices.
The finding is a first step toward preventing the bacteria from bonding to the devices.
“It will be useful to explore this in more detail and see if we can understand the basic science behind how these bonds form, and why they form,” Lower said. “Perhaps then we can exploit some fundamental force law.
Lower, a scientist with a background in geology, physics and biology, collaborated for a decade with Vance Fowler, a scientist at Duke’s Medical Center and the study’s co-lead author.
Lower specializes in atomic force microscopy and molecular dynamics simulations to explore molecular-level relationships between inanimate surfaces and living microorganisms.
Fowler, who specializes in infectious diseases, assembled a rare library of hundreds of Staphylococcus aureus isolates collected from patients.
Fowler hopes his samples might help answer a broader question related to varied patient responses to the blood infection bacteremia.
“I believe that our research is a critical first step towards understanding, and eventually preventing, cardiac device infections caused by Staphylococcus aureus,” Fowler said.
The researchers used 80 Staph isolates from three different groups: patients with a blood infection and a confirmed cardiac device infection, patients with a blood infection and an uninfected cardiac device, and Staph from the noses of healthy subjects living in the same area.
Single-cell studies of bacteria are complicated by their tiny size, one millionth of a meter, so an atomic-force microscope is required to visualize their behavior.
Co-author and Ohio State researcher Nadia Casillas-Ituarte performed these experiments, connecting single Staph bacteria to a protein-coated probe to allow bonds to form, and then rupturing the bonds to measure the strength of each connection.
Casillas-Ituarte simulated the human heartbeat, allowing bonds to form over the course of a second and then pulling the probe away.
By doing this at least 100 times on each cell and verifying the work on hundreds of additional cells, she generated more than a quarter-million force curve measurements for the analysis.
“The first step is to determine how a bacterium ‘feels’ a surface,” she said. “You can’t stop that process until you first understand how it happens.”
The researchers coated the probe with fibronectin, a common human blood protein found on the surface of implanted devices.
Staph bacteria can create a biofilm by forming bonds with this protein through a protein on their own surface called fibronectin-binding protein A.
To learn more about the bacterial protein, the scientists then sequenced the amino acids that make up fibronectin-binding protein A in each isolate they studied.
This is where they found the single-nucleotide polymorphisms (SNPs, pronounced “snips”), which were more common in the isolates collected from patients with infections related to their heart implants.
To further test the effects of these SNPs, the team used a supercomputer to simulate the formation of the bond between the bacterial and human proteins.
When they plugged standard amino acid sequences from each protein into the supercomputer, the molecules maintained a distance from each other.
When they altered the sequence of three amino acids in the bacterial surface protein and entered that data, hydrogen bonds formed between the bacterial and human proteins.
“We changed the amino acids to resemble the SNPs found in theStaph that came from cardiac device-infected patients,” Lower said. “So the SNPs seem to have a relationship to whether a bond forms or not.”
Fibronectin-binding protein A is one of about 10 of these types of molecules on the Staph surface that can form bonds with proteins on host cells, Lower noted.
It’s also possible that fibronectin, the human protein on the other side of the bond studied so far, might contain genetic variants that contribute to the problem.
What the scientists do know is that bacteria will do all they can to survive, so it won’t be easy to outsmart them.
“Bacteria obey Charles Darwin’s law of natural selection and can evolve genetic capabilities to allow them to live in the presence of antibiotics,” Lower said.
“Most physicists would tell you there are certain laws of physics that dictate what happens and when it happens, and you can’t evade or evolve ways around those.
“If you understand the basic physics of it, can you exploit a fundamental force law that bacteria can’t evade or evolve a mechanism around?”
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This work was also supported by grants from the National Institutes of Health, the Brazilian National Council for Scientific and Technological Development/Brazilian National Science and Technology Institute, and the Swiss National Science Foundation/Swiss Medical Association.
Additional co-authors include Supaporn Lamlertthon and L. Barth Reller of Duke; Roberto Lins of the Universidade Federal de Pernambuco, Recipfe, in Brazil; Ruchirej Yongsunthon, Eric Taylor, Alex DiBartola and Brian Lower of Ohio State; Catherine Edmonson and Lauren McIntyre of the University of Florida; Yok-Ai Que of the University of Lausanne in Switzerland; and Robert Ros of Arizona State University.
Viral films: Complex, highly structured films made using viruses could be used as optical devices and as templates for engineering tissue, bone, and teeth. Woo-Jae Chung, UC Berkeley
BIOMEDICINE
New Technique Turns Viruses Into Useful Tools
In one simple step, viruses can be turned into sophisticated structures with novel optical or biomedical properties.
Researchers have demonstrated a simple, one-step process in which genetically engineered viruses arrange themselves into extremely ordered patterns with distinctive properties, such as color or strength. The technique could be used to make novel optical devices or biological scaffolds to grow soft tissue, teeth, and bone.
The researchers, led by Seung-Wuk Lee, a bioengineering professor at the University of California, Berkeley, used the technique to make structured films. "We want to mimic nature and create many different types of functional structures with a very simple building block," Lee says.
This work is part of a broader effort to make new types of materials using viruses as microscopic building blocks. Researchers at MIT, led by Angela Belcher, a biological engineering and materials science professor, have previously engineered viruses to bind toinorganic materials—something they would never do naturally—and have them assemble intobattery components.
Lee and his colleagues have found a way to fine-tune the arrangement of individual viruses to create sophisticated structures with complex designs all on their own. Using a single virus as a building unit is "pretty exquisite," says Belcher, because its traits can be genetically modified and you can attach many different useful materials to its surface. What's even more important about the new work, which was published in the journal Nature last week, is the precise control over viral self-assembly, resulting in large-scale structures with multiple levels of organization. "This is very beautifully laid out," she says. "They can do so much with a single virus."
The researchers used a rod-shaped bacterial virus, called M13, for their work. First, they dip a flat glass sheet into a saline solution containing the viruses. As they pull the glass out slowly at a controlled speed, the viruses spontaneously configure themselves on the glass surface into orderly patterns. This assembly happens as the solvent evaporates. "Self-assembly is hard to achieve in a systematic way, but what the authors have come up with shows a potentially powerful route to do this," says George Schatz, a chemistry professor at Northwestern University.
By changing the virus concentration in the solution and the pulling speed, the researchers were able to create different structured films. One has regularly placed stripes made of virus bundles in which the viruses are aligned and twisted like corkscrews.
The most complex film has a "ramen-noodle-like" structure that bends light in certain ways. Various pulling speeds change the spacing and width of the viruses in this wavy structure, so that it shows distinct colors. Such films could be used as light reflectors and filters found in displays and photography. The technique could also be used to fabricate photonic crystals and organic photovoltaics.
The researchers also showed that the material could be made into a scaffold to engineer complex tissues. To do this, they genetically tweaked the virus to make it express certain proteins on its surface, which influence the growth of the tissue. They cultured cells on top of the films and found that the cells aligned themselves with the microstructure. What's more, when the films were dipped in a solution of calcium and phosphate ions, the ions mineralized on the film to form a tough material similar to tooth enamel.
"Developing a system like this that could regenerate bone or could be used for growth of materials for teeth is a very possible application," says Belcher.
