Posts tagged CNS
Articles and news from the latest research reports.
Presence of Enzyme May Worsen Effects of Spinal Cord Injury and Impair Long-term Recovery
Traumatic spinal cord injury (SCI) is a devastating condition with few treatment options. Studies show that damage to the barrier separating blood from the spinal cord can contribute to the neurologic deficits that arise secondary to the initial trauma. Through a series of sophisticated experiments, researchers reporting in The American Journal of Pathology suggest that matrix metalloproteinase-3 (MMP-3) plays a pivotal role in disruption of the brain/spinal cord barrier (BSCB), cell death, and functional deficits after SCI. This link also presents new therapeutic possibilities.
“Matrix metalloproteinases (MMPs) are enzymes known to degrade the extracellular matrix and other extracellular proteins and are essential for remodeling of the extracellular matrix and wound healing. Excessive proteolytic activity of MMPs can be detrimental, leading to numerous pathological conditions, including blood brain barrier (BBB)/BSCB disruption after injury,” explains Tae Young Yune, PhD, of the Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea. Although other MMPs have been linked to SCI (i.e. MMP-2, MMP-9, and MMP-12), there has been no previous direct evidence of a similar role for MMP-3.
By comparing mice that underwent spinal cord injury to a control group, investigators found that both MMP3 messenger RNA (mRNA) and MMP-3 protein levels in spinal cord segments were increased after SCI, peaking one day after surgery in the experimental group, whereas no changes were seen in the controls. MMP-3 immunoreactivity was detected in cells within the lesion site, invading neutrophils, and blood vessel endothelial cells in the area outside of the initial injured area (the penumbra).
Another series of experiments focused on the role of MMP-3 in BSCB permeability, using dye to visualize leakage through the BSCB. Similar to MMP-3 mRNA and protein levels, dye leakage reached a maximum one day after SCI. Leakage was lower in Mmp3 knockout mice that were genetically altered to be deficient in MMP-3 as well as in mice injected with either Mmp3 small interfering RNA (siRNA) or a general MMP inhibitor. Injection of MMP-3 into normal spinal cord also significantly increased dye leakage.
MMP-3 was found to contribute to the degradation of tight junction proteins that are responsible for maintaining the integrity of the BSCB barrier. In addition, the researchers reported that MMP-3 induced blood cell infiltration and hemorrhage after SCI in wild-type mice, but not in Mmp3 knockout mice. MMP-3 also mediated activation of other MMPs (MMP-2 and MMP-9) that are up-regulated after SCI. “This is the first study to demonstrate that MMP-3 is involved in MMP-9 activation in central nervous system injury,” says Dr. Yune.
A significant finding was that mice deficient in MMP-3 showed significantly better functional recovery 14 and 28 days after injury than non-deficient mice. Histological analysis showed that after SCI the mice deficient in MMP-3 had smaller volumes of injured tissue and more healthy axons than non-deficient wild-type mice.
“The evidence suggests that BBB/BSCB disruption plays a pivotal role in acute and chronic neurological disorders. The inhibition of MMP-3 may be a promising therapeutic target for human central nervous system disease, including SCI,” notes Dr. Yune.
Biologists ID process producing neuronal diversity in fruit flies’ visual system
New York University biologists have identified a mechanism that helps explain how the diversity of neurons that make up the visual system is generated.
“Our research uncovers a process that dictates both timing and cell survival in order to engender the heterogeneity of neurons used for vision,” explains NYU Biology Professor Claude Desplan, the study’s senior author.
The study’s other co-authors were: Claire Bertet, Xin Li, Ted Erclik, Matthieu Cavey, and Brent Wells—all postdoctoral fellows at NYU.
Their work, which appears in the latest issue of the journal Cell, centers on neurogenesis—the process by which neurons are created.
A central challenge in developmental neurobiology is to understand how progenitors—stem cells that differentiate to form one or more kinds of cells—produce the vast diversity of neurons, glia, and non-neuronal cells found in the adult Central Nervous System (CNS). Temporal patterning is one of the core mechanisms generating this diversity in both invertebrates and vertebrates. This process relies on the sequential expression of transcription factors into progenitors, each specifying the production of a distinct neural cell type.
In the Cell paper, the researchers studied the formation of the visual system of the fruit fly Drosophila. Their findings revealed that this process, which relies on temporal patterning of neural progenitors, is more complex than previously thought.
They demonstrate that in addition to specifying the production of distinct neural cell type over time, temporal factors also determine the survival or death of these cells as well as the mode of division of progenitors. Thus, temporal patterning of neural progenitors generates cell diversity in the adult visual system by specifying the identity, the survival, and the number of each unique neural cell type.
(Source: nyu.edu)
Researchers find new mechanism for neurodegeneration
A research team led by Jackson Laboratory Professor and Howard Hughes Investigator Susan Ackerman, Ph.D., has pinpointed a surprising mechanism behind neurodegeneration in mice, one that involves a defect in a key component of the cellular machinery that makes proteins, known as transfer RNA or tRNA.
The researchers report in the journal Science that a mutation in a gene that produces tRNAs operating only in the central nervous system results in a “stalling” or pausing of the protein production process in the neuronal ribosomes. When another protein the researchers identified, GTPBP2, is also missing, neurodegeneration results.
“Our study demonstrates that individual tRNA genes can be tissue-specifically expressed in vertebrates,” Ackerman says, “and mutations in such genes may cause disease or modify other phenotypes. This is a new area to look for disease mechanisms.”
Neurodegeneration—the process through which mature neurons decay and ultimately die—is poorly understood, yet it underlies major human diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease).
While the causes of neurodegeneration are still coming to light, there is mounting evidence that neurons are exquisitely sensitive—much more so than other types of cells—to disruptions in how proteins are made and how they fold.
tRNAs are critical in translating the genetic code into proteins, the workhorses of the cell. tRNAs possess a characteristic cloverleaf shape with two distinct “business” ends—one that reads out the genetic code in three-letter increments (or triplets), and another that transports the protein building block specified by each triplet (known as an amino acid).
In higher organisms, tRNAs are strikingly diverse. For example, while there are 61 distinct triplets that are recognized by tRNAs in humans, the human genome contains roughly 500 tRNA genes. To date little is known about why they are so numerous, whether they carry out overlapping or redundant functions, or whether they possibly have roles beyond the making of proteins.
“Multiple genes encode almost all tRNA types,” Ackerman says. “In fact, AGA codons are decoded by five tRNAs in mice. Until now, this apparent redundancy has caused us to completely overlook the disease-causing potential of mutations in tRNAs, as well as other repetitive genes.”
Ackerman and her colleagues at The Jackson Laboratory in Bar Harbor, Maine, and Farmington, Conn., The Scripps Research Institute in LaJolla, Calif., and Kumamoto University in Japan pinpointed a mutation in the tRNA gene n-Tr20 as a genetic culprit behind the neurodegeneration observed in mice lacking GTPBP2.
Remarkably, the tRNA’s activity is confined to the brain and other parts of the central nervous system, in both mice and humans. The tRNA encoded by n-Tr20 recognizes the triplet code, AGA (which specifies the amino acid arginine).
The n-Tr20 defect disrupts how proteins are made. Specifically, it causes the “factories” responsible for synthesizing proteins, called ribosomes, to stall when they encounter an AGA triplet.
Such stalling can be largely overcome, thanks to the work of a partner protein called GTPBP2. But when this partner is missing—as it is in the mutant mice that Ackerman and her colleagues studied—the stalling intensifies. This is thought to be a driving force behind the neurodegeneration seen in these mice.
(Source: jax.org)
Sublime Microglia: Expanding Roles for the Guardians of the CNS
Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS). Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS.
Fungal protein found to cross blood-brain barrier
In a remarkable series of experiments on a fungus that causes cryptococcal meningitis, a deadly infection of the membranes that cover the spinal cord and brain, investigators at UC Davis have isolated a protein that appears to be responsible for the fungus’ ability to cross from the bloodstream into the brain.
The discovery — published online June 3 in mBio, the open-access, peer-reviewed journal of the American Society for Microbiology — has important implications for developing a more effective treatment for Cryptococcus neoformans, the cause of the condition, and other brain infections, as well as for brain cancers that are difficult to treat with conventional medications.
“This study fills a significant gap in our understanding of how C. neoformans crosses the blood-brain barrier and causes meningitis,” said Angie Gelli, associate professor of pharmacology at UC Davis and principal investigator of the study. “It is our hope that our findings will lead to improved treatment for this fungal disease as well as other diseases of the central nervous system.”
Normally the brain is protected from bacterial, viral and fungal pathogens in the bloodstream by a tightly packed layer of endothelial cells lining capillaries within the central nervous system — the so-called blood-brain barrier. Relatively few organisms — and drugs that could fight brain infections or cancers — can breach this protective barrier.
The fungus studied in this research causes cryptococcal meningoencephalitis, a usually fatal brain infection that annually affects some 1 million people worldwide, most often those with an impaired immune system. People typically first develop an infection in the lungs after inhalation of the fungal spores of C. neoformans in soil or pigeon droppings. The pathogen then spreads to the brain and other organs.
Unique protein identified
In an effort to discover how C. neoformans breaches the blood-brain barrier, the investigators isolated candidate proteins from the cryptococcal cell surface. One was a previously uncharacterized metalloprotease that they named Mpr1. (A protease is an enzyme — a specialized protein — that promotes a chemical reaction; a metalloprotease contains a metal ion — in this case zinc — that is essential for its activity.) The M36 class of metalloproteases to which Mpr1 belongs is unique to fungi and does not occur in mammalian cells.
The investigators next artificially generated a strain of C. neoformans that lacked Mpr1 on the cell surface. Unlike the normal wild-type C. neoformans, the strain without Mpr1 could not cross an artificial model of the human blood-brain barrier.
They next took a strain of common baking yeast — Saccharomyces cerevisiae — that does not cross the blood-brain barrier and does not normally express Mpr1, and modified it to express Mpr1 on its cell surface. This strain then gained the ability to cross the blood-brain barrier model.
Investigators then infected mice with either the C. neoformans that lacked Mpr1 or the wild-type strain by injecting the organisms into their bloodstream. Comparing the brain pathology of mice 48 hours later, they found numerous cryptococci-filled cysts throughout the brain tissue of mice infected with the wild-type strain; these lesions were undetectable in those infected with the strain lacking Mpr1. In another experiment, after 37 days of being infected by the inhalation route, 85 percent of the mice exposed to the wild-type C. neoformans had died, while all of those given the fungus without Mpr1 were alive.
“Our studies are the first clear demonstration of a specific role for a fungal protease in invading the central nervous system,” said Gelli. “The details of exactly how it crosses is an important new area under investigation.”
New targeted therapies possible
According to Gelli, their discovery has significant therapeutic potential via two important mechanisms. Either Mpr1 — or an aspect of the mechanism by which it crosses the blood-brain barrier — could be a target of new drugs for treating meningitis caused by C. neoformans. In a person who develops cryptococcal lung infection, such a treatment would ideally make the fungus less likely to enter the brain and lead to a rapidly fatal meningitis.
Secondly, Mpr1 could be developed as part of a drug-delivery vehicle for brain infections and cancers. An antibiotic or cancer-fighting drug that is unable to cross the blood-brain barrier on its own could be attached to a nanoparticle containing Mpr1, allowing it to hitch a ride and deliver its goods to where it is needed.
“The biggest obstacle to treating many brain cancers and infections is getting good drugs through the blood-brain barrier,” said Gelli. “If we could design an effective delivery system into the brain, the impact would be enormous for treating some of these terrible diseases.”
Gelli’s group is currently pursuing such a nanoparticle drug-delivery system using Mpr1. They are also further investigating the exact molecular mechanism by which Mpr1 breaches the blood-brain barrier.
(Source: ucdmc.ucdavis.edu)
Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders
NMDA receptor (NMDAR)-induced excitotoxicity is thought to contribute to the cell death associated with certain neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. Targeting NMDARs therapeutically is complicated by the fact that cell signaling downstream of their activation can promote cell survival and plasticity as well as excitotoxicity. However, research over the past decade has suggested that overactivation of NMDARs located outside of the synapse plays a major role in NMDAR toxicity, whereas physiological activation of those inside the synapse can contribute to cell survival, raising the possibility of therapeutic intervention based on NMDAR subcellular localization. Here, we review the evidence both supporting and refuting this localization hypothesis of NMDAR function and discuss the role of NMDAR localization in disorders of the nervous system. Preventing excessive extrasynaptic NMDAR activation may provide therapeutic benefit, particularly in Alzheimer disease and Huntington disease.
Research sheds new light on impact of diabetes on the brain
The new findings published in the Diabetes Care journal reveal the extent of damage patients suffering with the disease can endure in areas of the brain called ‘grey matter’ – a key component of the central nervous system which is involved in touch and pain sensory perception.
During the study, which involved patients with Type 1 and Type 2 diabetes, researchers used recent advances in ground breaking brain imaging and analyses methods to take detailed nerve assessments of the brain using magnetic resonance imaging (MRI) techniques.
This revealed that the volume of certain brain regions in people with diabetic neuropathy was significantly lower compared to those without the disease. Previous studies have shown that the impact of the disease on the brain is limited and isolated to outside areas of the brain considered to be peripheral to core functions in the body.
The breakthrough could pave the way for better assessment and monitoring of the disease, which affects around a third of people with diabetes. This, in turn, could lead to better treatments for sufferers in the future.
Watching how the brain works
University of Miami researchers develop a method to visualize protein interactions in a living organism’s brain
There are more than a trillion cells called neurons that form a labyrinth of connections in our brains. Each of these neurons contains millions of proteins that perform different functions. Exactly how individual proteins interact to form the complex networks of the brain still remains as a mystery that is just beginning to unravel.
For the first time, a group of scientists has been able to observe intact interactions between proteins, directly in the brain of a live animal. The new live imaging approach was developed by a team of researchers at the University of Miami (UM).
(Image caption: Photonic resonance energy transfer described by Förster, or FRET, occurs when two small proteins come within a very small distance of each other — eight nanometers or less. The fluorescence lifetime of the donor molecule will become shorter — from 3 nanosecond to, perhaps, 2.5 nanoseconds. We then interpret this as evidence that the two proteins of interest are physically interacting with each other — a molecular signaling event. Credit: Akira Chiba/University of Miami)
"Our ultimate goal is to create the systematic survey of protein interactions in the brain," says Akira Chiba, professor of Biology in the College of Arts and Sciences at UM and lead investigator of the project. "Now that the genome project is complete, the next step is to understand what the proteins coded by our genes do in our body."
The new technique will allow scientists to visualize the interactions of proteins in the brain of an animal, along different points throughout its development, explains Chiba, who likens protein interactions to the way organisms associate with each other.
"We know that proteins are one billionth of a human in size. Nevertheless, proteins make networks and interact with each other, like social networking humans do," Chiba says. "The scale is very different, but it’s the same behavior happening among the basic units of a given network."
The researchers chose embryos of the fruit fly (Drosophila melanogaster) as an ideal model for the study. Because of its compact and transparent body, it is possible to visualize processes inside the Drosophila cells using a fluorescence lifetime imaging microscope (FLIM). The results of the observations are applicable to other animal brains, including the human brain.
The Drosophila embryos in the study contained a pair of fluorescent labeled proteins: a developmentally essential and ubiquitously present protein called Rho GTPase Cdc42 (cell division control protein 42), labeled with green fluorescent tag and its alleged signaling partner, the regulatory protein WASp (Wiskot-Aldrich Syndrome protein), labeled with red fluorescent tag. Together, these specialized proteins are believed to help neurons grow during brain development. The proteins were selected because the same (homolog) proteins exist in the human brain as well.
Previous methods required chemical or physical treatments that most likely disturb or even kill the cells. That made it impossible to study the protein interactions in their natural environment.
(Image caption: FRET (Förster resonance energy transfer) between the two interacting protein partners occurs, Cdc42 and WASp, within neurons, during the time and space that coincides with the formation of new synapses in the brain of the baby insect. Synapses connect individual neurons in the brain. Credit: Akira Chiba / University of Miami)
The current study addresses these challenges by using the occurrence of a phenomenon called Förster resonance energy transfer, or FRET. It occurs when two small proteins come within a very small distance of each other, (eight nanometers). The event is interpreted as the time and place where the particular protein interaction occurs within the living animal.
(Image caption: Proteins are one billionth of a human in size. Nevertheless, proteins make networks and interact with each other, like social networking humans do,” says Akira Chiba, professor of Biology in the College of Arts and Sciences at the University of Miami. “The scale is very different, but it’s the same behavior happening among the basic units of a given network.” Credit: Akira Chiba / University of Miami)
The findings show that FRET between the two interacting protein partners occurs within neurons, during the time and space that coincides with the formation of new synapses in the brain of the baby insect. Synapses connect individual neurons in the brain.
"Previous studies have demonstrated that Cdc42 and WASp can directly bind to each other in a test-tube, but this is the first direct demonstration that these two proteins are interacting within the brain," Chiba says.
(Source: eurekalert.org)
Robotic advances promise artificial legs that emulate healthy limbs
Recent advances in robotics technology make it possible to create prosthetics that can duplicate the natural movement of human legs. This capability promises to dramatically improve the mobility of lower-limb amputees, allowing them to negotiate stairs and slopes and uneven ground, significantly reducing their risk of falling as well as reducing stress on the rest of their bodies.
That is the view of Michael Goldfarb, the H. Fort Flowers Professor of Mechanical Engineering, and his colleagues at Vanderbilt University’s Center for Intelligent Mechatronics expressed in a perspective’s article in the Nov. 6 issue of the journal Science Translational Medicine.
For the last decade, Goldfarb’s team has been doing pioneering research in lower-limb prosthetics. It developed the first robotic prosthesis with both powered knee and ankle joints. And the design became the first artificial leg controlled by thought when researchers at the Rehabilitation Institute of Chicago created a neural interface for it.
In the article, Goldfarb and graduate students Brian Lawson and Amanda Shultz describe the technological advances that have made robotic prostheses viable. These include lithium-ion batteries that can store more electricity, powerful brushless electric motors with rare-Earth magnets, miniaturized sensors built into semiconductor chips, particularly accelerometers and gyroscopes, and low-power computer chips.
The size and weight of these components is small enough so that they can be combined into a package comparable to that of a biological leg and they can duplicate all of its basic functions. The electric motors play the role of muscles. The batteries store enough power so the robot legs can operate for a full day on a single charge. The sensors serve the function of the nerves in the peripheral nervous system, providing vital information such as the angle between the thigh and lower leg and the force being exerted on the bottom of the foot, etc. The microprocessor provides the coordination function normally provided by the central nervous system. And, in the most advanced systems, a neural interface enhances integration with the brain.
Unlike passive artificial legs, robotic legs have the capability of moving independently and out of sync with its user’s movements. So the development of a system that integrates the movement of the prosthesis with the movement of the user is “substantially more important with a robotic leg,” according to the authors.
Not only must this control system coordinate the actions of the prosthesis within an activity, such as walking, but it must also recognize a user’s intent to change from one activity to another, such as moving from walking to stair climbing.
Identifying the user’s intent requires some connection with the central nervous system. Currently, there are several different approaches to establishing this connection that vary greatly in invasiveness. The least invasive method uses physical sensors that divine the user’s intent from his or her body language. Another method – the electromyography interface – uses electrodes implanted into the user’s leg muscles. The most invasive techniques involve implanting electrodes directly into a patient’s peripheral nerves or directly into his or her brain. The jury is still out on which of these approaches will prove to be best. “Approaches that entail a greater degree of invasiveness must obviously justify the invasiveness with substantial functional advantage,” the article states.
There are a number of potential advantages of bionic legs, the authors point out.
Studies have shown that users equipped with the lower-limb prostheses with powered knee and heel joints naturally walk faster with decreased hip effort while expending less energy than when they are using passive prostheses.
In addition, amputees using conventional artificial legs experience falls that lead to hospitalization at a higher rate than elderly living in institutions. The rate is actually highest among younger amputees, presumably because they are less likely to limit their activities and terrain. There are several reasons why a robotic prosthesis should decrease the rate of falls: Users don’t have to compensate for deficiencies in its movement like they do for passive legs because it moves like a natural leg. Both walking and standing, it can compensate better for uneven ground. Active responses can be programmed into the robotic leg that helps users recover from stumbles.
Before individuals in the U.S. can begin realizing these benefits, however, the new devices must be approved by the U.S. Food and Drug Administration (FDA).
Single-joint devices are currently considered to be Class I medical devices, so they are subject to the least amount of regulatory control. Currently, transfemoral prostheses are generally constructed by combining two, single-joint prostheses. As a result, they have also been considered Class I devices.
In robotic legs the knee and ankle joints are electronically linked. According to the FDA that makes them multi-joint devices, which are considered Class II medical devices. This means that they must meet a number of additional regulatory requirements, including the development of performance standards, post-market surveillance, establishing patient registries and special labeling requirements.
Another translational issue that must be resolved before robotic prostheses can become viable products is the need to provide additional training for the clinicians who prescribe prostheses. Because the new devices are substantially more complex than standard prostheses, the clinicians will need additional training in robotics, the authors point out.
In addition to the robotics leg, Goldfarb’s Center for Intelligent Mechatronics has developed an advanced exoskeleton that allows paraplegics to stand up and walk, which led Popular Mechanics magazine to name him as one of the 10 innovators who changed the world in 2013, and a robotic hand with a dexterity that approaches that of the human hand.
Effects of Chronic Stress Can be Traced to Your Genes
New research shows that chronic stress changes gene activity in immune cells before they reach the bloodstream. With these changes, the cells are primed to fight an infection or trauma that doesn’t actually exist, leading to an overabundance of the inflammation that is linked to many health problems.
This is not just any stress, but repeated stress that triggers the sympathetic nervous system, commonly known as the fight-or-flight response, and stimulates the production of new blood cells. While this response is important for survival, prolonged activation over an extended period of time can have negative effects on health.
A study in animals showed that this type of chronic stress changes the activation, or expression, of genes in immune cells before they are released from the bone marrow. Genes that lead to inflammation are expressed at higher-than-normal levels, while the activation of genes that might suppress inflammation is diminished.
Ohio State University scientists made this discovery in a study of mice. Their colleagues from other institutions, testing blood samples from humans living in poor socioeconomic conditions, found that similarly primed immune cells were present in these chronically stressed people as well.
“The cells share many of the same characteristics in terms of their response to stress,” said John Sheridan, professor of oral biology in the College of Dentistry and associate director of Ohio State’s Institute for Behavioral Medicine Research (IBMR), and co-lead author of the study. “There is a stress-induced alteration in the bone marrow in both our mouse model and in chronically stressed humans that selects for a cell that’s going to be pro-inflammatory.
“So what this suggests is that if you’re working for a really bad boss over a long period of time, that experience may play out at the level of gene expression in your immune system.”
The findings suggest that drugs acting on the central nervous system to treat mood disorders might be supplemented with medications targeting other parts of the body to protect health in the context of chronic social stress.
Steven Cole, a professor of medicine and a member of the Cousins Center for Psychoneuroimmunology at UCLA, is a co-corresponding author of the study. The research is published in a recent issue of the journal Proceedings of the National Academy of Sciences.
The mind-body connection is well established, and research has confirmed that stress is associated with health problems. But the inner workings of that association – exactly how stress can harm health – are still under investigation.
Sheridan and colleagues have been studying the same mouse model for a decade to reveal how chronic stress – and specifically stress associated with social defeat – changes the brain and body in ways that affect behavior and health.
The mice are repeatedly subjected to stress that might resemble a person’s response to persistent life stressors. In this model, male mice living together are given time to establish a hierarchy, and then an aggressive male is added to the group for two hours at a time. This elicits a “fight or flight” response in the resident mice as they are repeatedly defeated by the intruder.
“These mice are chronically in that state, so our research question is, ‘What happens when you stimulate the sympathetic nervous system over and over and over, or continuously?’ We see deleterious consequences to that,” Sheridan said.
Under normal conditions, the bone marrow in animals and humans is making and releasing billions of red blood cells every day, as well as a variety of white blood cells that constitute the immune system. Sheridan and colleagues already knew from previous work that stress skews this process so that the white blood cells produced in the bone marrow are more inflammatory than normal upon their release – as if they are ready to defend the body against an external threat.
A typical immune response to a pathogen or other foreign body requires some inflammation, which is generated with the help of immune cells. But when inflammation is excessive and has no protective or healing role, the condition can lead to an increased risk for cardiovascular diseases, diabetes and obesity, as well as other disorders.
In this work, the researchers compared cells circulating in the blood of mice that had experienced repeated social defeat to cells from control mice that were not stressed. The stressed mice had an average fourfold increase in the frequency of immune cells in their blood and spleen compared to the normal mice.
Genome-wide analysis of these cells that had traveled to the spleen in the stressed mice showed that almost 3,000 genes were expressed at different levels – both higher and lower – compared to the genes in the control mice. Many of the 1,142 up-regulated genes in the immune cells of stressed mice gave the cells the power to become inflammatory rapidly and efficiently.
“There is no traditional viral or bacterial challenge – we’re generating the challenge via a psychological response,” said study first author Nicole Powell, a research scientist in oral biology at Ohio State. “This study provides a nice mechanism for how psychology impacts biology. Other studies have indicated that these cells are more inflammatory; our work shows that these cells are primed at the level of the gene, and it’s directly due to the sympathetic nervous system.”
The researchers confirmed that the sympathetic nervous system was activated by showing that a beta blocker reduced symptoms associated with chronic stress. The beta receptors that were turned off by this intervention are major participants in the sympathetic nervous system response.
Meanwhile, UCLA’s Cole performs specialized statistical analyses of genome function to determine how people’s perception of their surroundings affects their biology. He and colleagues analyzed blood samples both from Sheridan’s mice and from healthy young adult humans whose socioeconomic status had been previously characterized as either high or low.
The human analysis identified differing levels of expression of 387 genes between the low- and high-socioeconomic status adults – and as in the mice, the up-regulated genes were pro-inflammatory in nature. The researchers also noted that almost a third of the genes with altered expression levels in immune cells from chronically stressed humans were the same genes differentially expressed in mice that had experienced repeated social defeat – a much higher similarity than would occur by chance.
This same pro-inflammatory immune-cell profile has been seen in research on parents of children with cancer.
“What we see in this study is a convergence of animal and human data showing similar genomic responses to adversity,” Cole said. “The molecular information from animal research integrates nicely with the human findings in showing a significant up-regulation of pro-inflammatory genes as a consequence of stress – and not just experimental stress, but authentic environmental stressors humans experience in everyday life.”