June 5, 2019

It’s proven stress wears down the body and compromises the immune system—but why?

Scientists can’t yet fully explain how the association between stress and health plays out at the cellular level, but they are closer thanks to recent results from a collaborative study. Researchers at the Washington National Primate Research Center (WaNPRC) at the University of Washington (UW) in collaboration with researchers at Duke University, the University of Montreal and the Yerkes National Primate Research Center (YNPRC) at Emory University examined the cellular effects of one common stressor: social hierarchy.

“The goal is to understand the mechanisms through which social experiences or environment ‘get under the skin,’ so to speak, to affect health and survival,” said the study’s lead author, Noah Snyder-Mackler, a UW assistant professor of psychology.

In the study, scientists mixed up the existing social groupings of nearly four dozen rhesus macaques at the Yerkes Research Center, observed behaviors among the new groups and analyzed blood samples to determine the cellular effects of the new social order. The team specifically measured effects on the peripheral immune system, which are immune cells that patrol other systems of the body, such as muscles.

Organizing the macaques into novel groups effectively created a new social hierarchy.  The first in the group became the most dominant and held the highest rank, while the last to join the group typically held the lowest status.

After each group’s hierarchy was established and behavior observed, the researchers took blood samples and treated the macaques with a synthetic stress hormone. The results showed the cells of the lower-status macaques were less able to respond productively to the hormone than those of the higher-status animals.

One explanation for this lack of a response was found within the macaques’ immune cells’ genetic information. Low-status females had immune cells that were less accessible to the signal from the hormone. In humans, stressful or traumatic situations have been linked to similar hormonal resistance.

“We know that social adversity early in life can have far-reaching effects that extend into adulthood,” Snyder-Mackler said. “The questions are, when do these events have to occur, how severe do they have to be and are they reversible or even preventable?”

Further research will help the researchers answer these questions, identify the magnitude of the effects of stress and, in the pursuit of improved human health, determine what might protect people from those impacts.

October 29, 2018

Stress can lead to a host of health issues, including heart disease, digestive problems, asthma and diabetes. Stress can also be inherited, setting up infants and children for lives of anxiety as a result of stressors their parents faced before they were even conceived.

Fortunately, researchers at Emory University’s Yerkes National Primate Research Center have shown for the first time it is possible to reverse the hereditary influences of parental stress. The findings could lead to treatments to prevent intergenerational stress in humans.

The scientists used two pleasant odors on adult male mice to identify effective strategies to break the cycle of intergenerational stress. They began the study with each mouse participating in one of three protocols: 1) exposed the mice to an odor; 2) trained the mice to associate an odor with a mild stressor; or 3) trained the mice to associate the odor with a mild stressor and then extinguished the fear via extinction training during which the researchers presented the odor in the absence of any stress.

By extinguishing parental fear to the two specific odors, the researchers found three key results: 1) the offspring did not show any behavioral sensitivity to the same two odors; 2) the nervous systems of the offspring did not show any structural imprints of the parental olfactory stress; and 3) the sperm of the parental male mice did not bear chemical imprints of the olfactory stress.

“Our study results not only confirm conditioned stress can be extinguished in the parent without passing it on to the offspring, they are an important public health contribution because they provide optimism for applying similar interventional approaches in humans and breaking intergenerational cycles of stress,” said Brian Dias, an assistant professor at the Yerkes Research Center and the Emory University School of Medicine Department of Psychiatry and Behavioral Sciences. “These latest data provide our research team a platform from which we can address larger public health concerns, including the intergenerational influences of parental neglect and maltreatment during childhood. We want to know whether reversals such as what we showed in our current study can be observed after we apply interventions to populations exposed to these negative environmental influences.”

April 10, 2018

The effects of Zika on an adult are upsetting enough, but the impact it can have on unborn children and newborns is heart wrenching, which is why researchers at the Yerkes National Primate Research Center have made studying Zika virus a priority.

One of the most common consequences of Zika infecting an unborn child is microcephaly – a birth defect that leaves the baby with an unusually small head and undersized brain. It can be fatal, and infants who survive usually face intellectual disabilities and developmental delays.

When researchers at the Yerkes National Primate Research Center in collaboration with colleagues at Emory University School of Medicine and Children’s Healthcare of Atlanta wondered whether contracting the disease early after birth had the same effect, they noted some small, but important distinctions. For example, the disease did not appear to affect vision or visual memory.

“This gives us hope that in our future work, we can find ways to limit Zika’s effect on the developing brain,” said Ann Chahroudi, MD, PhD, the study’s lead researcher.

For now, because there is lasting damage to the nervous system and areas of the brain, the research team recommends more than just routine monitoring for pediatric patients known to be infected with Zika.

The researchers hope further work with the monkey model will allow them to study in more detail the effects of postnatal Zika virus infection on the brain and give them opportunities to test therapies for alleviating or even preventing the neurologic consequences of Zika virus infection.

March 6, 2018

Concerns about antibiotic-resistant bacteria have been growing in recent years, and researchers at the Yerkes National Primate Research Center (YNPRC) have added another to the list. Klebsiella pneumoniae, a bacterium that causes blood, soft tissue and urinary tract infections, has been found resistant to colistin, a powerful last resort antibiotic. In 2013, the Centers for Disease Control and Prevention (CDC) listed Carbapenem-resistant Enterobacteriaceae (CRE), which include Klebsiella, as one of the top three urgent antibiotic resistant threats.

According to the CDC, healthy people usually don’t contract this type of infection. It usually affects patients in hospitals, nursing homes and other health-care settings. Patients whose care requires devices such as ventilators, urinary catheters or intravenous catheters, and patients who are taking antibiotics for a long period of time are most at risk for CRE infections. Various types of Klebsiella are estimated to be responsible for 10 percent of infections acquired in health-care facilities.

“This is concerning because Klebsiella is a more common cause of infection than Enterobacter,” said David Weiss, a researcher at the Yerkes National Primate Research Center and the director of the Emory Antibiotic Resistance Center. “To our knowledge, this type of [antibiotic-resistant] Klebsiella has not been observed in the United States before.”

Despite the extra time required, Dr. Weiss and his colleagues recommend clinical laboratories consider testing for heteroresistance to colistin if this last line antibiotic is required for CRE treatment.

January 26, 2018

Nearly one million Americans live with Parkinson’s disease (PD). As the disease progresses, people who have PD are likely to lose motor functions and the ability to live an independent life. Much of this is attributable to the drug treatment for PD that leads to abnormal, involuntary movements known as dyskinesias. Scientists at Yerkes National Primate Research Center have been probing the origin of these abnormal responses to treatment and have successfully tested a tactic for controlling them.

Dyskinesias are believed to be caused by fluctuations in dopamine, the neurotransmitter whose production is lost in the brains of those with Parkinson’s. The standard drug levodopa restores dopamine, but sometimes, in the process of achieving symptom relief, dopamine levels become too high, and responses are unstable.

Researchers led by Stella Papa, a Yerkes researcher and associate professor of neurology at Emory University School of Medicine, showed striatal projection neurons (SPN), which become hyperactive when nearby dopamine-producing neurons degenerate, could be controlled by certain drugs, reducing the rate of unstable responses to dopamine that cause dyskinesias.

“Our focus was to prove SPN hyperactivity plays an important role and that glutamate signals are a major contributor,” says Papa. “Knowing this mechanism may serve to develop different therapeutic strategies: pharmacological treatments or gene therapies.”

Yerkes researchers tested whether the drug LY235959 (an NMDA receptor antagonist) or NBQX (an AMPA receptor antagonist) could control SPN hyperactivity and dyskinesia symptoms in Parkinson’s model monkeys. The nonhuman primate model of Parkinson’s uses the neurotoxin MPTP, which destroys dopamine-producing neurons. Both drugs interfere with signals by the neurotransmitter glutamate. In the presence of levodopa, the drugs had calming effects. After lowering the SPN firing frequency by 50 percent, the response to dopamine stabilizes and abnormal movements are markedly diminished.

The particular drugs used are not ideal for human application, but they do reveal mechanisms behind dyskinesias. Researchers say these insights will be valuable to advance their research and, ultimately, develop new treatments with improved effectiveness for people who have PD.

January 3, 2018

What doesn’t kill you might just save your life.

At least, that’s the new thinking on how to combat SIV, a variant of HIV. This comes after researchers at the Yerkes National Primate Research Center sequenced the genome of the sooty mangabey – a nonhuman primate that can coexist with SIV – and discovered how an immune system deficiency actually stops SIV from turning into AIDS.

“We found two big differences in proteins of the immune system in the sooty mangabey genome, which we hope will help us better understand why sooty mangabeys avoid AIDS despite SIV infection,” said David Palesch, a Yerkes postdoctoral fellow and co-author of the study documenting the discovery.

These differences aren’t some biological defense system or super-simian invulnerability. Technically, they’re handicaps. Instead of a more robust immune system, the sooty mangabey is playing a man down in the fight against SIV and winning.

So what are these immune deficiencies? A missing piece in the the ICAM2 gene stops the corresponding protein from functioning – a genetic anomaly unique to the mangabey species.

Similarly, the TLR4 protein – a molecule that senses bacteria and triggers an immune defense against it – has limited functioning because of a genetic alteration.

“This finding is intriguing because damage to intestinal barriers and bacterial release contributes to chronic immune activation, which is associated with AIDS progression in HIV-infected humans and SIV-infected non-natural hosts,” said Guido Silvestri, chief of Microbiology and Immunology at the Yerkes Research Center.

Inspired by these findings, the Yerkes team is already planning its next study where the ICAM2 and TLR4 proteins will be manipulated in a living nonhuman primate host to determine how those genetic anomalies halt SIV’s progression.

“It’s a really exciting time in AIDS research,” said Dr. Steve Bosinger, assistant professor of Pathology and Laboratory Medicine and director of Yerkes’ Genomics Core. “We’ve seen that an HIV cure is possible.” Now, that’s something to be excited about.

Photo credit: Yerkes National Primate Research Center

December 1, 2017

The road to addiction recovery might become a little less rocky, thanks to a recent study by researchers at the Yerkes National Primate Research Center. Researchers suggest the drug fasudil, approved in Japan for cerebral vasospasm and stroke, could be an effective tool for treating drug abuse and preventing relapse.

Most of our everyday actions come from habits, not from deliberate decision-making. This can be detrimental in the case of drug abuse and drug-seeking behavior, says lead author Shannon Gourley, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

“Some habits are adaptive – for example, turning off a light when you exit a room – but others can be maladaptive, for example in the case of habitual drug use. We wanted to try to figure out a way to help ‘break’ habits, particularly those related to the highly addictive drug cocaine,” says Gourley.

She and former graduate students Andrew Swanson and Lauren Depoy first tested fasudil in situations where they had trained mice to poke their noses in two chambers, based on rewards of both food and cocaine. Then, the researchers changed the rules of the game – mice could now only get a reward from one chamber, instead of both. Fasudil helped the mice adjust and display “goal-directed” behavior, rather than their previous habit-based behavior.

Next, the researchers trained the mice to supply themselves a sweet cocaine solution. After the mice formed habit-based behavior, researchers changed the nature of that experience: the cocaine was paired with lithium chloride, making the mice feel sick. Fasudil treatment nudged the mice to give themselves less cocaine afterward, rather than continuing to respond habitually. Fasudil didn’t make cocaine itself less pleasurable, but was specifically modifying the habit process.

Unlearning habits involves remodeling connections made by cells in the brain. Fasudil seems to promote the pruning of dendritic spines, structures that help neurons communicate, by inhibiting Rho kinase, which helps stabilize cells’ internal skeletons. The drug thereby loosens the cell structures and appears to reduce the density of dendritic spines in the region of the brain important for learning new behaviors. Importantly, tests show fasudil must be directly paired with new learning to have that effect.

While overactive synaptic pruning has been proposed to play roles in Alzheimer’s disease and schizophrenia, when used appropriately, fasudil and similar compounds are promising candidates for drug addiction therapy.

 

Reviewed August 2019

July 28, 2017

A collaborative research team at the Yerkes National Primate Research Center and Georgia Tech is studying non-invasive imaging as a way to detect immune rejection of transplanted organs, thanks to a $2.4 million, five-year grant from the National Institute of Allergy and Infectious Diseases.

Currently, medical professionals use blood tests and biopsies – removing a small sample of the organ tissue – to monitor how well a new kidney or liver is adapting to its new home. But with each biopsy, the patient must endure a small surgery so the organ can be accessed yet again. These follow-up procedures can result in hemorrhaging and infection – a major problem for anyone, but especially someone still recovering from the trauma of a transplant.

Andrew Adams, MD, PhD, a researcher at the Yerkes National Primate Research Center and an assistant professor of surgery in Emory University School of Medicine, is part of the team working to identify a non-invasive method for monitoring organs post-transplant.

“Patients often require multiple biopsies to assess response to treatment, thus putting them at risk of complications each time they undergo a separate procedure,” says Adams. “In addition, a biopsy only samples a small part of the transplanted organ.” In other words, just because part of the organ is adapting, doesn’t mean all of it is.

Adams and his colleague at Georgia Tech, Phil Santangelo, are studying the use of positron emission tomography (PET) to monitor post-transplant progress. PET is already used to diagnose heart disease and monitor cancer. Using a variant called “immunoPET,” the researchers can see particular types of immune cells infiltrating the transplanted organ, alerting them to the possibility of rejection. The researchers are conducting the study with mice and nonhuman primates first and hope the results will prove successful so they can advance to human clinical trials.

 

Reviewed August 2019

June 1, 2017

It can make a parent’s heart race – finding out your infant must undergo extensive surgery that requires general anesthesia. According to the U.S. Food and Drug Administration (FDA), approximately one million children under the age of four annually undergo surgery with general anesthesia, making understanding effects of early life exposure to anesthesia critical.

Yerkes National Primate Research Center researchers and their colleagues at Mt. Sinai’s Icahn School of Medicine set out to determine just that. Through animal research, the team discovered infant monkeys repeatedly exposed to a common anesthetic, sevoflurane, suffered impairment in visual recognition memory after the first year of life. Furthermore, results indicated the impairment may persist long term.

Dr. Maria Alvarado, first author and leader of the Yerkes team, noted, “Animal studies have shown exposure to general anesthesia in infancy can cause loss of cells in the central nervous system and long-term impairments in neurocognitive function.” This finding is consistent with previous human epidemiological studies, which have shown children with multiple exposures to general anesthesia before the age of four are at greater risk of learning disabilities and other cognitive impairments. Impairments may not become apparent until the child begins formal schooling.

The research team published these results in the British Journal of Anaesthesia, marking a significant advancement in anesthesia-related studies. Whereas past studies included variables for surgical procedures, the NPRC and Mt. Sinai teams eliminated these variables, allowing the team to focus specifically on the side effects of anesthesia. With this knowledge, the team is now conducting research to further clarify the extent and duration of these anesthesia-induced impairments.

“Our studies with rhesus monkeys are fundamental to making anesthesia exposure in infancy and childhood as safe as possible,” Dr. Alvarado explains.

Reviewed August 2019

May 31, 2017

Familiarity makes the heart grow fonder, at least when it comes to the prairie vole. This rodent species is monogamous, with partners forming lifelong bonds. Until recently, no one knew why. That “why” is exactly what researchers at the Yerkes National Primate Research Center at Emory University want to understand.

“Prairie voles were critical to our team’s findings because studying pair bonding in humans has been traditionally difficult,” said Dr. Elizabeth Amadei, a co-lead author on the research. “As humans, we know the feelings we get when we view images of our romantic partners, but until now, we haven’t known how the brain’s reward system works to lead to those feelings and to the voles’ pair bonding.”

The existing research suggests an interaction between chemicals, such as oxytocin and dopamine, and brain regions, including the prefrontal cortex, leads to these lifelong bonds. That, however, wasn’t enough information for this team that wants to understand the specific neural process and neural networks.

So why do prairie voles mate for life? When a male and female vole interact for extended periods of time, the prefrontal cortex increases the activity of the nucleus accumbens, the brain’s reward system. The decision to engage in affiliative behaviors, such as cuddling and mating, strengthens the animals’ bond and increases overall pleasure for both voles.

While this research has led to additional questions about how the brain impacts the sensational and emotional components of love, it also has longer-term implications. According to Dr. Larry Young, co-author, director of the Emory Conte Center and chief of the Behavioral Neuroscience and Psychiatric Disorders Division at Yerkes, “this discovery is just part of the larger effort to understand how brain circuits works during natural social behaviors. The more we understand, the easier it is to tackle disorders, such as autism, which impair social functioning.”

 

Reviewed August 2019

Back to top