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.

According to a new study by scientists at the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute, marmosets can mimic the sleep disturbances, changes in circadian rhythm and cognitive impairment in people with Parkinson’s disease.

This is a significant development since an effective animal model that can emulate both the motor and non-motor symptoms of Parkinson’s gives scientists a better chance of understanding the processes responsible for changes in the brain caused by the disease.

Parkinson’s disease affects one million people in the United States and 10 million people worldwide. With the aging population, the incidence of the neurodegenerative disorder is on the rise. Each year, 60,000 people are diagnosed with Parkinson’s in the U.S. alone. The hallmark symptoms include tremors, slow movements, balance problems and rigid or stiff muscles. However, non-motor symptoms—including disorders of the sleep-wake cycle and problems thinking clearly—can be just as difficult for patients to handle.

During the study, the researchers tracked marmosets using devices around their necks similar to popular human fitness tracking devices. They wanted to see if the marmosets with induced classic Parkinson’s motor symptoms could also serve as an effective model for non-motor symptoms. In addition, scientists videotaped the animals to monitor their ability to perform certain tasks and how those abilities were impacted over time by the disease.

As it turned out, the marmosets did exhibit both motor and non-motor symptoms similar to those experienced by humans with the disease.

“Most of the early studies in Parkinson’s have been conducted with rodents,” explained lead author and Associate Scientist Marcel Daadi, PhD, leader of the Regenerative Medicine and Aging Unit at the SNPRC. “But there are some complex aspects of this disease you simply cannot investigate using rodents in a way that is relevant to human patients.”

“This study is a great first step,” Dr. Daadi continued. “More studies are needed to expand on these non-motor symptoms in marmosets in the longer-term, and perhaps, include other nonhuman primates at the SNPRC like macaques and baboons.”

Ever wonder how your brain knows what a certain object is, even if the object is mostly hidden? Researchers at the Washington National Primate Research Center (WaNPRC) at the University of Washington (UW) may have discovered an explanation for this phenomenon.

Researchers studied brain signals and tracked eye movements in rhesus monkeys while the animals played a computer game in which they attempted to identify half-hidden, two-dimensional objects and specific shapes.

“Basically, when the task is simple, (the) visual cortex works just fine, but when the task becomes difficult, there needs to be communication between a higher brain region involved in memory and learning,” Anitha Pasupathy, PhD, Associate Professor at the UW School of Medicine Department of Biological Structure, said about the results of the study.

These findings make the researchers wonder if impaired communication between the brain’s thinking and sensory parts might lead to certain difficulties, like confusion in cluttered surroundings, for people who have autism or Alzheimer’s.   

“This, for us, is a very exciting demonstration because it breaks open a whole lot of questions we can ask about how different brain areas interact to solve this important problem of visual recognition,” noted Pasupathy.

The scientists said the next step in their research is to determine if more brain areas are involved in recognizing objects with more complex images.

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Photo credit: Kathy West for the California National Primate Research Center

Most of us enjoy listening to our favorite tunes while in the car or relaxing at home—but could music serve an even deeper purpose in our lives?

In September, Larry Sherman, PhD, a professor in the Division of Neuroscience at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU), joined OHSU research scientists Marc Freeman, PhD, and Erick Gallun, PhD, for an on-stage discussion about research exploring the importance of music for brain development and healing. The researchers were accompanied by internationally-renowned opera singer Renée Fleming.

Sherman, who has performed a series of talks explaining how listening and practicing music can influence brain development and delay cognitive decline in aging, said the soaring feeling of inspiration when we’re playing, singing or listening to music is rooted in brain chemistry. He cited research which has shown magnetic resonance imaging (MRI) reveals a spike in endorphins and dopamine among people exposed to music, which generates a feeling of belonging and of community.

Fleming added that one of the latest iterations of music therapy involves forming drumming circles for people struggling with addiction. Gallun suggested this technique may be soothing because the drumming echoes a rhythm from the earliest possible point of the brain’s development.

“When you’re in the womb, there are only a few things you can hear,” Gallun said. “One is your mother’s heartbeat.”

Fleming recently spent two hours in an MRI machine as part of a Sound Health initiative supported by National Institutes of Health (NIH) to study the specific neural circuits involved in the interaction between music and the brain. She believes that music can have a therapeutic effect, especially for underserved youth populations struggling with social and mental health issues.

“Music can really make a difference in their lives,” she said.

Reviewed: June 2020

Parkinson’s disease is most widely known for causing muscle tremors and motor-control symptoms, but most Parkinson’s sufferers also exhibit damage to their hearts’ connection to the sympathetic nervous system. In fact, that damage is one of the first signs of Parkinson’s, but the connection is often not made until the more visible symptoms develop.

Researchers at the Wisconsin National Primate Research Center (WiNPRC) and the University of Wisconsin (UW-Madison) have found a new way to examine stress and inflammation in the heart that could serve as an early indicator of Parkinson’s well before the more common symptoms begin.

The heart damage is significant because it contributes to a tendency for Parkinson’s patients to suffer physical injury as a result of blood pressure fluctuations.

“This neural degeneration in the heart means patients’ bodies are less prepared to respond to stress and to simple changes like standing up,” said Marina Emborg, a University of Wisconsin–Madison professor of medical physics and Parkinson’s researcher at the WiNPRC. “They have increased risk for fatigue, fainting and falling that can cause injury and complicate other symptoms of the disease.”

The sympathetic nervous system signals the heart to accelerate its pumping to match quick changes in activity and blood pressure. Researchers at WiNPRC developed a method for tracking the mechanisms that cause the damage to heart nerve cells, then tested the method in the nervous system and heart of monkeys.

Ten rhesus macaque monkeys served as models for Parkinson’s symptoms, receiving doses of a neurotoxin that caused damage to the nerves in their hearts in much the same way Parkinson’s affects human patients. Once before and twice in the weeks after, the monkeys underwent PET scans, a medical imaging technology that can track chemical processes in the body using radioactive tracers.

The UW–Madison researchers used three different tracers to map three different things in the left ventricle of the monkeys’ hearts: where the nerves extending into the heart muscle were damaged, where the heart tissue was experiencing the most inflammation, and where they found the most oxidative stress.

The scans were accurate enough to allow the researchers to focus on changes over time in specific areas of the heart’s left ventricle.

“We know there is damage in the heart in Parkinson’s, but we haven’t been able to look at exactly what’s causing it,” said researcher Jeannette Metzger. “Now we can visualize in detail where inflammation and oxidative stress are happening in the heart, and how that relates to how Parkinson’s patients lose those connections in the heart.”

By tracing the progression of nerve damage and its potential causes, the radioligands can also be used to test potential new treatments. The researchers gave half the monkeys in the study a drug, pioglitazone, that has shown promise in protecting central nervous system cells from inflammation and oxidative stress.

“The recovery of nerve function is much greater in the pioglitazone-treated animals,” added Emborg. “And what’s interesting is this method allows us to identify very specifically the differences the treatment made—separately for inflammation and for oxidative stress—across the heart.”

The heart problems opened to examination by the new imaging methods are not limited to Parkinson’s disease. Heart attacks, diabetes and other disorders cause similar damage to nerves in the heart, and those patients and potential therapies could also benefit from the new visualization method.

The results suggest human patients could benefit from the radioligand scans, and Metzger wonders if it could help catch some Parkinson’s patients before their other symptoms progress.

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.”

Anxiety disorders affect some 40 million Americans; more than 16 million Americans suffer from depression, according to the Anxiety and Depression Association of America. Researchers at the University of Wisconsin–Madison and the Wisconsin National Primate Research Center (WiNPRC) have discovered brain pathways in juvenile monkeys that may lead to the development of anxiety and depression later in life.

Extreme early life anxiety is a significant risk factor for anxiety disorders and depression in humans, and discovering a connection between two areas of the brain that are connected to anxious temperament in pre-adolescent rhesus macaques could be a significant breakthrough.

“We are continuing to discover the brain circuits that underlie human anxiety, especially the alterations in circuit function that underlie the early childhood risk to develop anxiety and depressive disorders,’’ said Ned Kalin, MD, chair of the psychiatry department at UW–Madison.

“In data from a species closely related to humans, these findings strongly point to alterations in human brain function that contribute to the level of an individual’s anxiety. Most importantly these findings are highly relevant to children with pathological anxiety and hold the promise to guide the development of new treatment approaches.”

The study used functional magnetic resonance imaging (fMRI) to study the connections between two regions of the brain. It builds on the group’s earlier study that used positron emission tomography (PET) scans to study metabolism in the same circuitry; fMRI detects oxygenation changes in blood while PET measures neuronal metabolic activity. Taken together, said Jonathan Oler, PhD, the study’s co-lead author, the new findings demonstrate that the degree of synchronization between these brain regions is correlated with anxious temperament.

“When we began this research, we knew so little about the brain regions involved, especially in primate species,’’ Oler says. “This study speaks to how important it is to study animals that are related to humans as they allow us to learn about the causes of human anxiety and by so doing we can potentially develop better treatment and hopefully prevention strategies.”

Oler and Kalin say their analysis suggests that the same genes that underlie the connectivity of this circuit also underlie anxious temperament. Studies underway in the Kalin laboratory are aimed at identifying gene alterations in the anxiety-related brain regions, and have the potential to lead to new treatments that are directed at the cause of anxiety rather than just the symptoms.

The holy grail of autism research is a reliable test for the condition – and researchers at the California National Primate Research Center (CNPRC), working with colleagues at the Stanford University School of Medicine, have made a promising discovery that may lead to just such a test.

According to the research team, reduced levels of vasopressin – a hormone found in the spinal fluid – may be connected to a reduction in socially acceptable behavior.

“What we consider this to be at this point is a biomarker for low sociability,” said John P. Capitanio, a CNPRC scientist and leader of the Neuroscience and Behavior Unit at the University of California-Davis.

Currently, medical professionals diagnose autism by looking for certain social behaviors. Unfortunately, these tell-tale signs often don’t appear until a child reaches age four or five, limiting opportunities for early treatments that can stem the condition’s progress.

“Right now, the diagnosis is based on parents’ reports of their children’s symptoms, and on clinicians observing children in the clinic,” said Karen Parker, associate professor of psychiatry and behavioral sciences at Stanford and the lead author of the new study.

Researchers looked for autism biomarkers in rhesus macaques, a species whose social capabilities are close to those of humans. The scientists measured levels of two hormones, oxytocin and vasopressin, in their blood and in their cerebrospinal fluid, which bathes the brain.

Monkeys in the less social group had significantly less vasopressin in their cerebrospinal fluid than nonhuman primates in the more social group. In particular, the levels accurately predicted the frequency with which individuals participated in social grooming, an important social activity for this species. Importantly, the team was able to replicate their finding that low vasopressin levels are associated with lower social functioning using a second, independent cohort of monkeys.

The researchers also compared vasopressin levels in seven boys with autism and seven others without the condition. Similar to the results with the rhesus macaques, children with autism had lower vasopressin levels than children without autism.

Moving forward, the researchers plan to test a larger group of nonhuman primates to determine whether the low hormone level can be detected before symptoms of impaired social ability emerge.

Reviewed August 2019

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Photo credit: Kathy West for the California National Primate Research Center

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.

Understanding the genetic code is one thing. Altering it is something different altogether. Researchers at the Washington National Primate Research Center (WaNPRC) have discovered a technique for inserting a specific gene into the brain’s membrane, which could modify how the brain works, alter behavior, and potentially correct neurological disorders.

Researchers think that this approach, which involves genetically altering a select number of cells, might lead to treatments for neurological conditions such as epilepsy. “The brain is made up of a mix of many cell types performing different functions. One of the big challenges for neuroscience is finding ways to study the function of specific cell types selectively without affecting the function of other cell types nearby,” said lead researcher and associate professor of physiology and biophysics Gregory Horwitz. “Our study shows it is possible to selectively target a specific cell type in an adult brain using this technique and affect behavior nearly instantly.”

The research team inserted a gene into cells in the cerebellum, the parts of the brain controlling motor movements. Those cells, Purkinje cells, are some of the largest in the brain and connect with hundreds of other cellular structures.

The inserted gene, channelrhodopsin-2, creates a light-sensitive protein that inserts itself into the brain cell’s membrane. When exposed to light, the protein allows ions – tiny charged particles – to pass through the membrane.

By attaching the gene to a modified virus and painlessly injecting it into a small area of the cerebellum of rhesus macaque monkeys, the channelrhodopsin-2 was taken up exclusively by the targeted Purkinje cells. The researchers then showed that when they exposed the treated cells to light, they could affect motor control.

“This ‘transgenic’ approach has proved invaluable in the study of the brain,” Horwitz said. “But if we are someday going to use it to treat disease, we need to find a way to introduce the gene later in life, when most neurological disorders appear.” With this discovery, the researchers are one step closer to understanding the elegant system that is the brain.

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Photo credit: Kathy West for the California National Primate Research Center