People who suffer from post-traumatic stress disorder (PTSD) and other stress- and anxiety-related conditions experience debilitating bouts of fear when they encounter certain environmental cues. In some cases, these bouts of fear come about when cues that merely resemble those that were directly associated with a traumatic or stressful episode are encountered. As a result, individuals find themselves becoming paralyzed with fear when they encounter harmless cues in their environment.

This is called fear generalization, and it can significantly hamper one’s quality of life. The major question for researchers is: What happens in the brain to cause this generalized fear? 

Previous research has focused on the amygdala, prefrontal cortex and hippocampus, all brain regions that monitor and detect threatening stimuli. However, a new study from the Yerkes National Primate Research Center (YNPRC) has demonstrated the zona incerta (ZI), a brain region previously thought insignificant, may play an important role.

Scientists at the YNPRC mapped and manipulated brain activity in the ZI of mice that demonstrated fear toward neutral stimuli of which they should not have been fearful.

Review of the neural activity in the mice’s brains revealed the ZI was less active in mice that showed fear generalization, and stimulating specific cells in the ZI dramatically reduced fear generalization. This suggests the ZI might serve to halt exaggerated fear responses.

These findings could hold therapeutic value for suppressing debilitating fear generalization and helping thousands of people with stress- and anxiety-related disorders live calmer, happier lives.

It has been known that a widely-used attention-deficit/hyperactivity disorder (ADHD) drug affected the brain—but the specifics of those effects hadn’t been fully understood until now.

Luis Populin, PhD, professor of neuroscience in the School of Medicine and Public Health at the University of Wisconsin-Madison, and colleagues at the Wisconsin National Primate Research Center (WiNPRC) have demonstrated for the first time the complete actions of Ritalin (methylphenidate, or MPH) on various regions and chemicals in the brain.

Ritalin can increase dopamine, a brain chemical associated with reward-motivated behavior, and is typically prescribed to children with ADHD. This increase changes the way the brain makes connections among its various networks, including those that affect attention, learning and motor processes.

In the study, the scientists used positron-emission tomography (PET) imaging to study the brains of three conscious adult male rhesus monkeys. Using simultaneous functional magnetic resonance imaging (fMRI), the researchers were able to directly link increases in dopamine from MPH to changes in functional connections between the caudate—the part of the brain critical to learning through storing and processing memories—and the prefrontal, hippocampal and motor regions.

Studies in humans using fMRI have explored how MPH alters the brain, but some of those studies have reported increases in dopamine after MPH administration, while others have reported decreases. The researchers noted that this may be because most studies used a single dose of the drug and different experimental conditions.

In this study, they “bridged the gap” between neurochemistry and functional organization by simultaneously measuring changes in extracellular dopamine using PET. Additionally, the doses given to the monkeys were comparable to those resulting in equivalent blood levels of the medication when used therapeutically in children.

“Our study sheds much needed light on understanding the mechanisms underlying the effects of therapeutically relevant doses of MPH,” said Populin, adding that future studies may go even further to understand how the drug works in the context of cognition. “We hope we can expand on this research to better understand how the drug works in the brain while it’s actually processing different things.”

Populin noted that the more scientists discover about the processes, the more effective doctors can be in prescribing ADHD medications for children.

Parkinson’s Disease is a complicated neurological illness, the causes of which are still not fully understood by the scientific community. Researchers at the Wisconsin National Primate Research Center (WiNPRC), however, recently made a discovery that could serve as a useful piece of the proverbial Parkinson’s puzzle.

The WiNPRC scientists conducted a study that found phosphorylated alpha-synuclein—a modified version of a protein common to nerve cells—in tissue samples from common marmosets with inflamed bowels. This type of chemical alteration is similar to abnormal protein deposits in the brains of Parkinson’s patients, which suggests that inflammation may play a key role in the development of the disease.

“It’s not entirely clear what its function is, but the typical version of the protein alpha-synuclein occurs normally in all neurons,” explained Marina Emborg, a professor of medical physics in the UW School of Medicine and Public Health. “A lot of neurodegenerative disorders seem to be related to the aggregation of certain proteins.”

In addition, people who suffer from inflammatory bowel disorders are more likely to be diagnosed with Parkinson’s, further bolstering the evidence that inflammation and oxidative stress may be involved in the disease.

“The colon, the gastrointestinal tract overall, has this dense network of nervous tissue, the enteric nervous system, which is sometimes called the gut brain,” said Emborg. “This has lots of neurons, and those neurons—like all neurons—have alpha-synuclein.”

 “(This study) shows us the relationship between inflammation and Parkinson’s-like alpha-synuclein pathology,” she continued. “It doesn’t mean if you have inflammatory bowel disorder, you will get Parkinson’s. The development of a neurodegenerative disorder is multifactorial. But this could be a contributing factor.”

Frequent alcohol use among adolescents and young adults has the potential to be dangerous for obvious reasons—and now, new research in nonhuman primates shows it can actually slow the rate of growth in developing brains.

Researchers at Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU) in Portland, Oregon, measured the brain growth of 71 rhesus macaques via magnetic resonance imaging (MRI). The macaques voluntarily consumed ethanol or beverage alcohol, and the scientists measured their intake, diet, daily schedules and health care, ruling out other factors which tend to confound results in observational studies involving humans.

The study shows heavy alcohol use reduced the rate of brain growth by 0.25 milliliters per year for every gram of alcohol consumed per kilogram of body weight, in addition to reduced growth of cerebral white matter and the subcortical thalamus. These findings help validate previous research examining the effect of alcohol use on brain development in humans.

“Human studies are based on self-reporting of underage drinkers,” said co-author Christopher Kroenke, PhD, an associate professor in the Division of Neuroscience at ONPRC. “Our measures pinpoint alcohol drinking with the impaired brain growth.”

The study is the first to identify normal brain growth in rhesus macaques in late adolescence and early adulthood as occurring at a rate of 1 milliliter per 1.87 years. It also supports previous studies which show a decrease in the volume of distinct brain areas due to voluntary consumption of ethanol.

Lead author Tatiana Shnitko, PhD, a research assistant professor in the Division of Neuroscience at ONPRC, said previous research has shown the brain has a capacity to recover at least in part following the cessation of alcohol intake. However, it’s not clear whether there would be long-term effects on mental functions as the adolescent and young adult brain ends its growth phase. The next stage of research will explore this question.

“This is the age range when the brain is being fine-tuned to fit adult responsibilities,” Shnitko explained. “The question is, does alcohol exposure during this age range alter the lifetime learning ability of individuals?”

Alcoholism isn’t easily explained, but it can have devastating effects for sufferers and their friends and families.

New research conducted at Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University has identified a gene which could be a new target for developing medication to prevent and treat this psychological disease.

In the study, researchers modified the levels of a protein in mice which is encoded by a single gene, GPR39—a zinc-binding receptor previously associated with depression. The prevalence rates of co-occurring mood and alcohol use disorders are high, and people with alcohol use disorder are 3.7 times more likely to have major depression than those who do not abuse alcohol.

Using a commercially available substance which mimics the activity of the GPR39 protein, the researchers found targeting this gene dramatically reduced alcohol consumption in the mice. The team also discovered a link between alcohol and how it modulates the levels of activity of this particular gene. Researchers found when they increased the levels of GPR39 protein in mice, alcohol consumption dropped by almost 50 percent without affecting the total amount of fluid consumed or overall well-being of the mice. 

 “The study highlights the importance of using cross-species approaches to identify and test relevant drugs for the treatment of alcohol use disorder,” said senior author Rita Cervera-Juanes, PhD, a research assistant professor in the divisions of Neuroscience and Genetics at ONPRC.

To determine whether the same mechanism affects people, the researchers are now examining postmortem tissue samples from the brains of people who suffered from alcoholism.

By testing the effect of this substance in reducing ethanol consumption in mice—in addition to its previously reported link in reducing depression-like symptoms—the findings may point the way toward developing a drug which both prevents and treats chronic alcoholism and mood disorders in people.

“We are finding novel targets for which there are drugs already available, and they can be repurposed to treat other ailments,” Cervera-Juanes said. “For alcoholism, this is huge because there are currently only a handful of FDA-approved drugs.”

Do certain changes in genes influence a person’s propensity to develop obesity? That’s what researchers at Texas Biomedical Research Institute, home to the Southwest National Primate Research Center, are aiming to find out in a new study.

The Centers for Disease Control (CDC) calls U.S. obesity an “epidemic,” with 40% of adults and 19% of children considered obese. Within children, however, there are disparities among ethnicities. Hispanic children have the highest rate of obesity at 26% compared to African American (22%), Caucasian (14%) and Asian (11%) children.

The team will be studying an area of research called epigenetics—which describes changes to DNA, RNA or proteins that are affected by both the environment and genetic makeup.

“If we start at the cellular level and then look at whole organisms like the human body and how we use energy, then we can identify pathways that are involved in the development of obesity and also potentially mechanisms by which we can intervene and treat obesity,” explained Associate Scientist Melanie Carless, PhD.

The first phase of the study will involve a group of 900 Texas Hispanic children who have a high propensity for obesity. Scientists will examine whether physical data like caloric intake, physical activity, energy expenditure, metabolic rate and glucose levels are related to another factor called DNA methylation to increase risk for obesity. In the second phase, scientists will compare changes in blood with changes in muscle tissue and muscle cells and see how these changes correlate. The third phase will involve the use of CRISPR (a new technology used to alter DNA sequences and modify gene function) to change the methylation levels in cells and see how this impacts energy use.

The information gathered from the study could lead to more targeted drug therapies for obesity, or someday, editing to correct an underlying issue at the DNA level. This could improve public health in a number of ways.

“Obesity can be a huge factor in serious medical problems including diabetes, high blood pressure, atherosclerosis and heart disease,” said Carless. “We need to understand how obesity develops at a young age and the impact this might have on health later in life. If we can start to reduce the rates of obesity in the U.S., we will start to see a decline in multiple other disorders.”

We all know that proper diet and exercise are supposed to help us maintain a healthy weight. But in some cases, genetics may make it incredibly difficult to keep excess fat away.

Texas Biomed researcher Raul Bastarrachea, MD, and the team at Southwest National Primate Research Center (SNPRC) recently set out to discover why exactly some people are naturally inclined toward obesity. In the process, they found a mutation that affects leptin — a protein produced by fat cells that travels to the brain and signals to the body that there is enough fat and no more food is needed.

Simply put, leptin is a hunger suppressor.

In the study, Bastarrachea and team examined the case of two sisters in Colombia who started their lives as normal-weight babies but who quickly experienced childhood-onset severe obesity. Both were found to have a mutation in the leptin gene on chromosome 7, causing their leptin levels to be so low they were below the detection limit of the manufactured test kit.

The gene mutation forced the leptin proteins to be “misfolded,” rendering them ineffective and destroying their function.

When researching the genetics of the family, scientists noted these women were children of lineal consanguinity, which means several generations before them married blood relatives. This is a common practice in about a fifth of the world population, mostly in the Middle East, West Asia and North Africa, and increases health risks for children of these unions, including rare diseases caused by recessive genes.

Bastarrachea noted a greater understanding of this mutation and its causes is another step toward fighting global obesity.

“We keep learning more and more about the role of fat in normal-weight people,” he noted. “By researching what goes wrong when genes don’t code correctly for the production of leptin, we are coming closer to answers that could help millions of people with metabolic disorders.”

To help get those answers, the SNPRC is looking at obesity within its nonhuman primate (NHP) colony. 

“Fortunately, we have less than 5% obesity in our 2,500 NHPs and an even lower rate of diabetes at 1.5%, due to the low-carb Purina chow they eat and the activity they display given the comfortable size of their housing,” said Bastarrachea. 

Occasionally, a few of SNPRC’s baboons may experience excessive growth leading to excess body fat. 

“We speculate these animals may have particular gene mutations that mimic the extreme obese phenotype of the few individuals reported in scientific literature. We consider our baboon subgroup a valuable model of extreme obesity given NHPs share up to 98% genetic similarities with humans, thus allowing obesity study results in NHPs to be easily translated to humans,” Bastarrachea concluded. 

A new understanding of microbial processes is helping to reveal the cause of ulcerative colitis through the study of a nonhuman primate disorder, idiopathic chronic diarrhea (ICD).

ICD affects 3 to 5 percent of all captive macaque monkeys, and researchers believe wild macaques could be affected at similar rates. ICD is unresponsive to medical intervention and not caused by any particular pathogens.

California National Primate Research Center (CNPRC) scientist Amir Ardeshir, PhD, first began investigating the relationship between microbiomes and intestinal diseases like ICD in macaques—and ulcerative colitis in humans—when he learned of a human patient who had temporarily treated their ulcerative colitis by consuming the eggs of a parasite called Trichuris trichiura.

Ardeshir tried this patient’s home remedy in ICD-affected monkeys and discovered, astonishingly, that the parasite was an effective treatment in four out of five monkeys.

Now, in his latest study, Ardeshir and a team of researchers have found an interesting relationship between the Trichuris parasite and the monkeys’ microbiome—the community of trillions of microbes living on and in primates’ bodies.

The study found that treated monkeys had different microbial communities than healthy control subjects, making them particularly good at building the protective mucosal layer along the intestinal wall. This layer is key in protecting intestinal epithelium from pathogens.

The team of scientists then identified some of the specific bacteria occurring in cases of ICD using a new software called SAMSA2. This software-based approach revealed not only which bacteria were present in each monkey’s gut, but also provided information about what those bacteria were doing and how they might be interacting.

The researchers found a dramatically high number of “bacteria that are very notorious for mucin degradation,” Ardeshir noted. Mucins are glycoproteins which are necessary for the maintenance of the mucosal layer lining human and nonhuman primate intestines. Without it, the mucosal layer and gut bacteria can’t maintain a healthy relationship. Biopsies of human patients with ulcerative colitis show dysfunctional mucosal layers, suggesting this may be the source of irritation and inflammation in both ICD and ulcerative colitis.

Though the exact causes are still unclear, Ardeshir noted that this study brings the field much closer to a full understanding of these types of intestinal bacterial diseases.

Reviewed: June 2020

Is it possible to reverse the effects of a life-threatening poison? In the case of one such toxic substance, it very well may be.

A recent study at the Tulane National Primate Research Center (TNPRC) showed for the first time that an experimental drug can save nonhuman primates exposed to deadly ricin toxin. Ricin is derived from the seeds of the castor oil plant, and a single dose of purified ricin powder the size of a few grains of table salt can kill an adult. Due to its toxicity and the availability of its source material, it is considered a leading bioterrorism threat.

It’s also difficult to counter the effects of the lethal toxin once a person has been exposed to it.

“Clinically, there is no treatment that can be administered currently to save someone in the event of an exposure to this toxin,” said study first author Chad Roy, PhD, director of infectious disease aerobiology and biodefense research programs at TNPRC.

In the study, researchers at TNPRC, Mapp Biopharmaceutical Inc., University of Texas Southwestern Medical Center and the New York State Department of Health used a drug comprised of humanized monoclonal antibodies against the toxin. This drug was developed from research of a successful ricin vaccine that was originally tested at TNPRC, and it was engineered to look very similar to the structure of antibodies that were generated from vaccinated nonhuman primates.

“Our study shows proof of concept in a near-clinical animal model, the nonhuman primate, that we finally have a life-saving treatment against one of the world’s most notorious toxin agents,” noted Roy.

Researchers also found the drug was much more effective four hours after exposure as opposed to 12 hours after exposure, indicating a short time window for successful treatment. They plan to develop a stronger version that would “expand the therapeutic window” for effective treatment longer after exposure, Roy said.

Additionally, the scientists hope to develop the drug as a possible preventative therapeutic that emergency workers or members of the military could take before they enter areas contaminated with ricin. The research is part of ongoing federal efforts to develop effective countermeasures against bioterrorism agents.

Reviewed: June 2020

In 2018, wildfires tore across the state of California, leaving smoldering remains in their wake. These were some of the worst natural disasters on U.S. soil in recent years, and what’s worse, similar occurrences are becoming increasingly common.

If there’s any good to come from these phenomena, it’s that scientists are collecting data in the aftermath that could help reduce the effects of fires on humans and animals. This new research will add to the existing body of knowledge on the subject, including a study originally conducted in 2008 at the California National Primate Research Center (CNPRC). During the study, researchers found altered immunity and lung function in juvenile monkeys that were exposed as infants to wildfire smoke in 2008.

Lisa Miller, leader of the CNPRC Respiratory Diseases Unit, and her team recently tested lung function and blood samples from adult monkeys (now 10 years of age) that were originally exposed to the 2008 wildfire smoke. Their findings were consistent with the earlier study, suggesting that infant exposure to fine particles from fire leads to long term impairment of the respiratory and immune systems in adulthood. 

“The idea behind this is that if we detected any changes in the animals this information might translate as a biomarker that can be used for kids,” said Miller. “The ability of the animals to respond to a real pathogen was reduced. It was a surprise and somewhat disturbing.”

In 2018, smoke from the Butte County Camp Fire—which burned more than 700 square miles—reached the CNPRC, and about 2,000 animals and roughly 500 infant nonhuman primates were exposed for a period of more than 10 days. Because the fires came so close to the UC Davis campus where the CNPRC is located, researchers will once again be able to test the health effects of wildfire smoke on the center’s nonhuman primates. 

Examination of the results is still ongoing, but the additional data from this blaze will help Miller and team continue the search for causes, preventative measures and treatments for the damaging health effects of these massive wildfires.

Reviewed: June 2020