Here’s a sobering statistic: one in every five American women and one in every 10 American men at the age of 45 are at risk of developing Alzheimer’s disease. Moreover, as the rate of the disease continues to increase and promising therapies tested in rodents fail in human subjects, the need for another option has become apparent.

Now, scientists at the California National Primate Research Center (CNPRC) have developed a monkey model of the earliest phase of Alzheimer’s. By selectively infusing protein fragments linked to the disease into the brain of middle-aged female rhesus monkeys, they have induced the earliest of the stages of Alzheimer’s, known as the synaptic phase, without neuron death. The researchers are focusing on middle-aged females, instead of the older populations previously studied, in hopes of identifying a treatment to stop the disease before irreversible degeneration occurs.

Some neurons, like those in the prefrontal cortex and hippocampus, are critically important for learning and memory and are more susceptible to the effects of Alzheimer’s than others. In a healthy brain, there is a delicate balance necessary for the cellular communication and plasticity necessary for learning—but in Alzheimer’s, this balance is compromised, leading to cognitive decline and possible neuron death.

The scientists believe that by instigating the synaptic damage, they have established a model of Alzheimer’s that isolates the synaptic phase before evidence of permanent damage.

Next, the researchers plan to examine ways of stopping Alzheimer’s progression before it reaches the degenerative phase. Primate models of the disease will greatly boost the capacity to outline an effective treatment plan for humans in the earliest phase of Alzheimer’s, prior to the worst symptoms and irreversible damage that results in dementia.

Interested in what else the NPRCs are doing to understand and improve brain health? Take a look at some related studies here.

Scientists have made one more step toward the treatment and cure of multiple sclerosis (MS) by developing a compound that successfully promotes the regeneration of the protective myelin sheath around nerve cells.

In a recent study, scientists at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU) described successfully testing the compound in mice, and they have already started to apply it to a rare population of macaque monkeys who develop a disease that is similar to MS in humans.

“I think we’ll know in about a year if this is the exact right drug to try in human clinical trials,” said senior author Larry Sherman, PhD, an OHSU professor in the Division of Neuroscience at the primate center. “If it’s not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains?” 

The discovery arrives after more than a decade of research following a 2005 breakthrough by Sherman’s lab. In that study, scientists discovered that a molecule called hyaluronic acid (HA), accumulates in the brains of patients with MS. The researchers then linked this accumulation of HA to the failure of cells called oligodendrocytes (which generate myelin) to mature. 

Myelin forms a protective sheath covering each nerve cell’s axon—the threadlike portion of a cell that transmits electrical signals between cells. Damage to myelin is associated with MS, stroke, brain injuries and certain forms of dementia like Alzheimer’s disease. Delay in myelination can also affect infants born prematurely, leading to brain damage or cerebral palsy. 

Other studies led by the Sherman lab have shown that HA is broken down into small fragments in multiple sclerosis lesions by enzymes called hyaluronidases, and these fragments send a signal to immature oligodendrocytes to not turn on their myelin genes. 

There is currently no cure for MS, but an international team of researchers led by OHSU has been working to develop a compound that neutralizes the hyaluronidase in the brains of patients with MS and other neurodegenerative diseases. This will ideally revive the ability of progenitor cells (descendants of stem cells that differentiate, or change, into specific cell types) to mature into myelin-producing oligodendrocytes and regenerate myelin sheath. 

The ONPRC macaque study describes a modified flavonoid—a class of chemicals found in fruits and vegetables—that does just that. The compound, called S3, reverses the effect of HA and promotes functional remyelination in mice. 

“It’s not only showing that the myelin is coming back, but it’s causing the axons to fire at a much higher speed,” Sherman said. “That’s exactly what you want functionally.”

The next phase of research involves testing, and possibly refining, the compound in macaque monkeys who carry a naturally occurring version of MS called Japanese macaque encephalomyelitis. The condition, which causes clinical symptoms similar to multiple sclerosis in people, is the only spontaneously occurring MS-like disease in nonhuman primates in the world. 

Researchers at the ONPRC and other NPRC locations are consistently making breakthrough discoveries to help treat and eradicate MS and other neurological diseases. Learn more about the latest findings here.

Is it possible for consciousness to be controlled through the brain? And if so, what implications could this have for people with serious brain disorders or conditions, like comas?

As it turns out, a small amount of electricity delivered at a specific frequency to a particular point in the brain will wake a nonhuman primate out of deep anesthesia, according to a study by a team led by researchers at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW).

Macaques put to sleep with general anesthetic drugs commonly administered to human surgical patients, propofol and isoflurane, were revived and alert within two or three seconds of applying a low electrical current.

“For as long as you’re stimulating their brain, their behavior — full eye opening, reaching for objects in their vicinity, vital sign changes, bodily movements and facial movements — and their brain activity is that of a waking state,” said Yuri Saalmann, UW-Madison psychology and neuroscience professor. “Then, within a few seconds of switching off the stimulation, their eyes closed again. The animal is right back into an unconscious state.”

Mice have been roused from light anesthesia before with a related method, and humans with severe disorders have improved through electric stimulation applied deep in their brains. The new study, however, is the first to pull primates in and out of a deep unconscious state.

In the study, the scientists focused on a spot deep in the core of the brain called the central lateral thalamus. Lesions in that area of the human brain are linked to severe consciousness disruptions, such as comas.

As the macaques moved from unconscious to conscious states, the researchers observed the central lateral thalamus stimulating parts of the cortex, or the outer folds of the brain. In turn, the cortex influenced the central lateral thalamus to keep it active, forming a loop—or an engine—of sorts.

Achieving this manipulation of consciousness in the brain required precisely stimulating multiple sites as little as 200 millionths of a meter apart simultaneously, as well as applying bursts of electricity 50 times per second. The researchers noted that designing and delivering electrical stimulation with such precision gives them hope that their approach could be used to help patients dealing with many types of abnormal brain activity.

 “We can now point to crucial parts of the brain that keep this engine running and drive changes in the cerebral cortex that affect your awareness, the richness of your conscious experience,” explained Saalmann.

The inner workings of the brain are complex and have yet to be fully unraveled, but scientists at the NPRCs are making daily progress in helping us to understand this fascinating and crucial organ. You can learn more about the other NPRC neuroscience studies here.

Could increasing just a single type of molecule in the brain alleviate anxiety? According to researchers at the California National Primate Research Center (CNPRC), it could indeed.

Anxiety disorders often emerge around adolescence and can continue to affect people for most of their lives. Researchers can now identify children who display an extreme anxious or inhibited temperament and determine that they are at risk to develop stress-related conditions as they transition to adulthood. However, little is known about how to effectively alleviate anxious symptoms.

CNPRC scientists recently conducted a study examining “dispositional anxiety”—the tendency to perceive many situations as threatening—in nonhuman primates. Researchers used an altered virus to boost levels of a molecule called neurotrophin-3 in the dorsal amygdala of juvenile rhesus macaques.

They found that this increase led to a decrease in anxiety-related behaviors, particularly behaviors associated with inhibition, a core part of the early-life risk for developing anxiety disorders in humans. Brain imaging studies of these animals found that neurotrophin-3 changed activity throughout the brain that contributes to anxiety.

Because current treatments work for only a subset of people and often only partially relieve symptoms, this finding provides hope for new methods of early-life intervention to treat people at risk for anxiety disorders, depression and related substance abuse.

Andrew Fox, an assistant professor in the UC Davis Department of Psychology and a researcher at the CNPRC, hopes that other scientists can further build on their research. The research team included a list of additional promising molecules for future investigation.

“We’re only just beginning,” noted Fox. “Neurotrophin-3 is the first molecule that we’ve been able to show in a nonhuman primate to be causally related to anxiety. It’s one of potentially many molecules that could have this effect. There could be hundreds or even thousands more.”

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.”

What if certain parts of the brain could be turned off to treat neurological disorders like Parkinson’s disease? Though it seems far-fetched now, such a solution could soon become reality.

During the last 10 years, the field of neuroscience research has been revolutionized by new genetic techniques, allowing neuroscientists to express artificial proteins in neurons that can then be modified to study diseases and disorders. One of the most commonly used genetic-based approaches is called chemogenetics.

Chemogenetic techniques use artificial receptor proteins that only become active in the presence of a specific drug. This means only the neurons containing the artificial receptor will change their activity in response to the drug, while other neurons remain unaffected. We can think of it as a chemical switch that turns specific neurons on or off.

While chemogenetics methods have been extensively used in basic research, they have yet to be translated to clinical treatment. However, researchers have recently developed new chemogenetic tools that have the potential to be used in clinical applications. The team, led by Scott Sternson (Howard Hughes Medical Institute’s Janelia Research Campus), included Yerkes National Primate Research Center researchers Adriana Galvan, PhD, and Xing Hu, MD.

In this new chemogenetic system, the researchers activated the artificial receptors by using drugs specifically designed for the receptors, as well as varenicline (Chantix™), an antismoking drug. The receptors and drugs were optimized during in vitro experiments and then successfully used to control the activity of neurons in rodents.

The Yerkes researchers then contributed an important step toward potential clinical application of the tools by duplicating the effects in a nonhuman primate’s brain. When the primate received a low dose of varenicline, the neurons containing the artificial receptors were silenced — all with no observable side effects. The results provide a critical proof of concept that chemogenetic methods can be effectively used in nonhuman primate studies.

Yerkes researchers are now expanding the chemogenetic experiments with the aim of using them in a nonhuman primate model of Parkinson’s disease, which is characterized by some movement-related brain regions being abnormally active. Chemogenetic manipulation could potentially silence or at least modulate the activity of these brain areas and help scientists develop a novel Parkinson’s therapy.