Tag Archives: monkey

Research Roundup: Lupus protein identified, vaccine for Type 1 diabetes, new chronic pain treatment, and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • A protein that may cause Lupus has been identified.Lupus is a chronic inflammatory disease that occurs when your body’s immune system attacks its own tissues and organs. An estimated 1.5 million Americans, and at least 5 million people worldwide, have a form of lupus. Previous research has implicated the gene PRDM1 as a risk factor for lupus. Scientists looking at Blimp-1, a protein that is encoded by the PRDM1 gene, have found in mice thatthat a low level of or no Blimp-1 in a particular cell type led to an increase in the protein cathepsin S (CTSS) which caused the immune system to identify healthy cells as something to attack — particularly in females.” These results are particularly striking as women have an increased risk for lupus compared to men. While this work needs to be replicated and validated, this research provides some valuable insight into the etiology and treatment of lupus. This research was published in the journal Nature Immunology.
lupus mice

Mice from the Lupus study. Source: AJP Renal Physiology.

  • Vaccine for virus induced Type 1 diabetes successful in mice. Coxsackie B viruses are the most common enteroviruses and are believed to be associated with the development of Type 1 diabetes. Type 1 diabetes is  a common human disease defined by a decrease in the production of insulin, which is a hormone that allows blood glucose (sugar) to enter energy producing cells. Thus, without insulin your body cannot effectively produce energy. This week, a team of Finnish researchers published a preclinical evaluation of a Coxsackie B1 vaccine using mice and found that the vaccine successfully protected the mouse after administering the Coxsackie B1 virus. Pre-clinical trials in humans are the next logical step for this vaccine, and the researchers believe that this research will aid in the development of vaccines for other disease caused by enteroviruses such as; hand-foot-and-mouth disease, meningitis, and myocarditis. This research was published in the journal Vaccine.
  • High iron levels in brain linked to progression of Alzheimer’s. Alzheimer’s is a degenerative neurological disease that causes dementia in humans. Previous research has linked Alzheimer’s to the buildup of amyloid protein in the brain, but research on drugs that reduce amyloid levels have not successfully slowed the progression of the disease. New research from the University of Melbourne however, discovered that humans with high levels of iron and amyloid were suffering from rapid dementia, while those with just high levels of amyloid protein were stable. This finding will fuel a five year trial on whether an anti-iron drug can slow the progression of the disease. This research was published the journal Brain.
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Brain MRI using Quantitative Susceptibility Mapping (QSM). Source: University of Melbourne.

  • Compound protects macaques from simian HIV. Research being presented this week at the National AIDS Treatment Advocacy Project (NATAP) Conference on HIV Pathogenesis Treatment and Prevention in Paris shows that weekly administration of a compound called MK-8591 repeatedly protected 8 of 8 macaques from simian HIV (SHIV) 6 days after treatment. Researchers from the Aaron Diamond AIDS Research Center in New York, Merck, and the Tulane National Primate Research Center studies 16 male macaques, 8 of which received weekly treatments of MK-8591 for up to 14 weeks, the other 8 of which received a placebo. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that thwarts HIV. All 8 monkeys treated with MK-8591 remained SHIV-free even after 12 challenges with SHIV, to the end of the 168-day study. In contrast, the monkeys not treated with the drug all became infected with SHIV. The researchers noted that protective intracellular active MK-8591 concentrations can be attained in humans at low drug doses. These new findings support the potential use of MK-8591 as a prophylactic treatment for high-risk individuals.
  • New drug acting at two opioid receptors shows promise to treat chronic pain without the adverse effects of morphine. An epidemic of opioid abuse is killing people by the hundred of thousands in the United States, becoming the main cause of death for people under 40. The epidemic has been traced to the prescription of new opioid analgesics like Oxycontin over the last years, which has led people to become addicted to it and then to harder drugs like heroin. A group of scientist followed the strategy of creating drugs that bind not only to the receptor for morphine in the brain, the mu-opioid receptor, but also to a new opioid receptor called the nociceptin FQ receptor. The new drug, BU08028, was shown to reduce pain responses in rats as effectively as morphine. Now the drug is being tested in rhesus monkeys, where it also decreased pain. Importantly, the monkeys showed no desire to self-administer BU08028, an indication that the drug is not addictive.
nhp_c2a9kathyweststudios-40

Male rhesus macaque. Source: Kathy West.

  • Computer-designed opioid drug may decrease pain without producing respiratory arrest. People dying during the current opioid epidemic do so because the drugs inhibit the centers in the brain that drive breathing, leading to suffocation. Scientists proposed that the pain-relieving and breathing-suppressive effects of the opioids depend on different interactions of these drugs with the mu-opioid receptor, and set up to produce a compound that would suppress pain but not breathing. To do that, they modeled the drug binding site at the receptor using computers. After testing millions of compounds in the computer, they found a drug, PZM21, that showed promise. Then they tested PZM21 in mice and found that it suppressed pain but not breathing. They also found that PZM21 did not show the rewarding effect that typically lead to addiction. This demonstrates how even when new drugs are designed using computer models, animal studies are still needed to evaluate their effects.

Research Roundup: Malaria vaccine, mouse sperm in space, animal welfare prizes, and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • New study finds that mouse sperm stored in space still functions on Earth. Increasingly in the news we read about the upcoming reality of commercial space travel (for example, here and here). Of course, with such advances there is caution with respect to feasibility — and of course imagination with respect to possibilities (e.g., colonizing Mars). With such goals on the horizons, these researchers investigated whether sperm that had been freeze dried, and transported to the International Space Station (ISS) and then back to Earth would be able to produce viable offspring. To accomplish this they used freeze dried mouse spermatozoa — which provided a unique advantage, as the addition of water — maintains the viability of the sperm to fertilize an egg and allows for the sperm to be stored at room temperature. Other sperm when freeze dried do not survive. Microinjection  of these “space” sperm into an egg on Earth — produced healthy viable  “space offspring”. Moreover, these offspring all grew to healthy adults and were able to produce offspring of their own. This study was published in the Proceedings of the National Academy of Sciences of the USA.

Space mouse and pups. Source: PNAS

Laboratory frogs. Source: University of Portsmouth

  • Modified experimental vaccine protects monkeys from deadly malaria. Researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, discovered that a modified version of an experimental malaria vaccine completely protected 4 of 8 monkeys from a malaria parasite, and delayed the first appearance of the parasites in 3 more monkeys. Scientists modified an existing malaria vaccine by including a particular protein, RON2L, so that it closely mimicked the protein complex used by the parasite to infect blood cells. Vaccination with the modified vaccine resulted in more neutralizing antibody, indicating a better quality response to parasitic infection. Additionally, the modified vaccine seemed to protect against other parasite strains that differed from those used to create the vaccine, suggesting that this new modified vaccine may protect against multiple parasite strains. This research will pave the way toward eventual human trials. The study was published in NPJ Vaccines.

A female Aedes mosquito. Source: NIAID.

 

 

 

 

 

 

 

 

 

 

 

  • Researchers at the University of Helsinki has found the lymphatic vessels extend into the brain – overturning 300 years of accepted wisdom. By genetically altering mice using the luminescent GFP gene, so that lymphatic vessels glowed under light, Aleksanteri Aspelund found that there were lymphatic vessels in the brain. The research was repeated by Karl Alitalo with the same results.  Other researchers have found evidence linking problems with the lymphatic and glymphatic systems to Alzheimer’s; one study in mice showed it could lead to the buildup of amyloid beta in the brain – a key sign of the Alzheimer’s. The study was published in the Journal of Experimental Medicine.

    Red fluorescence of the membrane protein aquaporin-4 in an individual with Alzheimer’s (left) and a healthy individual (right). Source: OHSU

  • Mice help researchers identify genes responsible for a severe congenital heart defect.  Congenital heart disease affect up to 1 percent of all live births. Hypoplastic Left Heart Syndrome (HLHS) is a rare congenital heart disease resulting in an inability to effectively pump blood  throughout the body.  Current treatment involves multiple complex surgeries during the first few years of a child’s life. For some, the surgical interventions improve heart function.  For others, it does not,  leading to heart failure and the need for heart transplants. It has been known that genetic risk factors play a role in HLHS but specific genes have been hard to identify.  Researchers at the University of Pittsburgh Schools of the Health Sciences used fetal ultrasound imaging to look for structural heart defects in genetically modified mice to identify HLHS.  Then by comparing the genomes of affected and non affected mice, and confirming using CRISPR technology they found that mutations in two specific genes that interact were required for HLHS.,   Dr. Cecilia Lo, a professor and the F. Sargent Cheever Chair in Developmental Biology at Pitt says, “Studying diseases with complex genetics is extremely challenging…By understanding the genetics and biology of HLHS, this can facilitate development of new therapies to improve the prognosis for these patients.” This study was published in the journal Nature Genetics.
  • The University of Bristol has awarded prizes in its first Animal welfare and 3Rs Symposium. The 3Rs, developed by Russel and Burch in 1954, have advanced the humane treatment of animals used in research by advocating for replacement (aiming to replace animals where possible, with alternatives), to reduce the number of animals used to the minimum required to answer and experimental question and and to refine their experiments to minimise any adverse effects experienced by the animals.These awards went to three research projects that have advanced the 3Rs in their various lines of research.

“The research project that won first prize has developed a refined method for producing aortic aneurysms in mice.  An aortic aneurysm is a bulge in a section of the aorta, which is the body’s main artery, and if the bulge ruptures it can cause sudden death. The research team has also developed a new human aortic aneurysm model in the laboratory, potentially replacing the need for animal models, using arteries taken from the discarded umbilical cord of newly born babies.

The second prize was awarded to a research team who has developed a method for giving oral drugs using solutions that mice and rats both like and which avoids the need for restraint and reduces stress in the animals. The research team found that liquid foods such as condensed milk, milkshake and fruit puree baby food are good solutions to use for giving a wide range of drugs.
The final prize was awarded to a research team who has developed photographic techniques that can be used in conscious animals.  This new technique has revolutionised preclinical eye research and has markedly reduced the number of animals needed for research studies.”

The 3Rs. Source: Bayer

SR-Research Roundup

July 21st-July 28th

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • A protein that may cause Lupus has been identified. Lupus is a chronic inflammatory disease that occurs when your body’s immune system attacks its own tissues and organs. An estimated 1.5 million Americans, and at least 5 million people worldwide, have a form of lupus. Previous research has implicated the gene PRDM1 as a risk factor for lupus. Scientists looking at Blimp-1, a protein that is encoded by the PRDM1 gene, have found in mice thatthat a low level of or no Blimp-1 in a particular cell type led to an increase in the protein cathepsin S (CTSS) which caused the immune system to identify healthy cells as something to attack — particularly in females.” These results are particularly striking as women have an increased risk for lupus compared to men. While this work needs to be replicated and validated, this research provides some valuable insight into the etiology and treatment of lupus. This research was published in the journal Nature Immunology.

Source: http://ajprenal.physiology.org/content/308/10/F1146

  • Vaccine for virus induced Type 1 diabetes successful in mice. Coxsackie B viruses are the most common enteroviruses and are believed to be associated with the development of Type 1 diabetes. Type 1 diabetes is a common human disease defined by a decrease in the production of insulin, which is a hormone that allows blood glucose (sugar) to enter energy producing cells. Thus, without insulin your body cannot effectively produce energy. This week, a team of Finnish researchers published a preclinical evaluation of a Coxsackie B1 vaccine using mice and found that the vaccine successfully protected the mouse after administering the Coxsackie B1 virus. Pre-clinical trials in humans are the next logical step for this vaccine, and the researchers believe that this research will aid in the development of vaccines for other disease caused by enteroviruses such as; hand-foot-and-mouth disease, meningitis, and myocarditis. This research was published in the journal Vaccine.
  • High iron levels in brain linked to progression of Alzheimer’s. Alzheimer’s is a degenerative neurological disease that causes dementia in humans. Previous research has linked Alzheimer’s to the buildup of amyloid protein in the brain, but research on drugs that reduce amyloid levels have not successfully slowed the progression of the disease. New research from the University of Melbourne however, discovered that humans with high levels of iron and amyloid were suffering from rapid dementia, while those with just high levels of amyloid protein were stable. This finding will fuel a five year trial on whether an anti-iron drug can slow the progression of the disease. This research was published the journal Brain.

Source:https://pursuit.unimelb.edu.au/articles/rusty-brains-linked-to-alzheimer-s?utm_source=twiter&utm_medium=social&utm_content=story

  • Compound protects macaques from simian HIV. Research being presented this week at the National AIDS Treatment Advocacy Project (NATAP) Conference on HIV Pathogenesis Treatment and Prevention in Paris shows that weekly administration of a compound called MK-8591 repeatedly protected 8 of 8 macaques from simian HIV (SHIV) 6 days after treatment. Researchers from the Aaron Diamond AIDS Research Center in New York, Merck, and the Tulane National Primate Research Center studies 16 male macaques, 8 of which received weekly treatments of MK-8591 for up to 14 weeks, the other 8 of which received a placebo. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that thwarts HIV. All 8 monkeys treated with MK-8591 remained SHIV-free even after 12 challenges with SHIV, to the end of the 168-day study. In contrast, the monkeys not treated with the drug all became infected with SHIV. The researchers noted that protective intracellular active MK-8591 concentrations can be attained in humans at low drug doses. These new findings support the potential use of MK-8591 as a prophylactic treatment for high-risk individuals.
  • New drug acting at two opioid receptors shows promise to treat chronic pain without the adverse effects of morphine. An epidemic of opioid abuse is killing people by the hundred of thousands in the United States, becoming the main cause of death for people under 40. The epidemic has been traced to the prescription of new opioid analgesics like Oxycontin over the last years, which has led people to become addicted to it and then to harder drugs like heroin. A group of scientist followed the strategy of creating drugs that bind not only to the receptor for morphine in the brain, the mu-opioid receptor, but also to a new opioid receptor called the nociceptin FQ receptor. The new drug, BU08028, was shown to reduce pain responses in rats as effectively as morphine. Now the drug is being tested in rhesus monkeys, where it also decreased pain. Importantly, the monkeys showed no desire to self-administer BU08028, an indication that the drug is not addictive.
  • Computer-designed opioid drug may decrease pain without producing respiratory arrest. People dying during the current opioid epidemic do so because the drugs inhibit the centers in the brain that drive breathing, leading to suffocation. Scientists proposed that the pain-relieving and breathing-suppressive effects of the opioids depend on different interactions of these drugs with the mu-opioid receptor, and set up to produce a compound that would suppress pain but not breathing. To do that, they modelled the drug binding site at the receptor using computers. After testing millions of compounds in the computer, they found a drug, PZM21, that showed promise. Then they tested PZM21 in mice and found that it suppressed pain but not breathing. They also found that PZM21 did not show the rewarding effect that typically lead to addiction. This demonstrates how even when new drugs are designed using computer models, animal studies are still needed to evaluate their effects.

Q & A With a Primatologist: Why Studying Rank Changes is Good for Primate Welfare

In this Q&A post, we talk with Lauren Wooddell, a laboratory assistant at the California National Primate Research Center. Lauren is the first author of a research paper about to be published in the May 2017 issue of the Journal of the American Association for Laboratory Animal Science (JAALAS) titled, “Elo-rating for Tracking Rank Fluctuations after Demographic Changes Involving Semi-free ranging Rhesus Macaques (Macaca mulatta).” The paper is available in early view online now. Here, Lauren describes this study and its implications for animal welfare, and also for a better understanding of primate societies.  

 

Lauren.jpg

Lauren Wooddell

 

Speaking of Research (SR): How did you get into this field of research?

Lauren Wooddell (LW): I’ve always loved animals. I wanted to become a veterinarian ever since I was a toddler, but I realized in college that I’m more interested in animal behavior. I ended up taking some courses on animal welfare research and completely fell in love with it. There’s research to better the lives of animals? Count me in. I originally wanted to work with pigs, but the opportunities were, and still are, scarce. Instead, I worked with cattle, chickens, gibbons, parrots, and dolphins, until I began working with primates at NIH. When my rhesus macaque troop at NIH endured an overthrow, where monkeys with lower dominance ranks displaced the alpha ranked monkey, it was a very devastating event. To be honest, I kicked myself for not seeing it coming. But I then became passionate about understanding why it occurred so that hopefully we can prevent overthrows in captive primates in the future.

SR: Can you explain dominance hierarchies to us?

LW: Most monkeys (and many other animals) naturally form what is called a dominance hierarchy, to gain social order and determine who has priority access to resources. Within a dominance hierarchy animals are “ranked”, usually based on their wins or losses in aggressive interactions. High-ranking monkeys may fight and win against most other members of the social group, but rarely receive threats from others. Low-ranking monkeys, however, generally receive threats  by most other monkeys, but start fights with  others. Within dominance hierarchies high-ranking monkeys will have greater access to food and mates — it “pays” to be high-ranking.

Chasing.png

Rhesus monkeys in an aggressive chase interaction.

SR:  Why is it important to study changes in social rank in rhesus monkeys?

LW: Rhesus monkeys have remarkably rigid hierarchies that can remain stable for decades. This means that monkeys will often have the same social rank for their entire lives. Changes in social rank therefore are generally rare and when they occur, they can occur violently — resulting in devastating consequences for the monkeys. These drastic changes occur both in captivity and in the wild. For example, our lab at NIH found that social upheavals, or intense fights, can result in reproductive consequences for the involved families, whether the monkeys won or lost. These violent upheavals are called “overthrows”, because usually a lower-ranking individual or family will take over a higher-ranking one. By understanding more about how and when these “overthrows” happen, we could learn to predict, and potentially prevent, these violent events from happening. Doing so would greatly benefit the care of rhesus monkeys in captivity —where similar breakdowns in the hierarchy happen.

SR: Can you briefly describe the nature of your study, and what results you discovered? Was there anything surprising that emerged?

LW: Hierarchical stability, or dominance stability, refers to the idea that when we construct dominance hierarchies, individuals hold the same ranks, or positions, over time. If I construct a dominance hierarchy today with individual X as rank #7 for example, I would expect to see that individual as rank #7 (or very close to that) a few months from now as well. The goal of the study was to examine how changes to the social group would influence this stability: how would troop stability change animals had to be removed for health or colony management reasons, or if an overthrow occurred? The important thing to note is that this study was retrospective, meaning that none of the changes were implemented as part of a study. Importantly, in the case of the overthrows, we knew who was involved. This allowed us to go back retrospectively and analyze their behavior before the overthrow to examine potential indicators.

To measure social rank, we used Elo-rating, which is a method originally devised to rank and compare chess players that has since been modified for use in other sports (i.e. soccer and basketball) and now in animal contests. Essentially, Elo-rating allows us to predict the outcome of a potential competition between two individuals, before the competition takes place. Each animal gets a score that reflects its wins and losses. Animals can go up and down in their rating, depending on whom they compete against. So a high-ranking animal won’t increase in Elo-rating for winning against a low-ranking animal, because this is expected. But a low-ranking animal would increase significantly in Elo-rating for winning against a high-ranking animal. In general, high Elo-ratings refer to highly ranked animals, whereas low Elo-ratings refer to lowly ranked animals. The advantage of Elo-rating is that scores can change over time and reflect potential challenges to higher-ranking monkeys.

Unsurprisingly, we found that changes in a social group do indeed affect the stability of the dominance hierarchy. For instance, when we removed a large group of natal males – males that are born into the social group – dominance stability improved. This is generally because young males will attempt to rise in rank as they age, and their mothers will support them (especially if they are high-ranking). The increased stability may explain why, in the wild, natal males naturally emigrate from their troop around puberty. On the contrary, removing top-ranking females resulted in unstable dominance relationships because the females ranked immediately below the removed females increased in Elo-rating. The rising females were also involved in the overthrows of the top-ranking females. Therefore, increases in Elo-rating over time for the #2 ranking families, especially following the removal of females in the #1 ranking family, may be an indicator of an imminent challenge to the hierarchy.

FamilyGrimace

A family of rhesus monkeys indicates submission to an adult male via fear grimaces.

Perhaps the most surprising result from this study was that after overthrows, dominance stability improved. This improvement indicates that overthrows may actually be a stabilizing mechanism for a troop. This poses a real conundrum for captivity though: if overthrows potentially stabilize a troop, should we prevent them from occurring? In terms of animal welfare, I would argue yes. Perhaps the better question is: how can we stabilize the troop before an overthrow occurs? That is what I hope future research will tackle.

SR: How did you study the animals? Can you tell us what this involved, day-to-day?

LW: We studied a troop of rhesus monkeys that lived in a naturalistic, yet captive, 5-acre habitat. The troop was structured around large family groups that totaled 80 monkeys comprised of three major families. On a daily basis, we observed and recorded dominance interactions by standing in the habitat with the animals and recording every time we saw monkeys threaten, chase, or bite each other. However, monkeys use submissive gestures as well, such as moving away from dominant individuals or using facial signals like a fear grimace, which we recorded as well. We recorded the identities of the monkeys involved, and from these interactions, we could then determine a dominance hierarchy by using Elo-rating. Tutorials and software code for Elo-rating using R Stats software package are freely available.

FearGrimace

Rhesus monkey fear grimace indicating subordinate status.

SR: What are the most important implications of this study in terms of animal welfare? And in terms of understanding primate societies? 

LW: In terms of animal welfare, I think this study effectively shows that with careful observation, we can potentially predict some of these major upheavals, which would collectively enhance the well-being of rhesus monkeys in captivity. In terms of understanding primate societies, I think this study shows that certain individuals, which we call keystone individuals, can have a large impact on the overall social stability of the troop. Understanding the presence of keystone individuals can allow us to understand the development, and breakdown, of social groups both in the wild and in captivity.

SR: Are there any implications for the social behavior of wild monkeys?

LW: Absolutely! Wild monkeys also exhibit dominance hierarchies that can fluctuate over time, and changes in their social groups can occur regularly. For example, males commonly transfer into and out of social groups. Males born into a group will leave that group as they mature as to not breed with kin. So how do social groups change in their stability following the emigration or immigration of males? Another potential application would be in the study of group fission events, which occur when a social group becomes so large that it breaks apart into two or more groups. These are rarely observed and poorly understood. A relatively recent group fission on Cayo Santiago, an island off of Puerto Rico that has approximately 1,000 rhesus macaques, occurred following the death of the troop’s alpha female. This resulted in an overthrow and a group fission. The research indicated that there were changes in the monkeys’ social behaviors, like grooming tendencies, before the event, and I would assume that prior to group fissions, there was probably some degree of dominance instability as well. Perhaps with time, researchers in the wild could predict these events, which would allow researchers to have a better understanding of why and when these events occur. In general, our results suggest that any major event could be analyzed to examine how the hierarchy changes in response to or even prior to the event.

 

Displacement

Rhesus monkey dominance is evident in subtle ways, such as the displacement occurring here.

SR: What are some of the most rewarding and some of the most difficult aspects of your job?

LW: The most rewarding aspect of the research is gaining an understanding of the highly complex social lives of the monkeys. It’s a constant soap opera, full of drama and plot-thickening twists. When you work that closely with the monkeys, you get to know them on a very individual level and you become inevitably intertwined in their stories as well, going through all of the changes with them. However, the most difficult aspect of this work is when the hierarchy is challenged in an overthrow, which, thankfully, is rare. There’s a notion in the general public that researchers are data-driven machines that only care about the bottom line: results. That’s simply not the case. I’ve lost monkeys that I’ve come to know on a very intimate level to overthrows, and it has been devastating. We deeply care about the monkeys we work with, more than just the data they provide. Researchers have emotions too, and I am willing to admit that. I hope other researchers will do the same.

SR: Thank you for sharing the important work that you do with us!

LW: Thank you for inviting me to discuss this research. I hope it will inspire future research!

Nonhuman primate research gives us otherwise impossible treatments

stuart-bakerLast week, Dr. Stuart Baker, a Professor of Movement Neuroscience at Newcastle University, wrote an article in The Conversation detailing not only the lifesaving research that nonhuman primates contribute to, but also the exceptional care they receive while contributing to human health. Stuart last week also published a paper describing his laboratory’s development of a new device that helps stroke patients to recover, a device that was dependent on development first in rhesus monkeys.  In his piece in The Conversation, Baker highlights the following:

  • Why it is important to understand how the brain controls movement
  • Why nonhuman primates are superior to other animal models for this type of research
  • The state-of-the-art care his laboratory primates receive

Why it is important to understand how the brain controls movement

“We typically take the ability to move in a fluid, coordinated way for granted,” Baker writes. Yet many adults “suffer damage to the brain’s pathways for movement, for example after a stroke. Suddenly, everyday tasks become a tiring, frustrating struggle.” Baker studies how the brain controls movement in order to understand the connections between our brains and our limbs. By understanding how brain cells adapt their neuronal activity during movements, how neurons are connected, and how they reconfigure after injury, Baker can then develop devices for therapeutic treatment like the one he published about in The Journal of Neuroscience last week.

Why nonhuman primates are superior to other animal models for this type of research

In his article in The Conversation, Baker emphasized the need for nonhuman primates in movement neuroscience research. In order to understand the deepest inner workings of the brain – those that don’t contribute to scalp recordings, which can be used in humans – one must probe deeper than the surface. Baker uses an analogy of an airport: “When we record from the scalp, we average the signals from many millions of cells. It’s a bit like placing a microphone on the ceiling of an airport departure hall, and measuring the sound levels.” This type of information is useful because it can tell you “what times of the day the airport is busy.” But “some aspects of the airport’s operations – those outside on the tarmac – would be missed.” Similarly, Baker says, some brain centers that control movement are so deep beneath the skull that a deeper exploration beyond scalp recordings is required. Enter monkey models: “Many pathways for movement control are different between primates such as humans and other animals such as rats. Only a primate model can give us information which is relevant to human diseases.

One of Newcastle’s macaque monkeys. Newcastle University, Photo credit: S. Baker

One of Newcastle’s macaque monkeys. Newcastle University, Photo credit: S. Baker

The state-of-the-art care his laboratory primates receive

Stuart is well aware that there are inaccurate and baseless claims that his lab animals suffer. In The Conversation, he describes in detail the care his monkey receive, from positive reinforcement training so that they learn to perform complex tasks with their hands or arm to undergoing surgery “in a fully equipped operating theatre, with sophisticated anaesthetics and painkilling medication borrowed from state-of-the-art human care.” The monkeys are carefully monitored to ensure they are not distressed or in pain.

Baker also emphasizes the “huge effort [that] goes into minimizing suffering every day.” This effort is not optional, but “an integral part of what we do and who we are.”

Baker’s article is a wonderful example of the type of transparency that scientists should engage in more frequently. Without such candor, the public is unaware of the extent to which animal models contribute to lifesaving therapeutics – and also of the excellent care they receive from the people who truly love working with them.

What can you share about your research and the animals you work with?

Zika research in nonhuman primates critical as fears among pregnant women, families grow

Jordana Lenon, B.S., B.A., is the outreach specialist for the Wisconsin National Primate Research Center and the Stem Cell & Regenerative Medicine Center, both at the University of Wisconsin-Madison. In this guest post Jordana talks about WNPRC research on Zika virus.

Wisconsin National Primate Research Center scientist David O’Connor is emphasizing using “as few animals as possible” to answer research questions that desperately need answers as the world watches Zika virus cause birth defects and raise fears among pregnant women and their families across the warmer Americas. These answers, O’Connor expects, will move him and his collaborators at the University of Wisconsin-Madison, Duke University, in Brazil and beyond forward as they learn more each day how Zika virus may be operating inside of infected pregnant women and their newborns, and could cause potential lifelong impairments we don’t even know about yet.

Researchers at the Wisconsin National Primate Research Center perform a fetal ultrasound on a pregnant rhesus macaque, in their quest to learn more about the link between the Zika virus and birth defects. (Images by Justin Bomberg, UW-Madison Communications)

Thanks to research using rhesus macaques, whose immune, reproductive and neurological systems are very similar to ours, the answers are starting to come in. Furthermore, O’Connor and his Zika Experimental Science Team, or “ZEST are sharing their raw research data through an online portal with the public – including of course and very importantly other Zika researchers. Their goal is to share data openly, to eliminate as many impediments as possible to spurring collaborative work around the globe to solve the Zika crisis.

David O'Connor, professor in the Department of Pathology and Laboratory Medicine at the University of Wisconsin-Madison, is pictured on April 19, 2016. (Photo by Bryce Richter / UW-Madison)

David O’Connor, professor in the Department of Pathology and Laboratory Medicine at the University of Wisconsin-Madison, is pictured on April 19, 2016. (Photo by Bryce Richter / UW-Madison)

Just how severe a problem are we looking at? O’Connor gave some perspective during a public lecture on the UW-Madison campus this week. While HIV – another pandemic virus he has studied exhaustively over the past 20 years – costs society about $400,000 per patient over their life spans, Zika virus impairments in newborns could cost between $1-10 million per patient (using US dollar estimates) over their life spans. Recent studies in macaques found that the Zika virus persisted for up to 70 days in the blood of pregnant female monkeys – much longer than the 10 days it remained in either males or non-pregnant females – this increases the chance of severe birth defects being found in babies.

There are already more than 300 pregnant women in the US with laboratory evidence of Zika. This number is growing daily. Infections in the US are largely being attributed to pregnant women picking up the virus while traveling outside the country: Zika is hitting hard right now in Puerto Rico, infecting nearly 50 pregnant women per day, as Aedes aegypti mosquitos, which can transmit viruses such as dengue and Zika, spread and move northward this summer from South to Central America, to the Caribbean and into the United States. Because Zika is also sexually transmitted, its borders of infection are not limited to places where the mosquitos live and bite.

Mother and infant rhesus monkeysThere is hope, however. A new experimental vaccine has shown to protect mice with just a single dose. Scientists from Walter Reed Army Institute of Research, the Beth Israel Deconess Medical Center and Harvard Medical School found two different vaccines effectively protected 100% of mice from the virus. This compares to a control group which were unprotected and all caught Zika after being exposed to the virus.

Jordana Lenon

See the team’s latest research updates on the ZEST web portal site.

View the Wednesday Night at the Lab lecture on Zika virus that Dr. O’Connor gave July 6 on the UW-Madison campus, including his responses to several questions about the virus, immunity, pregnancy, and vaccine development.

Macaque study explores best route of oxytocin administration

Oxytocin is a natural brain peptide most commonly thought of as the “love hormone” for its role in social bonding: it spikes during social contact, play, cuddling, and sex. Because of extensive research in animals including prairie voles, sheep, and monkeys demonstrating that oxytocin promotes affiliative behaviors and social bonding1,2, oxytocin is increasingly being studied for its effects on humans3. The jury is still out here: some studies show that oxytocin has no effect on social behavior, whereas others show a negative effect. The most attention, however, is given to those studies showing a positive effect, particularly in individuals with social deficits like those with autism spectrum disorder (ASD)4.

Consequently, oxytocin nasal sprays are increasingly being advertised as treatments for ASD, despite the inconclusive results from clinical trials and a lack of studies showing their long-term efficacy and side effects. These sprays are available online without a prescription but they are not regulated by the FDA. Thus little is known about the quantity of oxytocin they contain, their efficacy, or possible side effects.

Though nasal sprays are commonly used in clinical trials for ASD, oxytocin is often administered intravenously (IV). In both cases, study designs differ in the amount of oxytocin they use, the duration of treatment, and the delivery method, so it is no surprise that they have yielded conflicting results. Thus, the mechanisms by which oxytocin administered in different ways may act in the brain are unclear.

Macaque Monkey

Image Credit: Amanda M. Dettmer

An important and timely study just published online in Psychoneuroendocrinology by researchers at the California National Primate Center and the University of California-Davis tackles some of these methodological questions. Rhesus monkeys were implanted with intrathecal catheters to allow for repeated sampling of cerebrospinal fluid (CSF) in awake animals, and were treated with either intranasal (IN) or IV oxytocin at three different doses in a randomized, crossover study design (meaning animals were randomly assigned to IN, then IV, or vice versa). Blood and CSF samples were collected from awake animals (thus eliminating possible confounds of anesthesia) pre-dose (0 minutes), and at 5, 15, 30, 60, and 120 minutes after oxytocin administration. Importantly, this is the first study to use awake monkeys for oxytocin administration and sample collection, to directly compare more than two different doses of oxytocin in the same subjects, and to collect five concurrent post-oxytocin blood and CSF samples in a relatively short period. These methods would be extremely difficult, if not impossible, to carry out in human subjects.

The researchers found that blood and CSF levels of oxytocin were higher after IV vs. IN administration. Furthermore, they found that IV-administered oxytocin elevated blood and CSF oxytocin for a period of up to 30 minutes, whereas IN oxytocin had no effect on blood levels of oxytocin, regardless of the dose – an unexpected finding because IV oxytocin does not cross the blood-brain barrier5. The authors postulate that elevated levels of oxytocin in the bloodstream after IV oxytocin treatment might result in the release of oxytocin in the brain (as observed in CSF) via mechanisms that have yet to be identified, but which studies using nonhuman primate models will be critical for disentangling. They also argue that humans can be instructed to inhale deeply during IN administration, whereas animals cannot, yielding important methodological implications for studies relying on animal models of human behavior. Finally, the group reported that blood oxytocin cannot be used as a reference for CSF oxytocin (thus supporting earlier findings), yet most human studies rely on measuring blood oxytocin after oxytocin treatment.

The authors conclude that, “…it is…critical to use nonhuman primate models to better evaluate the effectiveness of the delivery method most commonly used in human studies and clinical use – the nasal spray.”6 Indeed, studies like this one are critical for informing dosing regimens and administration methods of oxytocin in humans, as we cannot conduct such detailed studies without animal models. Ultimately, animals – specifically nonhuman primates – will be key for identifying and understanding the mechanisms by which oxytocin and other drugs act to affect brain and behavioral responses.

Amanda M. Dettmer

References

  1. Stoesz, Hare & Snow, 2013, Neurosci Biobehav Rev, 37(2):123-32.
  2. Lim & Young, 2006, Hormones & Behavior, 50:506-17.
  3. Kuehn, 2011, JAMA, 305(7):659-61.
  4. Young & Barrett, 2015, Science, 347(6224):825-26.
  5. Ermisch et al., J Cereb. Blood Flow Metab, 5:350-57.
  6. Freeman et al., 2016, PNEC, 66:185-94.