Center News

Important neuroscience research being conducted by the Buffalo Lab at the Washington National Primate Research Center is being shared at the Pacific Science Center.

The “Memory: Past Meets Present” exhibit is part of the Portal to Current Research that showcases local scientific research and its impact. The exhibit is open now through March 5, 2017.

“We are excited to be a part of this exhibit,” says Dr. Beth Buffalo, Chief Investigator with the Division of Neuroscience at the Washington National Primate Research Center. “This is a great opportunity to teach the public about our efforts to detect early warning signs of Alzheimer’s disease in healthy human patients.”

The Buffalo lab uses nonhuman primate research to track the combination of eye movements and the firing of neurons in the hippocampus to predict memory performance. In the lab, monkeys play a video game that has special software to track eye movement as the monkey navigates a virtual world in search of bananas. When the monkey finds a banana, the system provides a treat to the research subject. Treats are normally a special recipe of various fruit sauces. A map of the virtual world correlates to specific neurons in the patient’s hippocampus region of the brain.

The exhibit allows visitors to learn about this virtual built-in GPS system that human and nonhuman primates share. While playing the game, you’ll discover what information is stored in our brains while foraging for food in a virtual forest.

Buffalo Lab graduate student, Seth Konig, will give a public lecture titled “The Neuroscience of Memory: Why We Forget Some Things but Remember Others” at the Pacific Science Center on November 1 at 7 p.m. Admission is $5.

Visit www.pacificsciencecenter.org/lectures for more information.

This exhibit series is funded by a grant from the Paul G. Allen Family Foundation. Learn more by visiting www.pacificsciencecenter.org.

Megan O’Connor, PhD., of the Fuller laboratory receives NIH-sponsored post-doctoral training fellowship from the University of Washington Center for AIDS and STD. The fellowship will pay O’Connor a yearly stipend to complete her post-doctoral research that will take place at the Washington National Primate Research Center.

The fellowship will assist O’Connor’s research by covering her salary and making funds available for her experiments. In addition, the fellowship program provides O’Connor with educational and networking opportunities designed to improve her knowledge of sexually transmitted diseases and AIDS research while enhancing her personal development as a post-doctoral fellow.

O’Connor joined the Fuller lab in January of 2016. The lab investigates therapeutic and prophylactic DNA vaccines for HIV. They are also testing new adjuvants designed to stimulate both systemic and mucosal antibody and T cell responses.

“Our lab has a major focus on investigating and improving therapeutic HIV vaccines using the simian immunodeficiency virus (SIV) macaque model for AIDS,” says O’Connor. “This research will help us to better understand how we can improve vaccine efficacy.”

HIV in humans is very similar to SIV, which is found in many species of nonhuman primates. The Fuller lab currently has several ongoing macaque model vaccine studies, of which O’Connor is involved in, which are planned to run through 2021.

HIV and SIV infection creates a misbalance of two cell types in the gut during infection. The misbalance of T-regulatory (Treg) and T helper 17 (Th17) cells is associated with HIV/SIV progression. The goal of O’Connor’s project is to determine whether SIV vaccination also has an effect on these different cell types in the gut mucosa.

Using the SIV macaque model for AIDS, they investigate the ability of vaccines to therapeutically treat SIV infection and residual virus in the gut mucosa. Previous studies in the Fuller lab showed that therapeutic immunization with a DNA vaccine that induces responses in the gut mucosa resulted in a functional cure from AIDS, or durable control of viral replication when administered to chronically infected animals in combination with short-term treatment with antiretroviral drugs (immunotherapy). These studies also aim to define the role of mucosal responses, in particular, and other immune mechanisms underlying the response to vaccination, protection from infection, or induction of durable viral control.

According to the World Health Organization, 37 million people are living with HIV globally. Since the beginning of the epidemic, more than 70 million people have been infected by the disease and 35 million have died from it. There are currently 17 million people worldwide on antiretroviral therapies for HIV/AIDS. The most promising vaccine approaches from these studies may lead to future clinical testing of these strategies in HIV infected humans.

Learn more about the AIDS-related disease research being conducted at the WaNPRC.

Learn more about the STD/AIDS Research Training Fellowship Program from the UW Center for AIDS and STD.

Dr. Kyes often travels for up to seven months each year as the leader of the Division of Global Programs for the Washington National Primate Research Center and Director of UW’s Center for Global Field Study. Students from around the world get to learn about the convergence of environmental and global health through field course programs in countries such as: Indonesia, Nepal, China, India and Thailand. Kyes has spent nearly 30 years leading field courses in a dozen countries. UW Today writer Deborah Bach recently interviewed Dr. Kyes about his experiences, outreach efforts, challenges and rewards of running this successful program. The piece is titled: From crop-raiding monkeys to political unrest: UW’s Randy Kyes embarks on 100th field course.

Researchers are studying memory formation in the primate brain—and finding clues for interventions for Alzheimer disease along the way.

Giuseppe sits in a small room playing a videogame, joystick in hand. He zooms through a grassy field, foraging for big yellow bananas. Banking left, he speeds along a stonewall and captures two. A sweet treat rolls down a tube into his mouth, and he munches on his reward. Giuseppe, a monkey, is a research participant in the Buffalo Lab at the University of Washington.

In the lab next door, researchers watch a thin yellow line zigzag across a computer screen, with a loud crackling sound. “That’s the sound of a neuron firing an action potential,” says graduate student Seth Koenig, who is recording the activity of single neurons in the monkey’s brain, via a hair-thin electrode implanted into the medial temporal lobe. A camera setup tracks his darting eye movements.

Along with four other monkeys trained to play various computer games, Giuseppe is helping researchers to figure out how the primate brain forms memories—and clues to interventions for the memory impairments of Alzheimer disease along the way.

Read full article from the UW Medicine Memory & Brain Wellness Center…

According to the Centers for Disease Control and Prevention, the Zika virus is spread to people primarily through the bite of an infected Aedes mosquito. Common symptoms for adults is very similar to a flu virus, including: fever, rash, joint pain, and dry and itchy eyes. Zika virus can be passed from a pregnant woman to her fetus. Infection during pregnancy can cause Microcephaly and other severe brain injuries.

The virus continues to spread. Women who are pregnant or planning to become pregnant should not travel to affected areas in South America, Central America and the Caribbean. Kristina Adams Waldorf, UW associate professor of obstetrics & gynecology and affiliate researcher at the Washington National Primate Research Center, is studying this viral disease. She was recently interviewed by KOMO news and offers advice to pregnant women on current recomendations on travel and provides basic Zika virus information. Click here to read the full article.

Link Between Hippocampus and Memory

The ability of the brain to store and later retrieve information is remarkable.  Detailed, complex memories can be formed after as little as one exposure, and those memories can be retained for decades.  This ability is compromised following damage to structures located in the medial temporal lobe, including the hippocampus and the adjacent entorhinal cortex.  The link between the hippocampus and memory has been appreciated since the report of the famous case of patient H.M., who suffered a dense amnesia following removal of the hippocampus and adjacent cortex in order to relieve otherwise intractable epilepsy. Subsequent studies in rats, nonhuman primates, and human patients have demonstrated that the integrity of medial temporal lobe structures is critical for normal memory ability.

Place Cells

While it has long been recognized that these structures are important for memory, a largely parallel line of research in rodents has highlighted the contribution of these same structures to our sense of space. This line of research began in the 1970’s with the discovery of hippocampal “place cells” – neurons that are selectively active when an animal moves through specific locations in an environment, with each neuron active in a distinct location. Recordings from many of these neurons simultaneously provide an exquisite map of the animal’s environment. Accordingly, these neurons are thought to aid in spatial navigation and constitute an internal or cognitive map.

What is currently unclear, however, is how this cognitive map contributes to memory formation, which is considered the primary function of these brain structures. While spatial information is a critical component of episodic memory, or memory for past events in one’s life, the details of how memories are formed and the relationship between spatial and mnemonic representations are not well understood, particularly in the primate brain.

Consensus between the memory and spatial views has been difficult because of differences in the species and approaches used – most experiments on memory involve human subjects, whereas most experiments on spatial cognition involve maze behavior in rodents. Research in nonhuman primates presents an opportunity to bridge the gap between the more invasive research of cells and circuits that have been investigated in rodents and complex behaviors that can be measured in humans. A recent focus of research in the Buffalo lab is to take advantage of the complex memory abilities that can be demonstrated by nonhuman primates, along with recordings from single neurons and neuronal ensembles, in order to try to bridge the gap between the spatial and mnemonic views of hippocampal function.

Using Virtual Reality to Examine Brain Activity

One exciting new way that we are addressing these issues involves the development of behavioral tasks for the monkey using virtual reality coupled with neurophysiological recordings. This technique allows us to examine hippocampal activity during environmental navigation and to investigate neural activity in the medial temporal lobe that may underlie complex behaviors.

We have successfully implemented techniques in our laboratory for assessing neuronal activity along with eye movements as monkeys are engaged in virtual 3D navigation.  In addition, we have successfully trained monkeys to use a joystick to navigate through the environment, obtaining reward for navigating to specific targets. One exciting preliminary result from our recordings in the hippocampus is the identification of a prominent theta rhythm (3-8 Hz) during virtual movement, the peak frequency of which is strongly correlated to the frequency of eye movements. We are also examining hippocampal activity as the monkeys perform spatial memory tasks in which they are rewarded for remembering the location of hidden targets in the virtual environment. We have identified patterns of neural activity, in the form of enhanced gamma-band (30-90 Hz) correlated activity that is predictive of successful memory performance.

Goal: Restore Memory

One goal of this work is to find ways to use deep brain stimulation to restore memory in individuals who have impaired abilities due to traumatic brain injury. An additional goal is to use information gained from studies in nonhuman primates to aid in the development of novel behavioral tools for early diagnosis of cognitive deficits due to neurodegenerative disease, including Alzheimer’s. Our expectation is that the findings from our studies in nonhuman primates will be used to inform clinical research and, hopefully, improve clinical practice in the future.

Beth Buffalo  |  Core Staff Scientist  |  Chair of WaNPRC Division of Neuroscience

Similarities of Vision and Brain Response in Macaques and Humans

Research conducted within the Pasupathy lab at the Washington National Primate Research Center capitalizes upon the similarities of macaque and human vision and brain response in its exploration of the primate visual cortex.

The primate visual system is especially adept at recognizing objects in cluttered environments where the object of interest is often partially blocked from view – occluded. Finding our keys amidst paper and books on a messy desk, spotting a friend in a crowd—these are difficult tasks that stump even the most advanced computer recognition systems. This is largely because of two reasons:

1. Occlusions cause parts of objects to be hidden, making recognition challenging.
2. Boundary conjunctions, a byproduct of occlusion, can produce spurious features in the retinal image that make it difficult to determine where one object ends and another begins.

Despite these difficulties, our visual system recognizes occluded objects quickly, accurately and seemingly effortlessly. How is this achieved? Research in the Pasupathy lab at the Washington National Primate Research Center tackles this question with a combination of neurophysiological recordings in monkeys trained to recognize shapes and computer modeling.

Object Recognition in Macaque and Human Visual Systems

Macaque monkeys are a great animal model to investigate object recognition because their visual system is very similar to that of humans. Monkeys and humans can easily discriminate complex images and objects that are only 2° in diameter at central fixation. Monkeys are very similar to humans in their voluntary eye-movements and their exploration of high-interest targets in scenes. Several behavioral studies in monkeys suggest that they segment visual scenes into objects and regions the way humans do. Monkey visual cortex is also similar to humans in terms of its organization into dorsal and ventral streams, and in terms of the receptive field size and tuning properties.

Recognition of Occluded (Partially Blocked) Objects

For the neurophysiological experiments, we focus on areas V4 and the inferotemporal cortex, brain regions known to play an important role in visual form processing. Recently we have also begun studies in the prefrontal cortex, which is important for the control of complex behavior, to investigate how feedback from higher cortices might play a role in the recognition under occlusion. Our computer modelling efforts help us reveal how neuronal responses in these brain areas arise from signals in earlier processing stages and how these signals solve the problem of occlusion. More recently, we have also begun a collaboration to compare the responses of neurons in visual cortex and those of units in deep convolutional nets, the current best visual recognition algorithms.

Utilization of this Research for Public Good

Past discoveries in visual neuroscience have driven advances in artificial and computer vision. Deep artificial networks now provide an important opportunity for insight from the artificial vision community to help understand the complex encoding at middle and higher levels in the primate visual cortex.

Dr. Anitha Pasupathy | Core Staff Scientist |  WaNPRC Division of Neuroscience  | Associate Professor Department of Biostructure

Targeted gene editing in nonhuman primate research model may hold key to unlocking mysteries of Fragile X and other genetic disorders.

Fragile X Syndrome (Martin-Bell Syndrome) can result in a spectrum of mental disabilities (such as autism) and physical characteristics such as elongated face and protruding ears. Nearly half of children with Fragile X meet the criteria for autism diagnosis.

Fragile X and associated disorders encompass a range of genetic conditions, all of which result as a function of changes within the FMR1 gene and abnormal production and/or expression of the FMR1 gene products. FMR1 was discovered as the causative gene in Fragile X syndrome in 1991 and is a unique dominant X-linked disorder where both males and females can exhibit pathophysiology.

The normal allele consists of anywhere between 5 to 54 trinucleotide repeats (CGG) that are stably transmitted to offspring.  However, 1 in 250 women and 1 in 800 men are carriers of the FMR1 pre-mutation, where the repeat sequence has expanded to within 55 to 200 repeats.

The FMR1 pre-mutation is associated with an adult onset tremor/ataxia syndrome (FXTAS) in both sexes as well as primary ovarian insufficiency and early onset menopause in women (FXPOI). Further expansion of the CGG repeats beyond 200 leads to Fragile X syndrome, the most common heritable form of intellectual disability and the most common known cause of autism or “autistic-like” behaviors with approximately 1 in 4,000 males and 1 in 6,000 females affected.

While the inheritance of the FMR1 pre-mutation and full mutation is of clinical significance to both men and women, the expansion of the mutation within a single generation shows a sex-bias, occurring exclusively upon transmission through the maternal germline. This renders women carrying the FMR1 pre-mutation at a significant risk of conceiving a child who is affected by Fragile X syndrome.

Animal Research Models for Fragile X and Early Onset of Menopause

To date there are no known naturally occurring animal models of Fragile X and while the rodent and fly models have been beneficial for studying the cellular and molecular mechanisms of Fragile X syndrome and FXTAS there are no clinically relevant models of FXPOI.

Work in the Reproductive Biology and Stem Cell Lab at the Washington National Primate Research Center is focused on developing a nonhuman primate model of FXPOI to define the associated ovarian pathophysiology and explore the mechanism(s) of FMR1 repeat expansion in females. To achieve these goals we employ recent advances in targeted gene editing strategies to macaque pluripotent stem cells and embryos and advanced embryo manipulation techniques to produce both cellular and whole animal model systems.

As a natural extension of this work additional models that support FXTAS and Fragile X syndrome are also underway and we have successfully knocked out the FMR1 gene in macaque embryos with high rates of efficiency. Our next step in this process of model development will be to generate live born macaque infants with the FMR1 gene modifications and characterize their neurodevelopmental and behavioral phenotype through the Infant Primate Research Laboratory.

Ultimately, the aim of these models is to provide a basis for defining the pathophysiology across the range of Fragile X disorders from which therapeutic strategies for their treatment can be identified and evaluated.

Dr. Eliza Curnow | Research Scientist | Reproductive Biology and Stem Cell Core| Division of Reproductive and Developmental Sciences