Center News

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

Roles and Responsibilities

Behavioral Management Services (BMS) is part of the WaNPRC Division of Primate Resources and is tasked with assuring the psychological well-being of the nonhuman primates housed at the Center. The overarching goal of Primate Resources is to provide an optimal environment for conducting biomedical research at the WaNPRC. In order to assure the psychological well-being of the animals housed at our center, BMS oversees the implementation of the WaNPRC Environmental Enhancement Plan.

BMS also monitors and treats any abnormal behaviors, should they arise, and trains all incoming personnel regarding the Environmental Enhancement Plan, nonhuman primate behavioral ecology and how to behave while in the vivarium to avoid causing undue stress to the animals. BMS has a dedicated trainer that utilizes positive reinforcement training techniques to encourage a variety of behaviors including voluntary cooperation with various research and veterinary procedures. Voluntary cooperation not only increases the well-being of the animals by decreasing stress that can be associated with these procedures it also increases the safety of personnel working with the animals. All species of NHPs housed at our facility live in large social groups in the wild and social contact is best way to enrich the lives of our NHPs as well avert and ameliorate any problematic behavior. Therefore, one of the most important aspects of our behavioral management program is providing a compatible social partner to all animals that are allowed to have one. BMS also monitors ongoing compatibility in social pairs.

Research Conducted by Behavior Management Services

Behavioral management programs at all National Primate Research Centers have another mission that is less well known. They are charged with contributing to the establishment of professional standards for animal care through research, publication of experimental results in peer reviewed journals. We also present on our research at scientific meetings. Research topics are expected to include evaluation of environmental enhancement strategies, behavioral monitoring and treatment strategies as well as other aspects of the behavioral management program. The BMS research program at the WaNPRC has been especially productive during the last several years during which time members of the BMS team have been authors or co-authors on eight manuscripts that are published or in press in peer-reviewed journals. They have also been authors or co-authors on 19 talks and posters presented at national and international meetings.

BMS has evaluated toys and foraging devices utilized by the WaNPRC as well as aspects of structural enrichment such as shelves and wheels in the compounds. They have also evaluated the feasibility of providing water enrichment pools to compound-housed juveniles. A significant contribution to behavioral management strategies has been the development of an innovative and effective treatment for locomotor stereotypy involving access to increased vertical space. BMS has also undertaken an assessment of WaNPRC nursery rearing strategies by evaluating behavioral outcomes for juveniles as well as adults housed at our various facilities. Both studies found that animals reared in our nursery exhibited normal behavioral repertoires. BMS has also made significant contributions to the understanding of alopecia (hair loss) which poses a significant management challenge and has received increased attention by regulatory agencies in recent years. It had been commonly thought that the two primary causes of alopecia were attributable to hair plucking and stress. Studies conducted by BMS in collaboration with the Oregon and Southwest Primate Research Centers and the University of Massachusetts Amherst have found that the majority of animals with alopecia do not hair pluck. This collaborative study also found that alopecia was associated with significantly higher levels of hair cortisol (possibly indicative of stress) at one center, but unrelated to hair cortisol at two other centers. Studies at the WaNPRC have also shown that, in general, pigtail macaques exhibit more alopecia than rhesus macaques. Studies have also shown that animals purchased from different vendors have significantly different levels of alopecia depending on their facility of origin. These differences can persist for extended periods of time (up to 10 months after entry into our facility). Thus, taken together, these studies demonstrate that the etiology of alopecia is considerably more complicated than has been commonly thought. BMS is currently investigating effects of various ameliorative therapies on alopecia as well as pharmaceutic therapies for abnormal and atypical behaviors.

Julie Worlein  |  Research Scientist  |  Behavioral Management Services

“Memory Enhancement with Modeling, Electrophysiology, and Stimulation (MEMES)”

Principal Investigator: Beth Buffalo

ABSTRACT:  The RAM Program seeks to develop new technologies for using brain stimulation to enhance human memory. The MEMES team seeks to achieve this goal via a diverse and experience group of neuroscientists, neurosurgeons and corporate partners that will perform theoretical and empirical studies designed to identify optimal stimulation parameters and methodologies for human memory enhancement. These parameters will be identified and refined via brain recordings in neurosurgical patients. These studies are designed to build towards the end goal of creating an implantable device that can be used by patients with memory disorders. The role of the University of Washington (PI: Elizabeth Buffalo, Ph.D.) in this research program is to oversee research studies regarding the neuronal representation of spatial knowledge in the nonhuman primate brain and the assessment of the ability of direct brain stimulation to enhance these representations. This work will be carried out via collaboration with clinical studies involving human patients, both here ate UW and with neurosurgeons and neurologists at multiple hospitals. The University of Washington’s work in this program consists of several components to support the MEMES research proposal. First, UW will adapt experimental paradigms that are designed to assess how the human brain represents spatial information for use in the nonhuman primate. Second, UW will perform neurophysiological recordings of both single units and network neural activity while monkeys perform tasks of spatial navigation in the presence and absence of direct brain stimulation. This will provide insight into the functional correlates of neural activity and reveal the neurophysiological effects of neuronal stimulation. Third, UW will collaborate with partner institutions in using the ensemble neural data obtained in monkeys to contrain and develop computational models of how direct brain stimulation might be used to alter a patient’s brain state to improve the efficiency of their memory encoding. Fourth, UW will develop and test a novel closed-loop real-time methodology for using brain stimulation to enhance spatial memory performance in monkeys. The overarching goal of all of these studies is to develop and test methodologies in nonhuman primates that can be directly translated into patients in the service of improving memory.

“Impact of cannabis on pathogenesis in treated HIV infection”

Principal Investigator: Nikki Klatt

ABSTRACT:  With 35 million HIV-infected individuals worldwide, containment and eventual eradication of the AIDS pandemic remains a top priority in contemporary biomedical research. While antiretroviral therapy (ART) can improve health during HIV infection, a cure is not yet available, and despite suppression of viremia with ART, these individuals still have increased morbidity and mortality compared to uninfected individuals. Indeed, HIV-infected subjects cannot discontinue ART, because residual HIV persists, and virus rebound is inevitable if ART is terminated. The HIV reservoir is complex, and at least two mechanisms drive this latent pool of infected cells, including residual low levels of virus replication in anatomical sanctuaries (such as the gastrointestinal tract), and persistent proviral HIV DNA that is integrated into the host genome in long-lived cellular reservoirs. Furthermore, HIV is closely associated with, and potentially driven by, immune activation and inflammation during HIV infection. The pathology of disease caused by HIV infection is complex and multifaceted. In addition to high levels of systemic viral replication, HIV infection results in a vicious cycle of mucosal damage, chronic inflammation and overall immunological dysfunction, which are closely associated with disease. This chronic immune activation is strongly associated with gastrointestinal (GI) mucosal damage and microbial translocation, which do not resolve completely with ART. While there is a clear positive correlation between measures of immune activation and HIV persistence in ART-suppressed individuals, whether immune activation is a cause, a consequence or both a cause and a consequence of HIV persistence is unknown. Here, we propose a provocative approach to directly evaluate whether decreasing inflammation during ART-suppressed lentiviral infection results in a decreased HIV reservoir, using an extremely novel therapeutic concept.

“Developmental Neurotoxicity of Domoic Acid in Nonhuman Primate Model”

Principal Investigator: Tom Burbacher

Domoic Acid (DA), is a naturally-occurring biotoxin that can contaminate harvestable populations of finfish and shellfish in ocean waters. Exposure to DA is associated with a constellation of clinical symptoms that can include gastrointestinal distress, confusion, transient and permanent memory loss, coma and death. Animal studies have demonstrated a strong fetal sensitivity to this environmental toxin. The toxic algal blooms that produce DA appear to be increasing in frequency and toxicity and pose a growing threat to human health and seafood safety. Very little is known about the effects of chronic, low-dose exposure to DA, a pattern of exposure that would particularly represent coastal-dwelling indigenous communities that rely on the ocean as a vital source of food and cultural identity. Given that episodes of DA contamination are becoming more frequent, a legitimate concern arises as to whether DA may negatively affect fetal development at levels of exposure that do not product overt signs of neurotoxicity or illness in pregnant women. To elucidate the maternal and developmental neurotoxicity of Domoic Acid, we propose to conduct the first study of chronic, low-level, oral DA exposure in a nonhuman primate model with outcome measures that embrace pharmacokinetics, neuropathology, stereology, neuroimaging and neurobehavioral assessment. The results of this study will provide important information on the neurotoxic consequences of DA exposure during pregnancy and the resulting effects on infant health and development.

“CRCNS: Information processing in cerebral cortex for visual-oculomotor behavior”

(CRCNS = Collaborative Research in Computational Neuroscience)

Principal Investigator: Mike Mustari

The primate visual and oculomotor system allows tracking of small visual objects and large moving visual scenes to support optimal visual acuity and visual motor behavior. We use volitional smooth pursuit (SP) eye movements and reflex-like optokinetic (OKR) eye movements to support visual function. Both classes of tracking eye movements require cerebral cortical processing of visual inputs to create initial commands for eye movements. Volitional SP and OKR behaviors offer important perspectives on neural mechanisms that produce sensory-motor behavior, perception and cognitive processing. Our studies focus on the frontal eye fields (FEF) and parietal cortex (MSTd, MSTl, MT), which have been shown to play a role in SP, OKR and perception. However, the information passed between these areas during tracking eye movements remains unknown. Our studies will address this gap in knowledge by providing the first comparative data on visual, eye movement and task related signals carried in feedforward and feedback pathways between frontal and parietal cortex. We will apply novel computational approaches for data analysis, model the functional contributions of frontal and parietal cortex to tracking eye movements, and finally test the model predictions using electrical stimulation and optogenetic techniques to reversibly perturb signaling in this cortical-cortical network. There are extensive cortical-cortical connections between brain regions but we lack specific information about the role of these connections in complex sensory-motor behavior. Our studies are organized under 3 specific aims to experimental and computational approaches that build on information theory and related statistical methods to account for how different signals(e.g., visual, eye movement) are combined and interact to support purposeful behavior. Our experimental work provides novel neurophysiological data taken from frontal and parietal cortical neurons that we identify as projecting from one brain region to another and 2) the experimental results will be directly compared to simulations developed in computational models of cortico-cortical interaction.