Nonhuman Primate Research Research Articles

The ethical justification for the use of non-human primates in research: the Weatherall report revisited

The Weatherall report on the use of non-human primates in research was published in 2006. Its main conclusion was that there is a strong scientific case for the use of...

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives.

In order to calibrate stem cell exploitation for cellular therapy in neurodegenerative diseases, fundamental and preclinical research in NHP (nonhuman primate) models is crucial. Indeed, it is consensually recognized that it is not possible to directly extrapolate results obtained in rodent models to human patients. A large diversity of neurological pathologies should benefit from cellular therapy based on neural differentiation of stem cells. In the context of this special issue of Primate Biology on NHP stem cells, we describe past and recent advances on cell replacement in the NHP model of Parkinson's disease (PD). From the different grafting procedures to the various cell types transplanted, we review here diverse approaches for cell-replacement therapy and their related therapeutic potential on behavior and function in the NHP model of PD.

Improved methods for acrylic-free implants in nonhuman primates for neuroscience research.

Traditionally, head fixation devices and recording cylinders have been implanted in nonhuman primates (NHP) using dental acrylic despite several shortcomings associated with acrylic. The use of more biocompatible materials such as titanium and PEEK is becoming more prevalent in NHP research. We describe a cost-effective set of procedures that maximizes the integration of headposts and recording cylinders with the animal's tissues while reducing surgery time. Nine rhesus monkeys were implanted with titanium headposts, and one of these was also implanted with a recording chamber. In each case, a three-dimensional printed replica of the skull was created based on computerized tomography scans. The titanium feet of the headposts were shaped, and the skull thickness was measured preoperatively, reducing surgery time by up to 70%. The recording cylinder was manufactured to conform tightly to the skull, which was fastened to the skull with four screws and remained watertight for 8.5 mo. We quantified the amount of regression of the skin edge at the headpost. We found a large degree of variability in the timing and extent of skin regression that could not be explained by any single recorded factor. However, there was not a single case of bone exposure; although skin retracted from the titanium, skin also remained adhered to the skull adjacent to those regions. The headposts remained fully functional and free of complications for the experimental life of each animal, several of which are still participating in experiments more than 4 yr after implant.NEW & NOTEWORTHY Cranial implants are often necessary for performing neurophysiology research with nonhuman primates. We present methods for using three-dimensional printed monkey skulls to form and fabricate acrylic-free implants preoperatively to decrease surgery times and the risk of complications and increase the functional life of the implant. We focused on reducing costs, creating a feasible timeline, and ensuring compatibility with existing laboratory systems. We discuss the importance of using more biocompatible materials and enhancing osseointegration.

Nonhuman Primates and Translational Research—Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Human epidemiological studies provide challenges for understanding mechanisms that regulate initiation and progression of CVD due to variation in lifestyle, diet, and other environmental factors. Studies describing metabolic and physiologic aspects of CVD, and those investigating genetic and epigenetic mechanisms influencing CVD initiation and progression, have been conducted in multiple Old World nonhuman primate (NHP) species. Major advantages of NHPs as models for understanding CVD are their genetic, metabolic, and physiologic similarities with humans, and the ability to control diet, environment, and breeding. These NHP species are also genetically and phenotypically heterogeneous, providing opportunities to study gene by environment interactions that are not feasible in inbred animal models. Each Old World NHP species included in this review brings unique strengths as models to better understand human CVD. All develop CVD without genetic manipulation providing multiple models to discover genetic variants that influence CVD risk. In addition, as each of these NHP species age, their age-related comorbidities such as dyslipidemia and diabetes are accelerated proportionally 3 to 4 times faster than in humans.In this review, we discuss current CVD-related research in NHPs focusing on selected aspects of CVD for which nonprimate model organism studies have left gaps in our understanding of human disease. We include studies on current knowledge of genetics, epigenetics, calorie restriction, maternal calorie restriction and offspring health, maternal obesity and offspring health, nonalcoholic steatohepatitis and steatosis, Chagas disease, microbiome, stem cells, and prevention of CVD.

Basal ganglia, movement disorders and deep brain stimulation: advances made through non-human primate research.

Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

Translational Research in the Nonhuman Primate Model of Tuberculosis.

Infection with Mycobacterium tuberculosis predominantly establishes subclinical latent infection over the lifetime of an individual, with a fraction of infected individuals rapidly progressing to active disease. The immune control in latent infection can be perturbed by comorbidities such as diabetes mellitus, obesity, smoking, and coinfection with helminthes or HIV. Modeling the varying aspects of natural infection remains incomplete when using zebrafish and mice. However, the nonhuman primate model of tuberculosis offers a unique and accurate model to investigate host responses to infection, test novel therapeutics, and thoroughly assess preclinical vaccine candidates. Rhesus macaques and cynomolgus macaques manifest the full gamut of clinical and pathological findings in human Mycobacterium tuberculosis infection, including the ability to co-infect macaques with Simian Immunodeficiency Virus to model HIV co-infection. Here we discuss advanced techniques to assay various clinical outcomes of the natural progression of infection as well as therapeutics in development and novel preclinical vaccines. Finally, we survey the translational aspects of nonhuman primate research and argue the urgent need to thoroughly examine preclinical therapeutics and vaccines using this model prior to clinical implementation.

Open-Source, Low Cost, Free-Behavior Monitoring, and Reward System for Neuroscience Research in Non-human Primates.

We describe a low-cost system designed to document bodily movement and neural activity and deliver rewards to monkeys behaving freely in their home cage. An important application is to studying brain-machine interface (BMI) systems during free behavior, since brain signals associated with natural movement can differ significantly from those associated with more commonly used constrained conditions. Our approach allows for short-latency (<500 ms) reward delivery and behavior monitoring using low-cost off-the-shelf components. This system interfaces existing untethered recording equipment with a custom hub that controls a cage-mounted feeder. The behavior monitoring system uses a depth camera to provide real-time, easy-to-analyze, gross movement data streams. In a proof-of-concept experiment we demonstrate robust learning of neural activity using the system over 14 behavioral sessions.

Nutrition modulation of human aging: The calorie restriction paradigm

Globally, the aging population is growing rapidly, creating an urgent need to attenuate age-related health conditions, including metabolic disease and disability. A promising strategy for healthy aging based on consistently positive results from studies with a variety of species, including non-human primates (NHP), is calorie restriction (CR), or the restriction of energy intake while maintaining intake of essential nutrients. The burgeoning evidence for this approach in humans is reviewed and the major study to date to address this question, CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy), is described. CALERIE findings indicate the feasibility of CR in non-obese humans, confirm observations in NHP, and are consistent with improvements in disease risk reduction and potential anti-aging effects. Finally, the mechanisms of CR in humans are reviewed which sums up the fact that evolutionarily conserved mechanisms mediate the anti-aging effects of CR. Overall, the prospect for further research in both NHP and humans is highly encouraging.

The use of nonhuman primate models to understand processes in Parkinson's disease.

Research with animal models has led to critical health advances that have saved or improved the lives of millions of human beings. Specifically, nonhuman primate's genetic and anatomo-physiological similarities to humans are especially important for understanding processes like Parkinson's disease, which only occur in humans. Unambiguously, the unique contribution made by nonhuman primate research to our understanding of Parkinson's disease is widely recognized. For example, monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonisms are responsive to dopamine replacement therapies, mimicking what is seen in PD patients. Moreover, groundbreaking neuroanatomical and electrophysiological studies using this monkey model in the 1980s and 1990s enabled researchers to identify the neuronal circuits responsible for the cardinal motor features of PD. This led to the development of subthalamic surgical ablation and deep brain stimulation, the current therapeutic gold standard for neurosurgical treatment. More recently, the mechanisms of α-synuclein spreading testing the prion hypothesis for PD have yielded exciting results. In this review, we discuss and highlight how the findings from nonhuman primate research contribute to our understanding of idiopathic Parkinson's disease.

Response-Modality-Specific Encoding of Human Choices in Upper Beta Band Oscillations during Vibrotactile Comparisons.

Perceptual decisions based on the comparison of two vibrotactile frequencies have been extensively studied in non-human primates. Recently, we obtained corresponding findings from human oscillatory electroencephalography (EEG) activity in the form of choice-selective modulations of upper beta band amplitude in medial premotor areas. However, the research in non-human primates as well as its human counterpart was so far limited to decisions reported by button presses. Thus, here we investigated whether the observed human beta band modulation is specific to the response modality. We recorded EEG activity from participants who compared two sequentially presented vibrotactile frequencies (f1 and f2), and decided whether f2 > f1 or f2 < f1, by performing a horizontal saccade to either side of a computer screen. Contrasting time-frequency transformed EEG data between both choices revealed that upper beta band amplitude (∼24–32 Hz) was modulated by participants’ choices before actual responses were given. In particular, “f2 > f1” choices were always associated with higher beta band amplitude than “f2 < f1” choices, irrespective of whether the choice was correct or not, and independent of the specific association between saccade direction and choice. The observed pattern of beta band modulation was virtually identical to our previous results when participants responded with button presses. In line with an intentional framework of decision making, the most likely sources of the beta band modulation were now, however, located in lateral as compared to medial premotor areas including the frontal eye fields. Hence, we could show that the choice-selective modulation of upper beta band amplitude is on the one hand consistent across different response modalities (i.e., same modulation pattern in similar frequency band), and on the other hand effector specific (i.e., modulation originating from areas involved in planning and executing saccades).

Advances in optogenetic and chemogenetic methods to study brain circuits in non-human primates.

Over the last 10years, the use of opto- and chemogenetics to modulate neuronal activity in research applications has increased exponentially. Both techniques involve the genetic delivery of artificial proteins (opsins or engineered receptors) that are expressed on a selective population of neurons. The firing of these neurons can then be manipulated using light sources (for opsins) or by systemic administration of exogenous compounds (for chemogenetic receptors). Opto- and chemogenetic tools have enabled many important advances in basal ganglia research in rodent models, yet these techniques have faced a slow progress in non-human primate (NHP) research. In this review, we present a summary of the current state of these techniques in NHP research and outline some of the main challenges associated with the use of these genetic-based approaches in monkeys. We also explore cutting-edge developments that will facilitate the use of opto- and chemogenetics in NHPs, and help advance our understanding of basal ganglia circuits in normal and pathological conditions.

Primitive Concepts of Number and the Developing Human Brain

ABSTRACTCounting is an evolutionarily recent cultural invention of the human species. In order for humans to have conceived of counting in the first place, certain representational and logical abilities must have already been in place. The focus of this article is the origins and nature of those fundamental mechanisms that promoted the emergence of the human number concept. Five claims are presented that support an evolutionary view of numerical development: (1) number is an abstract concept with an innate basis in humans; (2) maturational processes constrain the development of humans’ numerical representations between infancy and adulthood; (3) there is evolutionary continuity in the neural processes of numerical cognition in primates; (4) primitive logical abilities support verbal counting development in humans; and (5) primitive neural processes provide the foundation for symbolic numerical development in the human brain. We support these claims by examining current evidence from animal cognition, child development, and human brain function. The data show that at the basis of human numerical concepts are primitive perceptual and logical mechanisms that have evolutionary homologs in other primates and form the basis of numerical development in the human brain. In the final section of this article, we discuss some hypotheses for what makes human numerical reasoning unique by drawing on evidence from human and non-human primate neuroimaging research.

Beyond aerodigestion: Exaptation of feeding-related mouth movements for social communication in human and nonhuman primates.

Three arguments are advanced from human and nonhuman primate infancy research for the exaptation of ingestive mouth movements (tongue protrusion and lip smacking) for the purposes of social communication: their relation to affiliative behaviours, their sensitivity to social context, and their role in social development. Although these behaviours may have an aerodigestive function, such an account of their occurrence is only partial.

An Evaluation of 20 Years of EU Framework Programme-Funded Immune-Mediated Inflammatory Translational Research in Non-Human Primates.

Aging western societies are facing an increasing prevalence of chronic inflammatory and degenerative diseases for which often no effective treatments exist, resulting in increasing health-care expenditure. Despite high investments in drug development, the number of promising new drug candidates decreases. We propose that preclinical research in non-human primates can help to bridge the gap between drug discovery and drug prescription. Translational research covers various stages of drug development of which preclinical efficacy tests in valid animal models is usually the last stage. Preclinical research in non-human primates may be essential in the evaluation of new drugs or therapies when a relevant rodent model is not available. Non-human primate models for life-threatening or severely debilitating diseases in humans are available at the Biomedical Primate Research Centre (BPRC). These have been instrumental in translational research for several decades. In order to stimulate European health research and innovation from bench to bedside, the European Commission has invested heavily in access to non-human primate research for more than 20 years. BPRC has hosted European users in a series of transnational access programs covering a wide range of research areas with the common theme being immune-mediated inflammatory disorders. We present an overview of the results and give an account of the studies performed as part of European Union Framework Programme (EU FP)-funded translational non-human primate research performed at the BPRC. These data illustrate the value of translational non-human primate research for the development of new therapies and emphasize the importance of EU FP funding in drug development.

Genetic diversity of Klebsiella pneumoniae isolates during an outbreak in a non-human primate research colony.

Klebsiella pneumoniae can be a serious pathogen in non-human primates, particularly Neotropical monkeys. During a K.pneumoniae outbreak in an owl monkey research colony, 13 K.pneumoniae isolates were DNA fingerprinted by automated repetitive extragenic palindromic-polymerase chain reaction and the profiles compared to isolates obtained from other non-human primate species during the same time period and isolates from previous outbreaks. Eleven different types of K.pneumoniae were circulating in the owl monkey colony at the time of the outbreak. When comparing owl monkey isolates relatedness to previous colony outbreak isolates and squirrel monkey and capuchin monkey isolates, all were different. These results agree with recent reports where K.pneumoniae nosocomial isolates in hospital settings can have high genetic diversity, and multiple strains can be circulating simultaneously. This potential genetic diversity should be considered when designing strategies for controlling K.pneumoniae outbreaks in captive non-human primate colonies.

Editorial: Is the Language Faculty Nonlinguistic?

Editorial: Is the Language Faculty Nonlinguistic?

Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications.

In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site-specific selective pharmacology, receptor autoradiography, invivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential.

Ebola Virus, Its Manifestations and Reported Therapeutic Strategies

All five species of Ebolavirus discovered to date are known to cause a deadly disease known as Ebola hemorrhagic fever. This viral hemorrhagic fever is associated with severe manifestations and high case-fatality rate. It has caused several periodic outbreaks since its discovery in 1976, but the recent one in 2014 has affected a number of people than never before. It is endemic in the Philippines and Central Africa, showing that it has a strange geographic distribution. The Ebola virus (EBOV) comprises negative sense RNA which encodes seven viral proteins of which VP40 is of paramount importance in viral assemble, budding and egress. Its pathogenicity is multifactorial owing to which no licensed vaccines and approved treatments are currently available. However, several promising candidates have been produced by research in non-human primates. Here, we review the virology, manifestations, reported proposed therapeutic intervention strategies and the recent outbreak.

Non-human primates in neuroscience research: The case against its scientific necessity.

Public opposition to non-human primate (NHP) experiments is significant, yet those who defend them cite minimal harm to NHPs and substantial human benefit. Here we review these claims of benefit, specifically in neuroscience, and show that: a) there is a default assumption of their human relevance and benefit, rather than robust evidence; b) their human relevance and essential contribution and necessity are wholly overstated; c) the contribution and capacity of non-animal investigative methods are greatly understated; and d) confounding issues, such as species differences and the effects of stress and anaesthesia, are usually overlooked. This is the case in NHP research generally, but here we specifically focus on the development and interpretation of functional magnetic resonance imaging (fMRI), deep brain stimulation (DBS), the understanding of neural oscillations and memory, and investigation of the neural control of movement and of vision/binocular rivalry. The increasing power of human-specific methods, including advances in fMRI and invasive techniques such as electrocorticography and single-unit recordings, is discussed. These methods serve to render NHP approaches redundant. We conclude that the defence of NHP use is groundless, and that neuroscience would be more relevant and successful for humans, if it were conducted with a direct human focus. We have confidence in opposing NHP neuroscience, both on scientific as well as on ethical grounds.

NIH to review its policies on all nonhuman primate research

NIH to review its policies on all nonhuman primate research