Nonhuman Primate Research Research Articles

Using the NIMH Research Domain Criteria (RDoC) in human and nonhuman primate research.

In this article, we provide a commentary on Kozak and Cuthbert ()'s theoretical paper discussing the NIMH Research Domain Criteria (RDoC) initiative and on Latzman et al. (2016)'s empirical investigation of the RDoC negative valence systems domain in chimpanzees, conducted with experimental procedures across genetic, neurobiological, and behavioral levels of analysis. We discuss the pros and cons of the RDoC approach to research on mental illness as well as the strengths and weaknesses of the implementation of this approach in the chimpanzee study.

Contributions of Nonhuman Primates to Research on Aging.

Aging is the biological process of declining physiologic function associated with increasing mortality rate during advancing age. Humans and higher nonhuman primates exhibit unusually longer average life spans as compared with mammals of similar body mass. Furthermore, the population of humans worldwide is growing older as a result of improvements in public health, social services, and health care systems. Comparative studies among a wide range of organisms that include nonhuman primates contribute greatly to our understanding about the basic mechanisms of aging. Based on their genetic and physiologic relatedness to humans, nonhuman primates are especially important for better understanding processes of aging unique to primates, as well as for testing intervention strategies to improve healthy aging and to treat diseases and disabilities in older people. Rhesus and cynomolgus macaques are the predominant monkeys used in studies on aging, but research with lower nonhuman primate species is increasing. One of the priority topics of research about aging in nonhuman primates involves neurologic changes associated with cognitive decline and neurodegenerative diseases. Additional areas of research include osteoporosis, reproductive decline, caloric restriction, and their mimetics, as well as immune senescence and chronic inflammation that affect vaccine efficacy and resistance to infections and cancer. The purpose of this review is to highlight the findings from nonhuman primate research that contribute to our understanding about aging and health span in humans.

Translational Research on Habit and Alcohol.

Habitual actions enable efficient daily living, but they can also contribute to pathological behaviors that resistant change, such as alcoholism. Habitual behaviors are learned actions that appear goal-directed but are in fact no longer under the control of the action's outcome. Instead, these actions are triggered by stimuli, which may be exogenous or interoceptive, discrete or contextual. A major hallmark characteristic of alcoholism is continued alcohol use despite serious negative consequences. In essence, although the outcome of alcohol seeking and drinking is dramatically devalued, these actions persist, often triggered by environmental cues associated with alcohol use. Thus, alcoholism meets the definition of an initially goal-directed behavior that converts to a habit-based process. Habit and alcohol have been well investigated in rodent models, with comparatively less research in non-human primates and people. This review focuses on translational research on habit and alcohol with an emphasis on cross-species methodology and neural circuitry.

Online resources for improving the care and use of non-human primates in research

Published literature and scientific events provide opportunities to expand knowledge and develop skills in the care and use of non-human primates (NHPs) in research. Increasingly, these traditional routes of information exchange are being complemented by dedicated online resources aimed at sharing best practice in NHP care and use, and enhancing the training and professional development of laboratory staff working with NHPs. This article outlines some key online resources from the UK’s National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and other organisations with an interest in NHP research, and the ways in which the resources can be integrated into staff training and research practices to enhance animal welfare, quality of science and application of the 3Rs.

How motivation and reward learning modulate selective attention.

Motivational stimuli such as rewards elicit adaptive responses and influence various cognitive functions. Notably, increasing evidence suggests that stimuli with particular motivational values can strongly shape perception and attention. These effects resemble both selective top-down and stimulus-driven attentional orienting, as they depend on internal states but arise without conscious will, yet they seem to reflect attentional systems that are functionally and anatomically distinct from those classically associated with frontoparietal cortical networks in the brain. Recent research in human and nonhuman primates has begun to reveal how reward can bias attentional selection, and where within the cognitive system the signals providing attentional priority are generated. This review aims at describing the different mechanisms sustaining motivational attention, their impact on different behavioral tasks, and current knowledge concerning the neural networks governing the integration of motivational influences on attentional behavior.

Hierarchy is Detrimental for Human Cooperation.

Studies of animal behavior consistently demonstrate that the social environment impacts cooperation, yet the effect of social dynamics has been largely excluded from studies of human cooperation. Here, we introduce a novel approach inspired by nonhuman primate research to address how social hierarchies impact human cooperation. Participants competed to earn hierarchy positions and then could cooperate with another individual in the hierarchy by investing in a common effort. Cooperation was achieved if the combined investments exceeded a threshold, and the higher ranked individual distributed the spoils unless control was contested by the partner. Compared to a condition lacking hierarchy, cooperation declined in the presence of a hierarchy due to a decrease in investment by lower ranked individuals. Furthermore, hierarchy was detrimental to cooperation regardless of whether it was earned or arbitrary. These findings mirror results from nonhuman primates and demonstrate that hierarchies are detrimental to cooperation. However, these results deviate from nonhuman primate findings by demonstrating that human behavior is responsive to changing hierarchical structures and suggests partnership dynamics that may improve cooperation. This work introduces a controlled way to investigate the social influences on human behavior, and demonstrates the evolutionary continuity of human behavior with other primate species.

Using non-human primates to benefit humans: research and organ transplantation-response to César Palacios-González.

Using non-human primates to benefit humans: research and organ transplantation-response to César Palacios-González.

C-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study

To test the hypothesis that the c-Jun NH2-terminal kinase (JNK) inhibitor (JNKI) bentamapimod (AS602801/PGL5001) can reduce induced endometriosis in baboons. Prospective randomized placebo-controlled study. Nonhuman primate research center. Twenty baboons each underwent four laparoscopies. Initial screening laparoscopy (L1) was followed after one rest cycle by an endometriosis-induction laparoscopy (L2). Fifty days after L2, the baboons were randomized just before staging laparoscopy (L3). Treatment lasted for 60 days, followed by a post-treatment staging laparoscopy (L4). Randomization before a 60-day treatment in four groups: daily placebo (n = 5), daily oral administration of 20 mg/kg JNKI (n = 5), concomitant daily oral administration of 20 mg/kg JNKI and 10 mg medroxyprogesterone acetate (MPA; n = 5), or subcutaneous administration of 3 mg cetrorelix every 3 days (n = 5). Type, surface area and volume of endometriotic lesions, and revised American Society for Reproductive Medicine score and stage were recorded during L3 and L4. Menstrual cycle length and serum hormonal concentration were recorded before and after treatment. Compared with placebo, treatment with JNKI, JNKI + PMA, or cetrorelix resulted in lower total surface area and volume of endometriotic lesions. Remodeling of red active lesions into white lesions was observed more frequently in baboons treated with JNKI + MPA than in baboons treated with JNKI only. Menstrual cycle length and serum hormonal concentration were similar between placebo and JNKI groups. JNKI alone was as effective as JNKI + MPA or cetrorelix in reducing induced endometriosis in baboons, but without severe side effects or effect on cycle length or serum reproductive hormones.

Physiological approaches to understanding molecular actions on dorsolateral prefrontal cortical neurons underlying higher cognitive processing.

Revealing how molecular mechanisms influence higher brain circuits in primates will be essential for understanding how genetic insults lead to increased risk of cognitive disorders. Traditionally, modulatory influences on higher cortical circuits have been examined using lesion techniques, where a brain region is depleted of a particular transmitter to determine how its loss impacts cognitive function. For example, depletion of catecholamines or acetylcholine from the dorsolateral prefrontal cortex produces striking deficits in working memory abilities. More directed techniques have utilized direct infusions of drug into a specific cortical site to try to circumvent compensatory changes that are common following transmitter depletion. The effects of drug on neuronal firing patterns are often studied using iontophoresis, where a minute amount of drug is moved into the brain using a tiny electrical current, thus minimizing the fluid flow that generally disrupts neuronal recordings. All of these approaches can be compared to systemic drug administration, which remains a key arena for the development of effective therapeutics for human cognitive disorders. Most recently, viral techniques are being developed to be able to manipulate proteins for which there is no developed pharmacology, and to allow optogenetic manipulations in primate cortex. As the association cortices greatly expand in brain evolution, research in nonhuman primates is particularly important for understanding the modulatory regulation of our highest order cognitive operations.

ID: 225: New multiplex assay panels for accurate quantification of non-human primates biomarkers

Due to the immunological and physiological similarities between non-human primates (NHPs) and humans, understanding the disease progression and immune response in NHP species can predict response in humans. Therefore, NHPs are preferred model systems in drug safety test, vaccine development, and infectious disease and brain research. Correspondingly, accurate measurement of soluble biomarkers in NHPs is important for drug development and biomedical research. We have developed several NHP multi-analyte flow assay panels, including T Helper Cytokine Panel, Inflammation Panel, Growth Factor Panel, Adipokine Panel, and Cytokine/Chemokine Panel, for the quantification of a variety of NHP biomarkers including cytokines (IL-1 β , IL-2, 4, 5, 6, 10, IL-12p40, 17A, IL-17F, IL-21, IL-22, IL-23, IL-33, IFN- γ , TNF- α ) , chemokines (RANTES, MCP-1, MIP-1 α , MIP-1 β , IP-10, IL-8, MIG and I-TAC), growth factors (EGF, Ang-2, G-CSF, GM-CSF, PDGF-AA, PDGF-BB, FGF-b, etc.) and adipokines (Adiponectin, Adiosin, Resistin, Leptin, etc.). These assays are bead-based sandwich immunoassays, with fluorescence-encoded beads that can be separated by a variety of flow cytometers. In each panel, up to thirteen NHP biomarkers can be quantified simultaneously. Each panel has been validated for use in cell culture supernatant, serum, plasma and urine samples for both rhesus and cynomolgus monkey species. These panels provide higher sensitivities and broader dynamic ranges than traditional ELISA methods, offering useful tools for researchers dedicated to NHP research and drug discovery.

On balance: weighing harms and benefits in fundamental neurological research using nonhuman primates.

One of the most controversial areas of animal research is the use of nonhuman primates for fundamental research. At the centre of the controversy is the question of whether the benefits of research outweigh the harms. We argue that the evaluation of harms and benefits is highly problematic. We describe some common procedures in neurological research using nonhuman primates and the difficulties in evaluating the harm involved. Even if the harm could be quantified, it is unlikely that it could be meaningfully aggregated over different procedures, let alone different animals. A similar problem arises for evaluating benefits. It is not clear how benefits could be quantified, and even if they could be, values for different aspects of expected benefits cannot be simply added up. Sorting harms and benefits in three or four categories cannot avoid the charge of arbitrariness and runs the risk of imposing its structure on the moral decision. The metaphor of weighing or balancing harms and benefits is inappropriate for the moral decision about whether to use nonhuman primates for research. Arguing that the harms and benefits in this context are incommensurable, we suggest describing the moral consideration of harms and benefits as a coherent trade-off. Such a decision does not require commensurability. It must be well-informed about the suffering involved and the potential benefits, it must be consistent with the legal, regulatory and institutional framework within which it is made, and it must cohere with other judgments in relevant areas.

Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis.

A wealth of animal and human studies demonstrate that perinatal exposure to adverse metabolic conditions - be it maternal obesity, diabetes or under-nutrition - results in predisposition of offspring to develop obesity later in life. This mechanism is a contributing factor to the exponential rise in obesity rates. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of energy homeostasis as an underlying cause. Perinatal development of the hypothalamus (a brain region key to metabolic regulation) is plastic and sensitive to metabolic signals during this critical time window. Recent research in non-human primate and rodent models has demonstrated that exposure to adverse maternal environments impairs the development of hypothalamic structure and consequently function, potentially underpinning metabolic phenotypes in later life. This review summarizes our current knowledge of how adverse perinatal environments program hypothalamic development and explores the mechanisms that could mediate these effects.

Aggressive vocal expressions-an investigation of their underlying neural network.

Recent neural network models for the production of primate vocalizations are largely based on research in nonhuman primates. These models seem yet not fully capable of explaining the neural network dynamics especially underlying different types of human vocalizations. Unlike animal vocalizations, human affective vocalizations might involve higher levels of vocal control and monitoring demands, especially in case of more complex vocal expressions of emotions superimposed on speech. Here we therefore investigated the functional cortico-subcortical network underlying different types (evoked vs. repetition) of producing human affective vocalizations in terms of affective prosody, especially examining the aggressive tone of a voice while producing meaningless speech-like utterances. Functional magnetic resonance imaging revealed, first, that bilateral auditory cortices showed a close functional interconnectivity during affective vocalizations pointing to a bilateral exchange of relevant acoustic information of produced vocalizations. Second, bilateral motor cortices (MC) that directly control vocal motor behavior showed functional connectivity to the right inferior frontal gyrus (IFG) and the right superior temporal gyrus (STG). Thus, vocal motor behavior during affective vocalizations seems to be controlled by a right lateralized network that provides vocal monitoring (IFG), probably based on auditory feedback processing (STG). Third, the basal ganglia (BG) showed both positive and negative modulatory connectivity with several frontal (ACC, IFG) and temporal brain regions (STG). Finally, the repetition of affective prosody compared to evoked vocalizations revealed a more extended neural network probably based on higher control and vocal monitoring demands. Taken together, the functional brain network underlying human affective vocalizations revealed several features that have been so far neglected in models of primate vocalizations.

Neotropical primate nursery in a squirrel monkey breeding unit in Brazil.

Saimiri (squirrel monkey) is a neotropical primate of the Simian genus that has been bred in captivity for the development of research into human and animal health. They have been widely used in studies in ophthalmology, toxicology, pharmacology, psychiatry, neuroscience, vaccines and drug tests (such as malaria and measles agents), as well as effects on interactive behavior and cognition of Creutzfeldt-Jakob disease in man. The main concern of non-human primate (NHP) research centers is focused on the establishment of self-sustaining breeding colonies providing good quality research animals. Maternal rejection, dystocia and pneumonia are the main causes of newborn deaths in these species. Therefore, in order to ensure the survival of these valuable animals, the Laboratory Animals Breeding Center of the Oswaldo Cruz Foundation (CECAL)/Fiocruz, Rio de Janeiro, Brazil, has developed a protocol for the nursery rearing of these infants.

Prefrontal Neuronal Responses during Audiovisual Mnemonic Processing

During communication we combine auditory and visual information. Neurophysiological research in nonhuman primates has shown that single neurons in ventrolateral prefrontal cortex (VLPFC) exhibit multisensory responses to faces and vocalizations presented simultaneously. However, whether VLPFC is also involved in maintaining those communication stimuli in working memory or combining stored information across different modalities is unknown, although its human homolog, the inferior frontal gyrus, is known to be important in integrating verbal information from auditory and visual working memory. To address this question, we recorded from VLPFC while rhesus macaques (Macaca mulatta) performed an audiovisual working memory task. Unlike traditional match-to-sample/nonmatch-to-sample paradigms, which use unimodal memoranda, our nonmatch-to-sample task used dynamic movies consisting of both facial gestures and the accompanying vocalizations. For the nonmatch conditions, a change in the auditory component (vocalization), the visual component (face), or both components was detected. Our results show that VLPFC neurons are activated by stimulus and task factors: while some neurons simply responded to a particular face or a vocalization regardless of the task period, others exhibited activity patterns typically related to working memory such as sustained delay activity and match enhancement/suppression. In addition, we found neurons that detected the component change during the nonmatch period. Interestingly, some of these neurons were sensitive to the change of both components and therefore combined information from auditory and visual working memory. These results suggest that VLPFC is not only involved in the perceptual processing of faces and vocalizations but also in their mnemonic processing.

Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

Bringing non-human primate research into the post-genomic era: how monkeys are teaching us about elite controllers of HIV/AIDS.

Whole-genome sequencing of Mauritian cynomolgus macaques reveals novel candidate loci for controlling simian immunodeficiency virus replication.See related Research, http://genomebiology.com/2014/15/11/478

Neuronal bases of peripersonal and extrapersonal spaces, their plasticity and their dynamics: Knowns and unknowns

While space is perceived as unitary, experimental evidence indicates that the brain actually contains a modular representation of space, specific cortical regions being involved in the processing of extra-personal space, that is the space that is far away from the subject and that cannot be directly acted upon by the body, while other cortical regions process peripersonal space, that is the space that directly surrounds us and which we can act upon. In the present review, we focus on non-human primate research and we review the single cells, areal and cortical functional network mechanisms that are proposed to underlie extrapersonal and peripersonal space representations. Importantly, the current dominant framework for the study of peripersonal space is centered on the key notion that actions and specifically arm and hand-related actions, shape cortical peripersonal space representations. In the present review, we propose to enlarge this framework to include other variables that have the potential to shape peripersonal space representations, namely emotional and social information. In the initial section of the manuscript, we thus first provide an extensive up-to-date review of the low level sensory and oculomotor signals that contribute to the construction of a core cortical far and near space representation, in key parietal, premotor and prefrontal periarcuate cortical regions. We then highlight the key functional properties that are needed to encode peripersonal space and we narrow down our discussion to the specific parietal and periarcuate areas that share these properties: the parieto-premotor peripersonal space network and the parieto-premotor network for grasping. Last, we review evidence for a changing peripersonal space representation. While plastic changes in peripersonal space representation have been described during tool use and their underlying neural bases have been well characterized, the description of dynamical changes in peripersonal space representation as a function of the emotional or social context is quite novel and relies on behavioral human studies. The neural bases of such a dynamic adjustments of peripersonal space coding are yet unknown. We thus review these novel observations and we discuss their putative underlying neural bases.

Balancing the welfare: the use of non-human primates in research

Until now, there have been no ideal alternatives to replace non-human primates (NHPs) in biomedical research, yet the debate on whether it is appropriate to sacrifice NHPs for research never stops. With recent advances in genomics and the appearance of new technologies, the time is right to return to the problem of finding solutions to balance the welfare of both humans and NHPs.

Genotyping of non-human primate models: perspectives and challenges for the implementation of the "three R's"

Abstract. Although non-human primates (NHPs) represent only a minor fraction of all animals used in biomedical research, there is a continuous effort to further reduce, refine and replace research with NHPs in accordance with the principles of the three R's. Most of the NHP model species are genetically highly diverse, and significant variation occurs among populations of different geographic origins, particularly in macaques. Since such differences can considerably affect the outcome of biomedical experiments, genotyping represents a promising tool to refine research approaches and to reduce the number of NHPs in biomedical research. Accordingly, the European Primate Network (EUPRIM-Net) developed an anonymous online survey to evaluate possibilities and potential hindrances for the application of genotyping in NHP research. On the one hand, our results point to the importance of genetic variation in NHPs and the need to consider the genetic background for future research approaches. On the other hand, our survey identified several hindrances and limiting factors for the application of genotyping and its incorporation in research, primate husbandry and breeding. We provide some fundamental recommendations on how to meet these challenges and how genotyping can be efficiently used to refine NHP research and to reduce the number of NHPs in biomedical research in the long term.