Nonhuman Primate Research Research Articles

The Use of Primates as Experimental Models in Scientific Research and its Ethical Implications

Non-human primates (NHPs) are considered ideal experimental models for replicating human diseases, due to their physiological, anatomical and neurological similarities to humans. However, the use of NHPs in research has ethical considerations and requires significant financial and temporal investments, due to the costs involved in the process and evaluation time. In addition to ethical issues and legal protection, research with experimental primate models involves advantages, such as the extreme physiological similarity, and disadvantages, such as the difficulty in establishing parameters for pain management and assessment. This literature review analyzed articles from the Pubmed, Scopus and Web of Science databases published in the last five years. This review included 12 articles that addressed topics such as scientific research, primate therapies, animal welfare and legal protection, highlighting the relevance of NHPs in scientific studies and interest in using these models to understand human diseases in order to develop new therapies. Despite the ethical challenges involved in this issue, it was discussed that it is important to take into account the scientific benefits and ethical considerations, as well as developing alternative methods to reduce the use of primates in research.

Impact of Social Connectedness on Neuroinflammation and Brain Architecture in Non-Human Primates

Social connectedness plays a critical role in the mental and physical health of primates, including humans.1-3 Social isolation and loneliness have been linked to a variety of negative health outcomes, such as increased risk of neurological disorders like Alzheimer’s, anxiety, and depression.2 Despite extensive research on the effects of early isolation, there is limited understanding of the neurobiological consequences of social deprivation during adulthood. This project aims to fill this gap by exploring how changes in social connectedness influence neuroinflammation and brain architecture in non-human primates (NHPs). The study utilized a longitudinal design involving 19 adult cynomolgus macaques to examine the effects of social living conditions on neuroinflammation and brain structure. The NHPs were first housed in group living conditions, transitioned to single-living conditions, and finally returned to group living. Multimodal neuroimaging was conducted to evaluate changes in cortical thickness, myelination, and brain connectivity across these phases. Blood and cerebrospinal fluid samples were collected at multiple time points to assess levels of pro-inflammatory cytokines (TNF-a, IL-1β, IL-6) and a biomarker for neuroplasticity (BDNF).4-6 Advanced biomarker detection technology, such as SIMOA, ELISA, and Luminex, could be leveraged to achieve highly sensitive measurements of these markers.7,8 Preliminary findings indicate that social deprivation leads to decreases in cortical thickness and myelination in key brain regions associated with social cognition; however, these changes may be reversible upon reintroduction to group living.9-12 This study hypothesizes that the observed structural changes correlate with increases in neuroinflammatory markers. If confirmed, these results could highlight the critical role of social connectedness in maintaining brain health and suggest potential biomarkers for loneliness and related neuropsychiatric conditions. This research could inform interventions aimed at mitigating the negative health impacts of social isolation and improve welfare standards in NHP research, enhancing the translational relevance of such models to human health. References Holt-Lunstad J, Steptoe A. Social Isolation: An underappreciated determinant of physical health. Current Opinion in Psychology. 2022;43:232-237. doi:10.1016/j.copsyc.2021.07.012 Bzdok D, Dunbar RIM. The neurobiology of social distance. Trends in Cognitive Sciences. 2020;24(9):717-733. doi:10.1016/j.tics.2020.05.016 Cacioppo JT, Cacioppo S. The growing problem of loneliness. The Lancet. 2018;391(10119):426. doi:10.1016/s0140-6736(18)30142-9 Magalhães DM, Mampay M, Sebastião AM, Sheridan GK, Valente CA. Age-related impact of social isolation in mice: Young vs middle-aged. Neurochemistry International. 2024;174:105678. doi:10.1016/j.neuint.2024.105678 Van Bogart K, Engeland CG, Sliwinski MJ, et al. The association between loneliness and inflammation: Findings from an older adult sample. Frontiers in Behavioral Neuroscience. 2022;15. doi:10.3389/fnbeh.2021.801746 Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Archives of Medical Science. 2015;6:1164-1178. doi:10.5114/aoms.2015.56342 Lasseter HC, Provost AC, Chaby LE, Daskalakis NP, Haas M, Jeromin A. Cross-platform comparison of highly sensitive immunoassay technologies for cytokine markers: Platform performance in post-traumatic stress disorder and parkinson’s disease. Cytokine: X. 2020;2(2):100027. doi:10.1016/j.cytox.2020.100027 Platchek M, Lu Q, Tran H, Xie W. Comparative analysis of multiple immunoassays for cytokine profiling in drug discovery. SLAS Discovery. 2020;25(10):1197-1213. doi:10.1177/2472555220954389 Miller JG, López V, Buthmann JL, Garcia JM, Gotlib IH. A social gradient of cortical thickness in adolescence: Relationships with neighborhood socioeconomic disadvantage, family socioeconomic status, and depressive symptoms. Biological Psychiatry Global Open Science. 2022;2(3):253-262. doi:10.1016/j.bpsgos.2022.03.005 Yang Y, Cheng Z, Tang H, et al. Neonatal maternal separation impairs prefrontal cortical myelination and cognitive functions in rats through activation of Wnt Cerebral Cortex. Published online May 13, 2016. doi:10.1093/cercor/bhw121 Sallet J, Mars RB, Noonan MP, et al. Social network size affects neural circuits in macaques. Science. 2011;334(6056):697-700. doi:10.1126/science.1210027 Makinodan M, Rosen KM, Ito S, Corfas A critical period for social experience–dependent oligodendrocyte maturation and myelination. Science. 2012;337(6100):1357-1360. doi:10.1126/science.1220845

Humanity and Inhumanity of Nonhuman Primate Research.

This illustration depicts important biomedical advancements generated by nonhuman primate (NHP) research. NHPs' value in human-centered research is their unique evolutionary proximity to humans.

Histomorphometry specific to anthropological studies concerning the human condition.

Bone histomorphometry refers to the study of the structure and microscopic features of bone tissue. It involves the measurement and assessment of bone microanatomy, and it provides valuable information on bone properties. Through the application of histomorphometry, researchers can acquire information on bone metabolism and on remodeling dynamics, which is useful to the study of bone health. During the last 50 years, biological anthropologists have adopted the use of histomorphometry while examining issues specific to human health and evolutionary trends from prehistoric remains. Scientists coming from the medical field have applied histomorphometry in their research as it allows the study of bone changes, useful to describe pathological conditions among these ancient human remains. This paper reflects on some of the research that involves histomorphometric analysis specific to diet and health, forensic anthropology, taphonomic assessment of bone, non-human primate research and biomechanics. The purpose of the paper is to consider past and future applications of bone histomorphometry to enable a discussion which might direct research towards under-explored areas of bone biology. For example, looking at renewed interest in clavicular histology and stimulating investigations that focus on osteocyte density. Additionally, a discussion is offered concerning OPD values used to correlate chronological age to biological age estimations.

Consolation in the aftermath of violent public assaults: An interaction ethological study

AbstractAnimal ethologists suggest that non-human primates console victims of aggression in a manner similar to humans. However, the empirical basis for this cross-species comparison is fragile, given that few studies have examined consolation behavior among humans. To address this gap, we revive and apply the underappreciated ethological branch of micro-sociology, which advocates the study of human interactions by applying ethological observation techniques. We thus systematically observed naturally occurring human consolation captured by video surveillance cameras in the aftermath of violent public assaults. Consistent with prior human and non-human primate research, social affiliation promoted consolatory helping. By contrast, we found no main effect of sex. A further exploratory analysis indicated an interaction effect between social affiliation and sex, with female affiliates having the largest probability of providing consolation. We discuss implications for the cross-species study of primate consolation and advocate that micro-sociology should reappraise ethological perspectives.

The people behind the papers - Jiajia Ye and Qiang Sun.

Embryonic diapause can be induced by nutrient deprivation, but the molecular mechanisms underpinning this process are unclear. A new paper in Development shows that protein and carbohydrate depletion can trigger embryonic diapause via the nutrient sensors Gator1 and Tsc2. To learn more about the story behind the paper, we caught up with first author Jiajia Ye and corresponding author Qiang Sun, professor and director of the Non-Human Primate Research Facility at the Institute of Neuroscience, Chinese Academy of Sciences.

The Application and Challenge of Non-Human Primate Experimental Animals in the Field of Neuroscience

Non-human primates (NHPs) are highly valued in the field of neuroscience due to their similarity to humans in terms of brain structure and function. They exhibit complex social behaviors and cognitive abilities, and their use in research has led to significant breakthroughs in the understanding of brain development, neurodegenerative diseases, and psychiatric disorders. In recent years, the breeding and use of NHPs has expanded, making them increasingly important as experimental animals. However, with this expansion comes the need for researchers to address important biosafety and animal ethics concerns. It is critical that animal welfare is ensured and that scientific objectives are achieved while observing ethical guidelines. This paper aims to provide an overview of NHPs in neuroscience, their applications in research, and the ethical considerations that must be taken into account. It highlights the various breeding and handling practices that are employed to ensure the health and welfare of NHPs in experimental settings. Additionally, the paper summarizes the challenges associated with the use of NHPs in research and the benefits that have been realized from their use. Overall, this paper underscores the importance of recognizing the role of NHPs in neuroscience, and the responsibility that researchers have to ensure their welfare and to address ethical considerations. By doing so, researchers can continue to advance our understanding of the brain and develop new treatments for neurological and psychiatric disorders.

Chapter 3 - Autologous vs heterologous cell replacement strategies for Parkinson disease and other neurologic diseases

Successful cell replacement strategies for brain repair depend on graft integration into the neural network, which is affected by the immune response to the grafted cells. Using Parkinson disease as an example, in this chapter, we consider the immune system interaction and its role in autologous vs heterologous graft survival and integration, as well as past and emerging strategies to overcome the immunologic response. We also reflect on the role of nonhuman primate research to assess novel approaches and consider the role of different stakeholders on advancing the most promising new approaches into the clinic.

Comparison of retinal parameters between rhesus and cynomolgus macaques.

Nonhuman primates are important research models for basic vision research, preclinical pathogenesis, and treatment studies due to strong similarities in retinal structure and function with humans. We compared retinal parameters between 10 healthy normal rhesus macaques (Macaca mulatta) and 10 cynomolgus macaques (Macaca fascicularis) by optical coherence tomography and electroretinography. The Heidelberg Spectralis® HRA+OCT and Roland multifocal electrophysiometer were used to analyze retinal morphology, multifocal electroretinograms (mfERGs), and full-field electroretinograms (ff-ERGs). Mean retinal thickness was lowest in the central fovea of macaques and did not differ significantly between species, but the retinal thicknesses of the nerve fiber ganglion cell layer and the inner plexiform layer were significantly different. The amplitude density of the N1 wave was lower in rhesus macaques than in cynomolgus macaques in ring and quadrant areas. Dark-adapted 3.0 oscillatory potentials (reflection of amacrine cell activity) and light-adapted 30-hz flicker ERG (a sensitive cone-pathway-driven response) waveforms of the ff-ERG were similar in both species, while the times to peaks in dark-adapted 0.01 ERG (the rod-driven response of bipolar cells) and dark-adapted 3.0 ERG (combined rod and cone system responses) as well as the implicit times of the a- and b-waves in light-adapted 3.0 ERG (the single-flash cone response) were substantially different. This study provides normative retinal parameters for nonhuman primate research on basic and clinical ophthalmology, as well as a reference for researchers in the appropriate selection of rhesus or cynomolgus macaques as models for ophthalmology studies.

Imaging-based chemogenetics for dissecting neural circuits in nonhuman primates.

Nonhuman primates, particularly macaque and marmoset monkeys, serve as invaluable models for studying complex brain functions and behavior. However, the lack of suitable genetic neuromodulation tools has constrained research at the network level. This review examines the application of a chemogenetic technology, specifically, designer receptors exclusively activated by designer drugs (DREADDs), to nonhuman primates. DREADDs offer a means of reversibly controlling neuronal activity within a specific cell type or neural pathway, effectively targeting multiple brain regions simultaneously. The combination of DREADDs with imaging techniques, such as positron emission tomography and magnetic resonance imaging, has significantly enhanced nonhuman primate research, facilitating the precise visualization and manipulation of specific brain circuits and enabling the detailed monitoring of changes in network activity, which can then be correlated with altered behavior. This review outlines these technological advances and considers their potential for enhancing our understanding of primate brain circuit function and developing novel therapeutic approaches for treating brain diseases.

Veterinary management protocol for non-human primates: quarantine, anesthesia, and postoperative care for mastoidectomy at animal research institutions

Non-human primate (NHP) research faces challenges due to zoonosis risk and complex veterinary management yet lacks standardized guidelines for animal care. Therefore, we developed an advanced veterinary management protocol for NHP quarantine, anesthesia, and postoperative care. Three female 4 to 5-year-old cynomolgus monkeys were anesthetized and underwent various tests, including body weight, temperature, blood tests, urinalysis, microbiological monitoring, and physical and dental examinations. Ivermectin and medicated baths were administered to eradicate ectoparasites and endoparasites, and testing was repeated 30 days later. Following quarantine, we performed computed tomography and anesthesia maintenance for mastoidectomy. To relieve pain and maintain body weight, we administered tramadol intramuscularly 4 times/day for 3 days and meloxicam subcutaneously twice daily for 14 days. Feed replacements were provided. During the 33-day quarantine period, physical examinations revealed no abnormalities indicative of infectious diseases, and no specific clinical symptoms were observed. Through a preliminary test of anesthesia time, we selected ketamine 4 mg/kg + medetomidine 50 µg/kg for short experiments such as computed tomography, and ketamine 8 mg/kg + medetomidine 50 µg/kg for intubation. Ten days after mastoidectomy, NHPs consumed 100 kcal/kg and recovered their body weight. This study offers advanced veterinary management guideline for NHP research. Such protocols can lead to more standardized and ethical practices in NHP research, thereby enhancing the quality of studies on NHPs and the translation of findings to human health and disease.

A Comprehensive study on the application of deep brain stimulation in PTSD

Nowadays, with the rapid development of society, stress from all aspects promotes increasing rates of getting mental health issues or illness. Among them, Post Traumatic Stress Disorder (PTSD) is one of the famous mental problems that is noticed by people heavily in recent years. At the same time, great progress in the field of medical-surgical technology has also been made. Deep Brain Stimulation (DBS), a neurosurgical process that requires implanting electrodes in specific brain regions, can be used to treat PTSD to some extent. This reviewed the previous research and study conducted using DBS targeting PTSD, synthesized results and found that DBS treatment is currently mainly at the preclinical stage; Amygdala is the most common brain region that being targeted by DBS; The combination of several treatments is more effective than only DBS treatment; and most studies about the effects of DBS on PTSD were conducted on animal models. Whats more, the future study direction of this related topic including the Nonhuman Primate Research and DBS treatment with other disorders such as Parkinsons Disorder, and Obsessive-Compulsive Disorder(OCD) is also included.

The impact of housing on birth outcomes in breeding macaque groups across multiple research centers.

Demand for nonhuman primates in research has increased over the past several years, while nonhuman primate supply remains a challenge in the United States. Global nonhuman primate supply issues make it increasingly important to maximize domestic colony production. To explore how housing conditions across primate breeding colonies impact infant survival and animal production more broadly, we collected medical records from 7959 rhesus macaques (Macaca mulatta) and 492 pigtail macaques (Macaca nemestrina) across seven breeding facilities and used generalized mixed-effect modeling to determine prenatal and infant survival odds by housing type and group size. Infant survival odds for each housing type and group size varied for prenatal, neonatal, early infant, and late infant age groups. Odds of prenatal survival were lowest in paired indoor housing and small and medium outdoor groups. No housing type performed better than large outdoor groups for neonatal survival. Odds of early infant survival was greatest in indoor and mixed indoor/outdoor housing compared to large outdoor enclosures. Large outdoor housing was associated with higher survival odds for late infant survival compared to small and medium outdoor housing. These results may influence housing choices at macaque breeding facilities hoping to maximize infant success, although there are relative care costs, the promotion of species-typical behaviors, and infrastructure factors to also consider. Our study used an interinstitutional collaboration that allowed for the analysis of more infant macaque medical records than ever before and used the broad variations across the seven national primate research centers to make the results applicable to many other facilities housing macaques.

Current state of stem cell research in non-human primates: an overview.

The remarkable similarity between non-human primates (NHPs) and humans establishes them as essential models for understanding human biology and diseases, as well as for developing novel therapeutic strategies, thereby providing more comprehensive reference data for clinical treatment. Pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells provide unprecedented opportunities for cell therapies against intractable diseases and injuries. As continue to harness the potential of these biotechnological therapies, NHPs are increasingly being employed in preclinical trials, serving as a pivotal tool to evaluate the safety and efficacy of these interventions. Here, we review the recent advancements in the fundamental research of stem cells and the progress made in studies involving NHPs.

Fast prediction in marmoset reach-to-grasp movements for dynamic prey

Primates have evolved sophisticated, visually guided reaching behaviors for interacting with dynamic objects, such as insects, during foraging.1,2,3,4,5 Reaching control in dynamic natural conditions requires active prediction of the target's future position to compensate for visuo-motor processing delays and to enhance online movement adjustments.6,7,8,9,10,11,12 Past reaching research in non-human primates mainly focused on seated subjects engaged in repeated ballistic arm movements to either stationary targets or targets that instantaneously change position during the movement.13,14,15,16,17 However, those approaches impose task constraints that limit the natural dynamics of reaching. A recent field study in marmoset monkeys highlights predictive aspects of visually guided reaching during insect prey capture among wild marmoset monkeys.5 To examine the complementary dynamics of similar natural behavior within a laboratory context, we developed an ecologically motivated, unrestrained reach-to-grasp task involving live crickets. We used multiple high-speed video cameras to capture the movements of common marmosets (Callithrix jacchus) and crickets stereoscopically and applied machine vision algorithms for marker-free object and hand tracking. Contrary to estimates under traditional constrained reaching paradigms, we find that reaching for dynamic targets can operate at incredibly short visuo-motor delays around 80ms, rivaling the speeds that are typical of the oculomotor systems during closed-loop visual pursuit.18 Multivariate linear regression modeling of the kinematic relationships betweenthe hand and cricket velocity revealed that predictions of the expected future location can compensate for visuo-motor delays during fast reaching. These results suggest a critical role of visual prediction facilitatingonline movement adjustments for dynamic prey.

Harmonisation of welfare indicators for macaques and marmosets used or bred for research.

Background: Accurate assessment of the welfare of non-human primates (NHPs) used and bred for scientific purposes is essential for effective implementation of obligations to optimise their well-being, for validation of refinement techniques and novel welfare indicators, and for ensuring the highest quality data is obtained from these animals. Despite the importance of welfare assessment in NHP research, there is little consensus on what should be measured. Greater harmonisation of welfare indicators between facilities would enable greater collaboration and data sharing to address welfare-related questions in the management and use of NHPs. Methods: A Delphi consultation was used to survey attendees of the 2019 NC3Rs Primate Welfare Meeting (73 respondents) to build consensus on which welfare indicators for macaques and marmosets are reliable, valid, and practicable, and how these can be measured. Results: Self-harm behaviour, social enrichment, cage dimensions, body weight, a health monitoring programme, appetite, staff training, and positive reinforcement training were considered valid, reliable, and practicable indicators for macaques (≥70% consensus) within a hypothetical scenario context involving 500 animals. Indicators ranked important for assessing marmoset welfare were body weight, NHP induced and environmentally induced injuries, cage furniture, huddled posture, mortality, blood in excreta, and physical enrichment. Participants working with macaques in infectious disease and breeding identified a greater range of indicators as valid and reliable than did those working in neuroscience and toxicology, where animal-based indicators were considered the most important. The findings for macaques were compared with a previous Delphi consultation, and the expert-defined consensus from the two surveys used to develop a prototype protocol for assessing macaque welfare in research settings. Conclusions: Together the Delphi results and proto-protocol enable those working with research NHPs to more effectively assess the welfare of the animals in their care and to collaborate to advance refinement of NHP management and use.

Fostering nonhuman primate (NHP) brain research without animal sacrifice

Fostering nonhuman primate (NHP) brain research without animal sacrifice The MacBrain Resource Center (MBRC) at Yale University School of Medicine is positioning itself at the forefront of innovative ways to provide cost-effective means for scientists to conduct de novo nonhuman primate brain research with extant materials. This avoids superfluous animal sacrifice, increases study repeatability, decreases costs, and makes NHP brain research accessible to a much larger scientific community. Conditions that its Director, Dr. Alvaro Duque, believe will help advance neuroscience. The brain is a complex system and, as it is often the case with the study of complex systems, research is expensive and progress very slow.

Face-Selective Patches in Marmosets Are Involved in Dynamic and Static Facial Expression Processing.

The correct identification of facial expressions is critical for understanding the intention of others during social communication in the daily life of all primates. Here we used ultra-high-field fMRI at 9.4 T to investigate the neural network activated by facial expressions in awake New World common marmosets from both male and female sex, and to determine the effect of facial motions on this network. We further explored how the face-patch network is involved in the processing of facial expressions. Our results show that dynamic and static facial expressions activate face patches in temporal and frontal areas (O, PV, PD, MD, AD, and PL) as well as in the amygdala, with stronger responses for negative faces, also associated with an increase of the respiration rates of the monkey. Processing of dynamic facial expressions involves an extended network recruiting additional regions not known to be part of the face-processing network, suggesting that face motions may facilitate the recognition of facial expressions. We report for the first time in New World marmosets that the perception and identification of changeable facial expressions, vital for social communication, recruit face-selective brain patches also involved in face detection processing and are associated with an increase of arousal.SIGNIFICANCE STATEMENT Recent research in humans and nonhuman primates has highlighted the importance to correctly recognize and process facial expressions to understand others' emotions in social interactions. The current study focuses on the fMRI responses of emotional facial expressions in the common marmoset (Callithrix jacchus), a New World primate species sharing several similarities of social behavior with humans. Our results reveal that temporal and frontal face patches are involved in both basic face detection and facial expression processing. The specific recruitment of these patches for negative faces associated with an increase of the arousal level show that marmosets process facial expressions of their congener, vital for social communication.

Animal Models to Study Neurologic Manifestations of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the worldwide coronavirus (COVID-19) pandemic, has infected an estimated 525 million people with over 6 million deaths. Although COVID-19 is primarily a respiratory disease, an escalating number of neurologic symptoms have been reported in humans. Some neurologic symptoms, such as loss of smell or taste, are mild. However, other symptoms, such as meningoencephalitis or stroke, are potentially fatal. Along with surveys and postmortem evaluations on humans, scientists worked with several animal species to try to elucidate the causes of neurologic symptoms. Neurologic sequelae remain challenging to study due to the complexity of the nervous system and difficulties in identification and quantification of neurologic signs. We reviewed animal models used in the study of neurologic COVID-19, specifically research in mice, hamsters, ferrets, and nonhuman primates. We summarized findings on the presence and pathologic effects of SARS-CoV-2 on the nervous system. Given the need to increase understanding of COVID-19 and its effects on the nervous system, scientists must strive to obtain new information from animals to reduce mortality and morbidity with neurologic complications in humans.

Choice reaction time in pigeons fails to increase as predicted by Hick’s law

Being able to correctly identify a target when presented with multiple possible alternatives, or increasing uncertainty, is highly beneficial in a wide variety of situations. This has been intensely investigated with human participants and results consistently demonstrated that participant reaction time (RT) increases linearly with the number of response alternatives, described as Hick’s Law. Yet, the strength of this relationship is impacted by a variety of parameters, including stimulus-response compatibility, stimulus intensity, and practice. Different theories attempt to explain why these parameters affect the time to detect the target, but thus far these theories almost exclusively rely on human and nonhuman primate research. Therefore, it is unclear if these theories are universal or unique to primates, due to the scarcity of other animal models. A previous investigation showed that pigeon RT will increase in accordance with Hick’s Law though not as steeply as human RT, potentially due to differences in the procedure used on pigeons. To better understand pigeon RT under uncertainty and facilitate cross species comparisons, these experiments used a procedure that was more similar to what has been given to humans. Surprisingly, pigeon RT did not follow Hick’s Law as predicted. In Experiment 1, subjects showed an ‘anti-Hick’s’ effect due to an artefact of stimulus location on the monitor. Subsequent experiments controlled for location, still RT did not increase with the number of choices as predicted by Hick’s Law. Procedural changes that may have been responsible for this difference and the role of stimulus-response compatibility are discussed.