key: cord-0919476-m6p2b6o8
authors: Tramacere, Antonella; Iriki, Atsushi
title: A novel mind‐set in primate experimentation: Implications for primate welfare
date: 2021-11-29
journal: Animal Model Exp Med
DOI: 10.1002/ame2.12190
sha: aad5dee726e1412921d08cdd34afcb966eb570fd
doc_id: 919476
cord_uid: m6p2b6o8

We emphasize the importance of studying the primate brain in cognitive neuroscience and suggest a new mind‐set in primate experimentation within the boundaries of animal welfare regulations. Specifically, we list the advantages of investigating both genes and neural mechanisms and processes in the emergence of behavioral and cognitive functions, and propose the establishment of an open field of primate research. The latter may be conducted by implementing and harmonizing experimental practices with ethical guidelines that regulate (1) management of natural parks with free‐moving populations of target nonhuman primates, (2) establishment of indoor‐outdoor labs for both system genetics and neuroscience investigations, and (3) hotel space and technologies which remotely collect and dislocate information regarding primates geographically located elsewhere.

date, a detailed map of the human brain has benefited from findings achieved during neurophysiological experiments with primates.

The evolutionary relatedness between human and NHPs has made primate experimentation pivotal for cognitive neuroscience research. At the same time, their phylogenetic closeness has been one reason for questioning primate experimentation in its current ethical form. The line of reasoning is that, since the NHP brain and body are like our own, they also suffer like us, and therefore they deserve increased welfare compared to other species. Consequently, new regulations have produced restrictions in the use of NHP in laboratory research [see Box 1] .

One consequence of the new restrictions has been a progressive increase in rodent experimentation. To date, a great deal of experimental research in cognitive neuroscience is conducted in rodent species. Rodents have become among the most common animal models in cognitive neuroscience; many behavioral studies are also conducted with rodents, leading to an increase in the range of cognitive functions attributed to these mammals. Rodents are now known to possess astonishingly complex capacities, such as flexible behavior, spatial navigation, and episodic-like memory.

However, as we argue in this paper, if not combined with primate experimentation, cognitive neuroscience in rodents is limited. If the goal is to identify the neural correlates of the human mind, a knowledge of the specific neurobiological mechanisms that can inform generalizations about associated human cognitive functions is required. We contend that, if performed in parallel with human and rodent experimentation, NHP research has significant benefits, because it allows us to reach an understanding of human brain mechanisms through the study of a model brain more similar to human beings than that of rodents.

Our argument comes with concrete proposals for primate welfare. We claim that NHP experimentation in cognitive neuroscience can be conducted within a new mind-set that harmonizes the use of novel technologies with scientific practices promoting primate welfare. Specifically, we envisage a system of remote technologies and a combination of indoor-outdoor laboratory structures that are compatible with increased ethical standards for primate research.

After describing a series of tools and labs technologies that may fit the scope, we make a series of observations on the epistemic and economic benefits that our proposal may bring.

We start by reviewing the use of both rodents and primate models in cognitive neurobiological research (Section 2). In Section 3, we emphasize the importance of studying NHP by discussing recent research guidelines (i.e. Research Domain Criteria) launched by the National Institute of Health. In Section 4, we present the core of the proposal for studying NHP while improving welfare measures for NHP. We then review the potential benefits of studying NHPs in Section 5 and discuss more general costs and benefits trade-offs in Section 6.

In the past few decades, research with rodents has become prominent in various sub-fields of cognitive neuroscience, and progress has been made through rodent experimentation. Mechanistic features and functions of key neural circuits common to the mammalian order, such as reward and emotional systems, have been deeply investigated through brain research in mice and rats. Further, new techniques, such as deep brain stimulation and optogenetics, have been mostly tested in the rodent models, allowing generalizations of brain mechanisms to the human brain.

These achievements, however, should not lead us to forget the differences between the human and rodent brains, which matter for translation of rodent findings to human beings. For example, the size and cortical organization of the prefrontal cortex, von Enconomo neurons, neurotransmitters and neuromodulatory pathways 3 are different in rodents and primates. As a consequence, the neural mechanisms and processes underlying cognitive traits in the

In parallel with the study of primate cognition and the discovery of their genetic, neural and behavioral similarity with human beings, the status of NHP in research has generated much debate. While the similarity has scientific advantages, it poses ethical problems because of a likelihood that primate experience pain and suffering in ways that are similar to humans. 2 Consider attention as an example. Critical differences do exist between rodent and primate mechanisms and processes of attention. In humans and NHPs the allocation of attention is determined by a frontoparietal neural network. 4 This includes parts of the oculomotor system aligning the fovea with objects of interest, and provides spatially selective feedback signals to extrastriate visual cortex that cause attention-dependent changes in gain. 5, 6 Although rodents can and do move their eyes, they lack a fovea, and lack the prefrontal oculomotor infrastructure that serves to deploy spatial attention in primates. 7 Consequently, brain research in rodents can be informative to the extent that it highlights coarsegrained factors affecting the capacity to allocate attention in human.

However, it tends to be limited when the goal is uncovering how human cortical connectivity is affected by top-down neural processing in the ability to deploy attention. As consequence, experimentation with rodents may restrict successful development of therapies for psychiatric disorders in which attention processes are affected. This is just an example, but striking differences between rodents and primates also include communication based on mobility of facial expression, 8 capacity for mentalization, 9 and the use of both motor and sensory tools, and enhanced tactile specialization, 10 among others. In each of these cases, cognitive functions seem to depend on primate-specific brain specializations, which in turn may affect the way cognitive dysfunctions arise.

It is worth of emphasizing that we do not aim to dismiss the importance of rodent models in neuroscience. At the same time, we do not contend that NHP experimentation alone is sufficient for uncovering the biological bases of human cognition. Animal experimentation depends on being able to select the right model for addressing the right questions. The choice of the species to be used depends on many factors that are not only methodological in nature, but also ethical.

In line with this general maxim, experiments with mice and rats are important, not only to uncover brain mechanisms and processes which are common to rodents and humans, as described above in the case of attention. The rodent model is also important for inquiring into the genetic variability associated with atypical brain function, and increased vulnerability to diseases. Neurobiological experiments in rodents have proved useful to investigations of the effect size of specific sets of genes in neurocognitive functions that are common to human beings and rodents. For instance, screening for loss or gain of gene functions in mice has helped to highlight the mechanisms of action of specific molecules, and to determine neuromolecular pathways affecting aspects of sensorimotor control. To date, we already know of several molecular and neural circuitries associated with typical and atypical sensorimotor capacities in human beings that have guided mechanist studies in rodents.

Although rodents are optimal animal models for inquiring into neurobiological functions that are common to human beings and rodents, they are of limited use in uncovering the neurobiological bases of cognitive capacities that are specific to NHPs. Thus, addressing these questions in rodent species in order to formulate general mechanisms that also apply to humans is a gamble, which is already producing results that suffer from limitations. 3, 11 Experimentation with NHPs is more appropriate for studying the biological bases of human cognition for a number of reasons.

There are more consistent similarities between two primate species than between two different taxa, at the genetic, neural, and sociobehavioral levels. 12 Given the close biological similarities between NHPs and humans, NHP research could significantly reduce the uncertainty associated with translation of findings to humans and be instrumental in producing more realistic mechanist models of human cognitive functions.

Further, the phylogenetic proximity of humans and NHPs makes more likely that they will share many of the specific neural mechanisms involved in brain physiology, behavior, and susceptibility to disease. Gene maps of NHPs and humans are highly conserved and therefore NHPs will more closely model the complex gene-gene and gene-environment interactions that control human neurophysiological processes. 12 Further, beyond the phylogenetic (and thus genetic) closeness, there are anatomical similarities. Primate brains follow similar rules of cerebral changes, which do not apply to rodents. In rodents, variations in brain size outpace variations in the number of brain neurons.

Rodent brains vary in mass as a power function of the number of brain neurons, whereas in primates, brain size increases linearly as a function of the number of neurons. 13 This makes the rodent brain structurally dissimilar, in terms of number of neurons, layer structures and connectivity, to the primate brain and thus suitable as a model for studies targeting primate-specific cognitive functions.

We are aware that no animal models will ever fully recapitulate human cognition, which is the result of species-specific environmental and cultural influences, but NHP experimentation can still provide important information for identifying brain mechanisms implicated in the emergence of human cognitive functions. Human experimentation and alternative methods are not yet a mature branch of research. Until we can develop non-invasive, but nonetheless efficient experimental tools for investigating the fine-grained functional-mechanistic aspects of human cognition, to compare evidence obtained during investigations in humans with research on neurobiological mechanisms in animals closely related to us. As previously explained, research conducted with the most common animal models in neurobiology, i.e. rodents, is limited. The brain differences between rodent models (rats and mice) and human beings are such that the cognitive dysfunctions under investigation may be generated by primate specific biological features or speciespecific functions. Consequently, to study the neurobiological bases of psychiatric disorders through different levels of analysis, we need to conduct research in animal models that are closer to the human cerebral and molecular phenotypes.

Basing on these assumptions, we think that one possible way to proceed, among others, is the application of the RDoC guidelines to primate experimentation, to implement a research agenda that involves investigations of multilevel information in target species of monkeys. The research agenda would include the study of NHP brain, behavior and genetics. More specifically, systems genetics and cognitive neuroscience investigations in NHPs could be instrumental in collecting data in NHP subjects that allows analysis of multilevel information (from genetic profiles, to molecules, to neuronal circuitry), through large-scale investigation of behavior.

In this context, rodent research would still be fundamental. The rodent model would be important for disease modeling, to inquiring into the genetic variability associated with atypical brain functioning, and increased vulnerability to diseases. In parallel with rodent research, experimentation on NHPs would provide complementary information, with a set of brain and molecular high-resolution techniques being instrumental in inquiring into target brain functions in monkeys.

It is not the goal of this paper to delineate the exact combination of techniques and experimental methods that could be utilized in such an enterprise. A few examples, to be developed in future work, illustrate how NHP experimentation could include the systems genetics 16 tools that we have listed above. Through these tools, it will be possible to proceed to large genetic GWAS analysis, and molecular screening of central and peripheral tissues.

Furthermore, molecular imaging techniques could be used to detect fine-scale, diffuse, and slow activities of complex network structures. 18, 19 More detailed brain investigations could also benefit from newly emerging wireless implantable neural recording. 20 Finally, high throughput supercomputers and computer simulation techniques would be required to deal with huge amounts of data (i.e., Big Data), 21 collected at multiple levels of analysis. Big data supercomputers are utilized to detect patterns of significance in various types of input data. We will provide additional considerations on the use of these techniques in the next section, showing how they could enable systematic investigations of molecular, cellular and circuit-level landscapes of the primate brain across typical and atypical development. 22, 23 The focus of the remaining part of this article relates to the prac- These changes could have interesting implications for primate welfare. In the next sections, we make concrete proposals on how these desiderata could be implemented.

The investigation of molecules, neural circuitry and behavior in NHP populations would need novel structures and technologies for primate experimentation. Crucially, these structures must be in line with new standards for primate welfare. The scientific community and the general public are determined to provide improved conditions for NHP individuals participating in cognitive neuroscience research. We think that these desiderata can be satisfied both at the methodological and ethical level. We think that it is possible to establish wild-like environments for target populations of NHPs that allow free movement. In turn these conditions could allow scientists to inquire into cognitive phenomena and neurobiological correlates which are common to the primate order. In other words, the investigation of cognitive functions through collection of data at different levels of analyses in free-moving primate groups may serve both scientific and ethical purposes.

With the objective of maximizing the feasibility and the potential benefits of conducting brain research through the RDoC guidelines in NHPs, our proposal is to construct a niche allowing non-invasive or minimally invasive experimentation on target species of monkeys.

This niche for primate experimentation could make use of primate natural parks with a combination of indoor and outdoor spaces. We briefly describe the infrastructures and technologies underlie this proposal below. NHP living in naturalistic settings may further offer the possibility of inquiring into the range of naturally occurring dysfunctions in NHPs. Specifically, through focus observations and testing of NHP socio-cognitive behaviors, it may be possible to detect interindividual variability that is potentially predictive or reminiscent of human disease vulnerability (for a concrete example see Ref. [25] ).

The neurobiological mechanisms behind interindividual behavioral variability would constitute a valuable source of information for neuropsychiatric research. 26, 27 Another advantage of primate natural parks is that primates do not have to be transported for long distances, housed in facilities (e.g. where they live in restricted spaces, isolated cages, and artificial environments), and subjected to laboratory conditions. This reverses the logic of classical lab experimentation. Currently, most brain research is conducted in the lab, where animals are generally housed in cages and live in socially isolated spaces, in order to provide controlled conditions in which experiments and measurements can be performed. In contrast, in research in natural labs, it is the scientists, and not animals, that move. The hotel space would need to utilize telecommuting approaches to storing the data collected during animal experimentation, to analyze, and in some cases share data collected on site. 3 The hotel space would need to be endowed with remote technologies, such as the Internet of Things (i.e. a new paradigm in modern wireless telecommunication), that would allow the storage and transfer of information in real time, 28 IT based knowledge management (i.e. an information technology system to enhance and organize knowledge), 29 and cloud-based big data processing for allowing costefficient exploration for voluminous data sets. 22 For countries that are far from NHP natural habitats establishing primate natural parks may be difficult, but the existence of hotel spaces close to these parks could potentially offer unlimited possibilities for studying NHPs on site. The benefits deriving from these structures could thus be shared through different partners.

Establishing hotel spaces would be necessary for scientists who want to work with NHPs but are at an institute that lacks the 

Conducting primate experimentation through the establishment of natural parks, remote technologies and hotel spaces for scientists working on site is clearly an ambitious and visionary enterprise.

However, it could give short-and long-term benefits, by minimizing both ethical and scientific concerns, and could probably achieve balanced financial funding. risks. Further, it may help to track changes that might in turn endanger humans through processes of zoonosis. 32 It is also worth noting that this proposal is in accordance with current ethical frameworks, i.e. the '3Rs', which promote the search for alternatives and serve as the cornerstone for ethical guidelines in animal research. The 3Rs' set out three goals for experimenters: replacement of animals by alternative methods; reduction of their numbers by means of statistical techniques; and refinement of the experiment so as to cause less suffering. 33 More specifically, this proposal is in line with the goal of refinement, which not only aims to avoid or minimize pain or adverse effects, but also to maximize well-being, through the implementation of environmental enrichment and the promotion of positive elements of welfare, such as comfort and security. 34 Natural parks for primate experimentation may also be associated with economic and practical advantages. Besides being subjected to protests from animal activists, some traditional primate facilities have high running costs due to the expense of animal management and employing qualified personnel. In contrast, natural parks could balance the economic costs by generating income from research centers worldwide (which aim to send researchers to study and collect data on NHPs) by providing zoo/safari type experiences for visitors and through educational programs.

Countries endowed with natural habitats for NHPs, such as Japan, India, Sri Lanka or Singapore, have witnessed increasing degrees of conflict between humans and feral monkeys over the last several decades. 35 NHPs become pests when they seek to obtain food and water near human habitation. Artificial feeding leads to changes in monkey behavior, and in population ecology by causing overpopulation of relatively aggressive monkeys. The solutions that some countries have adopted, such as killing, sterilizing or translocating monkeys, are mostly unfeasible for ethical, practical and economic reasons. On the one hand, killing a large number of animals is considered unethical according to the welfare regulation of several countries, while on the other hand sterilization and translocation practices are expensive and very laborious, because they require specialized personnel and long-term commitment. 35 To sum up, natural parks for primate experimentation may be beneficial from both a methodological and ethical perspective and in particular may (1) enhance scientific validity, by providing a more suitable animal model for the study of mental functions and psychiatric disorders that can be translated into effective therapies, (2) provide naturalistic wild-like environments for NHPs, and avoid their translocation to different countries, and (3) allow data collection that can benefit primate conservation, and help control of risks from human-animal interactions.

In this paper, we have proposed that research on free-moving populations of primates (conducted in parallel with human and rodent experimentation) can provide key mechanistic information that can be generalized to explain and understand human cognitive functions. Recent advances in neural and molecular tools can be combined to investigate primate behavior and psychology, and their neurobiological underpinnings. These tools might include system genetics tools, experimental and statistical methods to quantitate phenotypes, and techniques for neuroimaging, electrophysiology and wireless neural recordings.

We have given examples of infrastructures (i.e. natural parks and hotel spaces) and technologies (e.g. remote labs, Internet of Things, cloud-based Big Data processing) that could be used to conduct primate experimentation in a way that can enrich primate welfare. We have proposed natural parks that allow target populations of some primate species to live in a more ecological setting with free movement and socially enriched spaces. Our proposal can be interpreted as offering a new mind-set for primate neurocognitive research, constituting an interdisciplinary effort to understand the mechanisms systemically operating in the brain and body of primate models, which could have important implications for the way we use primates in the field of neuroscience and neuropsychiatry research.

The establishment of primate natural parks for primate cognitive experimentation is in accordance with current ethical frameworks (i.e. the '3Rs'). However, it also subtly incentivizes an enrichment of current understanding of animal ethics. That is, the open field of primate cognitive research can provide a new perspective on animal ethics: some animal species have the potential to live and/or interact collaboratively with humans, and this can affect the relationship we can establish with these animal species and the value we assign to them. 36 Thus, beyond the protection of primates according to their capacity to experience pain (in accordance with existing regulations), this research approach could be used to harmonize human and NHP interests.

To apply this new mind-set to primate mental research and implement connected investigative practices would require the establishment of updated ethical guidelines, which could lead on the one hand to developing new rules for NHP experimentation, and on the other hand to new guidelines for collaboration between research centers, laboratories and researchers. Although the aim of this manuscript is not to propose these guidelines, but to advance the general proposal, we hope that this perspective can constitute a starting point for future discussion.

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

The ethics of research involving animals: a review of the Nuffield Council on Bioethics report from a three Rs perspective

Opportunities and challenges in modeling human brain disorders in transgenic primates

Mechanisms of visual attention in the human cortex

Visuomotor origins of covert spatial attention

Microstimulation of the frontal eye field and its effects on covert spatial attention

Comparison of plasticity and development of mouse optokinetic and vestibulo-ocular reflexes suggests differential gain control mechanisms

Faces in the mirror, from the neuroscience of mimicry to the emergence of mentalizing

Great apes anticipate that other individuals will act according to false beliefs

Acquisition of an externalized eye by Japanese monkeys

Modeling psychiatric disorders for developing effective treatments

Advantages and limitations of nonhuman primates as animal models in genetic research on complex diseases

The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost

Research domain criteria (RDoC): toward a new classification framework for research on mental disorders

Systems genetics approaches to understand complex traits

The road to precision psychiatry: translating genetics into disease mechanisms

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

Neuroimaging in the developmental disorders: the state of the science

Structural MRI connectome in development: challenges of the changing brain

An implantable wireless neural interface for recording cortical circuit dynamics in moving primates

Managing, analysing, and integrating big data in medical bioinformatics: open problems and future perspectives

Epigenetic mechanisms in schizophrenia

Spatio-temporal transcriptome of the human brain

Multielectrode recording in behaving monkeys

Single-neuron and genetic correlates of autistic behavior in macaque

Implementation, Monitoring, and Sharing of Performance Standards for Laboratory Animal Use: Summary of a Workshop

The Role of Clinical Studies for Pets with Naturally Occurring Tumors in Translational Cancer Research: Workshop Summary

The internet of things: a survey

Knowledge management and knowledge management systems: conceptual foundations and research issues

Use of primates in research: a global overview

United States Department of Agriculture, Animal and Plant Health Inspection Service

The human-primate interface in the New Normal: challenges and opportunities for primatologists in the COVID-19 era and beyond

Ethical and scientific considerations regarding animal testing and research

Harmonising the definition of refinement

An online forum for exchanging ideas for dealing with issues of pest monkeys

Animal Rights: Current Debates and New Directions

How to cite this article: Tramacere A, Iriki A. A novel mind-set in primate experimentation: Implications for primate welfare

The authors do not have acknowledgment.

The authors declare no conflict of interest.

Both authors contributed to the ideation and writing of the paper.

https://orcid.org/0000-0002-7522-4645