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“Natural Laboratory Complex” for novel primate neuroscience

October 2022
Frontiers in Integrative Neuroscience 16:927605

DOI:10.3389/fnint.2022.927605

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University of Bologna

We propose novel strategies for primate experimentation that are ethically valuable and pragmatically useful for cognitive neuroscience and neuropsychiatric research. Specifically, we propose Natural Laboratory Complex or Natural Labs, which are a combination of indoor-outdoor structures for studying free moving and socially housed primates in natural or naturalistic environment. We contend that Natural Labs are pivotal to improve primate welfare, and at the same time to implement longitudinal and socio-ecological studies of primate brain and behavior. Currently emerging advanced technologies and social systems (including recent COVID-19 induced “remote” infrastructures) can speed-up cognitive neuroscience approaches in freely behaving animals. Experimental approaches in natural(istic) settings are not in competition with conventional approaches of laboratory investigations, and could establish several benefits at the ethical, experimental, and economic levels.

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TYPE Hypothesis and Theory

PUBLISHED 05 October 2022

DOI 10.3389/fnint.2022.927605

OPEN ACCESS

EDITED BY

Elizabeth B. Torres,

Rutgers, The State University

of New Jersey, United States

REVIEWED BY

Yuxiang Liu,

University of Texas Southwestern

Medical Center, United States

Keisuke Kawasaki,

Niigata University, Japan

*CORRESPONDENCE

Atsushi Iriki

atsushi.iriki@riken.jp

RECEIVED 24 April 2022

ACCEPTED 23 August 2022

PUBLISHED 05 October 2022

CITATION

Iriki A and Tramacere A (2022) “Natural

Laboratory Complex” for novel primate

neuroscience.

Front. Integr. Neurosci. 16:927605.

doi: 10.3389/fnint.2022.927605

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“Natural Laboratory Complex”

for novel primate neuroscience

Atsushi Iriki1*and Antonella Tramacere2,3

1Laboratory for Symbolic Cognitive Development, RIKEN Center for Biosystems Dynamics

Research, Kobe, Japan, 2Department of Philosophy and Communication Studies, University of

Bologna, Bologna, Italy, 3Department of Cultural and Linguistic Evolution, Max Planck Institute for

the Science of Human History, Jena, Germany

We propose novel strategies for primate experimentation that are

ethically valuable and pragmatically useful for cognitive neuroscience

and neuropsychiatric research. Speciﬁcally, we propose Natural Laboratory

Complex or Natural Labs, which are a combination of indoor-outdoor

structures for studying free moving and socially housed primates in natural

or naturalistic environment. We contend that Natural Labs are pivotal to

improve primate welfare, and at the same time to implement longitudinal and

socio-ecological studies of primate brain and behavior. Currently emerging

advanced technologies and social systems (including recent COVID-19

induced “remote” infrastructures) can speed-up cognitive neuroscience

approaches in freely behaving animals. Experimental approaches in

natural(istic) settings are not in competition with conventional approaches of

laboratory investigations, and could establish several beneﬁts at the ethical,

experimental, and economic levels.

KEYWORDS

longitudinal studies, socio-ecological studies, natural(istic) environment, advanced

technologies, remote infrastructure, primate welfare, dilemma and trade-offs

Introduction

Neuroscience has made tremendous advancements in understanding the biological

mechanisms and processes of the human mind. A considerable part of these

advancements has been achieved through research in animal models, including non-

human primates (NHPs). Notwithstanding, in the last decades, in most Western

countries, NHP experimentation have faced practical challenges and ethical restrictions,

largely due to diﬃculties of keeping pace with economic costs of NHPs facilities,

and ethical concerns that primates experience suﬀering similarly to humans (EU

Commission,2013;Lankau et al.,2014).

Meanwhile, rodents have become (and very likely will continue to be) the

commonest animal model in neuroscience (Homberg et al.,2017), often replacing NHPs

in experiments about mechanisms of cognitive functions. One of the reasons for the

widespread use of the rodent model in neuroscience comes from rodent cognitive

complexity. Astonishingly complex cognitive capacities have been recognized in various

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species of rodents. Rodents are very skilled problem-solver,

have highly developed motor capacities and show a variety

of social and non-social cognitive mechanisms (Davis,1996;

Schweinfurth,2020).

Additionally, pragmatic reasons make rodents very much

investigated in neuroscience labs. Mice and rats are easy to

breed and to test in laboratory settings and have very ﬂexible

behavioral habits, which raise relatively few concerns from an

ethical and practical standpoint (Hickman et al.,2017).

Many have pointed out however that the rodent model is

limited when explanatory targets of the human mind do not ﬁnd

adequate counterparts in the rodent anatomy and physiology

(Roelfsema and Treue,2014;Camus et al.,2015). Diﬀerences

between rodents and humans become even more problematic

if one considers the recent pragmatic turn in cognitive science

(Engel et al.,2016), for which mental functions and dysfunctions

are not exclusively the result of internally regulated brain

mechanisms, but also of brain–body and brain–environmental

interactions. As the mind is progressively understood in terms of

bodily rules and situated aspects of environmental interactions,

approaches that abstract from the specie-speciﬁcity of these

aspects in the target animal models become outdated.

Every animal species possesses characteristics and

idiosyncrasies that are diﬃcult to generalize to other animal

species. Therefore, experimentations with animal models

will always show some range of limitations when the goal is

generalizations of mechanisms to humans. No animal model

could ever exactly recapitulate human cognitive capacities.

However, the evolutionary relatedness, as well as the similar

rules of interactions between biological and social factors in

complex environmental niches (Camus et al.,2015), often make

NHPs outstripping candidates for inquiring about processes

and mechanisms of the human mind.

If we agree with this assumption, then we face a dilemma

regarding the role of primates in neuroscience; that is, while

phylogenetic proximity with humans dictates primary relevance

of NHPs, the same proximity produces ethical concerns and

pave the way to diﬃculties in regulating research practices and

regulations. Taking primate research dilemma seriously implies

that neuroscience needs to balance the trade-oﬀs between

ethical considerations and practical beneﬁts for advancing

the understanding of the evolutionary precursors and basic

mechanisms of the human mind. The dilemma also implies

that, because of the standard of welfare that we want to grant

to NHPs in neuroscience research, any novel proposal for

NHP experimentation shall take into consideration cost-beneﬁts

trade-oﬀ for all partners, including the primates (Carvalho et al.,

2019).

In this article, we intend to lay the ground for such a project,

by advancing the conceptual basis and technical requirements

for novel strategies in primate experimentation. We start by

brieﬂy overviewing pros and cons of neuroscience research with

rodent and primate models to show that both models can be

instrumental to address diﬀerent, but complementary research

questions. Then, we propose a novel endurable setup of NHP

experimentation, as an ethically valuable and pragmatically

useful strategy for cognitive neuroscience and neuropsychiatric

research. Speciﬁcally, we propose Natural Laboratory Complex

or Natural Labs, as a combination of indoor-outdoor structures

for studying free moving and socially housed NHPs in

natural(istic) environment.

We argue that cognitive neuroscience approaches in freely

behaving animals could increment productive exchanges

between existing conventional approaches of laboratory

investigations. We further make a series of considerations

regarding how Natural Labs could establish beneﬁcial ethical,

ﬁnancial, and legal trade-oﬀs for leading NHP neuroscience

to the next stage.

Animal models in neuroscience

The rodent model

Mice and rats belong to the order Rodentia, which is the

closest to order Primates in the class Mammalia. Rodents possess

homologous features with human and NHPs, and numerous

similarities at the anatomical, physiological, and organizational

level (Ellenbroek and Youn,2016).

Many neurocognitive mechanisms which are common to

both primates and rodents have been discovered or delved into

through mice and rats research in the last decades, including

ﬁne-grained mechanisms of manual control, vocal plasticity,

and navigation capacities (Davis,1996;Arriaga and Jarvis,2013).

One obvious example of the latter is the discovery of place

cells in the hippocampus of rodent which has opened new

lines of research on memory and spatial cognition (O’Keefe and

Dostrovsky,1971;Thompson and Best,1989).

The diﬀusion of the rodent models is not exclusively due

to neuroanatomical and behavioral rationalizations, but also to

pragmatic reasons. Mice and rats have characteristics which

make their colonies cost eﬃcient to maintain. In fact, most

rodents are small, are easily housed in laboratory settings, have

short gestation time and large numbers of oﬀspring, rapid

development to adulthood and short life spans (Bryda,2013;

Hickman et al.,2017).

Further, many novel techniques of intervention, such as

tools for genetic modiﬁed engineering, have been developed

in rodents, because the rodent model is considered a good

compromise among animal species which approximate human

brain complexity and where these experimental procedures

are more ethically acceptable (Baker et al.,2020). Through

novel techniques, several molecular factors associated to

speciﬁc normal or abnormal cognitive states in human beings

have guided mechanist studies in rodents (Kaiser and Feng,

2015). As a consequence, pioneering advanced technologies in

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genome engineering have facilitated the creation of genetically

manipulated rodent models of various psychiatric disorders,

enabling investigations of underlying biological mechanisms (de

Hamilton,2013;Homberg et al.,2016).

Despite the advantages of rodent experimentation in pre-

clinical and clinical research, ﬁndings from rodent models

turned out not to be necessarily generalizable into humans

and have resulted in failure to develop treatments of targeted

mental and psychological disorders (Jennings et al.,2016). This

has discouraged some pharmaceutical companies to invest in

neuropsychiatric research which was largely based on earlier

experimentation with rodents, and to downplaying associated

drug trials (Ayesha,2021). The causes for these results are likely

various and heterogenous, see here for some recent analyses of

the question (Fernández,2019).

It is diﬃcult to exclude, however, that diﬀerences in

brain structure and functions between human and mice

could be partially responsible for the hurdles of generalizing

neurocognitive mechanisms from rodents to humans (Stephan

et al.,2019). Potential diﬀerences regard the number of neurons

in the brain, organization of the cerebral cortex (Figure 1),

resulting patterns of intracortical connections, and the

actions of neurotransmitters and neuro-modulatory pathways

(Herculano-Houzel,2012). These diﬀerences might well hinder

straightforward generalization of rodent neurobiological

mechanisms to humans, despite cognitive and behavioral

phenotypes look similar.

Another factor to consider is that in humans the emergence

of psychological and cognitive traits, and vulnerability to

disorders, is conditioned upon interactions of bodily and

developmental factors across individuals, which include

the speciﬁcity of the bodily plan and organization, and

the complexity and richness of the socio-ecological niche.

These aspects make human mental functions substantially

diﬀerent from caged laboratory animals. These diﬀerences are

particularly exacerbated for biologically controlled pure strain

rodent models which are bred in caged-based facilities.

In sum, signiﬁcant diﬀerences in the anatomical, brain

and aﬀective systems in small experimental animals and

humans provide strong limitations for modeling and studying

psychological and behavioral dysfunctions in mice and rats.

Therefore, basic and applied investigations of psychological and

cognitive functions which are mostly exclusively conducted in

rodents can be problematic.

Many previous contributions have analyzed pros and cons

of rodent research, and we will not repeat it here. We are

aware that none of the evidence listed above can constitute a

conclusive argument of what rodent research in neuroscience

can or cannot oﬀer for generalization of results to humans.

Consider however that our aim here is not to demonstrate that

the rodent models is per se limited in cognitive neuroscience

research. With this admittedly brief analysis of potentialities and

limitations of rodent research, our scope is only to point out that,

despite critical advancements, cognitive neuroscience research

in rodents is not alone suﬃcient for understanding the biological

mechanisms and processes of the human mind. We thus think it

is important to develop strategies to overcome experimentation

restrictions in NHP and beneﬁt of the NHP model in cognitive

and behavioral research.

The non-human primate model

Many neuroscientists have highlighted that the primate

models are unparallel animal models in cognitive neuroscience

and neuropsychiatry (Roelfsema and Treue,2014;Zhou,2014),

which oﬀer valuable mechanistic information for how the

human brain works, and for potential psychiatric vulnerabilities.

One obvious aspect regards similarity of brain organization

between most primate species and humans. Whereas rodent

species with signiﬁcant diﬀerence in brain size have the same

relative size ratio of cortical areas, primate species with larger

brain have higher numbers of associative cortical areas, with

consequent more varieties of intracortical connections leading

to drastic expansions of higher-order functional properties

(Herculano-Houzel,2009,2012;Figure 1). This makes at least

some NHP species optimal models for investigating neural

mechanisms of the human mind.

Further, various neurocognitive mechanisms are common

to humans and monkeys, while diﬀerent in rodents. These

include object recognition capacities, working memory, ﬁne-

grained processes of decision making, the frontal-parietal

processing of visuomotor behavior, the neural basis of

quantiﬁcation skills, the complexity of social learning, and the

interplay between conscious and unconscious processes, just to

nominate a few (Capitanio and Emborg,2008).

Primate experimentation facilitates studies of the functional

properties of single or populations of neurons involved in

behavior grounded on human-speciﬁc bodily plans, and which

contribute to the development of new treatments. Consider for

example, the discovery that electrical stimulation of subcortical

structures alleviates many of the symptoms of Parkinson’s

disease (Collier et al.,2005). These symptoms are linked to the

primate-speciﬁc motor organization and are diﬃcult to observe

in species with diﬀerent sensorimotor characteristics.

Another case regards the discovery of mirror neurons in the

premotor cortex of the macaque monkey (Ferrari and Rizzolatti,

2015), which inspired new experimental hypotheses in Autism

and Schizophrenia, and new therapeutic intervention in patients

e.g., suﬀering of facial paralysis and Mirror-Touch synesthesia

(Banissy et al.,2009;de Hamilton,2013). In all these cases, the

speciﬁc relationship between primate brain structure to bodily

and socially situated functions have been crucial to uncover

mechanisms generalizable to the human mind, paving the way

to critically therapeutic perspectives.

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FIGURE 1

Diagrams illustrating different organization principle between primates (left) and rodents (right) by comparing brain structures of species with

different body weight and brain sizes within respective mammalian order. Colored areas in brain illustrations indicate primary sensory (red for

somatosensory, blue for visual, and yellow for auditory) areas in representative extant primate (left) and rodent (right) species of body (ﬁrst

numbers in brackets) and brain (last numbers in brackets) sizes (adopted and modiﬁed from Krubitzer,2009;Krubitzer and Dooley,2013). Note

the difference in proportion of these primary areas and association areas (in white) in different sized-brain between primates and rodents. (Ref.

color symbols not directly related to the scope of this article, but illustrated in the original ﬁgures: green, motor area; pink, secondary

somatosensory area; light blue, secondary visual area.)

That embodied aspects of human mental functions and

mechanisms can be eﬃciently investigated in NHPs does

not imply that investigating these aspects in other animal

species is not instructive. For example, mirror neurons have

also been inquired about in rodents (Viaro et al.,2021) and

birds (Mooney,2014;Tramacere et al.,2019) and linked to

respectively manual and vocal behavior. While the comparative

approach in neuroscience is fruitful to inquire into the

biological bases of cognitive variations, it does not dispense of

the lack from primate experimentation. Rather, cross-species

comparison between non-primate species and humans requires

also analyzing the NHP brain connected to primate-speciﬁc

evolutionary variations in embodied and socio-ecologically

situated cognition and behavior.

From an anatomical point of view, primates possess

homologous bodily structures with humans making easier to

analyze certain functions related to posture, facial expression,

gaze, and manual gestures, which result from the use of the

body in interaction with the physical and social environment.

Consequently, the morphological commonalities also allow to

inquire the role of environmental and social interactions in the

emergence of cognitive functions and dysfunctions (Chang et al.,

2013).

Behaviors such as manual dexterity and tool-use (Iriki,

2006), communication based on the mobility of facial expression

(Tramacere and Ferrari,2016), important aspects of social and

individual cognition (O’Connell and Dunbar,2005;Dunbar,

2009), the mechanisms of attention and visuomotor behavior

(Rizzolatti et al.,2001;Peeters et al.,2009;Yang et al.,2016) are

diﬀerent among primate and non-primate animals.

Further, from a molecular genetic standpoint, the

phylogenetic proximity of humans and NHPs give more

guarantees that they will share more speciﬁc genetic

mechanisms involved in neurophysiology, behavior, and

susceptibility to disease. As NHPs and humans are part of

the same phylogenetic lineage, NHPs have largely shared

gene maps, over other mammalian orders, and therefore can

contribute to analyze complex gene-gene or gene-environment

interactions at the basis of human neurophysiological processes

(Rogers and Gibbs,2014).

To conclude this analysis with a further example, consider a

recent study from Yoshida et al. (2016) with macaque monkeys.

The authors serendipitously noticed that one individual of the

primate group presented a set of behavioral manifestations

that were consistent with autistic-like phenotype in human

beings. These manifestations included primate speciﬁc aﬀective

behavior, such as lack of grooming and facial interactions, and

presence of nail-biting stereotypes.

Although grooming in human beings vary across cultures

(Jaeggi et al.,2017), reciprocal cleaning practices, together

with facial exchanges and stress-related nail biting are primate

(including human)-speciﬁc behaviors that cannot be observed

in animal species with diﬀerent bodily and socio-environmental

components. We take this study as an example to suggest that

the primate model is important to understand the emergence of

cognitive mechanisms and functions that are common to human

and NHPs and illustrate how they are involved in the emergence

of psychiatric conditions.

Note however that NHP experimentations have

disadvantages in cognitive neuroscience and neuropsychiatry.

NHPs are larger than laboratory rodents, thus experiencing

discomfort when living in cages, especially because social

interactions and active exploration of the environment are

essential to their development and psychological wellbeing

(Conlee and Rowan,2012). Further, as previously mentioned,

NHP experimentation produce concerns from an ethical point

of view, because of evidence that primate species experience

suﬀering in a similar way to humans.

Among the disadvantages of primate experimentation,

technical challenges must also be considered. Not all

investigative tools are easily utilized in the NHP models. For

example, optogenetics, a genetically coded channel technique

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that allows high temporal and spatial resolution of cortical and

cerebellar brain circuits, have faced a slow progress in NHPs

(Galvan et al.,2018). The same is true for other techniques,

such as for example chemogenetics (Raper and Galvan,2022),

and transgenic tools (Coors et al.,2010), which are thought to

produce unacceptable suﬀering and pragmatic diﬃculties in

monkeys.

In the next sections, we will capitalize on the pros and cons

of primate and rodent research to propose a novel strategy

of primate experimentation that can increase productive

exchanges between experimental sub-ﬁelds conducted with

diﬀerent animal models.

Optimizing cognitive neuroscience

research with animal models

Research on animal models depends on many factors, such

as the nature of the questions and the characteristics of the

species. However, based on the pros and cons of rodent and

primate models brieﬂy depicted thus far, some generalizations

are possible. By considering both characteristics of the models

and of the current practices of research, rodent and primate

research can serve diﬀerent (and perhaps complementary) aims

in neuroscience and neuropsychiatry.

Many primate species share analogous principles of brain

organization with humans, homologous body plan and similar

rules of interactions between social and biological (i.e., genetic)

factors. Further, human psychological and cognitive traits, and

vulnerability to disorders, result from human evolutionary

history, and are conditioned upon the complexity of the

environmental and social world. The potential of primate

research, and the limitation of rodent experimentation, thus

critically depend on the importance of the ecological, embodied,

and situated aspects in the development of the human mind.

When the overarching goal is to understand the basic

mechanisms of the human mind and the target of research

is primate-speciﬁc neurocognitive factors, NHPs are likely

to be optimal candidates for cognitive neuroscience and

neuropsychiatry. In the perspective of a basic, pre-clinical and

clinical neuroscience which must take into consideration the

social, bodily, and environmental context of brain development

and function, research in NHP is going to be going to provide

information that are not possible to achieve through rodents.

Research with rodents (and eventually with other non-

mammals) can be used to inquire into conserved evolutionary

mechanisms or convergent functions that are realized through

instantiation of diﬀerent brain mechanisms. In addition, based

on the genetic, anatomical and socio-ecological similarity

between human and certain NHP species, NHPs shall be

investigated in a way that is deeply embedded in and integrated

with NHPs’ naturalistic settings, to inquire into the primate

brain and behavior in an ecologically, longitudinally, and

socially valid approach.

Experimentation of NHPs in naturalistic settings is currently

an underdeveloped ﬁeld of research, which may ﬁll existing

gaps between classical lab research in neuroscience and wildlife

investigations, where these gaps can be deﬁned as a lack of

harmonization and systematic exchanges between respective

research sub-ﬁelds (Figure 2A). Laboratory neuroscience, as

a branch of the biomedical ﬁeld, normally tries to identify

reproducible and generalizable causal brain mechanisms, by

decomposing structurally or functionally the target mental

phenomena through controlled conditions. In contrast, wildlife

studies rely on inquiring into the diversity and individual

uniqueness of animal lives in natural environments, through

descriptive observations of their behavior without intervention.

The laboratory and wildlife approaches retain important

diﬀerences also at the ethical level (see Figure 3A and

Box 1). Whereas laboratory statistically controlled conditions

are instrumental to the quality of research practices, they also

automatically imply that animals are subjected to them. These

conditions include isolation from peers and deprivation of social

interactions, living in captivity, research training with repetitive

behaviors which are often not intrinsically rewarding, and so

forth. In contrast, naturalistic and often descriptive observations

of animal behavior normally require no intervention and

operate easily by respecting animal welfare.

We think that in between the gaps at the ethical and research

level resides a strategic potential to integrate relevant research

ﬁelds through primate experimentation. Speciﬁcally, we propose

Natural primate labs as a combination of open and enclosed

spaces, where NHP populations can live in group and move

freely in a setting of (or resembling) their natural habitat.

These spaces would be open to the use of non-invasive or

minimally invasive methods of brain, behavioral and bodily

markers investigation.

The aim of these Natural Labs is to capitalize on the

descriptive approach of wildlife studies, by focused observations

of NHP behavior in naturalistic conditions (Figure 3B). At the

same time, the mechanistic approach to speciﬁc NHP cognitive

functions through the use of brain techniques can allow holding

some of the beneﬁts of the laboratory approach. These two

elements (descriptive and mechanistic) may put primate Natural

Labs in a fruitful communication with the traditionally opposite

frameworks of wildlife and laboratory research (Figure 3C).

Primate Natural Labs can allow to fruitfully connect

diﬀerent research approaches through the use of a range of

techniques to investigate primate brain, behavioral and bodily

manifestations (which we will describe in the next section).

The combination and ﬂexible integration of novel strategies of

primate experimentation in Natural Labs becomes even more

critical if we consider that, when released into naturalistic

environment, animal models start exhibiting much richer and

more complex behaviors than in cages [see for example, the

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FIGURE 2

Through the implementation of the Natural Laboratory Complex by the present proposal, it may be possible to increment exchanges between

different research ﬁelds. (A) Schematic representation of current research situation, depicting three sub-ﬁelds of primate research: wildlife

studies, laboratory experimentations (on the left), and non-primate animal model reduced experimentations, rodents or otherwise (on the right).

Communication and exchange between these three components are not systematic and left to personal exchanges among individual

researchers. (B) “Natural Laboratories Complexes” can provide bridges between existing experimental sub-ﬁelds. Speciﬁcally, investigation of

behavior, biological samples and brain activity in Natural Labs can be instrumental to (a) design classical laboratory experiments under

controlled conditions, which can inform additional experimental designs in Natural Labs; (b,c) investigate analogous mechanisms in primate and

non-primate animal models to identify potential conserved functions, and use results of these experiments to inform analysis and models

related to ﬁndings obtained in Natural Labs.

documentary of Berdoy (2017)] (Bottom et al.,2020). Therefore,

quantitative comparisons between free-moving and captive

primate and non-primate animals, could inform focus on

appropriate target mechanisms of behavior.

Finally, NHP experimentation needs to be adjusted for

a broad range of neuroscience investigation, that could

complement the research that is already done in laboratories

with human, primate, and rodents, and in the wild with

primates. This is where the integration with classical

laboratory research, in both primate and non-primate

models, become important and can pave the way to the

investigation of phenomena that could not be displaced in

classical research settings.

Novel strategies for primate

experimentation

Because in Natural Labs primates live freely in naturalistic

spaces, the realization of these structures could allow for the

collection of data in a multimodal, longitudinal, and ecological

perspective, leading to analysis of various types of behaviors and

their underlying neurobiological mechanisms.

In this settings, close collaboration with husbandry and

research personnel as equal partners is important to conduct

breadth of studies from observational ones (to observe and

record animals’ behavioral manifestations) to neurocognitive

investigations (to approach animals and perform cognitive,

neural and biological examinations), because animal hosted

in these structures need appropriate cleaning, space and

nutrition measures. Therefore, husbandry eﬀorts to secure

behavioral manifestations will necessarily become continuous

with research practices, and research endeavor will become a

part of husbandry, thus equally amalgamating both sectors.

The idea of making husbandry continuous with research

eﬀorts is partly similar to what William Conway called

“interactive management” of zoos and natural habitats (Conway,

1995). Conway deﬁned interactive management as a strategy

for both species and habitat preservation that relies upon

the coordination of species living both in a combination of

natural and artiﬁcial settings. Interactive managements usually

combine the resources of wildlife managers with those of

biologists working in zoos to ensure that animal individuals

are provided with opportune conditions, and do not suﬀer for

abrupt environmental or habitat changes.

Our proposal of a novel strategy for primate research in the

wild or in natural-like settings has a diﬀerent aim but rely on a

similar rationale, because primate species in Natural Labs shall

live in mixed natural-artiﬁcial conditions for research purposes,

and not for conservation eﬀorts per se. Although the type of

primate research that we are proposing can lead to conservation

advantages (which we will touch upon later), it primarily

concerns an ethically and pragmatically more sustainable way to

conduct neurobiological and ethological research on our closest

relatives (also see Box 2).

Someone could object that close collaboration between

husbandry and research personnel as equal partners might be

diﬃcult. This is because, in the existing animal experimentation

contexts, conventionally trained researchers do not directly take

care of the practical needs of their animal models, and animal

care taking staﬀs are normally neutral about the scopes of the

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FIGURE 3

Comparative representation of ethical and experimental frameworks in various domains of animal research, along progressive development of

interactions among multiple sectors (see Box 1 text for further explanations).

BOX 1 Harmonization of ethical and research gaps.

Animal welfare and human beneﬁt are in opposition depending on the ﬁeld of research. Diﬀerent ﬁelds often require diﬀerent approaches to animal

rights and welfare.

Figure 3A illustrates separation of methodologies between the existing biomedical (orange circle; middle) and the wildlife studies (blue circle; top). Gaps exist

between these studies (blue arrow), because biomedicine maximizes human beneﬁts, while wildlife studies are more respectful of primate welfare. Therefore, large

eﬀorts are put to balance and compromise between animal welfare and human beneﬁt with ethic regulations and guidelines, which consider harm-beneﬁt trade oﬀ

and 3Rs (replacement, reduction, and reﬁnement) to minimize suﬀering of laboratory animals. This situation changes once cognitive neuroscience and

neuropsychiatric research (pink circle; middle) comes to interplay (Figure 3B), because it can lead to bridging wildlife (blue circle; top) and biomedical (orange

circle; bottom) studies.

By implementing primate research in naturalistic settings (green circle; with similarity with domesticated and working animals, i.e., nursing, companion,

assistance, guide-animals, etc.; and conditions), the open ﬁeld of primate cognitive neuroscience and neuropsychiatric research (Natural Labs) emerges to be

carried out at the intersection of the existing research sub-ﬁelds (Figure 3C). Here, the use of a variety of novel (minimally invasive) techniques can grant the

mechanistic approach of biomedical research, while primates living in natural settings can beneﬁt of conditions that are normally proper to descriptive wildlife

studies. In this way, neuroscience research in Natural Labs overlaps with both formerly separated wildlife and biomedical research, and reduces the “gap” between

animal welfare and human beneﬁt. Through Natural Labs, former polarizations between primate and human welfare, and mechanist and descriptive approaches

become continuous. The application of new technology, subserving this new ﬁeld can aﬀect also the other ﬁeld of research to trigger a novel (methodological and

ethical) paradigm.

experiments, perhaps in order to avoid any implicit bias to aﬀect

on the scientiﬁc research outcomes using laboratory animals.

Coordinating the collaboration between husbandry and

research sectors requires focused reﬂection and dedicated

strategies, that go beyond the scope of this article. We would

like to provide however one potential clue. In order to secure

husbandry eﬀorts for behavioral manifestations as a portion

of research, and of research activities comprising a part of

husbandry, strategies could be extrapolated from the mode of

human commitments in collaborations with working animals

(i.e., nursing, companion, assistance, guide-animals, etc.) in

which caretaking and behavior analyses/control is undertaken as

an integrated endeavor, in an environment somewhat resembles

the laboratory conditions.

Natural laboratory complex

In order to realize the proposed research strategies,

studies should be designed to be conducted in structures

comprising ﬁeld sites in natural settings (in situ Lab-in-Nature)

and laboratories resembling primate natural habitats (ex situ

Nature-in-Lab), both of which are equipped with advanced

technologies appropriate to observe and investigate NHPs’

brain, biology and behaviors. We describe the technologies that

could be used in the Natural Laboratory Complex, together with

how they could balance cost and beneﬁts trade-oﬀs at the ethical

and economic level.

In situ Lab-in-Nature

Various types of technologies could be used in Natural

Labs to investigate primate neurobiological and behavioral

functions. Here, we elaborate on some examples to oﬀer

ideas of how these indoor-outdoor research space could be

technically organized.

Firstly, a few deep learning algorithm techniques, each

tailored to the research question, can be employed to estimate

behavioral poses in monkeys interacting in the social group or

during speciﬁc tasks (Nath et al.,2019;Lauer et al.,2022). These

data could be integrated with ﬁne-grained behavioral analysis

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BOX 2 Rationale and examples of Natural Labs.

The concept of Natural Labs relies on the awareness that the traditional view of protecting animals by letting them live in a vast self-sustaining “wild” need to be

rethought. We must begin to face the reality of a world that is and will remain vastly altered by human activities. Consequently, taking actions for ensuring that

many more wildlife communities can survive if they are intensively cared as a form of “megazoos” (Conway,1995) could be more eﬃcient than being stacked in

searching a wildlife for animals untouched from human intervention. The interactive management proposal is thus a wide way for zoos, working with local

communities to support the survival of species under risk of extinction.

The idea of Natural Labs for primate experimentation can be framed in this perspective. One obvious example of Natural Labs is the primate bio-park. They are

zoo-like spaces for hosting various species of NHPs, and where it is possible to collect multiple socio-behavioral, neural, and molecular information associated to

cognitive phenomena in a longitudinal perspective, and in accordance with the application of novel technologies. NHP populations hosted in these bio-parks

mimic natural population living in the wild and constitute a natural source of variability that may be critical for achieving mechanist models of cognitive and

behavioral development.

The most similar examples of bio-parks we are here illustrating can be found in the Pongoland Wolfgang Köhler Primate Research Center, which operates in

collaboration with the Leipzig zoo, or in The Apenheul Primate Park in the Netherlands. Both of them are zoos where visitors can see and interact with diﬀerent

species of primates, but they also house a research center, where diﬀerent types of investigations are conducted. To make these bio-parks more similar to our

proposal, they should be equipped with technologies for experimenters to inquire the primate neurobiology beyond the observation of behavioral aspects.

Incidentally, genetic biodiversity in these parks may be guaranteed through periodic assisted reproduction in females, or through migration of male or female

specimens, in accordance with the sexual behavior of the considered species.

Another form of Natural Labs would require that scientists conduct research in the primate natural environment. This would require the establishment of what

has been called hotel space next to primate natural environment, where visiting researchers can carry out various types of experiments. Telecommuting approaches

may be utilized to share information with scientists on site (Jennings et al.,2016).

We are referring to the types of novel technologies that allow the storage and transfer of information in real-time, such as Internet of things (i.e., a new paradigm

in modern wireless telecommunication) (Atzori et al.,2010), IT based knowledge management (i.e., information technology system to enhance and organize

knowledge) (Alavi and Leidner,1999), and cloud-based Big Data processing for allowing cost-eﬃcient exploration for voluminous data set (Fang et al.,2015).

Alternatively, scientists could utilize telecommunication technologies (i.e., remote labs) from a separate geographical location, to remotely conduct real

experiments at the physical location of the operating technology (Quesada-González and Merkoçi,2017).

The rationale of the hotel space with remote technologies can be appealing also to investigate the number of NHP individuals living wildly or semi-wildly in

countries, such as Japan, Singapore or anywhere close to primates’ natural habitat. In Japan, for example, several monkey parks are spread throughout the territory

and are open to visitors. In Singapore, although not speciﬁcally for primates, there are many Safaris where animals live in wild-like environment and are managed

by caretakers under international standards of animal welfare. These animals can constitute a further source for studying inter-individual variability at the

behavioral level, and analyzing various biological samples (e.g., from the feces to the blood or the buccal mucosa).

in socio-environmental set-ups (Nishikawa and Kinjo,2018),

allowing investigation of previously unavailable ecological

variations.

Fully non-invasive AI (artiﬁcial intelligence)-based motion

capture of monkeys in the wild, deriving VR (virtual reality)

and IT (internet technologies) for sharing and analyses of those

motion data may be important technologies for integrative

neuroscience investigations of in situ Lab-in-Nature. The social

or individual behavior of primates could be recorded and

analyzed by ﬁxed-point live digital cameras installed at the

ﬁeld site and subjected to AI-based motion capture and

3D reconstruction using online deep transfer learning-based

automated motion analysis technologies (Nath et al.,2019;Lauer

et al.,2022).

Non-human primate behavioral datasets could be

embedded (as avatars) in digitized environmental information

(i.e., laser-scanned landscape, vegetation, meteorological

conditions by remote-sensing devices, etc.) using VR

technologies to comprise “Real-time 3D Digital Zoo”

accessible to world-wide academic professionals for

research purposes through IT-based cloud technologies,

which have achieved prevalent development under current

COVID-19 restrictions of inter-regional traﬃcs. This set

of technologies could contribute to organize eﬀective

and eﬃcient international collaborations to fully utilize

this opportunity.

In addition, molecular biological information of subject

NHPs in the natural environment (i.e., population genomics,

epigenetics, microbiome, nutrition isotope, etc.) can be

collected, and correlated with above in situ socio-behavioral

characteristics of individual animals, to tracking mechanisms

of ecological and social variations. Patterns of molecular

expression can be measured through the analysis of a variety

of discharged bio-samples (feces, saliva, and hair) (Sawaswong

et al.,2020), or of exhalation by laser spectroscopy (Selvaraj

et al.,2020). Close collaborations with researchers and local

personnel (such as staﬀs of natural parks at NHP habitat)

to design the observation system and sample collection,

as well as to maintain and operate sensing devices at

the ﬁled sites are mandatory to make this infrastructure

functional.

Finally, at the physiological and neural levels, a number

of novel tools can be used. For example, ultra-thin ﬁlm bio-

sensors attached to the body surface (Nishinaka et al.,2021)

and a number of emerging technologies allowing measurements

of brain activities through embedded wireless multi-electrode

and electrocorticography techniques (Matsuo et al.,2011;Ando

et al.,2016) or miniature PET (positron emission tomography)

technologies (Schulz et al.,2011) could be utilized. Although

these investigations would only oﬀer correlational information

and not controlled causal pathways, a number of dynamical

networks techniques (Bramson et al.,2019;Aihara et al.,

2022) can be applied to detect plausibility of multi-level causal

pathways (Stokes and Purdon,2017).

The hypothesized causal pathways between variables

obtained in Natural Labs at multiple level of analysis (from

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behavioral to molecular) can be useful to design controlled

experiments in captivity with primates that are hosted under

traditional laboratory facilities (Figure 2Ba). In addition, basic

elements of these pathways can be investigated under traditional

laboratory settings in non-primate animal models, with the

goal of inquiring into potential conserved mechanisms present

across species (Figure 2Bb,c). In this way, Natural Labs

(with both in situ- and ex situ-, to be depicted below) can

constitute a bridgehead between classical laboratory and wildlife

research approaches (Figure 2B): the multilevel investigations

executed on primate groups in natural(istic) settings would

provide results and ﬁndings to inquire into NHP and non-

primate models under controlled conditions in classical captive

experiments.

Ex situ Nature-in-Lab

Above in situ Lab-in-Nature is not adapted for neuroscience

experimental interventions. A compatible and complementary

laboratory setup that simulates (perhaps by being located

close to) natural environment and house minimal numbers

of NHPs (namely, ex situ Nature-in-Lab) could be established

to allow longitudinal scientiﬁc investigations with minimally

invasive neuroscience techniques. In ex situ Nature-in-

Lab, scientists can study the mechanistic basis of various

cognitive functions; perform, along the developmental

lifespan of the primate individuals large-scale genetic,

epigenetic and metabolite screens; interrogate circuit-level

processes of mental functions; and keep tracking of the

social behavior of various individuals constituting a primate

population group.

In ex situ Nature-in-Lab, scientists can collect a large

number of heterogeneous data and conduct analysis of

multilevel information (from genetic proﬁle to neuronal

circuitry, to social behavior), through large-scale investigation

of brain, body, cognitive, and behavioral traits. This has the

potential to enable systematic characterization of molecular,

cellular and circuit-level landscapes of the primate brain and

behavior across development and context.

Similar research settings have been utilized in the last

decades for testing primate cognitive and behavioral abilities

through Computerized Test Systems, which allow animals

to live with their social group and to enter some test

stations at some time points of the day (Perdue et al.,2018).

However, experimental tests in these spaces rarely include

neural and molecular investigations; cognitive, neural, and

genetic analyses mostly pertain to diﬀerent laboratories that

study biological or imaging samples. In contrast, Natural Labs

should be intended as spaces where it is possible to train

novel, minimally invasive techniques in complex environments,

with the aim to collect information that are not possible

to obtain in classical laboratory settings, therefore factually

being a step forward in the type of information available for

research.

Again, like in situ Lab-in-Nature, close collaboration with

researchers and husbandry personnel is important to promote

maximum scientiﬁc potential of the ex situ Nature-in-Lab. That

is, ways to maintain colony in this setup is a part of experimental

design and collecting quality scientiﬁc data can be completed

through daily husbandry activities. Also, collected data could be

made accessible real-time on-line, via internet, from laboratories

located remotely world-wide in which scientists are interested in

further analyses of their interest. Hotel space might be associated

with ex situ Nature-in-Lab for occasional site visits for such

remote scientists whenever physical activities are required on

site, and perhaps also to make comparative investigations in

relation to closely located complementary in situ Lab-in-Nature

(Tramacere and Iriki,2021).

Natural Labs with novel technologies would become world’s

hub of laboratories conducting novel research paradigms. In

order for such Natural Labs to become a bridgehead between

diﬀerent research approaches, conceptual foundations need

to be established to defend following criticisms from mind-

sets of current experimental paradigms. Objections could

range from lack of experimental sessions, lack of reproducible

results under strictly controlled conditions (e.g., ﬁxed head

recordings with operantly conditioned tasks in identical

experimental environment), or diﬃculties for applying methods

to record neural activity. Importantly however, the present

proposal does not aim to completely substitute, but to initially

complement existing primate laboratory research. Therefore,

neuroscientists can still have the possibilities to conduct primate

experimentation in a classical laboratory setting when it is

necessary to do so.

On the other hand, classically positioned primatologists

may object that is aberrant to violate the life of the animals

hosted in semi-natural environments or in the wild. We

agree this is a fundamental issue that needs to be addressed

through careful discussions. It seems obvious, however, that

only a limited number of observations and experiments should

be made possible in NHPs living in natural conditions,

carefully considering only measures for minimal invasiveness

and disturbance, which are very much in accordance with the

widely accepted welfare rules in primates.

In the next section, we will delve deeper in the cost-beneﬁt

trade-oﬀ that this novel strategy of primate experimentation

would require, both at the ethic and scientiﬁc level.

Harmonization of cost and beneﬁt

trade-offs

Ethical balance

Natural Laboratory Complex (combinations of ex situ and

in situ Natural Labs) fulﬁlls current ethical standards (CIOMS-

ICLAS,2015) but also provide increased ethical conditions

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for primates. This is because, on our proposal, researchers of

in situ Lab-in-Nature would team up with wild-life conservation

sectors, and of ex situ Nature-in-Lab work together with

husbandry team, to ensure obtained data to represent primates’

ecological characteristics, whereby incorporate into extant

animal experimentation frameworks (Figure 3) has embedded

within it the means to merge formerly segregated wildlife and

laboratory research.

From a strictly primate welfare perspective, housing NHPs

in natural-like environments, such as ex situ Nature-in-Lab,

would relief at least some of them from most of the current

costs they are paying for neurobiological research, such as

being removed and bread distant from their natural and social

environment, transported, and subjected to the living conditions

of the facilities.

This proposal would be suitable only for the primates

subjected to neurobiology studies in the labs, which utilize

about the 19% of the total of NHP used in research (Carlsson

et al.,2004). However, its potential beneﬁts should not be

underestimated. In fact, according to the report of United

States Department of Agriculture 2017, a consistent number of

primates are held by facilities but not used in any experimental

protocols (Grimm,2020).

This would imply that a minor number of NHPs could be

housed in facilities in the future for the scope of behavioral

and neurobiological research and produce a situation in which

it would be humans who move to study primates, instead

to move primates in order to be studied by humans. This

is in line with an interpretation of welfare, which not only

aims to avoid or minimize pain and adverse eﬀects, but

also to maximize well-being, through the implementation

of environmental enrichment and the promotion of positive

elements of comfort and security.

Another beneﬁt of the Natural Labs proposal would

derive from its possible eﬀects in terms of primate welfare

and conservation. According to our proposal, research

infrastructures would be established in the wild (in situ Lab-in-

Nature) and would provide a research basis for neuroscientists

and molecular biologists, other than for classical primatologists.

Implementing Natural Labs would thus have the consequence

to increase the amount of ﬁeld research, and the amount of

information related to primate individuals who live in the

wild that can be utilized for scopes that could beneﬁt primate

welfare in the wild.

Speciﬁcally, monitoring the conditions and changes of

primates living in the wild may have positive inﬂuences on the

enterprise associated to wildlife conservation and protection

against extinction risks. Because of the documented sudden

leaps in aberrant ecosystem behavior, wild populations of

NHPs become increasingly susceptible to stochastic genetic,

demographic changes, new infectious diseases, and destructive

infestations of invasive insects. A detailed understanding of

animal biology, ecology, life history, behavior, habitat needs,

evolutionary ﬂexibility, and phenotypic plasticity is necessary

for promoting their conservation, and preventing extinction

dangers (Estrada et al.,2017).

The protection of non-human life and ecological processes

necessarily pass through an opportune knowledge of animal

and habitat conditions. Therefore, large-scale molecular and

behavioral analyses in wildlife through the establishment of

research infrastructure can be utilized for tracking extinction

dangerous in primate species, their level of distress and other

indicators of wellness (Paquet and Darimont,2010). In addition,

by inquiring more in details NHP wildlife behavior, through

focus observations or the use of tissue-sample analysis, it is also

possible to acquire information that are critical for reproducing

naturalistic settings for NHP living in natural parks. Knowledge

of the behavior of the animals in the wild it is in fact critical

to understand their needs and necessity while they live in semi-

natural environments.

Non-human primate living in naturalistic settings

may further oﬀer the possibility to investigate a range of

naturally occurring dysfunctions in NHPs. In fact, primates

show inter-individual variability and diﬀerential susceptibility

to mental diseases, which can be inquired in order to understand

cognitive mechanisms and functions. An example regards the

spontaneous development of autistic- or depressive-like

phenotype in macaque monkeys (Yoshida et al.,2016). When

sample sizes are suﬃcient, the observation of social behavior

in monkeys is likely to be useful in latent variable models

that combine indicators of various psychopathologies across

multiple levels of analysis (Maestripieri and Lilienfeld,2016).

These cases may constitute precious source of information

for biomedical research through medical device testing, drug

development and imaging technique reﬁnement.

Socioeconomic balance

Natural Labs might appear costly and hinder continue

running on-going experimentations under currently existing

academic funding schemes. However, introduction of latest

AI, IT, and VR technologies (see section “Natural laboratory

complex”) oﬀer Natural Labs an opportunity for collaborations

with various research sectors, including non-academic

sectors, such as various industries and regional economy,

to attain autonomous ﬁnancial foundations for its shared and

mutual beneﬁts still yet securing academic independence of

research communities.

Such models could include “Real-time 3D Digital Zoo”

in entertainment businesses, or the one by governmental

supports allowing visitors to the educational programs to be

settled in the Natural Labs within a traditional zoo/safari

perspective (see also Box 3 for potential schemes of cross-sector

collaborations). Hence, these self-supported Natural Labs would

enable researchers in countries far from NHP natural habitat,

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BOX 3 Development of sustainable business–academia–government collaborations.

Biodiversity education for the Natural Lab’s local site population is paramount to preserve the natural equilibrium of native ecosystems with tourism providing cash

input. Online interactive datasets could be created to construct a “Real-time 3D Digital Zoo” as an ex situ global research center located adjacent to the Natural

Labs. Technological development for this research will contribute to environmental protection with future proﬁtability. Data comprising “Real-time 3D Digital

Cloud Zoo” will be shared between the scientiﬁc community and various business models.

A novel neurobiological principle established through the Natural Labs characterizes human gene-culture co-evolution through environmental interactions.

Novel non-invasive technologies (perhaps AI and VR-based) developed through these studies will fulﬁll the requirements of primate research ethics and wildlife

conservation. This will also emphasize how humanity can evolve as a part of holistic ecosystems and allow us to envision how our biodiversity should be developed

in the future within this ever-changing world.

This research setup can immediately detect “skeleton” behaviors of monkeys for motion analyses, together with rough geometry of the landscape for interactions

with the environment at each Natural Labs site. While this data will comprise core information to establish the “Digital Cloud Zoo,” it would be ideal if supports by

businesses and industries to create further sophisticated appearances of the animals and landscape suitable for exhibition to the public. Also, initial setup is limited

to only a small part of the nature for research, and thereafter industry and government-supported collection of data covering larger areas of the local natural habitat

will promote more systematic and wider range of knowledge eventually contribute to preservation of the species across the habitat.

Extension of these scheme desires to create mechanisms that reveal basic data and share ﬁndings with the worldwide research community (this is of particular

importance to establish novel global ethical standards for primate research that contribute to future studies for human mental welfare). Procedures enabling this

research-oriented “Digital Cloud Zoo” will share common IT and cloud technologies for exhibition at museums run by local governments, which can further

promote this research through entertainment and businesses that can reach global audiences.

Thus, it would be ideal to institute mechanisms that are equally beneﬁcial for research, government, and industry/business partners. This could be in turn

contribute to scheme governmental policies to plan a new strategy that will include ecotourism and employment of local people to serve as a natural resource for

the local countries.

with minimal expenses for participation, to access data remotely

at home laboratories, and hotel space at Natural Labs oﬀers

conductive possibilities for studying various natural behaviors

of NHPs on site.

Another beneﬁt of this approach is related to those countries

endowed with natural habitats for NHP, such as Japan, India, or

Southeast Asian countries, which suﬀer from increasing conﬂict

between humans and feral monkeys over the last several decades

(Dittus,2012). NHPs become pests because they pilfer food and

water near human habitation. Artiﬁcial feeding leads to changes

in monkey behavior, resulting in overpopulation of aggressive

monkeys. Exterminating a large number of these monkeys is

unethical according to religious beliefs, and also according to

the welfare standards developed in several countries.

Further, castration and trans-location practices are overly

expensive and laborious because they require specialized

personnel and long-lasting procedures. In Japan, for example,

several monkey parks are spread throughout the territory and

are open to visitors. In Singapore, although not speciﬁcally

for primates, there are many Safaris where animals live

in wild-like environment and are managed by caretakers

under international standards of animal welfare. Revenues to

Natural Labs from above business models could create similar

mechanisms for social visiting and education beneﬁts, and

these animals can constitute a further source for studying

inter-individual variability at the behavioral level and analyzing

various biological samples.

Legal balance

A novel factor of the present proposal of Natural Labs which

requires additional consideration is the management of the

data acquired here are shared globally across multiple parties

under having potential conﬂict of interest. This is an essential

requisite due to its geographically biased natural distribution

of NHPs by ecological limitation, which is complemented by

web-based international data sharing among various sectors.

While such situation secures transparencies to fulﬁll ethical

and scientiﬁc standards of subjected experimentations, at the

same time risks protection of intellectual properties, originality

and privacy of ideas that might belong to parties (individuals,

groups, institutions, nations, etc.) who participate in the project.

Rules to legally harmonize conﬂicting interests among

such parties yet need to be established [Iriki quoted by Marx

(2016)]. Such harmonization should include legal measures of,

(a) how to ensure priority of shared data among international

academic members across borders of national sovereignty

and security, (b) how to protect intellectual properties, if

any emerged, upon data sharing among industry, academia,

and other relevant sectors, (c) how to manage, or restrict,

balances between scientiﬁc accuracy/signiﬁcance and public

stakeholders’ interests/perception especially when related with

socioeconomical aspects or public policies. Considering novel

aspects of presently proposed Natural Labs paradigms, we

just exemplify these, among many other potential issues, for

future considerations to be incorporated into international

public policy frameworks, in addition to digital technologies

for managing general security of data transferred via internet

environments.

Conclusion

We have proposed novel strategies for primate

experimentation with potential ethical, scientiﬁc, and economic

beneﬁts. Speciﬁcally, we have proposed the establishment of

Natural Labs, as combination of indoor-outdoor structures

where to conduct cognitive neuroscience investigation in

naturalistic environments with various species of monkeys.

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Natural Labs are thought to studying various aspects of

mind, body, and behavior in the primates, where the goal is

generalization of this knowledge to understand the mechanistic

bases of human mental functions and vulnerability to disorders.

Research in primate Natural Labs may be beneﬁcial for (1)

enhancing scientiﬁc validity, through the study of the embodied

and socially situated aspects of mental functions in primates,

in longitudinal fashion and ecological settings, (2) providing

naturalistic settings and wild-like environment for primates,

thus increasing primate welfare, (3) reducing the monkey-

human conﬂict in areas where monkeys are becoming pest

and allowing data collection that can be instrumental to

primate conservation.

This proposed novel strategy of primate experimentation

is of particular importance for understanding mechanisms of

human mind, in its functional and dysfunctional manifestation,

because human beings are tropical primates and have expanded

their habitat by explosive mental development (without physical

changes) in the last tens of thousands of years (Iriki et al.,

2021).

Although the realization of Natural Labs is in accordance

with current ethical framework, it subtly incentivizes an

enrichment of the current understanding of animal ethics.

Natural Labs can enrich primate welfare with a novel

perspective: primates have the potential for living and/or

interacting collaboratively with humans and exchange needs

and requirements with them. This species diﬀerences aﬀect the

relationship we can establish with and the value we assign to

them: beyond the protection of primates according to their

capacity to experience pain, the approach of Natural Labs would

actively increase primate welfare.

Realizing Natural Labs for primate research and

implement correlated investigative practices could require the

establishment of updated ethical guidelines, which can regulate

from the one hand, the interactions between human and NHPs,

and from the other hand, rules and regulations between various

research centers, laboratories and researchers. Although the aim

of this manuscript is not to propose these guidelines but to

generate discussion, we hope that this perspective can constitute

a fruitful addition for achieving further progress in primate

experimentation and welfare.

Author contributions

AI and AT contributed to conception and design of the

study. Both authors contributed to manuscript revision, read,

and approved the submitted version.

Conﬂict of interest

The authors declare that the research was conducted in the

absence of any commercial or ﬁnancial relationships that could

be construed as a potential conﬂict of interest.

Publisher’s note

All claims expressed in this article are solely those of the

authors and do not necessarily represent those of their aﬃliated

organizations, or those of the publisher, the editors and the

reviewers. Any product that may be evaluated in this article, or

claim that may be made by its manufacturer, is not guaranteed

or endorsed by the publisher.

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Aug 2021
CURR BIOL

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May 2020
MOLECULES

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Dec 2020

Abstract Psychiatric disorders are a prevalent global health problem, over 900 million individuals affected by a continuum of mental and substance use disorders. Due to this high prevalence, and the substantial direct and indirect societal costs, it is essential to understand the underlying mechanisms of these disorders to facilitate development of new and more effective treatments. Since the advent of recombinant DNA technologies in the early 1980s, genetically modified rodent models have significantly contributed to the genetic and molecular basis of psychiatric disorders. Despite significant advancements, many challenges remain after unsuccessful drug development based on rodent models. Recent human genetics show the polygenetic nature of mental disorders, identifying hundreds of allelic variants that confer increased risk. However, given the complexity of the brain, with many unique cell types, gene expression profiles, and developmental trajectories, proper animal models are needed more than ever to dissect genes and circuits in a cell type-specific manner to advance our understanding and treatment of psychiatric disorders. In this mini-review, we highlight current challenges and promises of using rodent models in advancing science and drug development, focusing on advanced techniques, and their applications to rodent models of psychiatric disorders.

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Mar 2022
CURR OPIN PHARMACOL

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Article

Aug 2021

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Article

Dec 2020

Organic electrochemical transistors (OECTs) have been widely used for monitoring electrophysiological activities by exploiting advantages such as flexibility, biocompatibility, low‐voltage operation, and high transconductance. Transconductance is a major factor that determines the sensitivity of OECT‐based sensors. In comparison with other field‐effect transistors, the transconductance of OECTs having the poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) channel layer is proportional to the channel thickness because the entire film acts as a channel. Therefore, the formation of a thick channel layer is essential for OECTs. However, it is difficult to form a thick film by spin coating. Herein, we introduce spray coating and successfully form a thick and uniform PEDOT:PSS layer (1.05 µm) by controlling the compressed air pressure and number of coating cycles. Moreover, we fabricated a high‐transconductance (7.5 mS) ultraflexible OECT with a sufficiently rapid response (2.3 kHz). This article is protected by copyright. All rights reserved.

Oral-fecal Mycobiome in Wild and Captive Cynomolgus Macaques (Macaca fascicularis)

Article

Sep 2020
FUNGAL GENET BIOL

Cynomolgus macaque (Macaca fascicularis) is currently a common animal model for biomedical research. The National Primate Research Center of Thailand, Chulalongkorn University (NPRCT-CU) translocated wild-borne macaques to reared colony for research purposes. At present, no studies focus on fungal microbiome (Mycobiome) of this macaque. The functional roles of mycobiome and fungal pathogens have not been elucidated. Thus, this study aimed to investigate and compare oral and fecal mycobiome between wild and captive macaques by using high-throughput sequencing on internal transcribed spacer 2 (ITS2) rDNA. The results showed that the mycobiome of wild macaque has greater alpha diversity. The fecal mycobiome has more limited alpha diversity than those in oral cavity. The community is mainly dominated by saprophytic yeast in Kasachstania genus which is related to aiding metabolic function in gut. The oral microbiome of most captive macaques presented the Cutaneotrichosporon suggesting the fungal transmission through skin-oral contact within the colony. The potential pathogens that would cause harmful transmission in reared colonies were not found in either group of macaques but the pathogen prevention and animal care is still important to be concerned. In conclusion, the results of gut mycobiome analysis in Thai Cynomolgus macaques provide us with the basic information of oral and fecal fungi and for monitoring macaques' health status for animal care of research use.

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