PBPrimate BiologyPBPrimate Biol.2363-4715Copernicus GmbHGöttingen, Germany10.5194/pb-2-111-2015Tree shrews at the German Primate CenterFuchsE.efuchs@gwdg.deGerman Primate Center, Kellnerweg 4, 37077 Göttingen, GermanyE. Fuchs (efuchs@gwdg.de)25September2015211111184August201531August20151September2015This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/This article is available from https://pb.copernicus.org/articles/2/111/2015/pb-2-111-2015.htmlThe full text article is available as a PDF file from https://pb.copernicus.org/articles/2/111/2015/pb-2-111-2015.pdf
For many years, Tupaia (family Tupaiidae), most commonly known as tree
shrews, have been studied almost exclusively by zoologists resulting in a
controversial debate on their taxonomic status among mammals. Today, tree
shrews are placed in the order Scandentia; they are valuable, widely accepted
and increasingly used model animals as an alternative to rodents and
non-human primates in biomedical research. After a brief description on how
tree shrews entered science and their taxonomic odyssey, the present article
describes the history of the tree shrew (Tupaia belangeri) colony at
the German Primate Center and selected aspects of our work with special
emphasis on the psychosocial stress model in these animals.
History and taxonomic odyssey
In a comprehensive survey of the family of Tupaiidae Lyon Jr. (1913) provides
in the first chapters of his article the following historical summary on the
discovery of tree shrews:
Tupaia dissimilis, Pulo Condore. Reproduction of the original Figure of William Ellis'
Sciurus dissimilis, in his natural history journal, written during Captain Cook's third
voyage, 1776–1780; now in the British Museum (Natural History). A scale of
100 mm was laid on the page when the photograph was made. Picture taken from
Lyon Jr. (1913).
The earliest published account of treeshrews is that of Ellis
(1780
Description and colored illustration of Tupaia dissimilis. The description published by Gray (1860), p. 71. A copy of
Ellis's drawing is Fig. 1 of this paper.
, 1782
On p. 340 of Vol. 2 the
tree shrews of Pulo Condore are referred to as squirrels.
), one of the
surgeons of Captain Cook's expedition. On Tuesday or Wednesday, 25th or 26th
of January, 1780, Ellis remarks: “Our sportsmen … having seen only a
few monkeys, squirrels, and a cock and a hen, the latter of which they shot.
According to Linnaeus this island is their native place.” The island
referred to is Pulo Condore, off the coast of Cochin China. The squirrels
mentioned in the account are not squirrels, but Tupaias. One of them was
evidently shot. A rough but very accurate sketch of the animal was made by
Ellis and a Latin diagnosis of it written in his journal. This description of
the animal was published by Gray in 1860
Original publication of
W. Ellis's account of “Sciurus dissimilis” (i.e., Tupaia dissimilis).
. A reproduction of a photograph of Ellis' drawing is here
printed. There can be no doubt from Ellis' picture or description that his
squirrels were Tupaias (see Fig. 1).
Tupaias as such were first brought to the attention of the world by Diard, a
French naturalist, at one time an assistant of
Sir Thomas Stamford Raffles, in November, 1820, under
the designation of Sorex glis (Diard, 1820
The first published account of a tree shrew and original description of Sorex glis (=Tupaia glis glis) from Penang.
).
Six months later, May, 1821, the genus Tupaia was first proposed by
Sir Raffles (1821
Original description of the genus Tupaia
and species ferruginea and tana; remarks on
habits.
), and the species ferruginea and
tana described, the latter in the present paper being made the type
of a new genus.
Specimens of Tupaias had been seen by Europeans several years earlier, and
one even sent to Europe. Geoffroy Saint-Hilaire (1835
Original description of
Tupaia belangeri.
) remarks:
“The discovery of this remarkable group of Insectivores has been attributed
to both M. Diard and Sir Raffles. The fact is that it belongs to neither of
these celebrated travelers, but to Leschenault de la Tour, who had sent in
1807 to the Museum of Paris an individual of the species which has since been
called Tupaia javanica. Nevertheless it is only since 1820 that the
attention of naturalists has called to Tupaias, and that these animals have
really entered the domain of science.
Geoffroy was naturally quite unaware of the existence of Ellis's manuscript
notes and drawings. Since Diard's and Raffles's time the group has become
better and better known and its geographic range widely extended.”
Uncertainties concerning the taxonomic affinities of tree shrews originated
with Ellis' description in which tree shrews were designated “squirrels”, a
confusion that still occasionally persists today. The Malay word tupai is
used for both tree shrews and squirrels (Nowak, 1991). In this context it is
interesting to mention that Tupaia was the name of a legendary leader of the Polynesian
island of Raiatea and a navigator who traveled with Captain Cook's ship
Endeavour acting as the expedition's interpreter
(http://www.bbc.co.uk/history/british/empire_seapower/cook_tupaia_maori_01.shtml).
Thus it remains a matter of discussion whether the generic name is derived
from the Malay word or is a tribute to the Polynesian navigator.
Despite their name, tree shrews have nothing to do with real shrews and most
species of tree shrews are semi-arboreal and usually forage on the ground. In
general, they all are relatively small, agile and omnivorous animals with a
preference for fruits and invertebrates, especially arthropods. Although
there are clear differences between tree shrew species, they share a basic
common pattern that can be described with reference to the well known
Belanger's tree shrew, Tupaia belangeri (Fig. 2). The geographic
distribution of tree shrews extends from India to the Philippines and from
southern China to Java, Borneo, Sumatra, and Bali. Natural habitats are
tropical forests and plantation areas.
Adult male tree shrew (Tupaia belangeri) from the DPZ colony.
For many years, a variety of reports described similarities between tree
shrews and primates, and the conclusion that there was a direct phylogenetic
relationship between tree shrews and primates was predominantly made by Le
Gros Clark (1924), largely on the basis of brain anatomy. His view was
confirmed in Simpson's classification of the mammals (Simpson, 1945). In the
following years, several authors had doubts about this phylogenetic link and,
as a result, excluded tree shrews from primates. An intensive discussion of
tree shrews and their phylogenetic relationships is provided by, for example,
Luckett (1980), Martin (1990) and Emmons (2000). Today, tree shrews are
placed in their own order, Scandentia (see also Knabe and Washausen, 2015).
According to recent molecular phylogenetic studies they are placed together
with primates and Dermoptera within the clade Euarchonta (Kriegs et al.,
2007). In 2008, the Broad Institute provided the first assembly of the genome
of Tupaia belangeri
(http://www.ensembl.org/Tupaia_belangeri/Info/Index). On the basis of
more advanced genome information of the Chinese tree shrew (Tupaia belangeri chinensis), Fan et al. (2013) postulated that tree shrews have a relatively close relationship to
non-human primates. Nevertheless, the long-running debate regarding the
phylogenetic position of the tree shrew within eutherian mammals seems not
fully settled.
The tree shrew colony at the German Primate Center
In December 1983, Hans-Jürg Kuhn transferred a group of 18 male and
23 female Tupaia belangeri from the Zoological Institute, University
of Munich, to Göttingen. Originally housed in the former Department of
Forensic Medicine at the University of Göttingen, more than 50 tree shrews
moved in January 1985 to the animal facility of the German Primate Center
(DPZ). This was the starting point for nearly 30 years of successful work in
the author's group resulting in more than 100 publications on tree shrews.
With substantial support of Hans-Jürg Kuhn and Eckhard W. Heymann, the
housing and breeding protocol was optimized with the aim to become
independent of imports from Thailand and to generate animals with known
background for our own investigations. Routine colony health screening
procedures were carried out and veterinary as well as pathological assistance
was available. Tree shrews from the DPZ colony experienced relatively few
health problems; the most frequent ones are summarized in the contribution by
Brack (2015). A detailed description of housing and breeding tree shrews at
the DPZ is given by Fuchs and Corbach-Söhle (2010).
Parallel to the colony at the DPZ Hans-Jürg Kuhn maintained a back-up
colony at the Department of Anatomy, University of Göttingen, until his
retirement. From time to time tree shrews from other colonies were introduced
– in particular from Elke Zimmermann, now director of the Institute of
Zoology, University of Veterinary Medicine Hanover, Germany – to avoid
inbreeding. Over the years animals from the tree shrew colony at the DPZ were
provided to other research institutes in Germany and Europe.
The development of the tree shrew colony of the DPZ from 1985 to
2013.
As shown in Fig. 3, the DPZ colony constantly developed with a maximum of
more than 200 animals between 2004 and 2009. With the help of Klaus Nebendahl
(at that time head of the animal facilities of the University Medical Center,
University of Göttingen) we extended in 2004 the housing capacity mainly
for breeding tree shrews at Gut Holtensen, located about 5 km away from the
DPZ. In the processes of closing the Clinical Neurobiology Laboratory at the
DPZ and the author's retirement, the tree shrew colony was also closed. Most
of the animals were moved to the Department of Behavioral Physiology, Center
for Behavior and Neurosciences, University of Groningen, the Netherlands. The
history of tree shrews at the DPZ ended on 24 September 2013 with the transfer
of a view remaining animals to the Institute of Anatomy, Faculty of
Veterinary Medicine, University of Leipzig, Germany.
Kidney sections of a control (a) and a stressed (b) male tree shrew.
The black arrows indicate inflammatory infiltrating cells, while the green
arrows indicate atrophic tubuli. Qualitative analysis did not reveal any
indication of stress-induced renal damage. Blue bars represent 100 µm.
Tree shrews in laboratory
Tree shrews have proved to be useful experimental animal in many instances
where a small omnivorous non-rodent species is required (e.g., Cao et al.,
2003). They can be investigated in many fields of preclinical research such
as toxicology and virology, in particular in studies investigating herpes and
hepatitis viruses (Hunt, 1993; Zhao et al., 2002; Xu et al., 2007; Amako et
al., 2010). Further, various aspects of behavior including learning (Ohl et
al., 1998; Nair et al., 2014), infant development, communication, social
structures (e.g., Martin, 1968a, b; Hertenstein et al., 1987; Binz et al.,
1990), emotions (Schehka et al., 2007; Schehka and Zimmermann, 2009, 2012)
and various neurobiological questions (e.g., Norton et al., 2006; Kaas et
al., 2013, and Table 1) including the effects of psychosocial stress (e.g., Fuchs, 2005) can be studied in tree shrews.
Based on a study by von Holst (1972), psychosocially stressed male tree
shrews were thought to be a suitable model to study the mechanisms of acute
renal failure. However, we (see Fig. 4) and others (Steinhausen et al., 1978)
were unable to replicate these results.
A high degree of genetic homology between tree shrews and primates was found
for several receptor proteins of neuromodulators (see Fuchs and Flügge,
2002) and the amyloid-beta precursor protein (Pawlik et al., 1999). The 3–4 times longer life span of tree shrews than rodents (Keuker et al.,
2005) suggests that tree shrews may be useful for studies focusing on
aging-related brain changes (e.g., Michaelis et al., 2001; Yamashita et
al., 2012).
The psychosocial stress model
In their natural habitats male tree shrews defend their territories
vigorously against intruding conspecifics (Kawamichi and Kawamichi, 1979).
Originally developed by Raab (1971) and later adopted by von Holst (1972) we
used this pronounced territoriality (Sorenson, 1974) to establish a naturally
occurring challenging situation under experimental control in the laboratory.
All animal experimentation was carried out in accordance with the European
Council Directives and the German Animal Welfare Acts in force and was
approved by the responsible authorities of the federal state of Lower Saxony,
Germany.
Summary of stress-induced changes in male tree shrews. With
modifications from Fuchs and Flügge (2002).
Effects of chronic psychosocial stress Physiological and neuroendocrine parameters Body weightDecreased (Fuchs et al., 1993)HPA axisNon-adapting increase of urinary cortisol – no suppression by dexamethasone (Kramer et al., 1999; Kohlhause et al., 2011) and enlarged adrenal glands (Fuchs et al., 1993)Sympathetic nervous systemIncreased urinary adrenaline and noradrenaline (Fuchs et al., 1993)Gonadal systemDecreased testosterone (Kohlhause et al., 2011) and testes weight (Fischer et al., 1985)SleepReduced slow wave sleep, more/longer awake phases (Fuchs and Flügge, 2002)Circadian rhythmElevated core body temperature (Kohlhause et al., 2011; Schmelting et al., 2014), heart rate (Stöhr, 1986) and oxygen consumption (Fuchs and Kleinknecht, 1986) during resting periodBehavior and memory General motor activityReduced (Kramer et al., 1999; Schmelting et al., 2014)Self-groomingReduced (Kramer et al., 1999)Scent marking activityReduced (Kramer et al., 1999)Food and water intakeReduced (Kramer et al., 1999)Hippocampus-mediated memoryPersistently impaired (Ohl and Fuchs, 1999)Structural and functional changes in the brain Neurogenesis in the dentate gyrusInhibition of the proliferation of granule precursor cells (Gould et al., 1997; Czéh et al., 2001)Retraction of dendritesRetraction of apical dendrites of pyramidal neurons in the CA3 of the hippocampus (Magariños et al., 1996)Volume of the hippocampal formationVolume reduced by approximately 10 % (Ohl et al., 2000; Czéh et al., 2001)Brain metabolitesSignificantly decreased in vivo concentrations of N-acetyl-aspartate, creatine/phosphocreatine, and choline-containing compounds (Czéh et al., 2001)Hippocampal gluco- andmineralocorticoid receptorsDownregulation of glucocorticoid receptors; regional up- and downregulation of mineralocorticoid receptors (Meyer et al., 2001)CRH receptorsDownregulation of binding sites for 125I-ovine corticotropin releasing hormone (CRH) in anterior pituitary, dentate gyrus, CA1 and CA3 of the hippocampus, area 17, superior colliculus; upregulation of binding sites for 125I-ovine CRH in cortical regions, amygdala, choroid plexus (Fuchs and Flügge, 1995)5-HT1A receptorsGradual downregulation of heteroreceptors in hippocampus and cortical regions; fast renormalization after stress or hormonal replacement (Flügge, 1995; Flügge et al., 1998)Alpha2-adrenoceptorsDownregulation in brain regions involved in autonomic functions (Flügge, 1996; Flügge et al., 1992; Meyer et al., 2000)Beta1-adrenoceptorsAfter 4 weeks downregulation in hippocampus and parietal cortex; transient effects in prefrontal cortex, olfactory area, and pulvinar nucleus (Flügge et al., 1997)Beta2-adrenoceptorsAfter 4 weeks upregulation in pulvinar nucleus; transient effects in prefrontal cortex (Flügge et al., 1997)
For the stress exposure we developed the following standard protocol (e.g.,
Schmelting et al., 2014). In brief, in the first experimental phase
(pre-stress) – during which all animals remained undisturbed – body weight and
behavior was recorded daily, and morning urine samples were collected daily by
a slight massage of the hypogastrium. After this period animals were divided
into two groups: the non-stressed control and stressed group. The
animals from the stress group were exposed to daily psychosocial conflict,
while the non-stressed controls remained undisturbed elsewhere in the animal
facility. Psychosocial stress was induced by introducing a inexperienced animal into
the cage of another male that had already become dominant in previous
confrontations with a subordinate. During confrontation the animals were
closely monitored; in case of severe fights, the animals were separated
immediately by a wire mesh barrier to avoid physical injuries. Thus, direct
physical contact was only allowed for approximately 1 h every day. During
the stress phase, the wire mesh barrier was removed daily at random time
points to enhance unpredictability. Using this procedure, the subordinate
male was protected from repeated attacks but was constantly exposed to
olfactory, visual, and acoustic cues from the dominant male (Fig. 5). To exclude
the effects of individual differences in the intensity of attacks by the
dominant male and to avoid habituation, the subordinate animal was confronted
daily with another dominant male according to a Latin square design.
Schematic presentation of the psychosocial stress model in male tree
shrews. For the subordinate male the situation is characterized by a lack of
outlets, no predictability and no sense of control.
Subordinate tree shrews show significant changes in behavior, physiology,
endocrine function and neuronal activity. They lose body weight and have
reduced locomotor activity; their sleeping pattern is characterized by an
increasing number of early morning waking episodes, and their circadian
rhythm is profoundly disturbed. Analysis of endocrine function in
subordinates reveals consistently elevated concentrations of the
adrenocortical hormone cortisol, enlarged adrenals, increased concentrations
of noradrenalin and adrenalin indicating enhanced sympathetic activity and
reduced gonadal function (see Table 1). Since the distinct, stress-induced
behavioral, physiological, and central nervous system alterations in
subordinate animals result exclusively from cognitive interpretation of the
continuous visual presence of the dominant conspecific (Raab and Storz, 1976;
Raab and Ostwald, 1980), this paradigm has been termed “psychosocial
stress”. Importantly, the bio-behavioral responses observed in subordinate
tree shrews are similar to the signs and symptoms seen in depressed patients.
Thus, the chronic psychosocial stress model in tree shrews has clear “face
validity” (Willner, 1984) for human depression (for review see Fuchs, 2005).
To investigate whether the tree shrew model also possesses predictive validity
(Willner, 1984), we treated subordinate shrews with established and
as well as potential antidepressants such as clomipramine, fluoxetine,
tianeptine, agomelatine and different NK1 receptor antagonists. It is
important to note that (i) we determined and used the appropriate dose of the
antidepressants necessary to reach therapeutically relevant serum
concentrations (e.g., Czéh et al., 2006); (ii) the daily oral
treatment commenced only when the stress-induced behavioral and endocrine
changes became obvious; (iii) the psychosocial stress situation was continued
during the treatment; and (iv) the therapeutic action of the drug was
assessed for the clinically appropriate period of time of 4 weeks
(Fig. 6).
Schematic presentation of the experimental design of antidepressant
drug studies. Control: no stress; AD: antidepressant.
Using this approach we found in subordinate animals a time-dependent
restoration of endocrine, behavioral and central nervous parameters such as
neurogenesis, hippocampal volume and brain metabolism (Czéh et al., 2001,
2005; Fuchs et al., 1996; van der Hart et al., 2002, 2005; Schmelting et al.,
2014). In contrast, the anxiolytic diazepam was ineffective in this
experimental setting (van Kampen et al., 2000).
Despite its obvious attractiveness there are, as in other stress models,
limitations of the tree shrew psychosocial stress paradigm. One major
limitation is housing and breeding, which are space and time consuming, and
therefore only a limited number of experimental animals is available.
Obviously, this constraint explains why only a few other laboratories are
capable of using this model. One is at the Kunming Institute of Zoology, Chinese
Academy of Sciences, China, performing intensive research on Tupaia belangeri chinensis a close relative of Tupaia belangeri. Using a
similar stress model Wang et al. (2013) could confirm our finding with
clomipramine showing that depression-like core symptoms in subordinate tree
shrews could be reversed by a chronic treatment with this established
tricyclic antidepressant.
Conclusion
The chronic psychosocial stress paradigm in tree shrews characterized and
validated at the DPZ can be regarded a “homologous model” of depression. It
mimics several aspects of the human disease in the subordinate animal; the
state of the animal is induced by similar stimuli that cause the condition in
humans, and pharmacotherapy, which is efficacious in human illness, is effective
in the model. The advantage of such a homologous model is that it can
probably contribute to the understanding of the pathophysiology of depression
and it might also lead to the development of new effective drugs for
treatment of the illness. Although more research is required to further
validate the tree shrew model, it provides an adequate and interesting
non-rodent experimental paradigm for preclinical research on depression.
The work on tree shrews conducted for nearly 3 decades at the German
Primate Center would not have been possible without the encouragement of
Hans-Jürg Kuhn, the never-ending great enthusiasm of all members of the
research group and the substantial support provided by many collaborators,
grant agencies and industrial partners.Edited by: E. W. Heymann Reviewed by: F.-J. Kaup and E. Zimmermann
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