Topology of ON and OFF inputs in visual cortex enables an invariant columnar architecture.

Circuits in the visual cortex integrate the information derived from separate ON (light-responsive) and OFF (dark-responsive) pathways to construct orderly columnar representations of stimulus orientation and visual space. How this transformation is achieved to meet the specific topographic constraints of each representation remains unclear. Here we report several novel features of ON-OFF convergence visualized by mapping the receptive fields of layer 2/3 neurons in the tree shrew (Tupaia belangeri) visual cortex using two-photon imaging of GCaMP6 calcium signals. We show that the spatially separate ON and OFF subfields of simple cells in layer 2/3 exhibit topologically distinct relationships with the maps of visual space and orientation preference. The centres of OFF subfields for neurons in a given region of cortex are confined to a compact region of visual space and display a smooth visuotopic progression. By contrast, the centres of the ON subfields are distributed over a wider region of visual space, display substantial visuotopic scatter, and have an orientation-specific displacement consistent with orientation preference map structure. As a result, cortical columns exhibit an invariant aggregate receptive field structure: an OFF-dominated central region flanked by ON-dominated subfields. This distinct arrangement of ON and OFF inputs enables continuity in the mapping of both orientation and visual space and the generation of a columnar map of absolute spatial phase.

Regional Specialization of Pyramidal Neuron Morphology and Physiology in the Tree Shrew Neocortex.

The mammalian cerebral cortex is divided into different areas according to their function and pattern of connections. Studies comparing primary visual (V1) and prefrontal cortex (PFC) of primates have demonstrated striking pyramidal neuron (PN) specialization not present in comparable areas of the mouse neocortex. To better understand PFC evolution and regional PN specialization, we studied the tree shrew, a species with a close phylogenetic relationship to primates. We defined the tree shrew PFC based on cytoarchitectonic borders, thalamic connectivity and characterized the morphology and electrophysiology of layer II/III PNs in V1 and PFC. Similar to primates, the PFC PNs in the tree shrew fire with a regular spiking pattern and have larger dendritic tree and spines than those in V1. However, V1 PNs showed strikingly large basal dendritic arbors with high spine density, firing at higher rates and in a more varied pattern than PFC PNs. Yet, unlike in the mouse and unreported in the primate, medial prefrontal PN are more easily recruited than either the dorsolateral or V1 neurons. This specialization of PN morphology and physiology is likely to be a significant factor in the evolution of cortex, contributing to differences in the computational capacities of individual cortical areas.

Juvenile Tree Shrews Do Not Maintain Emmetropia in Narrow-band Blue Light.

SIGNIFICANCE: In spectrally broad-band light, an emmetropization mechanism in post-natal eyes uses visual cues to modulate the growth of the eye to achieve and maintain near emmetropia. When we restricted available wavelengths to narrow-band blue light, juvenile tree shrews (diurnal dichromatic mammals closely related to primates) developed substantial refractive errors, suggesting that feedback from defocus-related changes in the relative activation of long- and short-wavelength-sensitive cones is essential to maintain emmetropia. PURPOSE: The purpose of this study was to examine the effects of narrow-band ambient blue light on refractive state in juvenile tree shrews that had completed initial emmetropization (decrease from hyperopia toward emmetropia). METHODS: Animals were raised in fluorescent colony lighting until they began blue-light treatment at 24 days of visual experience, at which age they had achieved age-normal low hyperopia (mean ± SEM refractive error, 1.2 ± 0.5 diopters). Arrays of light-emitting diodes placed atop the cage produced wavelengths of 457 (five animals) or 464 nm (five animals), flickered in a pseudo-random pattern (temporally broad band). A third group of five animals was exposed to steady 464-nm blue light. Illuminance on the floor of the cage was 300 to 500 human lux. Noncycloplegic autorefractor measures were made daily for a minimum of 11 days and up to 32 days. Seven age-matched animals were raised in colony light. RESULTS: The refractive state of all blue-treated animals moved outside the 95% confidence limits of the colony-light animals' refractions. Most refractions first moved toward hyperopia. Then the refractive state decreased monotonically and, in some animals, passed through emmetropia, becoming myopic. CONCLUSIONS: From the tree shrew cone absorbance spectra, the narrow-band blue light stimulated both long-wavelength-sensitive and short-wavelength-sensitive cones, but the relative activation would not change with the refractive state. This removed feedback from longitudinal chromatic aberration that may be essential to maintain emmetropia.

Variability and constraint of vertebral formulae and proportions in colugos, tree shrews, and rodents, with special reference to vertebral modification by aerodynamic adaptation.

BACKGROUND: The aim of the present study is to provide the first large data set on vertebral formulae and proportions, and examine their relationship with different locomotive modes in colugos (Dermoptera), tree shrews (Scandentia), and rodents (Rodentia), which have been considered less variable because they were thought to have a plesiomorphic number of 19 thoracolumbar vertebrae. MATERIALS AND METHODS: The data included 33 colugos and 112 tree shrews, which are phylogenetically sister taxa, and 288 additional skeletons from 29 other mammalian species adapted to different locomotive modes, flying, gliding, arboreal, terrestrial, digging, and semi-aquatic habitats. RESULTS: The following results were obtained: (1) intra-/interspecies variability and geographical variation in thoracic, lumbar, and thoracolumbar counts were present in two gliding colugo species and 12 terrestrial/arboreal tree shrew species; (2) in our examined mammals, some aerodynamic mammals, such as colugos, southern flying squirrels, scaly-tailed squirrels, and bats, showed exceptionally high amounts of intraspecific variation of thoracic, lumbar, and thoracolumbar counts, and sugar gliders and some semi-aquatic rodents also showed some variation; (3) longer thoracic and shorter lumbar vertebrae were typically shared traits among the examined mammals, except for flying squirrels (Pteromyini) and scaly-tailed squirrels (Anomaluridae). CONCLUSIONS: Our study reveals that aerodynamic adaptation could potentially lead to strong selection and modification of vertebral formulae and/or proportions based on locomotive mode despite evolutionary and developmental constraints. (Folia Morphol 2018; 77, 1: 44-56) Background: The aim of the present study is to provide the first large data set on vertebral formulae and proportions, and examine their relationship with different locomotive modes in colugos (Dermoptera), tree shrews (Scandentia), and rodents (Rodentia), which have been considered less variable because they were thought to have a plesiomorphic number of 19 thoracolumbar vertebrae. MATERIALS AND METHODS: The data included 33 colugos and 112 tree shrews, which are phylogenetically sister taxa, and 288 additional skeletons from 29 other mammalian species adapted to different locomotive modes, flying, gliding, arboreal, terrestrial, digging, and semi-aquatic habitats. RESULTS: The following results were obtained: (1) intra-/interspecies variability and geographical variation in thoracic, lumbar, and thoracolumbar counts were present in two gliding colugo species and 12 terrestrial/arboreal tree shrew species; (2) in our examined mammals, some aerodynamic mammals, such as colugos, southern flying squirrels, scaly-tailed squirrels, and bats, showed exceptionally high amounts of intraspecific variation of thoracic, lumbar, and thoracolumbar counts, and sugar gliders and some semi-aquatic rodents also showed some variation; (3) longer thoracic and shorter lumbar vertebrae were typically shared traits among the examined mammals, except for flying squirrels (Pteromyini) and scaly-tailed squirrels (Anomaluridae). CONCLUSIONS: Our study reveals that aerodynamic adaptation could potentially lead to strong selection and modification of vertebral formulae and/or proportions based on locomotive mode despite evolutionary and developmental constraints. (Folia Morphol 2018; 77, 1: 44-56).

Umbilical cord mesenchymal stem cells are able to undergo differentiation into functional islet-like cells in type 2 diabetic tree shrews.

Islet transplantation is arguably one of the most promising strategies to treat patients suffering with diabetes mellitus. However, a combination of a lack of donors and chronic immune rejection limit clinical applications. Here, we evaluated the efficacy of cell therapy using islet-like cells differentiated from umbilical cord mesenchymal stem cells (UC-MSCs) of tree shrews for the treatment of type 2 diabetes. Enhanced green fluorescent protein (eGFP) labeled UC-MSCs were directly injected into type 2 diabetic tree shrews, where UC-MSC differentiated into functional islet-like cells and alleviated disease severity, as evidenced by improved biochemical features and reduced concentrations of inflammatory cytokines. We also demonstrated that in vitro culture of UC-MSCs for six days in a high-glucose environment (40 mmol/L or 60 mmol/L glucose) resulted in significant gene methylation. The potency of UC-MSCs differentiated into insulin-secreting cells was attributed to the activation of Notch signal pathways. This study provides evidence that cell therapy of islet-like cells differentiated from UC-MSCs is a feasible, simple and inexpensive approach in the treatment of type 2 diabetes.

Auditory brainstem responses after electrolytic lesions in bilateral subdivisions of the medial geniculate body of tree shrews.

This study aimed to establish a tree shrew model of bilateral electrolytic lesions in the medial geniculate body (MGB) to determine the advantages of using a tree shrew model and to assess the pattern of sound processing in tree shrews after bilateral electrolytic damage in different parts of the MGB. The auditory brainstem responses (ABRs) of a normal control group (n = 30) and an electrical damage group (n = 30) were tested at 0 h, 24 h, 48 h, 72 h, 7 days, 15 days, and 30 days after surgery. (1) The bilateral ablations group exhibited a significant increase in the ABR threshold of the electrolytic damage group between pre- and post-operation. (2) There were significant increases in the I-VI latencies at 0 h after MGBd and MGBm lesions and at 24 h after MGBv lesion. (3) The amplitudes of wave VI were significantly decreased at 24 h and 48 h after MGBd lesion, at 72 h and 7 days after MGBm lesion, and at 24 h, 48 h, 72 h, and 7 days after MGBv lesion. (1) The electrolytic damage group suffered hearing loss that did not recover and appeared to be difficult to fully repair after bilateral ablation. (2) The latencies and amplitudes of responses in the MGB following bilateral electrolytic lesion were restored to pre-operation levels after 15-30 days, suggesting that a portion of the central nuclei lesion was reversible. (3) The tree shrew auditory animal model has many advantages compared to other animal models, such as greater complexity of brain structure and auditory nuclei fiber connections, which make the results of this experiment more useful for clinical diagnoses compared with studies using rats and guinea pigs.

Link between orientation and retinotopic maps in primary visual cortex.

Maps representing the preference of neurons for the location and orientation of a stimulus on the visual field are a hallmark of primary visual cortex. It is not yet known how these maps develop and what function they play in visual processing. One hypothesis postulates that orientation maps are initially seeded by the spatial interference of ON- and OFF-center retinal receptive field mosaics. Here we show that such a mechanism predicts a link between the layout of orientation preferences around singularities of different signs and the cardinal axes of the retinotopic map. Moreover, we confirm the predicted relationship holds in tree shrew primary visual cortex. These findings provide additional support for the notion that spatially structured input from the retina may provide a blueprint for the early development of cortical maps and receptive fields. More broadly, it raises the possibility that spatially structured input from the periphery may shape the organization of primary sensory cortex of other modalities as well.

Scleral gene expression during recovery from myopia compared with expression during myopia development in tree shrew.

PURPOSE: During postnatal refractive development, the sclera receives retinally generated signals that regulate its biochemical properties. Hyperopic refractive error causes the retina to produce "GO" signals that, through the direct emmetropization pathway, cause scleral remodeling that increases the axial elongation rate of the eye, reducing the hyperopia. Myopia causes the retina to generate "STOP" signals that produce scleral remodeling, slowing the axial elongation rate and reducing the myopia. Our aim was to compare the pattern of gene expression produced in the sclera by the STOP signals with the GO gene expression signature we described previously. METHODS: The GO gene expression signature was produced by monocular -5 diopter (D) lens wear for 2 days (ML-2) or 4 days (ML-4); an additional "STAY" condition was examined after eyes had fully compensated for a -5 D lens after 11 days of lens wear (ML-11). After 11 days of -5 D lens wear had produced full refractive compensation, gene expression in the STOP condition was examined during recovery (without the lens) for 2 days (REC-2) or 4 days (REC-4). The untreated contralateral eyes served as a control in all groups. Two age-matched normal groups provided a comparison with the treated groups. Quantitative real-time PCR was used to measure mRNA levels for 55 candidate genes. RESULTS: The STAY group compensated fully for the lens (treated eye versus control eye, -5.1±0.2 D). Wearing the lens, the hyperopic signal for elongation had dissipated (-0.3±0.3 D). In the STOP groups, the refraction in the recovering eyes became less myopic relative to the control eyes (REC-2, +1.3±0.3 D; REC-4, +2.6±0.4 D). In the STAY group, three genes showed significant downregulation. However, many genes that were significantly altered in GO showed smaller, nonsignificant, expression differences in the same direction in STAY, suggesting the gene expression signature in STAY is a greatly weakened form of the GO signature. In the STOP groups, a different gene expression pattern was observed, characterized by mostly upregulation with larger fold differences after 4 days than after 2 days of recovery. Eleven of the 55 genes examined showed significant bidirectional GO/STOP regulation in the ML-2 and REC-2 groups, and 13 genes showed bidirectional regulation in the ML-4 and REC-4 groups. Eight of these genes (NPR3, CAPNS1, NGEF, TGFB1, CTGF, NOV, TIMP1, and HS6ST1) were bidirectionally regulated at both time points in the GO and STOP conditions. An additional 15 genes showed significant regulation in either GO or STOP conditions but not in both. CONCLUSIONS: Many genes are involved in scleral remodeling and the control of axial length. The STOP (recovery) gene expression signature in the sclera involves some of the same genes, bidirectionally regulated, as the GO signature. However, other genes, regulated in GO, are not differentially regulated in STOP, and others show differential regulation only in STOP.

Mediodorsal thalamus and ventral pallidum contribute to subcortical regulation of the default mode network.

Humans and other animals readily transition from externally to internally focused attention, and these transitions are accompanied by activation of the default mode network (DMN). The DMN was considered a cortical network, yet recent evidence suggests subcortical structures are also involved. We investigated the role of ventral pallidum (VP) and mediodorsal thalamus (MD) in DMN regulation in tree shrew, a close relative of primates. Electrophysiology and deep learning-based classification of behavioral states revealed gamma oscillations in VP and MD coordinated with gamma in anterior cingulate (AC) cortex during DMN states. Cross-frequency coupling between gamma and delta oscillations was higher during DMN than other behaviors, underscoring the engagement of MD, VP and AC. Our findings highlight the importance of VP and MD in DMN regulation, extend homologies in DMN regulation among mammals, and underline the importance of thalamus and basal forebrain to the regulation of DMN.

Enhanced long-term potentiation in the anterior cingulate cortex of tree shrew.

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Energy metabolism, thermogenesis and body mass regulation in tree shrew (Tupaia belangeri) during subsequent cold and warm acclimation.

Environmental cues play important roles in the regulation of an animal's physiology and behavior. The purpose of the present study was to test the hypothesis that ambient temperature is a cue to induce adjustments in body mass, energy intake and thermogenic capacity, associated with changes in serum leptin levels in tree shrews (Tupaia belangeri). We found that tree shrews increased basal metabolic rate (BMR), energy intake and subsequently showed a significant decrease in body mass after being returned to warm ambient temperature. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) increased during cold acclimation and reversed after rewarming. The trend of energy intake increased during cold acclimation and decreased after rewarming; the trend of energy intake during cold acclimation was contrary to the trend of energy intake during rewarming. Further, serum leptin levels were negatively correlated with body mass. Together, these data supported our hypothesis that ambient temperature was a cue to induce changes in body mass and metabolic capacity. Serum leptin, as a starvation signal in the cold and satiety signal in rewarming, was involved in the processes of thermogenesis and body mass regulation in tree shrews.

Neural response dynamics of spiking and local field potential activity depend on CRT monitor refresh rate in the tree shrew primary visual cortex.

Entrainment of neural activity to luminance impulses during the refresh of cathode ray tube monitor displays has been observed in the primary visual cortex (V1) of humans and macaque monkeys. This entrainment is of interest because it tends to temporally align and thus synchronize neural responses at the millisecond timescale. Here we show that, in tree shrew V1, both spiking and local field potential activity are also entrained at cathode ray tube refresh rates of 120, 90, and 60 Hz, with weakest but still significant entrainment even at 120 Hz, and strongest entrainment occurring in cortical input layer IV. For both luminance increments ("white" stimuli) and decrements ("black" stimuli), refresh rate had a strong impact on the temporal dynamics of the neural response for subsequent luminance impulses. Whereas there was rapid, strong attenuation of spikes and local field potential to prolonged visual stimuli composed of luminance impulses presented at 120 Hz, attenuation was nearly absent at 60-Hz refresh rate. In addition, neural onset latencies were shortest at 120 Hz and substantially increased, by ∼15 ms, at 60 Hz. In terms of neural response amplitude, black responses dominated white responses at all three refresh rates. However, black/white differences were much larger at 60 Hz than at higher refresh rates, suggesting a mechanism that is sensitive to stimulus timing. Taken together, our findings reveal many similarities between V1 of macaque and tree shrew, while underscoring a greater temporal sensitivity of the tree shrew visual system.

Immunocytochemical and ultrastructural organization of the taste thalamus of the tree shrew (Tupaia belangeri).

Ventroposterior medialis parvocellularis (VPMP) nucleus of the primate thalamus receives direct input from the nucleus of the solitary tract, whereas the homologous thalamic structure in the rodent does not. To reveal whether the synaptic circuitries in these nuclei lend evidence for conservation of design principles in the taste thalamus across species or across sensory thalamus in general, we characterized the ultrastructural and molecular properties of the VPMP in a close relative of primates, the tree shrew (Tupaia belangeri), and compared these to known properties of the taste thalamus in rodent, and the visual thalamus in mammals. Electron microscopy analysis to categorize the synaptic inputs in the VPMP revealed that the largest-size terminals contained many vesicles and formed large synaptic zones with thick postsynaptic density on multiple, medium-caliber dendrite segments. Some formed triads within glomerular arrangements. Smaller-sized terminals contained dark mitochondria; most formed a single asymmetric or symmetric synapse on small-diameter dendrites. Immuno-EM experiments revealed that the large-size terminals contained VGLUT2, whereas the small-size terminal populations contained VGLUT1 or ChAT. These findings provide evidence that the morphological and molecular characteristics of synaptic circuitry in the tree shrew VPMP are similar to that in nonchemical sensory thalamic nuclei. Furthermore, the results indicate that all primary sensory nuclei of the thalamus in higher mammals share a structural template for processing thalamocortical sensory information. In contrast, substantial morphological and molecular differences in rodent versus tree shrew taste nuclei suggest a fundamental divergence in cellular processing mechanisms of taste input in these two species.

Whole-brain mapping of afferent projections to the suprachiasmatic nucleus of the tree shrew.

The suprachiasmatic nucleus (SCN) is essential for the neural control of mammalian circadian timing system. The circadian activity of the SCN is modulated by its afferent projections. In the present study, we examine neuroanatomical characteristics and afferent projections of the SCN in the tree shrew (Tupaia belangeri chinensis) using immunocytochemistry and retrograde tracer Fluoro-Gold (FG). Distribution of the vasoactive intestinal peptide was present in the SCN from rostral to caudal, especially concentrated in its ventral part. FG-labeled neurons were observed in the lateral septal nucleus, septofimbrial nucleus, paraventricular thalamic nucleus, posterior hypothalamic nucleus, posterior complex of the thalamus, ventral subiculum, rostral linear nucleus of the raphe, periaqueductal gray, mesencephalic reticular formation, dorsal raphe nucleus, pedunculopontine tegmental nucleus, medial parabrachial nucleus, locus coeruleus, parvicellular reticular nucleus, intermediate reticular nucleus, and ventrolateral reticular nucleus. In summary, the morphology of the SCN in tree shrews is described from rostral to caudal. In addition, our data demonstrate for the first time that the SCN in tree shrews receives inputs from numerous brain regions in the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. This comprehensive knowledge of the afferent projections of the SCN in tree shrews provides further insights into the neural organization and physiological processes of circadian rhythms.

Aspects of tree shrew consolidated sleep structure resemble human sleep.

Understanding human sleep requires appropriate animal models. Sleep has been extensively studied in rodents, although rodent sleep differs substantially from human sleep. Here we investigate sleep in tree shrews, small diurnal mammals phylogenetically close to primates, and compare it to sleep in rats and humans using electrophysiological recordings from frontal cortex of each species. Tree shrews exhibited consolidated sleep, with a sleep bout duration parameter, τ, uncharacteristically high for a small mammal, and differing substantially from the sleep of rodents that is often punctuated by wakefulness. Two NREM sleep stages were observed in tree shrews: NREM, characterized by high delta waves and spindles, and an intermediate stage (IS-NREM) occurring on NREM to REM transitions and consisting of intermediate delta waves with concomitant theta-alpha activity. While IS-NREM activity was reliable in tree shrews, we could also detect it in human EEG data, on a subset of transitions. Finally, coupling events between sleep spindles and slow waves clustered near the beginning of the sleep period in tree shrews, paralleling humans, whereas they were more evenly distributed in rats. Our results suggest considerable homology of sleep structure between humans and tree shrews despite the large difference in body mass between these species.

A Novel Tree Shrew Model of Diabetic Retinopathy.

Existing animal models with rod-dominant retinas have shown that hyperglycemia injures neurons, but it is not yet clearly understood how blue cone photoreceptors and retinal ganglion cells (RGCs) deteriorate in patients because of compromised insulin tolerance. In contrast, northern tree shrews (Tupaia Belangeri), one of the closest living relatives of primates, have a cone-dominant retina with short wave sensitivity (SWS) and long wave sensitivity (LWS) cones. Therefore, we injected animals with a single streptozotocin dose (175 mg/kg i.p.) to investigate whether sustained hyperglycemia models the features of human diabetic retinopathy (DR). We used the photopic electroretinogram (ERG) to measure the amplitudes of A and B waves and the photopic negative responses (PhNR) to evaluate cone and RGC function. Retinal flat mounts were prepared for immunohistochemical analysis to count the numbers of neurons with antibodies against cone opsins and RGC specific BRN3a proteins. The levels of the proteins TRIB3, ISR-1, and p-AKT/p-mTOR were measured with western blot. The results demonstrated that tree shrews manifested sustained hyperglycemia leading to a slight but significant loss of SWS cones (12%) and RGCs (20%) 16 weeks after streptozotocin injection. The loss of BRN3a-positive RGCs was also reflected by a 30% decline in BRN3a protein expression. These were accompanied by reduced ERG amplitudes and PhNRs. Importantly, the diabetic retinas demonstrated increased expression of TRIB3 and level of p-AKT/p-mTOR axis but reduced level of IRS-1 protein. Therefore, a new non-primate model of DR with SWS cone and RGC dysfunction lays the foundation to better understand retinal pathophysiology at the molecular level and opens an avenue for improving the research on the treatment of human eye diseases.

The evolution of the upright posture and gait--a review and a new synthesis.

During the last century, approximately 30 hypotheses have been constructed to explain the evolution of the human upright posture and locomotion. The most important and recent ones are discussed here. Meanwhile, it has been established that all main hypotheses published until the last decade of the past century are outdated, at least with respect to some of their main ideas: Firstly, they were focused on only one cause for the evolution of bipedality, whereas the evolutionary process was much more complex. Secondly, they were all placed into a savannah scenario. During the 1990s, the fossil record allowed the reconstruction of emerging bipedalism more precisely in a forested habitat (e.g., as reported by Clarke and Tobias (Science 269:521-524, 1995) and WoldeGabriel et al. (Nature 412:175-178, 2001)). Moreover, the fossil remains revealed increasing evidence that this part of human evolution took place in a more humid environment than previously assumed. The Amphibian Generalist Theory, presented first in the year 2000, suggests that bipedalism began in a wooded habitat. The forests were not far from a shore, where our early ancestor, along with its arboreal habits, walked and waded in shallow water finding rich food with little investment. In contrast to all other theories, wading behaviour not only triggers an upright posture, but also forces the individual to maintain this position and to walk bipedally. So far, this is the only scenario suitable to overcome the considerable anatomical and functional threshold from quadrupedalism to bipedalism. This is consistent with paleoanthropological findings and with functional anatomy as well as with energetic calculations, and not least, with evolutionary psychology. The new synthesis presented here is able to harmonise many of the hitherto competing theories.

Plasma volume, cell volume, total blood volume and F factor in the tree shrew.

In this study, the physiological values of volumes of plasma, cells, total blood and the F blood factors were identified in 24 adult tree shrews (Tupaia belangeri; 12 male and 12 female; average BW of 123.9±19.19 g). The two-compartment model method of Evans Blue dye was used to obtain the plasma volume and the venous hematocrit was measured by microhematocrit method. To establish the relationship between body weight (BW) and blood volume of tree shrews, We performed linear fitting for these two datasets. Results were analyzed according to gender and weight (<120g vs.>120g). Statistical significance was assessed using the unpaired student t test and one-way ANOVA. The average volumes per 100g body weight of plasma, red blood cell (RBC) and total blood were 5.42±0.543, 3.24±0.445, and 8.66±0.680ml respectively. The mean body hematocrit, cardiac hematocrit, jugular vein hematocrit, femoral vein hematocrit, and tail vein hematocrit was 37.43±4.096, 39.72±3.219, 43.04±4.717, 40.84±3.041, and 38.71±3.442% respectively. The F cardiac was 0.94±0.072, F jugular vein 0.88±0.118, F femoral vein 0.92±0.111, and the F tail vein 0.97±0.117. Blood volume (ml) was 85.89103×BW (kg). This is the first study to provide the parameters of plasma volume, cell volume, total blood volume and F factor and a baseline for future research on blood physiology of tree shrews.

Social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics in the laboratory.

Adult male tree shrews vigorously defend against intruding male conspecifics. However, the characteristics of social behavior have not been entirely explored in these males. In this study, male wild-type tree shrews ( Tupaia belangeri chinensis) and C57BL/6J mice were first allowed to familiarize themselves with an open-field apparatus. The tree shrews exhibited a short duration of movement (moving) in the novel environment, whereas the mice exhibited a long duration of movement. In the 30 min social preference-avoidance test, target animals significantly decreased the time spent by the experimental tree shrews in the social interaction (SI) zone, whereas experimental male mice exhibited the opposite. In addition, experimental tree shrews displayed a significantly longer latency to enter the SI zone in the second 15 min session (target-present) than in the first 15 min session (target-absent), which was different from that found in mice. Distinct behavioral patterns in response to a conspecific male were also observed in male tree shrews and mice in the first, second, and third 5 min periods. Thus, social behaviors in tree shrews and mice appeared to be time dependent. In summary, our study provides results of a modified social preference-avoidance test designed for the assessment of social behavior in tree shrews. Our findings demonstrate the existence of social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics. The tree shrew may be a new animal model, which differs from mice, for the study of social avoidance and prosocial behaviors.

Technical advance: The use of tree shrews as a model of pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with a high morbidity and mortality. Some of the mechanisms of fibrosis development have been described using rodent models; however, the relevance of findings in these animal models is difficult to assess. New innovative models are needed that closely mimic IPF disease pathology. METHODS: To overcome this unmet need of investigating IPF with a relevant model, we utilized tree shrews, which are genetically, anatomically, and metabolically similar to primates and humans. Using human antibodies and primers, we investigated the role of macrophage phenotypic switching in normal and IPF subjects and bleomycin-injured tree shrews. RESULTS: Bronchoalveolar lavage (BAL) cells from tree shrews expressed human markers, and there was recruitment of monocyte-derived macrophages (MDMs) to the lung in IPF subjects and bleomycin-injured tree shrews. MDMs were polarized to a profibrotic phenotype in IPF and in bleomycin-injured tree shrews. Resident alveolar macrophages (RAMs) expressed proinflammatory markers regardless of bleomycin exposure. Tree shrews developed bleomycin-induced pulmonary fibrosis with architectural distortion in parenchyma and widespread collagen deposition. CONCLUSION: The profibrotic polarization of macrophages has been demonstrated to be present in IPF subjects and in fibrotic mice. Although the lung macrophages have long been considered to be homogeneous, recent evidence indicates that these cells are heterogeneous during multiple chronic lung diseases. Here, we show new data that indicate a critical and essential role for macrophage-fibroblast crosstalk promoting fibroblast differentiation and collagen production. in the development and progression of fibrosis. The current data strongly suggest development of therapeutics that attenuate of the profibrotic activation of MDMs may mitigate macrophage-fibroblast interaction. These observations demonstrate that tree shrews are an ideal animal model to investigate the pathogenesis of IPF as they are genetically, anatomically, and metabolically closer to humans than the more commonly used rodent models.