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.

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.

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.

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.

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.

COVID-19-like symptoms observed in Chinese tree shrews infected with SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/ HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here, different aged Chinese tree shrews (adult group, 1 year old; old group, 5-6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days post-inoculation (dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3, 5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase (AST) and blood urea nitrogen (BUN). Histological analysis of lung tissues from animals at 3 dpi (adult group) and 7 dpi (old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.

Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (tree shrew).

Mammary gland cancer is the most common cancer occurring in women globally. Incidences of this cancer in Japan are on the increase. Annually, more than 70,000 new cases are recorded in Japan and about 1.7 million in the world. Many cases are still difficult to cure completely, and animal models are required for the characterization of the biology, therapeutic strategy, and preventive measures for spontaneous mammary tumor. The mouse model used currently has some limitations owing to structural differences between mouse and human mammary glands. Tupaia belangeri (tree shrew), which belongs to the Tupaiidae family, shows relatively high genetic homology and structural similarity to human mammary glands. Here, we characterized the spontaneous mammary tumors in 61 female tree shrews of different ages. The incidence rate was 24.6% (15/61), and the rate of simultaneous or metachronous multiplex tumors was 60% (9/15). From the incidence pattern, some cases seemed to be of familial mammary gland tumor, as the offspring of female tree shrews No. 3 and 9 and male tree shrew No. 11 showed a high incidence rate, of 73.3% (11/15). Average incidence age for tumor development was 2 years and 3 months, and the earliest was 10 months. Histochemical analysis indicated that spontaneous mammary gland tumors in the tree shrew show the features of intraductal papillary adenomas (22 cases), except 2 tubulopapillary carcinoma cases (No. 75 and 131). All the cases were positive for the progesterone receptor, whereas 91.3% were positive for the estrogen receptor, and 4.3% were HER-2 positive. We have also confirmed the expression of nectin-4 in some mammary tumor cells. Additionally, we subjected tree shrews to cytodiagnosis or X-ray CT. Thus, the findings of this study highlight the potential of the tree shrew as a valuable new animal model for mammary gland tumor study.

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.

Establishment of brain ischemia model in tree shrew.

BACKGROUND: Tree shrew, as a kind of small and inexpensive animal between insectivores and primates with the general anatomy being similar to human, could be considered as developed animal model for brain ischemia (BI) study. However, there is no neural behavior scores criterion from tree shrew with BI up to now. METHODS: To produce BI model of tree shrew, a novel systematic neurobehavioral assessment scale, named as neural behavior scores (NBS) including aggressive behavior, seeking behavior, gait, startle reflex, high jump and warped-tail phenomenon was firstly established and used in this study. Moreover, magnetic resonance imaging (MRI) was performed on the first day after the operation to detect the imaging changes caused by ischemia. Then TTC, HE staining and immunofluorescent staining for GFAP and NeuN, were performed 24 h after surgery respectively. RESULTS: NBS in BI group were significantly higher than that of sham operation group at 1d, 3d, 5d and 7d after ischemia. Meanwhile, compared with the sham operation group, the T2 images demonstrated significant higher signal and local brain swelling after cerebral ischemia in tree shrews. The staining of TTC and HE showed apparent infarction and necrosis of the cerebral region, and most of neurons exhibited a shrink. CONCLUSION: We have successfully established the BI model of tree shrew, confirmed by NBS (a new developed method), MRI, HE staining, TTC staining and immunofluorescence staining. It is the first time to report a novel neurobehavioral assessment scale for BI in tree shrew.

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.

The tree shrew cerebellum atlas: Systematic nomenclature, neurochemical characterization, and afferent projections.

The cerebellum is involved in the control of movement, emotional responses, and reward processing. The tree shrew is the closest living relative of primates. However, little is known not only about the systematic nomenclature for the tree shrew cerebellum but also about the detailed neurochemical characterization and afferent projections. In this study, Nissl staining and acetylcholinesterase histochemistry were used to reveal anatomical features of the cerebellum of tree shrews (Tupaia belangeri chinensis). The cerebellar cortex presented a laminar structure. The morphological characteristics of the cerebellum were comprehensively described in the coronal, sagittal, and horizontal sections. Moreover, distributive maps of calbindin-immunoreactive (-ir) cells in the Purkinje cell layer of the cerebellum of tree shrews were depicted using coronal, sagittal, and horizontal schematics. In addition, 5th cerebellar lobule (5Cb)-projecting neurons were present in the pontine nuclei, reticular nucleus, spinal vestibular nucleus, ventral spinocerebellar tract, and inferior olive of the tree shrew brain. The anterior part of the paramedian lobule of the cerebellum (PMa) received mainly strong innervation from the lateral reticular nucleus, inferior olive, pontine reticular nucleus, spinal trigeminal nucleus, pontine nuclei, and reticulotegmental nucleus of the pons. The present results provide the first systematic nomenclature, detailed atlas of the whole cerebellum, and whole-brain mapping of afferent projections to the 5Cb and PMa in tree shrews. Our findings provide morphological support for tree shrews as an alternative model for studies of human cerebellar pathologies.

Distinct Frequency Specialization for Detecting Dark Transients in Humans and Tree Shrews.

Despite well-known privileged perception of dark over light stimuli, it is unknown to what extent this dark dominance is maintained when visual transients occur in rapid succession, for example, during perception of moving stimuli. Here, we address this question using dark and light transients presented at different flicker frequencies. Although both human participants and tree shrews exhibited dark dominance for temporally modulated transients, these occurred at different flicker frequencies, namely, at 11 Hz in humans and 40 Hz and higher in tree shrews. Tree shrew V1 neuronal activity confirmed that differences between light and dark flicker were maximal at 40 Hz, corresponding closely to behavioral findings. These findings suggest large differences in flicker perception between humans and tree shrews, which may be related to the lifestyle of these species. A specialization for detecting dark transients at high temporal frequencies may thus be adaptive for tree shrews, which are particularly fast-moving small mammals.

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).

Characterization of excitatory synaptic transmission in the anterior cingulate cortex of adult tree shrew.

The tree shrew, as a primate-like animal model, has been used for studying high brain functions such as social emotion and spatial learning memory. However, little is known about the excitatory synaptic transmission in cortical brain areas of the tree shrew. In the present study, we have characterized the excitatory synaptic transmission and intrinsic properties of pyramidal neurons in the anterior cingulate cortex (ACC) of the adult tree shrew, a key cortical region for pain perception and emotion. We found that glutamate is the major excitatory transmitter for fast synaptic transmission. Excitatory synaptic responses induced by local stimulation were mediated by AMPA and kainate (KA) receptors. As compared with mice, AMPA and KA receptor mediated responses were significantly greater. Interestingly, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in tree shrews was significantly less than that of mice. Moreover, both the ratio of paired-pulse facilitation (PPF) and the time of 50% decay for fast blockade of NMDA receptor mediated EPSCs were greater in the tree shrew. Finally, tree shrew neurons showed higher initial firing frequency and neuronal excitability with a cell type-specific manner in the ACC. Our studies provide the first report of the basal synaptic transmission in the ACC of adult tree shrew.

Basal forebrain activation enhances between-trial reliability of low-frequency local field potentials (LFP) and spiking activity in tree shrew primary visual cortex (V1).

Brain state has profound effects on neural processing and stimulus encoding in sensory cortices. While the synchronized state is dominated by low-frequency local field potential (LFP) activity, low-frequency LFP power is suppressed in the desynchronized state, where a concurrent enhancement in gamma power is observed. Recently, it has been shown that cortical desynchronization co-occurs with enhanced between-trial reliability of spiking activity in sensory neurons, but it is currently unclear whether this effect is also evident in LFP signals. Here, we address this question by recording both spike trains and LFP in primary visual cortex during natural movie stimulation, and using isoflurane anesthesia and basal forebrain (BF) electrical activation as proxies for synchronized and desynchronized brain states. We show that indeed, low-frequency LFP modulations ("LFP events") also occur more reliably following BF activation. Interestingly, while being more reliable, these LFP events are smaller in amplitude compared to those generated in the synchronized brain state. We further demonstrate that differences in reliability of spiking activity between cortical states can be linked to amplitude and probability of LFP events. The correlated temporal dynamics between low-frequency LFP and spiking response reliability in visual cortex suggests that these effects may both be the result of the same neural circuit activation triggered by BF stimulation, which facilitates switching between processing of incoming sensory information in the desynchronized and reverberation of internal signals in the synchronized state.

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.

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.

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.