Nucleus accumbens-linked executive control networks mediating reversal learning in tree shrew brain

Herpes Simplex Virus type I (HSV-1) latently infects peripheral nervous system (PNS) sensory neurons, and its reactivation leads to recurring cold sores. The reactivated HSV-1 can travel retrograde from the PNS into the central nervous system (CNS) and is known to be causative of Herpes Simplex viral encephalitis. HSV-1 infection in the PNS is well documented, but little is known on the fate of HSV-1 once it enters the CNS. In the murine model, HSV-1 genome persists in the CNS once infected through an ocular route. To gain more details of HSV-1 infection in the CNS, we characterized HSV-1 infection of the tree shrew (Tupaia belangeri chinensis) brain following ocular inoculation. Here, we report that HSV-1 enters the tree shrew brain following ocular inoculation and HSV-1 transcripts, ICP0, ICP4, and LAT can be detected at 5 days post-infection (p.i.), peaking at 10 days p.i. After 2 weeks, ICP4 and ICP0 transcripts are reduced to a basal level, but the LAT intron region continues to be expressed. Live virus could be recovered from the olfactory bulb and brain stem tissue. Viral proteins could be detected using anti-HSV-1 antibodies and anti-ICP4 antibody, during the acute stage but not beyond. In situ hybridization could detect LAT during acute infection in most brain regions and in olfactory bulb and brain stem tissue well beyond the acute stage. Using a homogenate from these tissues’ post-acute infection, we did not recover live HSV-1 virus, supporting a latent infection, but using a modified explant cocultivation technique, we were able to recover reactivated virus from these tissues, suggesting that the HSV-1 virus latently infects the tree shrew CNS. Compared to mouse, the CNS acute infection of the tree shrew is delayed and the olfactory bulb contains most latent virus. During the acute stage, a portion of the infected tree shrews exhibit symptoms similar to human viral encephalitis. These findings, together with the fact that tree shrews are closely related to primates, provided a valuable alternative model to study HSV-1 infection and pathogenesis in the CNS.

Early efforts to reconstruct the course of the evolution of the human brain relied on comparing the brains of a few related mammals with brains at successively higher levels of complexity. This Clark or ladder of levels approach is now seen as having limited usefulness in that species are not easily assigned to levels, and extant mammals are now recognized as mosaics of primitive and derived features. In addition, direction of change does not necessarily proceed from simple to complex, small to large, or diffuse to differentiated. A modern cladistic approach reconstructs the brains of ancestors by identifying brain characters within and across phylogenetic groups (clades), and uses parsimony or likelihood to infer direction of change and distinguish ancestral features from independently evolved convergences. Unfortunately, an idealized cladistic approach is often difficult to realize because characters may be hard to identify and validate, key species may be unavailable for study, and broadly based comparative studies can be costly, poorly funded, and labor intensive. Thus, many investigators pursue a truncated approach that is superficially Clark-like but conceptually cladistic. A truncated approach that relies on the extensive study of a few species may compensate for weaknesses by including niche-matched species that offer the opportunity to estimate the likelihood of similar brain features evolving as convergent adaptations. Because inferences about the brains of the primate ancestor are often made from the brains of tree shrews, we compare the brains of squirrel-like tree shrews with the brains of diurnal squirrels, and suggest that many of the primate-like features of the visual system of tree shrews arose independently of those in primates.

Beta-adrenoceptors in the tree shrew brain. I. Distribution and characterization of [125I]iodocyanopindolol binding sites.

Distribution of corticotropin-releasing factor in the tree shrew brain

Whole-brain mapping of afferent projections to the bed nucleus of the stria terminalis in tree shrews

Day-active tree shrews are promising animals as research models for a variety of human disorders. Neuropeptide Y (NPY) modulates many behaviors in vertebrates. Here we examined the distribution of NPY in the brain of tree shrews (Tupaia belangeri chinensis) using immunohistochemical techniques. The differential distribution of NPY-immunoreactive (-ir) cells and fibers were observed in the rhinencephalon, telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon of tree shrews. Most NPY-ir cells were multipolar or bipolar in shape with triangular, fusiform, and/or globular perikarya. The densest cluster of NPY-ir cells were found in the mitral cell layer of the main olfactory bulb (MOB), arcuate nucleus of the hypothalamus, and pretectal nucleus of the thalamus. The MOB presented a unique pattern of NPY immunoreactivity. Laminar distribution of NPY-ir cells was observed in the MOB, neocortex, and hippocampus. Compared to rats, the tree shrews exhibited a particularly robust and widespread distribution of NPY-ir cells in the MOB, bed nucleus of the stria terminalis, and amygdala as well as the ventral lateral geniculate nucleus and pretectal nucleus of the thalamus. By contrast, a low density of neurons were scattered in the striatum, neocortex, polymorph cell layer of the dentate gyrus, superior colliculus, inferior colliculus, and dorsal tegmental nucleus. These findings provide the first detailed mapping of NPY immunoreactivity in the tree shrew brain and demonstrate species differences in the distribution of this neuropeptide, providing an anatomical basis for the participation of the NPY system in the regulation of numerous physiological and behavioral processes.

Localization of dopamine receptors in the tree shrew brain using [ [formula omitted]]-SCH23390 and [ [formula omitted]]-epidepride

Cloning of glucocorticoid receptor and mineralocorticoid receptor cDNA and gene expression in the central nervous system of the tree shrew ( Tupaia belangeri)

Stereotaxic 18F-FDG PET and MRI templates with three-dimensional digital atlas for statistical parametric mapping analysis of tree shrew brain

Amyloid beta (Aβ) accumulates in the human brain in an age-dependent manner during normal aging. However, Aβ accumulation has not been observed in rodents during normal aging. Tree shrews, the experimental animals studied here, are as small as rats but have a longer life span than rodents. We investigated Aβ accumulations in the brains of young and aged tree shrews by amyloid histochemistry and immunohistochemistry using antibodies to Aβ-42, Aβ-40, Aβ-16 and amyloid precursor protein (APP). In the brain of young tree shrews, there were no Aβ- immunoreactive (-ir) and APP-ir profiles. In the brains of aged tree shrews, Aβ-42-ir neuronal profiles were observed in the cortex, subiculum, basal ganglia, mammillary body and hypothalamus, but there were only a few weak Congo red-positive amyloid deposits. Aβ-42-, Aβ-40-, Aβ-16- and APP-ir blood vessels were observed. An early stage of amyloid accumulation occurs in the brains of aged tree shrews, indicating that this animal may be a good model for studying the start of Aβ accumulation.

Nucleus accumbens-linked executive control networks mediating reversal learning in tree shrew brain

The amino acid cystathionine is reported to show higher concentrations in the brains of man as compared to those of other species. Two-dimensional separation by electrophoresis-chromatography and densitometric analysis of amino acids showed that the brains of tree shrews had levels of cystathionine intermediate between those of man and other mammals such as tamarins, hedgehogs, and rats. Cystathionine may be involved in the circadian rhythms ofTupaiidae. In man a 10 fold variation in cerebral cystathionine is related to pathological conditions. Greater concentrations in white matter as compared to grey matter and other regional differences in brain tissue support the findings from inherited disorders that cystathionine plays an important role in the normal as well as the abnormal functioning of the brain.

Postnatal development of central nervous α2-adrenergic binding sites: an in vitro autoradiography study in the tree shrew

Astrocytes are associated with varying brain size between rodents and primates. As a close evolutionary relative of primates, the tree shrew (Tupaia belangeri) provides a valuable comparative model for investigating glial architecture. However, the anatomical distribution and morphological characteristics of astrocytes in the tree shrew brain remain poorly characterized. In this study, glial fibrillary acidic protein (GFAP) immunofluorescence was employed to systematically examine the spatial distribution and morphology of astrocytes in the whole brain of tree shrews. Notably, GFAP-immunoreactive (ir) astrocytes were detected throughout the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. Distinct laminar distribution was evident in regions such as the main olfactory bulb and hippocampus. Semi-quantitative comparisons revealed significant regional differences in astrocyte density between tree shrews and mice, encompassing the main olfactory bulb, accessory olfactory bulb, olfactory tubercle, cortex, hippocampus, cortical amygdaloid nucleus, hypothalamus, thalamus, superior colliculus, interpeduncular nucleus, median raphe nucleus, and parabrachial nucleus. Compared to mice, tree shrews exhibited higher astrocyte density with increased morphological complexity in the posterior hypothalamic nucleus, dorsomedial hypothalamic nucleus, ventromedial hypothalamic nucleus, and periaqueductal gray, but lower density with greater morphological complexity in the hippocampus and substantia nigra. In the paraventricular hypothalamic nucleus and lateral hypothalamic area, GFAP-ir astrocytes displayed comparable densities between tree shrews and mice but exhibited region-specific differences in morphological complexity. This study provides the first brain-wide mapping of GFAP-ir astrocytes in tree shrews, revealing marked interspecies differences in their distribution and morphology, and establishing a neuroanatomical framework for understanding astrocyte involvement in diverse physiological and behavioral functions.

The tree shrew brain has garnered considerable attention due to its remarkable similarities to human brain. However, the cellular composition and genetic signatures of tree shrew hippocampus across postnatal life remain poorly characterized. Here, we establish the first single-nucleus transcriptomic atlas of tree shrew hippocampus spanning postnatal life, detailing the dynamics and diversity of the neurogenic lineage, oligodendrocytes, microglia, and endothelial cells. Notably, cross-species transcriptomic comparison among humans, macaques, tree shrews, and mice reveals that the tree shrew transcriptome resembles that of macaques, making it a promising model for simulating human neurological diseases. More interestingly, we identified a unique class of tree shrew-specific neural stem cells and established SOX6, ADAMTS19, and MAP2 as their markers. Furthermore, aberrant gene expression and cellular dysfunction in the tree shrew hippocampus are linked to neuroinflammation and cognitive impairment during tree shrew aging. Our study provides extensive resources on cell composition and transcriptomic profiles, serving as a foundation for future research on neurodevelopmental and neurological disorders in tree shrews.