Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume.
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The neuropeptide substance P and its receptor, the neurokinin 1 receptor (NK(1)R) have been proposed as possible targets for new antidepressant therapies. The present study investigated the effect of the NK(1)R antagonist L-760,735 and the tricyclic antidepressant clomipramine in the chronic psychosocial stress paradigm of adult male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of L-760,735 (10 mg kg(-1) day(-1)) or clomipramine (50 mg kg(-1) day(-1)). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Cell proliferation in the dentate gyrus and hippocampal volume were measured post mortem. Stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-14%), creatine and phosphocreatine (-15%) and choline-containing compounds (-15%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-45%), and hippocampal volume was decreased (-14%). The stress-induced changes of brain metabolites, hippocampal volume and dentate cytogenesis rate were prevented by concomitant drug administration. Elevated myo-inositol concentrations after both treatments hint to an astrocytic enhancement. These results suggest that-despite a different pharmacological profile-the NK(1)R antagonist L-760,735, a member of a novel class of antidepressant drugs, has comparable neurobiological efficacy to tricyclic antidepressants such as clomipramine. (+info)
Characterization of novel Alu- and tRNA-related SINEs from the tree shrew and evolutionary implications of their origins.
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We characterized two novel 7SL RNA-derived short interspersed nuclear element (SINE) families (Tu types I and II) and a novel tRNA-derived SINE family (Tu type III) from the tree shrew (Tupaia belangeri). Tu type I contains a monomer unit of a 7SL RNA-derived Alu-like sequence and a tRNA-derived region that includes internal RNA polymerase III promoters. Tu type II has a similar hybrid structure, although the monomer unit of the 7SL RNA-derived sequence is replaced by a dimer. Along with the primate Alu, the galago Alu type II, and the rodent B1, these two families represent the fourth and fifth 7SL RNA-derived SINE families to be identified. Furthermore, comparison of the Alu domains of Tu types I and II with those of other 7SL RNA-derived SINEs reveals that the nucleotides responsible for stabilization of the Alu domain have been conserved during evolution, providing the possibility that these conserved nucleotides play an indispensable role in retropositional activity. Evolutionary relationships among these 7SL RNA-derived SINE families, as well as phylogenetic relationships of their host species, are discussed. (+info)
Emergent properties of layer 2/3 neurons reflect the collinear arrangement of horizontal connections in tree shrew visual cortex.
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The superficial layers of primary visual cortex, unlike layer 4, have an extensive network of long-range horizontal connections linking sites of similar orientation preference. To identify possible functional consequences of this distinct anatomy, we compared the receptive field properties of layers 2/3 and 4 neurons in tree shrew primary visual cortex with electrophysiological recordings. We found that elongated receptive fields, strong orientation tuning, and length summation (properties predicted by the anatomy of the horizontal connections) are present in layer 2/3 neurons, but not in layer 4 neurons. We further characterized the summation fields of layer 2/3 neurons and found axis and orientation-specific facilitation that matched the distribution of horizontal connections. The functional signature of horizontal connections was also evident in the population response of layer 2/3 neurons; the intrinsic signal activation pattern elicited by an array of collinear Gabor elements was significantly stronger than that elicited by a noncollinear array. Furthermore, our results showed that this enhancement of population response was achieved without compromising spatial resolution along the collinear axis, providing stimulus-specific facilitation without filling in between stimuli. Taken together, these results suggest that horizontal connections play a significant role in shaping the visual responses of layer 2/3 neurons. (+info)
Cloning and characterization of cholesteryl ester transfer transfer protein isolated from the tree shrew.
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OBJECTIVE: To obtain the nucleotide sequence and deduced amino acid sequence of cholesteryl ester transfer protein (CETP) cDNA from the tree shrew (Tupaia glis). METHODS: The cDNA sequence of the tree shrew CETP was obtained by utilizing the technique of switching mechanism at 5' end of RNA transcript (SMART) and rapid amplification of cDNA end (RACE) from the first strand of the cDNA. The amino acid sequence of CETP was deduced from the cDNA sequence and its primary and secondary structures were predicted. RESULTS: The sequence of CETP cDNA from tree shrew (GenBank accession number AF334033) covers 1636 bp, including 178 bp at the 3' end of the untranslated region and a 1458 bp fragment in a coding region, which provides the complete sequence of mature tree shrew CETP, although not the initiator methionine. The first 24 bp encodes a partial signal peptide. The mature protein consists of 477 amino acids and is longer than the human version by one amino acid (Gly318). Comparing this amino acid sequence with those of other animals' CETPs, the identity between tree shrew and human and rabbit CETP is 88% and 82%, respectively. The protein is extremely hydrophobic as it contains many hydrophobic residues, especially at the C-terminal, consistent with its function in the transfer of neutral lipids. The amino acid residues concerning with binding and transferring neutral lipids are highly conserved. There is a deletion of an N-linked glycosylation site at Asn342 in the tree shrew CETP protein that may participate in the removal of peripheral cholesterol and cholesteryl ester by increasing its activity of transferring cholesteryl ester. CONCLUSION: The possible glycosylation in the tree shrew CETP may be involved in the molecular mechanism of its insusceptibility to atherosclerosis. (+info)
The morphological basis for binocular and ON/OFF convergence in tree shrew striate cortex.
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We used retrograde and anterograde transport methods and single-cell reconstructions to examine the projection from layer IV to supragranular layers in the tree shrew's striate cortex. We found that neurons in the ON and OFF subdivisions of layer IV (IVa and IVb, respectively) have overlapping terminal fields throughout layers II and III. Despite their overlap, these projections are organized in a highly stratified, mirror-symmetric fashion that respects the vertical position of neurons within each sublayer. Neurons in the middle of layer IV (lower IVa and upper IVb) project to layers IIIa/b, II, and I; neurons located at the edges of layer IV (upper IVa and lower IVb) project to the lower half of layer IIIc; and neurons in the middle of IVa and the middle of IVb project to upper IIIc. The stratified nature of the projections from layer IV to layer III is reminiscent of the pattern of ipsilateral and contralateral eye inputs to layer IV. Inputs from the ipsilateral eye are limited to the edges of layer IV (upper IVa and lower IVb), while those from the contralateral eye terminate throughout the depth of IVa and IVb. Thus, cells near the edges of layer IV should receive strong input from both eyes, while those in the middle of layer IV should receive mostly contralateral input. Taken together, these results suggest that the projections from layer IV to layer III bring together the information conveyed by the ON and OFF pathways, but do so in a way that matches the ocular dominance characteristics for each pathway. (+info)
Refractive state of tree shrew eyes measured with cortical visual evoked potentials.
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PURPOSE: To determine the refractive state of tree shrew eyes using visual evoked potentials (VEP's) recorded from primary visual cortex and compare the values with those obtained with streak retinoscopy and with an autorefractor. METHODS: VEP's were recorded in seven normal tree shrews and three animals in which approximately 5 D of myopia (relative to control eye) was induced by monocular -5 D lens wear. While the animals were awake, refractive correction was measured with an autorefractor before and after cycloplegia (1% atropine and 2.5% phenylepherine). When anesthetized, cycloplegic refractive correction was measured with streak retinoscopy. Then VEP's were produced with square-wave counterphased (1 Hz) high-contrast checkerboard patterns near the animals' high spatial frequency cutoff. Spherical lenses (2 D steps) were placed before the eye, and the VEP (average of 128 sweeps) was measured to determine the lens that produced the largest first positive peak (P1). RESULTS: VEP's were obtained over a broad range of trial lenses. Tuning was narrower when check sizes were small. In normal and control eyes, the P1 amplitude was largest, on average, for a trial lens of (mean +/- SD) -0.6 +/- 1.6 D (corrected for working distance but not vertex distance). The mean streak retinoscopy value (spherical equivalent at the corneal plane) was 7.0 +/- 0.8 D, and mean autorefractor values were 4.0 +/- 1.1 D (cycloplegic) and 3.7 +/- 1.2 D (noncycloplegic). In the eyes that compensated for a -5 D lens, the largest P1 values occurred with lenses with a power of -6.3 +/- 3.2 D. Thus, the VEP measure showed a similar treated vs. control eye difference as did streak retinoscopy (treated eyes, 4.7 +/- 0.4 D myopic) and the autorefractor (treated eyes, 4.8 +/- 0.5 D myopic). CONCLUSIONS: Normal tree shrew eyes are approximately emmetropic. The hyperopic values obtained with streak retinoscopy and the autorefractor are consistent with the presence of a "small-eye artifact" in tree shrews. Eyes that have compensated for a -5 D lens are myopic by approximately the value of the lens. (+info)
Alteration of the p53 gene during tree shrews' hepatocarcinogenesis.
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OBJECTIVE: To detect the expression and variation of the p53 gene in hepatocarcinogenesis of tree shrews induced by hepatitis B virus (HBV) and aflatoxin B1 (AFB1). METHODS: Tree shrews were divided into four groups: group A, infected with HBV and fed with AFB1; group B, only infected with HBV; group C, fed with AFB1 alone; and group D normal control. The tree shrews underwent liver biopsy every 15 weeks. Liver and tumor tissues were detected by immunohistochemistry and molecular biotechnologies. RESULTS: The incidence of hepatocellular carcinoma (HCC) was higher in group A (66.7%) than in groups B (0) and C (30%). HCC occurrence was earlier in group A than in group C (120.0+/-16.6 wk vs 153.3+/-5.8 wk, t=3.336, P<0.01). Mutated p53 protein was not found in all groups before 75 weeks of experiment. At the 105th week, the expression rates of mutated p53 protein were 78.6%, 60.0% and 71.4% in groups A, B and C respectively, which were significantly higher than that in group D (10%) (chi2> or =5.03, P<0.05). An abnormal band of the p53 gene was detected in groups A and C. The mutational points of the p53 gene in liver cancer of tree shrews were at codon 275, 78 and 13. Nucleotide sequence and amino acids sequence of tree shrew's wild-type p53 were 91.7% and 93.4% in homology compared with those of human p53, respectively. CONCLUSIONS: Remarkable synergistic effect on HCC exists between HBV and AFB1. Mutated p53 protein expressed before occurrence of HCC promotes the development of HCC. HBV and AFB1 may synergistically induce p53 gene mutation. (+info)
Isoform-specific changes in scleral transforming growth factor-beta expression and the regulation of collagen synthesis during myopia progression.
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The development of high myopia is associated with altered scleral extracellular matrix biochemistry. Previous studies highlight the importance of collagen turnover in this process, yet it is unclear which factors control scleral remodeling. This study used a mammalian model of myopia to investigate the capacity of TGF (transforming growth factor)-beta1, -beta2, and -beta3 to influence scleral remodeling in myopia. RT-PCR confirmed the presence of all mammalian TGF-beta isoforms in scleral tissue and scleral fibroblasts. Myopia was experimentally induced via monocular deprivation of pattern vision, and animals were allocated to two groups depending on the duration of treatment (1 or 5 days). Down-regulation of each isoform was apparent after only 1 day of myopia development (TGF-beta1, -32%; TGF-beta2, -27%; TGF-beta3, -42%). Whereas the decrease in TGF-beta1 and -beta3 expression was relatively constant between the two time points, differential down-regulation of TGF-beta2 was found between days 1 (-27%) and 5 (-50%). In vitro experiments, using primary scleral fibroblasts, demonstrated the capacity of all isoforms to increase collagen production in a dose-dependent manner. Changes in TGF-beta levels, which mimicked those during myopia induction, caused an approximately 15% reduction in collagen synthesis, which is qualitatively similar to those previously reported in vivo. These data represent the first demonstration of TGF-beta3 expression in the sclera and implicate all three TGF-beta isoforms in the control of scleral remodeling during myopia development. In addition, the early alterations in TGF-beta expression levels may reflect a role for these cytokines in mediating the retinoscleral signal that controls myopic eye growth. (+info)