垂体腺瘤组织DCX表达水平与肿瘤侵袭性的关系

目的 探讨垂体腺瘤组织双皮质素（DCX）的表达水平与肿瘤侵袭性的关系。方法 采用免疫组化染色和qRT-PCR检测2017年1月~2020年1月手术切除的88例垂体腺瘤组织和56例瘤旁垂体组织DCX表达情况和DCX mRNA表达量。根据Knosp分类方法评估肿瘤侵袭性,并分成侵袭组、无侵袭组。利用多因素logistic回归分析检验发生侵袭性的危险因素。受试者工作特征（ROC）曲线分析DCX mRNA预测垂体腺瘤侵袭性的效能。结果 88例中,侵袭组41例,无侵袭组47例。垂体腺瘤组织DCX阳性率（71.59%,63/88）明显高于瘤旁组织（17.86%,10/56;P<0.05）。垂体腺瘤组织DCX mRNA表达量（5.65±1.87）明显高于瘤旁组织（0.85±0.28;P<0.05）。侵袭组DCX mRNA表达量（6.42±0.86）明显高于无侵袭组（4.98±0.94;P<0.05）。多因素logistic回归分析显示DCX表达阳性是垂体腺瘤发生侵袭的独立危险因素（P<0.05）。ROC曲线显示,DCX mRNA表达量预测垂体腺瘤侵袭性的曲线下面积为0.775（95% CI 0.676~0.874;P<0.001）,最佳界值为5.640,敏感度为78.00%,特异度为61.70%。结论 垂体腺瘤组织DCX呈高表达,检测DCX表达水平对肿瘤侵袭性有一定的预测作用。     

Doublecortin is preferentially expressed in invasive human brain tumors

Doublecortin (DCX) is required for neuroblastic migration during the development of the cerebral cortex. DCX is a microtubule-associated protein that plays a role in cellular motility. These facts led us to hypothesize that DCX is increased in invasive brain tumors. DCX expression was assessed in 69 paraffin-embedded brain tumors of neuroepithelial origin. In addition, mouse brain sections of the subventricular zone and dentate gyrus were used as positive controls for immunostaining, and specificity of antibody staining was demonstrated by peptide neutralization. DCX was highly expressed in both high-grade invasive tumors (glioblastoma, n=11; anaplastic astrocytoma/oligoastrocytoma, n=7; and medulloblastoma/PNET, n=6) and low-grade invasive tumors (oligodendroglioma, n=3; and astrocytoma/oligoastrocytoma, n=5). However, DCX was less intensely expressed in the circumscribed group of tumors (pilocytic astrocytoma, n=6; ependymoma/subependymoma, n=7; dysembryoplastic neuroepithelial tumor, n=4; ganglioglioma, n=2; meningioma, n=9; and schwannoma, n=9). By the Cochran-Mantel-Haenszel statistical test, the circumscribed group was significantly different from both the high-grade invasive group (P<0.0001) and the low-grade invasive group (P<0.0001). We conclude that DCX is preferentially expressed in invasive brain tumors. In addition, DCX immunostaining was stronger at the margin of the tumor than at the center. For a subset of these tumors, we also detected DCX mRNA and protein by Northern and Western blotting. DCX mRNA and protein was detected in glioma cell lines by Northern blotting, immunofluorescence microscopy and Western blotting. Collectively, the immunohistochemistry, Western blots and Northern blots conclusively demonstrate expression of DCX by human brain tumors.     

Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.     

Differences in immunoreactivities of Ki-67 and doublecortin in the adult hippocampus in three strains of mice

Neurogenesis in the adult hippocampus is differentially influenced by the genetic background. We examined the differences in Ki-67 (a proliferating cell marker) and doublecortin (DCX; an immature progenitor cell marker) immunolabelling in the dentate gyrus (DG) of the adult hippocampus in three strains of mice (ICR, C57BL/6, and BALB/c) to evaluate the effect of genetic background on adult hippocampal neurogenesis. All strains showed constitutive immunoreactivity of either Ki-67 or DCX in the DG of the adult hippocampus. C57BL/6 mice showed significantly higher levels of Ki-67-immunopositive cells in the subgranular zone (SGZ) of the DG (approximately 2.2-fold) compared to ICR and BALB/c mice. The greatest number of DCX-immunopositive cells was found in C57BL/6 (approximately 1.6-fold), which differed significantly from ICR and BALB/c mice. However, there was no significant difference in the number of Ki-67- and DCX-immunopositive cells between BALB/c and ICR mice. Genetic differences with respect to certain aspects of hippocampal neurogenesis in adult mice may influence hippocampal functions, including learning and memory.     

Doublecortin expression continues into adulthood in horizontal cells in the rat retina

The doublecortin (DCX) protein is associated with microtubules, and is essential for neuronal migration, differentiation, and plasticity. In mammals, it is expressed in developing neurons and new immature neuroblasts in the adult brain, but not generally in mature neurons. In the retina, doublecortin is detectable as early as embryonic day 15 (E15), is highly expressed between E18 and E20, and is poorly expressed postnatally. In this study, we investigated immunohistochemically the expression and cellular localization of doublecortin in the adult rat retina. Doublecortin was expressed in the outer plexiform layer (OPL), and in cells in the outer border of the inner nuclear layer (INL). No other layers were labeled by anti-doublecortin antibodies. In double-labeling experiments, doublecortin expression co-localized with the expression of the marker for horizontal cells, calbindin D. By contrast, the marker for immature neuroblasts, polysialylated neural cell-adhesion molecule, was not expressed in horizontal cells. These results suggest that either horizontal cells have the capacity to continuously remodel their neurites or doublecortin has a different function in horizontal cells from the control of neuronal plasticity that it is known to modulate other neurites. In addition, doublecortin might be an alternative molecular marker for horizontal cells in the adult rat retina.     

Hippocampal neurovascular and hypothalamic-pituitary-adrenal axis alterations in spontaneously type 2 diabetic GK rats

Metabolic and vascular consequences of diabetes mellitus induce several CNS complications. The dentate gyrus of the hippocampus, a well-recognized target for diabetic alterations, is a neurogenic area associated with memory and learning processes. Here, we explored the hippocampal neurogenesis and its microenvironment (astrocytes, vascularisation and glucocorticoid influence) in a spontaneous model of type 2 diabetes, the Goto-Kakizaki rat. The number of proliferative Ki67⁺ cells and young doublecortin⁺ neurons was 2-fold higher in the hippocampus from diabetic rats than in normoglycemic control Wistar at 4 months of age. However, there was no difference in cell survival, studied 3 weeks after bromodeoxyuridine administration. Labeling of endothelial cells against von Willebrand factor, demonstrated a 50% decrease in the granular cell layer fractional area covered by blood vessels and a diminished capillary branching in diabetic rats. Finally, Goto-Kakizaki rats exhibited decreased glucocorticoid receptor immunolabeling in CA1, associated with higher corticosteronemia. In conclusion, diabetic rats showed increased cell proliferation and neuronal differentiation without concomitant survival modification. A high proliferation rate, potentially reflecting a compensatory mechanism for neuronal suffering, also exists in various pathological situations. However, endothelial alteration induced by chronic hyperglycemia, hyperleptinemia and insulin resistance and associated with deleterious glucocorticoid effects might impair effective neurogenesis in diabetic Goto-Kakizaki rats.     

Psychotic experiences in the general population: a twenty-year prospective community study

Adult neurogenesis is one of the most rapidly growing areas in neuroscience research and there is great interest in its potential role in the pathophysiology of psychiatric illness. In parallel with early development, adult neurogenesis occurs through the proliferation of precursor cells which migrate to specific regions and differentiate into neurons with characteristics indistinguishable from existing mature neurons. These findings have led to the re-definition of the concept of network plasticity in the adult brain, to include the formation of new neurons as well as new connections. This review examines the idea that adult neurogenesis may be disturbed in schizophrenia. We discuss evidence for abnormal mechanisms of neurogenesis and expression of developmental genes in schizophrenia, the influence of antipsychotic drugs on neurogenesis and the role of candidate schizophrenia susceptibility genes in adult neurogenesis. The recent discovery of molecular markers transiently expressed in newborn neurons within adult neurogenic brain regions could be used to probe whether neurogenesis is disturbed in schizophrenia. Adult neurogenesis could also be used as a unique tool for investigating genes involved in early brain development using post-mortem brains. This is particularly relevant for brain disorders with developmental origins such as schizophrenia.     

Temporal distribution of mRNA expression levels of various genes in the developing human inferior colliculus

The inferior colliculus (IC) is a major binaural integration center in the auditory pathway. Interestingly, studies on the prenatal development of the human IC are lacking. During development of the nervous system a large repertoire of proteins is involved in transforming simple neuroblast cells into functional elements of the adult neural circuits. The present study reports on the mRNA levels produced by 12 genes involved in pre- [12–29 weeks of gestation (WG)], postnatal [40 postnatal days (PND) as well as 2 and 5 postnatal months (PNM)] developing human IC. The mRNA expression levels of nestin, vimentin, GFAP and DCX during 12–24 WG indicate the stages of neurogenesis, migration and differentiation of the human fetal IC. A decrease in the GAP-43 mRNA levels along with an increase in synaptophysin and PSD-95 mRNA levels during late gestational ages (24–29 WG) suggests the formation of primitive contacts by neurons with their targets and the onset of synapse formation. Expression levels of EGAD mRNA were transient with an increase in the early gestational ages, whereas that of GAD-67 mRNA increased in late gestational ages, indicating the changing role of GABA from a trophic factor to that of a neurotransmitter. High levels of BDNF, NT-3 and MBP mRNA in the late gestational ages reveal that the human IC undergoes neuronal maturation, synaptogenesis and myelination by 29 WG. Therefore, it may be suggested that the morphological maturation of the human IC occurs between 22 and 29 WG and that this period appears to be critical in the shaping of adult-like physiological attributes.