血管性痴呆的动物模型、神经病理及其胆碱能机制

目的建立血管性痴呆(VD)的动物模型,并探讨VD认知障碍的发病机制。方法建立老龄大鼠VD模型,进行数字减影血管造影(DSA)检查、穿梭箱试验、神经病理检查和胆碱乙酰转移酶(ChAT)免疫组化测定。结果慢性脑血流灌注不足2月后出现明显的认知功能障碍,缺血4月后更明显;海马CA1区ChAT免疫反应阳性神经元分布及其数量较对照组显著减少,且与学习记忆障碍呈正相关。结论多发性脑梗死、进行性的皮层和海马神经元退变以及白质损害是VD的病理基础;额叶皮层和海马胆碱能神经元的损伤可能是认知功能受损害的形态学基础。     

Hyperbaric oxygen therapy improves cognitive functioning after brain injury

Hyperbaric oxygen therapy has been widely applied and recognized in the treatment of brain injury; however, the correlation between the protective effect of hyperbaric oxygen therapy and changes of metabolites in the brain remains unclear. To investigate the effect and potential mechanism of hy- perbaric oxygen therapy on cognitive functioning in rats, we established traumatic brain injury models using Feeney＇s free falling method. We treated rat models with hyperbaric oxygen therapy at 0.2 MPa for 60 minutes per day. The Morris water maze test for spatial navigation showed that the average escape latency was significantly prolonged and cognitive function decreased in rats with brain injury. After treatment with hyperbaric oxygen therapy for 1 and 2 weeks, the rats＇ spatial learning and memory abilities were improved. Hydrogen proton magnetic resonance spectroscopy analysis showed that the N-acetylaspartate/creatine ratio in the hippocampal CA3 region was sig- nificantly increased at 1 week, and the N-acetylaspartate/choline ratio was significantly increased at 2 weeks after hyperbaric oxygen therapy. Nissl staining and immunohistochemical staining showed that the number of nerve cells and Nissl bodies in the hippocampal CA3 region was significantly increased, and glial fibrillary acidic protein positive cells were decreased after a 2-week hyperbaric oxygen therapy treatment. Our findings indicate that hyperbaric oxygen therapy significantly im- proves cognitive functioning in rats with traumatic brain injury, and the potential mechanism is me- diated by metabolic changes and nerve cell restoration in the hippocampal CA3 region.     

The simultaneous presence of neuroepithelial cells and neuroepithelial bodies in the respiratory gas bladder of the longnose gar, Lepisosteus osseus, and the spotted gar, L. oculatus

Anatomical and functional studies on the autonomic innervation as well as the location of airway receptors in the air-bladder of lepisosteids are very fragmentary. These water-breathing fishes share in common with the bichirs the presence of a glottis (not a ductus pneumaticus) opening into the esophagus. In contrast to a high concentration of neuroepithelial cells (NECs) contained in the furrowed epithelium in the lung of Polypterus, these cells are scattered as solitary cells in the glottal epithelium, and grouped to form neuroepithelial bodies (NEBs) in the mucociliated epithelium investing the main trabeculae in the air-bladder of Lepisosteus osseus and L. oculatus. The present immunohistochemical studies also demonstrated the presence of nerve fibers in the trabecular striated musculature and a possible relation to NEBs in these species, and identified immunoreactive elements of this innervation. Tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), 5-HT and neuropeptide immunoreactivities were detected in the intramural nerve fibers. 5-HT and VIP immunopositive nerve fibers are apparently associated with NEBs. TH, VIP and SP immunoreactivities are also present in nerve fibers coursing in the radially arranged striated muscle surrounding the glottis and its submucosa. 5-HT positive neurons are also found in submucosal and the muscle layers of the glottis. The physiological function of the adrenergic and inhibitory innervation of the striated muscle as well as the neurochemical coding and morphology of the innervation of the NEBs are not known. Future studies are needed to provide evidence for these receptors with the capacity of chemoreceptors and/or mechanoreceptors.     

The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features

As the population ages, the economic and societal impacts of neurodegenerative and neuropsychiatric disorders are expected to rise sharply. Like dementia, late-life depressive disorders are common and are linked to increased disability, high healthcare utilisation, cognitive decline and premature mortality. Considerable heterogeneity in the clinical presentation of major depression across the life cycle may reflect unique pathophysiological pathways to illness; differentiating those with earlier onset who have grown older (early-onset depression), from those with illness onset after the age of 50 or 60 years (late-onset depression). The last two decades have witnessed significant advances in our understanding of the neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical functioning are implicated. New biomedical models extend well beyond perturbations of traditional monoamine systems to include altered neurotrophins, endocrinologic and immunologic system dysfunction, inflammatory processes and gene expression alterations. This more recent research has highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute to the various phenotypic presentations. This review highlights the major features of late-life depression, with specific reference to its associated aetiological, clinical, cognitive, neuroimaging, neuropathological, inflammatory and genetic correlates. Data examining the efficacy of pharmacological, non-pharmacological and novel treatments for depression are discussed. Ultimately, future research must aim to evaluate whether basic biomedical knowledge can be successfully translated into enhanced health outcomes via the implementation of early intervention paradigms.     

Neurotransmitter segregation: functional and plastic implications

Synaptic cotransmission is the ability of neurons to use more than one transmitter to convey synaptic signals. Cotransmission was originally described as the presence of a classic transmitter, which conveys main signal, along one or more cotransmitters that modulate transmission, later on, it was found cotransmission of classic transmitters. It has been generally accepted that neurons store and release the same set of transmitters in all their synaptic processes. However, some findings that show axon endings of individual neurons storing and releasing different sets of transmitters, are not in accordance with this assumption, and give support to the hypothesis that neurons can segregate transmitters to different synapses. Here, we review the studies showing segregation of transmitters in invertebrate and mammalian central nervous system neurons, and correlate them with our results obtained in sympathetic neurons. Our data show that these neurons segregate even classic transmitters to separated axons. Based on our data we suggest that segregation is a plastic phenomenon and responds to functional synaptic requirements, and to 'environmental' cues such as neurotrophins. We propose that neurons have the machinery to guide the different molecules required in synaptic transmission through axons and sort them to different axon endings. We believe that transmitter segregation improves neuron interactions during cotransmission and gives them selective and better control of synaptic plasticity.     

An evaluation of motion compensation strategies and repeatability for abdominal (1)H MR spectroscopy measurements in volunteer studies and clinical trials

Increased expression of choline kinase has frequently been shown in tumours and is thought to be associated with disease progression. Studies using magnetic resonance spectroscopy have shown an increase in total choline-containing metabolites (tCho) in tumour compared with healthy tissue. Subsequent reductions in tCho following successful treatment support the use of tCho as a biomarker of disease and response. However, accurate measurement of tCho using MRS in abdominal tumours is complicated by respiratory motion, blurring the acquisition volume and degrading the lineshape and signal-to-noise ratio (SNR) of metabolites. Motion compensation using prospectively gated acquisitions or offline correction of phase and frequency distortions can help restore the SNR and linewidth of metabolites. Prospectively gated acquisitions have the advantage of confining the volume of acquisition to the prescribed volume but are constrained by the repetition time (TR) of the respiratory motion. In contrast, data acquired for offline correction may use a shorter repetition time and therefore yield an increased SNR per unit time. In this study abdominal spectra acquired from single-voxel 'free-breathing' measurements in liver of healthy volunteers and in abdominal tumours of cancer patients were compared with those of prospective gating and with an implementation of offline correction. The two motion compensation methodologies were assessed in terms of SNR, linewidth and repeatability. Our experiments show that prospective gating and offline correction result in a 12-22% reduction in median tCho linewidth, while offline correction also provides a significant increase in SNR. The repeatability coefficient (the expected interval for 95% of repeat measurements) for tCho/water ratio was reduced by 37% (prospective gating) and 41% (offline correction). Both methods of motion compensation substantially improved the reproducibility of the tCho/water measurement and the tCho linewidth. While offline correction also leads to a significant improvement in SNR, it may suffer more from out-of-voxel contamination.     

Multimodal assessment of early tumor response to chemotherapy: comparison between diffusion-weighted MRI, 1H-MR spectroscopy of choline and USPIO particles targeted at cell death

The aim of this study was to determine the value of different magnetic resonance (MR) protocols to assess early tumor response to chemotherapy. We used a murine tumor model (TLT) presenting different degrees of response to three different cytotoxic agents. As shown in survival curves, cyclophosphamide (CP) was the most efficient drug followed by 5-fluorouracil (5-FU), whereas the etoposide treatment had little impact on TLT tumors. Three different MR protocols were used at 9.4 Tesla 24 h post-treatment: diffusion-weighted (DW)-MRI, choline measurement by (1) H MRS, and contrast-enhanced MRI using ultrasmall iron oxide nanoparticles (USPIO) targeted at phosphatidylserine. Accumulation of contrast agent in apoptotic tumors was monitored by T(2) -weighted images and quantified by EPR spectroscopy. Necrosis and apoptosis were assessed by histology. Large variations were observed in the measurement of choline peak areas and could not be directly correlated to tumor response. Although the targeted USPIO particles were able to significantly differentiate between the efficiency of each cytotoxic agent and best correlated with survival endpoint, they present the main disadvantage of non-specific tumor accumulation, which could be problematic when transferring the method to the clinic. DW-MRI presents a better compromise by combining longitudinal studies with a high dynamic range; however, DW-MRI was unable to show any significant effect for 5-FU. This study illustrates the need for multimodal imaging in assessing tumor response to treatment to compensate for individual limitations.     

七氟醚对幼年大鼠空间学习记忆功能及海马区胆碱能神经元活力的影响

目的探讨七氟醚对幼年大鼠空间学习记忆功能及海马区乙酰胆碱酯酶（acetylcholinesterase,AchE）活力、胆碱乙酰转移酶（choline acetyltransferase,ChAT）活力的影响。方法出生7dSD大鼠48只随机分为3组,各16只,吸入体积分数3%七氟醚2h和6h者分别为S1和S2组,不作任何处理者为C组。于出生后第16～20天行Morris水迷宫实验测试3组空间学习记忆功能;于吸入麻醉结束后次日（Ⅰ期）、水迷宫实验结束后次日（Ⅱ期）取大鼠海马组织,比色法测定AchE和ChAT活力。结果 S1组第2～4天和S2组第2～5天逃避潜伏期较C组延长（P〈0.05）,S2组第4～5天逃避潜伏期较S1组延长（P〈0.01）;S1和S2组Ⅰ期AchE活力较C组增加、ChAT活力较C组降低（P〈0.01）;S2组Ⅱ期AchE活力较C组及S1组增加（P〈0.05）,各组间ChAT活力比较差异无统计学意义（P〉0.05）。结论体积分数3%七氟醚通过增加海马AchE活力、降低ChAT活力而降低幼年大鼠空间学习记忆功能,吸入6h较吸入2h影响更明显。     

Interaction between total body gamma-irradiation and choline deficiency triggers immediate modulation of choline and choline-containing moieties

Abstract

Purpose: The objective of this study was to examine the effect of ⁶⁰Co-gamma (γ) radiation on acute phase modulation, if any, of choline and choline-containing moieties in choline-deficient subjects. Corresponding results could provide information that might be useful in the management of adverse effects of γ-radiation.

Materials and methods: Male Swiss mice maintained on a choline-sufficient diet (CSD) and choline-free diet (CFD) based on AIN-93M formula, were subjected to whole body γ-irradiation (2–6 Gy). Liver, serum and brain samples from each group were then tested for: (i) Alterations in choline and choline-containing moieties such as phosphatidylcholine (PC) and sphingomyeline (SM); and (ii) modulation of choline profile modulating enzymes such as phospholipase D (PLD) and total sphingomyelinase (t-SMase). Liver and brain samples were also subjected to histo-pathological examinations.

Results: No significant changes were observed in folate, choline, choline-containing moieties and choline-modulating enzymes in choline-sufficient mice. In contrast, interaction between cytotoxic effects of γ-radiation and choline deficiency modulated choline and choline-containing moieties. Feeding CFD reduced hepatic concentrations of choline, PC and SM whereas PLD and t-SMase activities were significantly raised. The decrease in liver choline and choline-containing moieties was accompanied by an increase in blood choline concentration. Despite choline deficiency, the level of choline and acetylcholine synthesizing enzyme choline acetyltransfease (ChAT) significantly increased in the brain.

Conclusions: We propose that choline deprivation and γ-radiation interact to modulate choline reserves of hepatic tissue, which might release choline to blood. Our studies also clearly showed that interaction between choline deficiency and γ-radiation might substantially enhance liver adipogenesis.