促红细胞生成素干预早产儿脑损伤机制的研究进展

早产儿脑损伤可继发多种严重并发症,其严重的神经系统后遗症已成为新的临床、公共卫生和社会问题.目前研究发现促红细胞生成素(erythropoietin,EPO)能减轻早产儿脑损伤,对损伤的脑神经细胞有保护和修复作用,并可能提高远期神经预后.EPO发挥神经保护作用的主要机制是促进早产儿脑血管成熟、缓解血管痉挛,促进血管新生,在缺血部位建立侧枝循环改善脑缺血情况;对缺血缺氧(hypoxic ischemic,HI)后神经元凋亡和炎性坏死的双重阻断作用;抗氧化效果;减少谷氨酸毒性;营养神经及促进神经元的增值、树突增多、功能增强等.EPO对早产儿脑损伤后的多重保护作用为早产儿脑损伤的治疗提供了临床应用前景.     

Symposium: Normal and abnormal REM sleep regulation: The importance of REM sleep for brain maturation

A number of studies, some done by us, are reviewed concerning the function of foetal/neonatal REM sleep. The hypothesis is put forward that REM sleep in early life serves as an indicator for: (1) the degree of brain maturation, and (2) the promotion of further brain development. This hypothesis, although not exclusive, differs from: the original theory of Roffwarg et al. (1966) that REM sleep serves as "wakefulness" during the period in which wakefulness is limited; and also from the theory of Crick and Mitchson (1983-the "unlearning" hypothesis of REM sleep). As the functions of sleep in general, and REM sleep in particular, are still unclear, we hope this review will suggest new possibilities for future research.     

Connection between gut microbiome and brain development in preterm infants

Dysbiosis of the gut microbiome in preterm infants predisposes the neonate to various major morbidities including neonatal necrotizing enterocolitis and sepsis in the neonatal intensive care unit, and adverse neurological outcomes later in life. There are parallel early developmental windows for the gut microbiota and the nervous system during prenatal to postnatal of life. Therefore, preterm infants represent a unique population in which optimization of initial colonization and microbiota development can affect brain development and enhance neurological outcomes. In this review, we will first discuss the factors affecting the assembly of neonatal gut microbiota and the contribution of dysbiosis in preterm infants to neuroinflammation and neurodevelopmental disorders. We then will discuss the emerging pathways connecting the gut microbiome and brain development. Further we will discuss the significance of current models for alteration of the gut microbiome (including humanized gnotobiotic models and exposure to antibiotics) to brain development and functions. Understanding the role of early optimization of the microbiome in brain development is of paramount importance for developing microbiome-targeted therapies and protecting infants from prematurity-related neurodevelopmental diseases.     

The functional neuroanatomy of working memory: contributions of human brain lesion studies

Studies of patients with focal brain lesions remain critical components of research programs attempting to understand human brain function. Whereas functional imaging typically reveals activity in distributed brain regions that are involved in a task, lesion studies can define which of these brain regions are necessary for a cognitive process. Further, lesion studies are less critical regarding the selection of baseline conditions needed in functional brain imaging research. Lesion studies suggest a functional subdivision of the visuospatial sketchpad of working memory with a ventral stream reaching from occipital to temporal cortex supporting object recognition and a dorsal stream connecting the occipital with parietal cortex enabling spatial operations. The phonological loop can be divided into a phonological short-term store in inferior parietal cortex and an articulatory subvocal rehearsal process relying on brain areas necessary for speech production, i.e. Broca's area, the supplementary motor association area and possibly the cerebellum. More uncertainty exists regarding the role of the prefrontal cortex in working memory. Whereas single cell studies in non-human primates and functional imaging studies in humans have suggested an extension of the ventral and dorsal path into different subregions of the prefrontal cortex, lesion studies together with recent single-cell and imaging studies point to a non-mnemonic role of the prefrontal cortex, including attentional control of sensory processing, integration of information from different domains, stimulus selection and monitoring of information held in memory. Our own data argue against a modulatory view of the prefrontal cortex and suggest that processes supporting working memory are distributed along ventral and dorsal lateral prefrontal cortex.     

Upregulation of cystathione β‐synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury

Encephalopathy of prematurity (EOP) is a complex form of cerebral injury that occurs in the setting of hypoxia‐ischemia (HI) in premature infants. Using a rat model of EOP, we investigated whether neonatal HI of the brain may alter the expression of cystathionine β‐synthase (CBS) and the components of the mammalian target of rapamycin (mTOR) signaling. We performed unilateral carotid ligation and induced HI (UCL/HI) in Long‐Evans rats at P6 and found increased CBS expression in white matter (i.e. corpus callosum, cingulum bundle and external capsule) as early as 24 h (P7) postprocedure. CBS remained elevated through P21, and, to a lesser extent, at P40. The mTOR downstream target 70 kDa ribosomal protein S6 kinase (p70S6K and phospho‐p70S6K) and 40S ribosomal protein S6 (S6 and phospho‐S6) were also overexpressed at the same time points in the UCL/HI rats compared to healthy controls. Overexpression of mTOR components was not observed in rats treated with the mTOR inhibitor everolimus. Behavioral assays performed on young rats (postnatal day 35–37) following UCL/HI at P6 indicated impaired preference for social novelty, a behavior relevant to autism spectrum disorder, and hyperactivity. Everolimus restored behavioral patterns to those observed in healthy controls. A gait analysis has shown that motor deficits in the hind paws of UCL/HI rats were also significantly reduced by everolimus. Our results suggest that neonatal HI brain injury may inflict long‐term damage by upregulation of CBS and mTOR signaling. We propose this cascade as a possible new molecular target for EOP—a still untreatable cause of autism, hyperactivity and cerebral palsy.     

The neuroanatomy of depression: A review

Depression is the most common psychiatric disorder, the number one cause of disability and affects up to 15% of the population. The aim of this review is to present a brief synopsis of the various biochemical imbalances thought to contribute to depression, aspects of anatomy possibly implicated in depression, and treatments related to targeting these specific locales. Multiple neurotransmitters and parts of the brain are involved with the disorder of depression. Although an exact etiology for depression has not been found in most cases, various treatments, medicinal, psychiatric and surgical, exist for this disabling disease. An improved knowledge of anatomical sites involved in patients with depression will help in future treatment modalities. Clin. Anat. 30:44–49, 2017. © 2016 Wiley Periodicals, Inc.     

The effects of maternal anti-alpha-enolase antibody expression on the brain development in offspring

Anti-alpha-enolase autoantibodies have not only been found to play an important role in autoimmune diseases but also cause neurological damage in adults. In this study, a pregnant mouse model with high serum alpha-enolase (ENO1)-specific antibody (ENO1Ab) was established by immunization with ENO1 protein to explore the effects of maternal circulatory ENO1Ab on the brain development in offspring. The pups showed impaired learning and memory abilities with obviously thinner tight junctions in the brain tissue. IgG deposits colocalized with both ENO1 protein and complement 3 (C3), and the membrane attack complex was obviously detectable in the brain tissues of pups from dams with high serum ENO1Ab expression. Our findings suggest that highly expressed ENO1Ab in the maternal circulation can pass through the blood-placenta-barrier and the compromised blood-brain barrier into the brain tissues of offspring and may cause neurological development impairment mainly through complement-dependent cytotoxicity.     

Age-related characteristics of brain development in children living in the north

The morphofunctional age-related development of the brain was studied in schoolchildren living in the difficult climatological-geographic and socioeconomic conditions of the north (Arkhangel’sk region). Of the 62 students in country middle schools, EEG amplitude-frequency, time, and spatial measures corresponded to age norms (European norms) in only 10 cases (16%). A further 26 children (53%) showed minor abnormalities in the form of an inadequate degree of organization of the temporospatial EEG pattern, mainly in the frontal and temporal lobes of the brain, with increases in the levels of the theta and delta rhythms, and the absence of any marked “functional nucleus” in the alpha rhythm. In the remaining 14 children (29%), EEG measures showed more marked delays in mental development (DMD), which were combined with learning difficulties and abnormal behavior. The retardation in the morphofunctional development of the brain in northern children averaged 1.5–2 years, which coincides with delays in hormonal and physical development described by other authors. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 7, pp. 729–739, July, 2005.     

A primer on investigating the role of the microbiome in brain and cognitive development

Incorporating information regarding the gut microbiota into psychobiological research promises to shed new light on how individual differences in brain and cognitive development emerge. However, the investigation of the gut-brain axis in development is still in its infancy and poses several challenges, including data analysis. Considering that the gut microbiome is an eco-system containing millions of bacteria, one needs to utilize a breadth of methodologies and data analytic techniques. The present review serves two purposes. First, this review will inform developmental psychobiology researchers about the emerging study of the gut-brain axis in development and second, this review will propose methodologies and data analytic strategies for integrating microbiome data in developmental research.     

甲基丙二酸血症脑损伤机制研究进展

甲基丙二酸血症是由于甲基丙二酰辅酶A变位酶或其辅酶腺苷钴胺素缺陷所致的一种遗传性代谢疾病。患者体内甲基丙二酸及其他代谢产物蓄积，造成脑组织损伤，可表现为各种不同程度的智力发育迟缓及严重的神经功能障碍。甲基丙二酸血症的脑损伤机制至今尚不完全明确，目前研究主要集中在：线粒体功能障碍、神经元细胞凋亡、细胞骨架磷酸化改变及髓鞘形成障碍等脑神经结构损伤；神经节苷脂和突触可塑性异常等脑神经发育损伤；以及认知和行为改变等脑功能损伤。     

Combined age- and trauma-related proteomic changes in rat neocortex: a basis for brain vulnerability

This proteomic study investigates the widely observed clinical phenomenon, that after comparable brain injuries, geriatric patients fare worse and recover less cognitive and neurologic function than younger victims. Utilizing a rat traumatic brain injury model, sham surgery or a neocortical contusion was induced in 3 age groups. Geriatric (21 months) rats performed worse on behavioral measures than young adults (12-16 weeks) and juveniles (5-6 weeks). Motor coordination and certain cognitive deficits showed age-dependence both before and after injury. Brain proteins were analyzed using silver-stained two-dimensional electrophoresis gels. Spot volume changes (>2-fold change, p<0.01) were identified between age and injury groups using computer-assisted densitometry. Sequences were determined by mass spectrometry of tryptic peptides. The 19 spots identified represented 13 different genes that fell into 4 general age- and injury-dependent expression patterns. Fifteen isoforms changed differentially with respect to both age and injury (p<0.05). Further investigations into the nature and function of these isoforms may yield insights into the vulnerability of older patients and resilience of younger patients in recovery after brain injuries.     

Early development of the cortical layers in the human brain

The cortical plate (CP) first appears at seven postconceptional weeks (pcw), when it splits the preexisting preplate into two layers, the marginal zone and the presubplate (pSP). Although three-dimensional (3D) analysis using fetal magnetic resonance imaging and two-dimensional tissue observations have been reported, there have been no studies analyzing the early development of the layer structure corresponding to the pSP stage in 3D. Here, we reconstructed 3-D models of the brain with a focus on the cortical layers in pSP stage. To achieve this, we digitized serial tissue sections of embryos between CS20 and CS23 from the Kyoto Collection (n = 7, approximately 7–8.5 pcw), and specimens at early fetal phase from the Blechschmidt Collection (n = 2, approximately 9.5–12 pcw, crown rump length [CRL] 39 and 64 mm). We observed tissue sections and 3D images and performed quantitative analysis of the thickness, surface area, and volume. Because the boundary between pSP and the intermediate zone (IZ) could not be distinguished in hematoxylin and eosin-stained sections, the two layers were analyzed together as a single layer in this study. The histology of the layers was observed from CS21 and became distinct at CS22. Subsequently, we observed the 3-D models; pSP-IZ was present in a midlateral region of the cerebral wall at CS21, and an expansion centered around this region was observed after CS22. We observed it over the entire cerebral hemisphere at early fetal phase (CRL 39 mm). The thickness of pSP-IZ was visible in 3D and was greater in the midlateral region. At the end of the pSP stage (CRL 64 mm), the thick region expanded to lateral, superior, and posterior regions around the primordium of the insula. While, the region near the basal ganglia was not included in the thickest 10% of the pSP-IZ area. Middle cerebral artery was found in the midlateral region of the cerebral wall, near the area where pSP-IZ was observed. Feature of layer structure growth was revealed by quantitative assessment as thickness, surface area, and volume. The maximum thickness value of pSP-IZ and CP increased significantly according to CRL, whereas the median value increased slightly. The layer structure appeared to grow and spread thin, rather than thickening during early development, which is characteristic during pSP stages. The surface area of the cerebral total tissue, CP, and pSP-IZ increased in proportion to the square of CRL. The surface area of CP and pSP-IZ approached that of the total tissue at the end of the pSP stage. Volume of each layer increased in proportion to the cube of CRL. pSP-IZ and CP constituted over 50% of the total tissue in volume at the end of the pSP stages. We could visualize the growth of pSP-IZ in 3D and quantify it during pSP stage. Our approach allowed us to observe the process of rapid expansion of pSP-IZ from the midlateral regions of the cerebral wall, which subsequently becomes the insula.     

Review: Accounting for prematurity in developmental assessment and the use of age-adjusted scores

OBJECTIVE: This review summarizes the literature to date concerning age adjustment in developmental assessment and illustrates relevant issues for clinicians and researchers in this area. METHODS: Pubmed, Medline, Premedline, and PsycInfo databases were used to search the following terms: assessment, prematurity, age adjustment, and adjusted age. Additional sources were obtained through the references listed in the primary articles. RESULTS: Differences in clinical opinions persist with regard to whether, what type, and how long age adjustments are to be made for premature infants. Research is inconclusive regarding the most appropriate method for accounting for prematurity. CONCLUSIONS: Previous data may no longer describe the current population of premature infants. Current research is needed to inform developmental assessment practices for this population. Meanwhile, clinicians should remain aware of the issues regarding whether and how to adjust for prematurity. The authors recommend a multifaceted approach to clinical decision making and provide suggestions for future research.     

Brief report: birth status, medical complications, and social environment: individual differences in development of preterm, very low birth weight infants

OBJECTIVE: To assess whether medical complications mediate the relationship between birth status (i.e., birth weight and gestational age) and developmental outcome of preterm, very low birth weight (VLBW) infants, as well as the role of the early social environment (maternal distress and social support) in infant development. METHOD: Birth status and medical complication information was collected during the child's NICU stay. Maternal distress was assessed with the Beck Depression Inventory and the Parenting Stress Index at 4 months corrected infant age. Social support was measured with the Dunst Scales at 4 months corrected age. Child development measures were collected at 4 and 13 months corrected age (Bayley MDI and PDI), and at 36 months chronological age (PPVT-R and Achenbach CBCL). RESULTS: Medical complications mediated the birth status-outcome relationship at 4 and 13 months, but not at 36 months. The 36-month outcomes were predicted by 4-month maternal distress and social support. CONCLUSIONS: Prematurity and VLBW are indirectly related to early developmental outcome through their association with medical complications. However, by 36 months, developmental outcomes are more closely related to aspects of the early social environment than to early physiological factors.     

Brain edema and protein expression of c-Fos and c-Jun in the brain after diffused brain injury

Objective: To investigate brain edema and protein expression of c-Fos and c-Jun in brain after diffuse brain injury, and to investigate the pathological change after brain injury, which may provide evidence for the clinical treatment of diffused brain injury. Methods: Marmarou method was used to establish the diffuse brain injury in rats. Results: After diffused brain injury, brain water content increased at 1 h, reached the peak at 1 d and remained at a high level at 7 d when compared with control group. One day after injury, diffuse subarachnoid hemorrhage was observed in the brain. HE staining showed vascular swelling and bleeding at the cortex and corpus callosum at 1 d. β-APP expression was found at the brainstem, hippocampus, thalamus, corpus callosum and periventricular regions. Pathological examination of ultrathin sections showed evidence edema and fracture of axons at 3 d after brain injury. The brain injury caused severe cerebral ischemia. The c-Fos and c-Jun expression increased at 1 h. The c-Fos expression peaked at 3 h (P < 0.05), then reduced, reached a maximal level again at 3 d (P < 0.05), and reduced significantly at 7 d but remained at a higher level when compared with control group (P < 0.05). The number of c-Jun positive cells peaked at 6 h (P < 0.05), then reduced, reached a maximal level again at 3 d and reduced markedly but still remained at a higher level when compared with control group (P < 0.05). Conclusion: After diffuse brain injury, brain water content and c-Fos/c-Jun expression change over time.     

Nnat基因在大鼠脑发育过程中表达的初步研究

目的:观察Nnat基因在大鼠脑发育过程中基因表达的变化规律,藉以探讨Nnat在神经系统发育过程中的作用。方法:采用半定量RT-PCR法分析出生前后大鼠脑内Nnat表达水平的变化,Western blot检测Nnat蛋白的表达。结果:在大鼠胚胎第9 d(E9)脑内Nnat mRNA开始表达,但表达量较低,以后其表达量逐渐升高,出生前有轻微下调。出生后大鼠的不同脑区Nnat mRNA的表达量都呈现下降趋势,60 d时达到较低的水平。Nnat蛋白在不同脑区都具有表达,但不同亚型蛋白量的相对比例不同。结论:Nnat基因在胚胎期及出生后大鼠脑内的表达量与中枢神经系统发育及分化过程的时间上有一定的同步性,提示Nnat的作用可能与神经元分化的调节有关。     

绒毛膜羊膜炎与早产儿脑损伤的相关性研究

目的探讨早产儿脑损伤与母亲绒毛膜羊膜炎的关系。方法选取2005年10月到2006年10月在我院出生的早产儿共98例。根据胎盘病检结果分为有绒毛膜羊膜炎组(41例)和无绒毛膜羊膜炎组(57例)。所有病例在生后3～7天内进行头颅B超检查,并在纠正胎龄40周时予NBNA(新生儿行为神经测定)评分。通过B超及NBNA评分观察两组脑损伤的发生情况。结果孕母有绒毛膜羊膜炎的早产儿脑损伤的发生率达39.02%,NBNA得分35.36±2.55,与对照组相比,差异显著(P<0.05)。结论绒毛膜羊膜炎与早产儿脑损伤的发生有一定关系。