脑电图与早产儿脑损害的相关性研究

脑电图（Electroencephalography EEG）是观察早产儿（premature infants）脑损害的敏感方法。急性和慢性EEG的改变与早产儿以后的神经和认知功能异常有相关性,应用神经生理学的方法诊断早产儿脑损害,早期持续在ICU病房的EEG监测和在以后阶段的EEG检查相结合是比较理想的手段。     

感染与早产儿脑损伤临床关系探讨

目的:探讨感染与早产儿脑损伤(HIE,ICH,CWMD)的临床表现,治疗,预后和预防的关系。方法:对2000年1月-2006年10月214例早产儿进行临床分析。结果:胎膜早破32例,母亲妊高症23例,胎儿宫内窘迫33例,脐带扭转打结7人,母亲妊娠糖尿病4人,胎儿畸形4人;早产儿肺炎101人,早产儿寒冷损伤综合征7人,早产儿急性坏死性小肠结肠炎5人,低血糖症27人,低血钙症13人,早产儿缺氧缺血性脑病(HIE)76人,早产儿颅内出血(ICH)21人,早产儿脑白质损伤(CWMD)3人。早期诊断、合理抗感染治疗可减少早产儿HIE及ICH以及CWMD患儿的神经系统后遗症。结论:早产儿感染与HIE及ICH以及CWMD的关系密切,预防产前、产时、产后感染对减少或减轻早产儿脑损伤至关重要。     

Inhibition of the cGAS‐STING pathway ameliorates the premature senescence hallmarks of Ataxia‐Telangiectasia brain organoids

Ataxia‐telangiectasia (A‐T) is a genetic disorder caused by the lack of functional ATM kinase. A‐T is characterized by chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A‐T remains elusive. Here, we utilize human pluripotent stem cell‐derived cortical brain organoids to study A‐T neuropathology. Mechanistically, we show that the cGAS‐STING pathway is required for the recognition of micronuclei and induction of a senescence‐associated secretory phenotype (SASP) in A‐T olfactory neurosphere‐derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self‐DNA‐triggered SASP expression in A‐T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A‐T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A‐T and constitutes a novel therapeutic target for treating neuropathology in A‐T patients.     

Regulation of brain water during acute glucose-induced hyperosmolality in ovine fetuses, lambs, and adults.

We tested the hypothesis that, during acute glucose-induced hyperosmolality, the brain shrinks less than predicted on the basis of an ideal osmometer and that brain volume regulation is present in fetuses, premature and newborn lambs. Brain water responses to glucose-induced hyperosmolality were measured in the cerebral cortex, cerebellum, and medulla of fetuses at 60% of gestation, premature ventilated lambs at 90% of gestation, newborn lambs, and adult sheep. After exposure of the sheep to increases in osmolality with glucose plus NaCl, brain water and electrolytes were measured. The ideal osmometer is a system in which impermeable solutes do not enter or leave in response to an osmotic stress. In the absence of volume regulation, brain solute remains constant as osmolality changes. The osmotically active solute demonstrated direct linear correlations with plasma osmolality in the cerebral cortex of the fetuses at 60% of gestation (r = 0.72, n = 24, P = 0.0001), premature lambs (r = 0.58, n = 22, P = 0.005), newborn lambs (r = 0.57, n = 24, P = 0.004), and adult sheep (r = 0.70, n = 18, P = 0.001). Similar findings were observed in the cerebellum and medulla. Increases in the quantity of osmotically active solute over the range of plasma osmolalities indicate that volume regulation was present in the brain regions of the fetuses, premature lambs, newborn lambs, and adult sheep during glucose-induced hyperosmolality. We conclude that, during glucose-induced hyperosmolality, the brain shrinks less than predicted on the basis of an ideal osmometer and exhibits volume regulation in fetuses at 60% of gestation, premature lambs, newborn lambs, and adult sheep.     

Regulation of brain water during acute hyperosmolality in ovine fetuses, lambs, and adults.

In adult rats, when plasma osmolality increases, water flows across the blood-brain barrier down its concentration gradient from brain to plasma, and brain volume deceases. The brain responds to this stress by gaining osmotically active solutes, which limit water loss. This phenomenon is termed brain volume (water) regulation. We tested the hypothesis that brain volume regulation is more effective in young lambs and adult sheep than in fetuses, premature lambs, and newborn lambs. Brain water responses to acute hyperosmolality were measured in the cerebral cortex, cerebellum, and medulla of fetuses at 60 and 90% of gestation, premature ventilated lambs at 90% of gestation, newborn lambs, young lambs at 20-30 days of age, and adult sheep. After exposure of the sheep to increases in systemic osmolality with mannitol plus NaCl, brain water content and electrolytes were quantified. The ideal osmometer is a system in which impermeable solutes do not enter or leave in response to an osmotic stress. There were significant differences from an ideal osmometer in the cerebral cortex of fetuses at 90% of gestation, cerebral cortex, and cerebellum of newborn lambs, and cerebral cortex, cerebellum, and medulla of young lambs and adult sheep; however, there were no differences in the brain regions of fetuses at 60% of gestation and premature lambs, cerebellum and medulla of fetuses at 90% of gestation, and medulla of newborn lambs. We conclude that 1) brain water loss is maximal and brain volume regulation impaired in most brain regions of fetuses at 60 and 90% of gestation and premature lambs; 2) brain volume regulation develops first in the cerebral cortex of the fetuses at 90% of gestation and in the cerebral cortex and cerebellum of newborn lambs, and then it develops in the medulla of the lambs at 20-30 days of age; 3) brain water loss is limited and volume regulation present in the brain regions of young lambs and adult sheep; and 4) the ability of the brain to exhibit volume regulation develops in a region- and age-related fashion.     

Quantitative and dynamic expression profile of premature and active forms of the regional ADAM proteins during chicken brain development

The ADAM (A Disintegrin and Metalloprotease) family of transmembrane proteins plays important roles in embryogenesis and tissue formation based on their multiple functional domains. In the present study, for the first time, the expression patterns of the premature and the active forms of six members of the ADAM proteins — ADAM9, ADAM10, ADAM12, ADAM17, ADAM22 and ADAM23 — in distinct parts of the developing chicken brain were investigated by quantitative Western blot analysis from embryonic incubation day (E) 10 to E20. The results show that the premature and the active forms of various ADAM proteins are spatiotemporally regulated in different parts of the brain during development, suggesting that the ADAMs play a very important role during embryonic development.     

Phenotypic integration of neurocranium and brain

Evolutionary history of Mammalia provides strong evidence that the morphology of skull and brain change jointly in evolution. Formation and development of brain and skull co-occur and are dependent upon a series of morphogenetic and patterning processes driven by genes and their regulatory programs. Our current concept of skull and brain as separate tissues results in distinct analyses of these tissues by most researchers. In this study, we use 3D computed tomography and magnetic resonance images of pediatric individuals diagnosed with premature closure of cranial sutures (craniosynostosis) to investigate phenotypic relationships between the brain and skull. It has been demonstrated previously that the skull and brain acquire characteristic dysmorphologies in isolated craniosynostosis, but relatively little is known of the developmental interactions that produce these anomalies. Our comparative analysis of phenotypic integration of brain and skull in premature closure of the sagittal and the right coronal sutures demonstrates that brain and skull are strongly integrated and that the significant differences in patterns of association do not occur local to the prematurely closed suture. We posit that the current focus on the suture as the basis for this condition may identify a proximate, but not the ultimate cause for these conditions. Given that premature suture closure reduces the number of cranial bones, and that a persistent loss of skull bones is demonstrated over the approximately 150 million years of synapsid evolution, craniosynostosis may serve as an informative model for evolution of the mammalian skull.     

早产儿语言发展及其脑机制

早产儿语言发展存在特殊规律.行为研究发现,早产儿在词汇、句法、语义言语流畅性等方面存在发展滞后的现象.早产对语言发展的影响可能持续到成年早期,但具体的滞后程度受到生物因素和社会因素的影响.随着脑成像技术的发展,有研究开始考察早产儿的脑发育情况.研究者发现,青少年时期的早产儿在大脑白质、皮层下灰质和小脑结构等方面发生了改变,但关于早产儿语言发展的脑机制还有待进一步的研究来确证.简述了早产儿语言发展的行为研究和脑神经研究方面的最新进展,以揭示早产儿这一特殊群体在语言发展和认知神经方面的规律.研究认为,应结合行为研究与脑神经研究的优势,进一步深化对早产儿语言发展机制的探讨,也为考察正常儿童语言获得规律提供特殊的科学依据.     

Effects of acute hyperosmolality on blood-brain barrier function in ovine fetuses and lambs

We examined the effects of hyperosmolality on blood-brain barrier (BBB) permeability during development to test the vulnerability of the immature barrier to stress. The BBB response to hyperosmolality was quantified using the blood-to-brain transfer constant (Ki) with alpha-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Ki plotted against osmolality increased as a function of increases in osmolality in all groups and brain regions. The relationship was described (P < 0.05) by a segmented regression model. At lower osmolalities, changes in Ki were minimal, but after a break point (threshold) was reached, the increase (P < 0.05) was linear. We examined the responses of Ki to hyperosmolality within each brain region by comparing the thresholds and slopes of the second regression segment. Lower thresholds and higher slopes imply greater vulnerability to hyperosmolality in the younger groups. Thresholds increased (P < 0.05) with development in the thalamus, superior colliculus, pons, and spinal cord, and slopes of the second regression segment decreased (P < 0.05) in the cerebellum, hippocampus, inferior colliculus, medulla, and spinal cord. BBB resistance to hyperosmolality increased (P < 0.05) with development in most brain regions. The pattern of the Ki plotted against osmolality was (P < 0.05) heterogenous among brain regions in fetuses and premature and newborn lambs, but not in older lambs. We conclude that 1) BBB permeability increased as a function of changes in osmolality, 2) the barrier becomes more resistant to hyperosmolality during development, and 3) the permeability response to hyperosmolality is heterogenous among brain regions in fetuses and premature and newborn lambs.     

MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway

Primary microcephaly 1 is a neurodevelopmental disorder caused by mutations in the MCPH1 gene, whose product MCPH1 (also known as microcephalin and BRIT1) regulates DNA-damage response. Here we show that Mcph1 disruption in mice results in primary microcephaly, mimicking human MCPH1 symptoms, owing to a premature switching of neuroprogenitors from symmetric to asymmetric division. MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle. This misorients the mitotic spindle alignment and shifts the division plane of neuroprogenitors, to bias neurogenic cell fate. Silencing Cdc25b, a centrosome substrate of Chk1, corrects MCPH1-deficiency-induced spindle misalignment and rescues the premature neurogenic production in Mcph1-knockout neocortex. Thus, MCPH1, through its function in the Chk1-Cdc25-Cdk1 pathway to couple the centrosome cycle with mitosis, is required for precise mitotic spindle orientation and thereby regulates the progenitor division mode to maintain brain size.     

Acute and long-term proteome changes induced by oxidative stress in the developing brain

The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.     

Influence of neonatally administered gonadotropin on the sexual function of adult rats]

Male and female rats were daily injected with 10 IU HCG plus 10 IU FSH from the 1st to 14th day of life in order to investigate the influence of neonatal gonadotrophin administration on the sex-specific differentiation of the brain. When adult, the males showed hypogonadism associated with approximately normal sexual activity. In the females, precocious puberty, indicated by premature vaginal opening and spontaneous estrus, occurred. Furthermore, bisexuality with a tendency towards more male behavioural patterns was observed, but no impairment of ovarian cyclicity. Thus, hypergonadotrophic hypergonadism during the hypothalamic differentiation phase gave rise to bisexual behaviour in adult female rats associated with normal ovarian cycles. The question of a direct or indirect influence of gonadotrophins on the sex-specific brain differentiation is discussed.     

VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.     

Role of premature leptin surge in obesity resulting from intrauterine undernutrition

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to “developmental origins of health and disease.”     

TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ∼70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.     

Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain

Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C_18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C_18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.     

DISAGGREGATION OF BRAIN POLYSOMES AFTER d-LYSERGIC ACID DIETHYLAMIDE ADMINISTRATION IN VIVO: MECHANISM AND EFFECT OF AGE AND ENVIRONMENT1

Abstract— The cell-free protein synthesis activity and tRNA content of the increased pool of brain monosomes produced after d -lysergic acid diethylamide (LSD) administration were analyzed. Decreased reinitiation of protein synthesis rather than RNase activation or premature termination was shown to be the mechanism which results in brain polysome disaggregation after administration of the drug in vivo. At a constant dosage of 50 μg/kg the degree of polysome shift increases with age from 3-week-old rabbits to adults. There is also an extensive disaggregation of fetal brain polysomes when LSD is administered maternally. The LSD-induced polysome shift was shown to be altered by holding cage environment, pre-LSD sedation and post-LSD handling with brief restraint. It was apparent that elements of environment and physiological arousal were involved in the macromolecular effect of the drug on the protein synthesis apparatus of the brain.