Interspecies avian brain chimeras reveal that large brain size differences are influenced by cell-interdependent processes

Like humans, birds that exhibit vocal learning have relatively delayed telencephalon maturation, resulting in a disproportionately smaller brain prenatally but enlarged telencephalon in adulthood relative to vocal non-learning birds. To determine if this size difference results from evolutionary changes in cell-autonomous or cell-interdependent developmental processes, we transplanted telencephala from zebra finch donors (a vocal-learning species) into Japanese quail hosts (a vocal non-learning species) during the early neural tube stage (day 2 of incubation), and harvested the chimeras at later embryonic stages (between 9-12 days of incubation). The donor and host tissues fused well with each other, with known major fiber pathways connecting the zebra finch and quail parts of the brain. However, the overall sizes of chimeric finch telencephala were larger than non-transplanted finch telencephala at the same developmental stages, even though the proportional sizes of telencephalic subregions and fiber tracts were similar to normal finches. There were no significant changes in the size of chimeric quail host midbrains, even though they were innervated by the physically smaller zebra finch brain, including the smaller retinae of the finch eyes. Chimeric zebra finch telencephala had a decreased cell density relative to normal finches. However, cell nucleus size differences between each species were maintained as in normal birds. These results suggest that telencephalic size development is partially cell-interdependent, and that the mechanisms controlling the size of different brain regions may be functionally independent.     

Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8

Although TLR7 and TLR8 are phylogenetically and structurally related, their relative functions are largely unknown. The role of TLR7 has been established using TLR7-deficient mice and small molecule TLR7 agonists. The absence of TLR8-selective agonists has hampered our understanding of the role of TLR8. In this study TLR agonists selective for TLR7 or TLR8 were used to determine the repertoire of human innate immune cells that are activated through these TLRs. We found that TLR7 agonists directly activated purified plasmacytoid dendritic cells and, to a lesser extent, monocytes. Conversely, TLR8 agonists directly activated purified myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells (GM-CSF/IL-4/TGF-beta). Accordingly, TLR7-selective agonists were more effective than TLR8-selective agonists at inducing IFN-alpha- and IFN-regulated chemokines such as IFN-inducible protein and IFN-inducible T cell alpha chemoattractant from human PBMC. In contrast, TLR8 agonists were more effective than TLR7 agonists at inducing proinflammatory cytokines and chemokines, such as TNF-alpha, IL-12, and MIP-1alpha. Thus, this study demonstrated that TLR7 and TLR8 agonists differ in their target cell selectivity and cytokine induction profile.     

Patterns of fMRI activity dissociate overlapping functional brain areas that respond to biological motion

Accurate perception of the actions and intentions of other people is essential for successful interactions in a social environment. Several cortical areas that support this process respond selectively in fMRI to static and dynamic displays of human bodies and faces. Here we apply pattern-analysis techniques to arrive at a new understanding of the neural response to biological motion. Functionally defined body-, face-, and motion-selective visual areas all responded significantly to "point-light" human motion. Strikingly, however, only body selectivity was correlated, on a voxel-by-voxel basis, with biological motion selectivity. We conclude that (1) biological motion, through the process of structure-from-motion, engages areas involved in the analysis of the static human form; (2) body-selective regions in posterior fusiform gyrus and posterior inferior temporal sulcus overlap with, but are distinct from, face- and motion-selective regions; (3) the interpretation of region-of-interest findings may be substantially altered when multiple patterns of selectivity are considered.     

The circulation,metabolism, and functional activity of the human brain

Special issue dedicated to Dr. Louis Sokoloff.     

Steroid sulfatase and sulfuryl transferase activity in monkey brain tissue

Dehydroepiandrosterone and its sulfated form are commonly known as modulators of gamma-aminobutyrate A and N-methyl-D-aspartate receptors. In spite of poor permeability of the blood-brain barrier for sulfated steroids, high concentrations of dehydroepiandrosterone and also its sulfate have been found in brain tissue. Physiological concentrations of these neuromodulators are maintained by two enzymes present in the blood and many peripheral tissues, including the brain, namely, steroid sulfatase and neurosteroid sulfuryl transferase (NSST). This prompted us to investigate activities of these enzymes in primate brain tissue. Rather low neurosteroid sulfuryl transferase activity was detectable in in vitro incubations of cytosol fractions from male and female Macaca mulatta brains, dissected to cerebral cortex, subcortex, and cerebellum. In male monkeys, the highest activity was found in the cerebellum followed by cortex and subcortex. On the other hand, in female monkeys, the highest activity was determined in the cortex followed by subcortex and cerebellum. Steroid sulfatase activity was determined in in vitro microsomal samples from each of the above-mentioned brain regions. Specific activities in female cerebral regions declined in the order: cerebellum, cortex, and subcortex. In male monkeys, no significant difference among the studied regions was observed. Using dehydroepiandrosterone sulfate as a substrate, the apparent kinetic characteristics of steroid sulfatase were determined as follows: K(M) 36.10 +/- 8.33 microM, V(max) 8.38 +/- 1.68 nmol/h/mg protein. These results will serve as a basis for further studies concerning the pathophysiology of human brain tumors.     

Negative heterozygosity-fitness correlations observed with microsatellites located in functional areas of the genome

Genome-wide heterozygosity inferred from neutral markers such as microsatellites is often expected to (i) reflect individual inbreeding and (ii) covary positively with fitness, generating positive heterozygosity-fitness correlations (HFCs). The often forgotten other end of the inbreeding-outbreeding continuum is outbreeding depression: past a certain degree of heterozygosity, heterozygotes tend to have lower fitness than homozygotes. Outbreeding depression arises from the breakup of co-adapted gene complexes and/or the introgression of nonlocally adapted genes. Provided that a correlation in heterozygosity exists across loci, outbreeding depression will be reflected in negative HFCs. In this issue, Olano-Marin et al. (2011a) describe negative heterozygosity-fitness correlations (HFCs) in blue tits Cyanistes caeruleus (Fig. 1), whereby heterozygosity has a significant, negative effect on female hatching success and recruitment. This study, together with a similar study by the same authors published in Evolution (Olano-Marin et al. 2011b), forms an original contribution in two respects. First, in the same population, positive and negative HFCs were recorded, revealing both inbreeding and outbreeding depression depending on the trait studied (whereby both processes were reliant on unknown, and possibly different, sets of coding loci). Second, a large number of microsatellite markers were split into two functional groups: microsatellite markers were either designed using zebra finch expressed sequence tags (ESTs) or derived using traditional cloning methods and presumed to be neutral. Contrasting large classes of loci and their varying levels of polymorphism, rather than looking for one locus that would stand out among tens of randomly selected markers, pave the way for a more elegant and powerful approach to explore how HFCs vary across traits and among regions of the genome. [Figure: see text].     

Absence of correlations between glutamine-synthetase activity and dysmyelination-associated modifications of astroglia in the brain of murine mutants

Glutamine Synthetase (GS) activity was investigated in cerebellum (ce), cerebral cortex (cc), olfactory bulb (ob), and medulla oblongata (mo) of murine dysmyelinating mutants for correlations with modifications of astroglia associated with genetic dysmyelination. One of these mutants, jimpy, develops a strong gliosis throughout the CNS. The other three mutants: shiverer, mld, and quaking, exhibit various astrocytic responses to dysmyelination, but reduced gliosis if any. Comparison between CNS areas in control animals showed a higher GS activity in the olfactory bulb than in the cerebral cortex, medulla, and cerebellum. The developmental patterns of GS activity were similar in mutants and in controls in all four areas investigated. Data on Jimpy suggest that GS activity is not associated with reactive astrocytes.     

Gallium distribution in several human brain areas

Gallium is an element of increasing biological interest: It is involved in problems related to environmental pollution (Ga compounds are used in electronics industry) and to clinical treatments (Ga radionuclides are employed to detect neoplastic lesions). Moreover, since its chemical behavior is similar to that of aluminum, gallium could play a role in the health effects attributed to this element. Data on naturally occurring Ga levels in human samples from healthy subjects are scanty; regarding the brain, the only reliable values available in the literature were published by Hamilton in 1972/73. In this work, the gallium distribution in several human brain areas, evaluated by radiochemical neutron activation analysis (RNAA), was found to be dishomogeneous. The element concentration determined in dry samples was, in any case, lower than the ppb level.     

RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain

microRNAs (miRNAs) are small (approximately 22 nucleotide) regulatory RNAs which play fundamental roles in many biological processes. Recent studies have shown that the expression of many miRNAs is altered in various human tumors and some miRNAs may function as oncogenes or tumor suppressor genes. However, with the exception of glioblastoma multiforme, the expression of miRNAs in brain tumors is unknown. Furthermore, methods to profile miRNAs from formalin-fixed, paraffin-embedded (FFPE) archival tissues or to study their cellular and subcellular localization in FFPE tissues have been lacking. Here we report the coordinated miRNA expression analysis from the tissue level to the subcellular level, using the RAKE (RNA-primed, array-based, Klenow Enzyme) miRNA microarray platform in conjunction with Locked Nucleic Acid (LNA)-based in situ hybridization (LNA-ISH) on archival FFPE human brains and oligodendroglial tumors. The ability to profile miRNAs from archival tissues at the tissue level, by RAKE microarrays, and at the cellular level by LNA-ISH, will accelerate studies of miRNAs in human diseases.     

Cathepsin H activity in the human brain and human brain neoplasms

The human brain cathepsin H is shown to be a specific cysteine aminopeptidase with the optimum activity at pH 6.0. Human brain tumours of neuroectodermal (astrocytomas and glioblastomas) and epithelial (meningiomas) origin were used to study the cathepsin H activity in the malignant brain tissue. A significant increase in the aminopeptidase cathepsin H activity was found in malignant human brain tumours as compared to benign tumours and normal brain tissues.     

参与不同难度数字计算的脑区——脑功能磁共振成像研究

本研究用功能磁共振成像技术观察了人脑进行不同难度数字加减计算时的脑区激活情况,并探讨大脑皮层和皮层下结构在数字计算中的作用.用Siemens 1.5 Tesla磁共振机对16名右利手健康志愿者进行简单及复杂数字加减任务的fMRI扫描.实验采用组块设计.刺激任务分为简单加减计算任务、复杂加减计算任务和基线任务.用SPM99软件进行数据分析和脑功能区定位.分别比较同一任务各个脑区平均激活强度和同一脑区在两种任务中的激活强度.结果显示,简单及复杂加减计算激活的被试者的脑区基本相同,激活的皮层区主要见于额叶、顶叶、枕叶、扣带回、丘脑及小脑;简单及复杂加减计算激活的皮层下结构包括两侧尾状核、左纹状体边缘区等基底核结构和丘脑.在简单及复杂计算中,纹状体与皮质结构(额叶、顶叶)间激活强度均无显著性差异.简单计算与复杂计算比较,右顶叶,在复杂任务时出现激活,在简单任务时未出现激活.上述结果提示,完成数字计算任务的脑区除了额叶、顶叶、扣带回等皮层结构外,大脑皮层下的一些结构如纹状体、纹状体边缘区,也是参与数字计算的重要部位.皮层下结构纹状体和优势半球的纹状体边缘区参与了数字工作记忆,可能是进行数字计算神经环路的重要组成部位.右项叶(缘上回)只在复杂任务出现激活,该区可能是视空间记忆和加工的重要部位.     

Fronto-striatal correlations in normal and pathologic aging of the human brain

In psychically healthy persons of three age groups (30-40, 50-60, 80-90 years), as well as in those suffering from Alzheimer's disease (50-60 years) right and left hemispheres formations, including into a single functional system (fields 8, 10, 47 and the nucleus caudatus) have been investigated. Using the series of frontal paraffin sections 20 mcm thick, stained after Nissl and Bielschowsky methods, cyto-glioarchitectonics and neuronal composition of the structures mentioned have been studied. In 0.001 mm3 of the brain substance, in cortical layers II and V and in the nucleus caudatus head density of neurons, perineuronal glia, neurons with lipofuscin, size of the neurons have been calculated. Various degree of manifestation of morphological changes is revealed in different stages of the single functional system. These changes are directly proportional to the organizational level of the structures studied and depend on the stage of the process, on accompanying diseases and individual peculiarities of the person. They are more intensive in the frontal fields and weaker in the nucleus caudatus. At Alzheimer's disease they are more distinct in the associative fields 10 and 47, at normal ageing--in the motor structures--in the field 8 and then in the nucleus caudatus. Spreading of the pathological process occurs with a predominant damage of neurons of cholinergic origin.     

Interspecies chimeric complementation for the generation of functional human tissues and organs in large animal hosts

The past decade’s rapid progress in human pluripotent stem cell (hPSC) research has generated hope for meeting the rising demand of organ donation, which remains the only effective cure for end-stage organ failure, a major cause of death worldwide. Despite the potential, generation of transplantable organs from hPSCs using in vitro differentiation is far-fetched. An in vivo interspecies chimeric complementation strategy relying on chimeric-competent hPSCs and zygote genome editing provides an auspicious alternative for providing unlimited organ source for transplantation.     

Metabolic and functional studies on post-mortem human brain

The evidence that samples of human brain tissue obtained at autopsy may be used as starting material for the isolation of cellular and subcellular preparations which exhibit metabolic and functional activity when incubated in vitro has been reviewed. Supporting evidence has been found in data from model experiments which used animal brain as the source material. Active preparations have been obtained after considerable (up to 24 h) post mortem delays. Such findings are less surprising when the post mortem stability of key tissue components (enzymes, receptors, nucleic acids) and the retention of cellular integrity are examined. The data from these fields have been reviewed and their relevance to functional studies assessed. Studies which use human autopsy material must consider many additional sources of variation not found in experiments with animal brain and the major problems are briefly discussed. It is argued that functional experiments present few, if any, difficulties not already inherent in static analyses of autopsy material and some procedures which help to minimise these difficulties are outlined. Experimentation in this area is greatly aided by the finding that metabolically and functionally active preparations may be obtained from frozen tissue pieces. Dynamic studies provide a new approach for testing hypotheses of the mechanisms underlying human brain disorders and for studying the actions of neuroactive drugs in man.     

Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging

Functional MRI is a popular tool for investigating central processing of visceral pain in healthy and clinical populations. Despite this, the reproducibility of the neural correlates of visceral sensation by use of functional MRI remains unclear. The aim of the present study was to address this issue. Seven healthy right-handed volunteers participated in the study. Blood oxygen level-dependent contrast images were acquired at 1.5 T while subjects received nonpainful and painful phasic balloon distensions ("on-off" block design, 10 stimuli per "on" period, 0.3 Hz) to the distal esophagus. This procedure was repeated on two further occasions to investigate reproducibility. Painful stimulation resulted in highly reproducible activation over three scanning sessions in the anterior insula, primary somatosensory cortex, and anterior cingulate cortex. A significant decrease in strength of activation occurred from session 1 to session 3 in the anterior cingulate cortex, primary somatosensory cortex, and supplementary motor cortex, which may be explained by an analogous decrease in pain ratings. Nonpainful stimulation activated similar brain regions to painful stimulation, but with greater variability in signal strength and regions of activation between scans. Painful stimulation of the esophagus produces robust activation in many brain regions. A decrease in subjective perception of pain and brain activity from the first to the final scan suggests that serial brain imaging studies may be affected by habituation. These findings indicate that for brain imaging studies that require serial scanning, development of experimental paradigms that control for the effect of habituation is necessary.