The mechanism underlying acrylamide-induced neurotoxicity remains controversial. Previous studies have focused on acrylamide-induced toxicity in adult rodents, but neurotoxicity in weaning rats has not been investigated. To explore the neurotoxic effect of acrylamide on the developing brain, weaning rats were gavaged with 0, 5, 15, and 30 mg/kg acrylamide for 4 consecutive weeks. No obvious neurotoxicity was observed in weaning rats in the low-dose acrylamide group (5 mg/kg). However, rats from the moderate- and high-dose acrylamide groups (15 and 30 mg/kg) had an abnormal gait. Furthermore, biochemical tests in these rats demonstrated that glutamate concentration was significantly reduced, and γ-aminobutyric acid content was significantly increased and was dependent on acrylamide dose. Immunohistochemical staining showed that in the cerebral cortex, γ-aminobutyric acid, glutamic acid decarboxylase and glial fibrillary acidic protein expression increased remarkably in the moderate- and high-dose acrylamide groups. These results indicate that in weaning rats, acrylamide is positively associated with neurotoxicity in a dose-dependent manner, which may correlate with upregulation of γ-aminobutyric acid and subsequent neuronal degeneration after the initial acrylamide exposure.

Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to Alzheimer's disease (AD). Here we demonstrate deposition of fragments from the Vps10p member sortilin at senile plaques (SPs) in aged and AD human cerebrum. Sortilin changes were characterized in postmortem brains with antibodies against the extracellular and intracellular C-terminal domains. The two antibodies exhibited identical labeling in normal human cerebrum, occurring in the somata and dendrites of cortical and hippocampal neurons. The C-terminal antibody also marked extracellular lesions in some aged and all AD cases, appearing as isolated fibrils, mini-plaques, dense-packing or circular mature-looking plaques. Sortilin and β-amyloid (Aβ) deposition were correlated overtly in a region/lamina- and case-dependent manner as analyzed in the temporal lobe structures, with co-localized immunofluorescence seen at individual SPs. However, sortilin deposition rarely occurred around the pia, at vascular wall or in areas with typical diffuse Aβ deposition, with the labeling not enhanced by section pretreatment with heating or formic acid. Levels of a major sortilin fragment ~15 kDa, predicted to derive from the C-terminal region, were dramatically elevated in AD relative to control cortical lysates. Thus, sortilin fragments are a prominent constituent of the extracellularly deposited protein products at SPs in human cerebrum.

The mammalian cerebrum performs high-level sensory perception, motor control and cognitive functions through highly specialized cortical and subcortical structures1. Recent surveys of mouse and human brains with single-cell transcriptomics2-6 and high-throughput imaging technologies7,8 have uncovered hundreds of neural cell types distributed in different brain regions, but the transcriptional regulatory programs that are responsible for the unique identity and function of each cell type remain unknown. Here we probe the accessible chromatin in more than 800,000 individual nuclei from 45 regions that span the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to map the state of 491,818 candidate cis-regulatory DNA elements in 160 distinct cell types. We find high specificity of spatial distribution for not only excitatory neurons, but also most classes of inhibitory neurons and a subset of glial cell types. We characterize the gene regulatory sequences associated with the regional specificity within these cell types. We further link a considerable fraction of the cis-regulatory elements to putative target genes expressed in diverse cerebral cell types and predict transcriptional regulators that are involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of noncoding risk variants associated with various neurological diseases and traits in humans.

Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs)1, and recent studies have identified primate-specific neuronal populations at the molecular level2. However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution.

The changes in Asn-linked oligosaccharide composition in the murine cerebrum during development have been examined by high-performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS). The oligosaccharides, obtained from murine cerebrum in several developmental stages, were separated by HPLC on anion-exchange and reverse-phase columns. We found that two Asn-linked oligosaccharides, designated oligosaccharide I and oligosaccharide II, had their expression changed during postnatal development. Whereas oligosaccharide I was reduced during brain development, oligosaccharide II was increased. The structures of oligosaccharides I and II were analyzed by ESI-MS and sequential exoglycosidase digestions. Judging from the molecular and fragment ions in each oligosaccharide, the oligosaccharide I was composed of 5Hex+2HexNAc+ABOE (MW 1467.2) and the oligosaccharide II was 3Hex+4HexNAc+DoHex+ABOE (MW 1695.2). The results of sequential exoglycosidase digestion indicated that the oligosaccharide I was an oligomannose type saccharide and the oligosaccharide II was a biantennary complex type saccharide including fucose. The proposed structures are shown below. These results offer an important clue to the role of Asn-linked oligosaccharides associated with development of the central nervous system.

Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28-33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V-VI projection neurons (p = 0.02), Tbr1-positive layers V-VI projection neurons (p < 0.0001), astrocytes (p = 0.03), and oligodendrocytes (p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II-IV projection neurons (p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum (p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference (p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short-term; the long-term structural and functional consequences of these alterations need to be investigated.

Normal volunteers, aged 30 to 99 years, were studied with MRI. Age was related to estimated volumes of: gray matter, white matter, and CSF of the cerebrum and cerebellum; gray matter, white matter, white matter abnormality, and CSF within each cerebral lobe; and gray matter of eight subcortical structures. The results were: 1) Age-related losses in the hippocampus were significantly accelerated relative to gray matter losses elsewhere in the brain. 2) Among the cerebral lobes, the frontal lobes were disproportionately affected by cortical volume loss and increased white matter abnormality. 3) Loss of cerebral and cerebellar white matter occurred later than, but was ultimately greater than, loss of gray matter. It is estimated that between the ages of 30 and 90 volume loss averages 14% in the cerebral cortex, 35% in the hippocampus, and 26% in the cerebral white matter. Separate analyses were conducted in which genetic risk associated with the Apolipoprotein E epsilon4 allele was either overrepresented or underrepresented among elderly participants. Accelerated loss of hippocampal volume was observed with both analyses and thus does not appear to be due to the presence of at-risk subjects. MR signal alterations in the tissues of older individuals pose challenges to the validity of current methods of tissue segmentation, and should be considered in the interpretation of the results.

Myelin water imaging, a magnetic resonance imaging technique capable of resolving the fraction of water molecules which are located between the layers of myelin, is a valuable tool for investigating both normal and pathological brain structure in vivo. There is a strong need for pulse sequences which improve the quality and applicability of myelin water imaging in a clinical setting. In this study, we validated the use of a fast multi echo T(2) relaxation sequence for myelin water imaging. Using a multiple combined gradient and spin echo (GRASE) technique, we attain whole cerebrum myelin water images in under 15 minutes. Region of interest analysis indicates that this fast GRASE imaging sequence produces results which are in good agreement with pure spin echo measurements (R(2)=0.95, p<0.0001). This drastic improvement in speed and brain coverage compared to current spin echo standards will allow increased inclusion of myelin water imaging in neurological research protocols and opens up the possibility of applications in a clinical setting.

Many predatory animals, such as the praying mantis, use vision for prey detection and capture. Mantises are known in particular for their capability to estimate distances to prey by stereoscopic vision. While the initial visual processing centers have been extensively documented, we lack knowledge on the architecture of central brain regions, pivotal for sensory motor transformation and higher brain functions. To close this gap, we provide a three-dimensional (3D) reconstruction of the central brain of the Asian mantis, Hierodula membranacea. The atlas facilitates in-depth analysis of neuron ramification regions and aides in elucidating potential neuronal pathways. We integrated seven 3D-reconstructed visual interneurons into the atlas. In total, 42 distinct neuropils of the cerebrum were reconstructed based on synapsin-immunolabeled whole-mount brains. Backfills from the antenna and maxillary palps, as well as immunolabeling of γ-aminobutyric acid (GABA) and tyrosine hydroxylase (TH), further substantiate the identification and boundaries of brain areas. The composition and internal organization of the neuropils were compared to the anatomical organization of the brain of the fruit fly (Drosophila melanogaster) and the two available brain atlases of Polyneoptera-the desert locust (Schistocerca gregaria) and the Madeira cockroach (Rhyparobia maderae). This study paves the way for detailed analyses of neuronal circuitry and promotes cross-species brain comparisons. We discuss differences in brain organization between holometabolous and polyneopteran insects. Identification of ramification sites of the visual neurons integrated into the atlas supports previous claims about homologous structures in the optic lobes of flies and mantises.

Vimentin-containing cells (VCCs) are potential neural precursor cells in central nervous systems, Thus, we studied the alteration of VCCs proliferation, differentiation and migration in the cerebrum during different stages of Tg(SOD1*G93A)1Gur mice. It aims to search potential ways regulating the proliferation, differentiation and migration of endogenous VCCs, to enhance their neural repair function and to cure or prevent from the development of ALS. We observed and analyzed the proliferation, differentiation and migration of VCCs in different anatomic regions and cell types of cerebrum at different stages including the pre-onset (60-70 days), onset (90-100 days) and progression (120-130 days) of wild-type (WT) and Tg(SOD1*G93A)1Gur mice using the fluorescent immunohistochemical technology. Results showed that VCCs in the cerebrum were mostly distributed in the ventricular system, periventricular structures, the hippocampus and the cerebral cortex in WT mice. VCCs significantly reduced in the motor cortex and the cingulate cortex in Tg(SOD1*G93A)1Gur mice. All vimentin expressed in the extranuclear and almost all VCCs were astrocytes in WT mice and Tg(SOD1*G93A)1Gur mice. There were no significant difference in the number of Brdu and nestin positive cells in left and right brains of WT mice and Tg(SOD1*G93A)1Gur mice in the period of 60-130 days. Our data suggested that there existed extensively NPCs in the cerebrum of adult mice. In ALS-like Tg(SOD1*G93A)1Gur mice, VCCs in the motor cortex, the olfactory cortex and the cingulate cortex showed that no any proliferation and redistribution in neural cells of VCCs in the cerebrum occurred in all stages of ALS, might migrate to damaged regions.

Protein SUMOylation regulates multiple processes involved in the differentiation and maturation of cells and tissues during development. Despite this, relatively little is known about the spatial and temporal regulation of proteins that mediate SUMOylation and deSUMOylation in the CNS. Here we monitor the expression of key SUMO pathway proteins and levels of substrate protein SUMOylation in the forebrain and cerebellum of Wistar rats during development. Overall, the SUMOylation machinery is more highly-expressed at E18 and decreases thereafter, as previously described. All of the proteins investigated are less abundant in adult than in embryonic brain. Furthermore, we show for first time that the profiles differ between cerebellum and cerebrum, indicating differential regional regulation of some of the proteins analysed. These data provide further basic observation that may open a new perspective of research about the role of SUMOylation in the development of different brain regions.

Danionella cerebrum is a new vertebrate model that offers an exciting opportunity to visualize dynamic biological processes in intact adult animals. Key advantages of this model include its small size, life-long optical transparency, genetic amenability and short generation time. Establishing a reliable method for longitudinal in vivo imaging of adult D. cerebrum while maintaining viability will allow in-depth image-based studies of various processes involved in development, disease onset and progression, wound healing, and aging in an intact live animal. Here, a method for both prolonged and longitudinal confocal live imaging of adult D. cerebrum using custom-designed and 3D-printed imaging chambers is described. Two transgenic D. cerebrum lines were created to test the imaging system, i.e. Tg(mpeg1:dendra2) and Tg(kdrl:mCherry-caax). The first line was used to visualize macrophages and microglia, and the second for spatial registration. By using this approach, differences in immune cell morphology and behavior during homeostasis as well as in response to a stab wound or two-photon-induced brain injury were observed in intact adult fish over the course of several days.

Primary and secondary traumatic brain injury (TBI) can cause tissue damage by inducing cell death pathways including apoptosis, necroptosis, and autophagy. However, similar pathways can also lead to senescence. Senescent cells secrete senescence-associated secretory phenotype proteins following persistent DNA damage response signaling, leading to cell disorders. TBI initially activates the cell cycle followed by the subsequent triggering of senescence. This study aims to clarify how the mRNA and protein expression of different markers of cell cycle and senescence are modulated and switched over time after TBI. We performed senescence-associated-β-galactosidase (SA-β-gal) staining, immunohistochemical analysis, and real-time PCR to examine the time-dependent changes in expression levels of proteins and mRNA, related to cell cycle and cellular senescence markers, in the cerebrum during the initial 14 days after TBI using a mouse model of controlled cortical impact (CCI). Within the area adjacent to the cerebral contusion after TBI, the protein and/or mRNA expression levels of cell cycle markers were increased significantly until 4 days after injury and senescence markers were significantly increased at 4, 7, and 14 days after injury. Our findings suggested that TBI initially activated the cell cycle in neurons, astrocytes, and microglia within the area adjacent to the hemicerebrum contusion in TBI, whereas after 4 days, such cells could undergo senescence in a cell-type-dependent manner.

This data article contains complementary tables related to the research article entitled, 'Effects of repetitive transcranial magnetic stimulation on ER stress-related genes and glutamate, γ-aminobutyric acid, and glycine transporter genes in mouse brain' (Ikeda et al. (2017) [1]), which showed that rTMS modulates glutamate, GABA and glycine transporters and regulates ER stress-related genes. Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in mouse cerebrum treated with rTMS for 30 days (Tables 1-10).

A considerable number of cells expressing typical immature neuronal markers including doublecortin (DCX+) are present around layer II in the cerebral cortex of young and adult guinea pigs and other larger mammals, and their origin and biological implication await further characterization. We show here in young adult guinea pigs that these DCX+ cells are accompanied by in situ cell division around the superficial cortical layers mostly in layer I, but they co-express proliferating cell nuclear antigen (PCNA) and an early neuronal fate determining factor, PAX6. A small number of these DCX+ cells also colocalize with BrdU following administration of this mitotic indicator. Cranial X-ray irradiation causes a decline of DCX+ cells around layer II, and novel environmental exploration induces c-Fos expression among these cells in several neocortical areas. Together, these data are compatible with a notion that DCX+ cortical neurons around layer II might derive from proliferable neuronal precursors around layer I in young adult guinea pig cerebrum, and that these cells might be modulated by experience under physiological conditions.

The global features of H3K4 and H3K27 trimethylations (H3K4me3 and H3K27me3) have been well studied in recent years, but most of these studies were performed in mammalian cell lines. In this work, we generated the genome-wide maps of H3K4me3 and H3K27me3 of mouse cerebrum and testis using ChIP-seq and their high-coverage transcriptomes using ribominus RNA-seq with SOLiD technology. We examined the global patterns of H3K4me3 and H3K27me3 in both tissues and found that modifications are closely-associated with tissue-specific expression, function and development. Moreover, we revealed that H3K4me3 and H3K27me3 rarely occur in silent genes, which contradicts the findings in previous studies. Finally, we observed that bivalent domains, with both H3K4me3 and H3K27me3, existed ubiquitously in both tissues and demonstrated an invariable preference for the regulation of developmentally-related genes. However, the bivalent domains tend towards a "winner-takes-all" approach to regulate the expression of associated genes. We also verified the above results in mouse ES cells. As expected, the results in ES cells are consistent with those in cerebrum and testis. In conclusion, we present two very important findings. One is that H3K4me3 and H3K27me3 rarely occur in silent genes. The other is that bivalent domains may adopt a "winner-takes-all" principle to regulate gene expression.

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.

Although there has been much neurobiological research on major depressive disorder, research on the neurological function of depressive symptoms (DS) or subclinical depression is still scarce, especially in older women with DS.

The developing brain is known to be sensitive to the toxic effects of methylmercury (MeHg). The effects of toxic levels of MeHg exposure during the most seemingly vulnerable window of the cerebrum are not well studied. In this study, we aimed to examine the specific effects of toxic levels of MeHg on neurobehavior, neurodegeneration, and selenoenzyme activity in the cerebrum of infant rats. Male Wistar rats (n = 8/group) were orally treated with MeHg at an acute toxic dose (8 mg Hg/kg/day) for 10 consecutive days starting on postnatal day 14 (P14). The MeHg-exposed rats showed a significant reduction in body weight after day 8 and severe neurological symptoms similar to dystonia on day 12 (P25). Motor coordination deficits determined using the rotarod performance test and short-term memory impairment determined using the Y-maze task were observed in the MeHg-exposed rats on day 11 (P24). The MeHg-exposed rats sacrificed on day 12 showed severe cerebral neuronal degeneration, reactive astrocytosis, and TUNEL-positive apoptotic nuclei, with the cerebral Hg concentration of 15.0 ± 1.6 μg/g. Furthermore, the activities of glutathione peroxidase and thioredoxin reductase in the cerebrum in MeHg-exposed rats were lower than those in control. These results indicate that MeHg exposure to infant rats will be useful to predict the effects of MeHg at the cerebral growth spurt in humans.

The four described species of Danionella are tiny, transparent fishes that mature at sizes between 10-15 mm, and represent some of the most extreme cases of vertebrate progenesis known to date. The miniature adult size and larval appearance of Danionella, combined with a diverse behavioral repertoire linked to sound production by males, have established Danionella as an important model for neurophysiological studies. The external similarity between the different species of Danionella has offered an important challenge to taxonomic identification using traditional external characters, leading to confusion over the identity of the model species. Using combined morphological and molecular taxonomic approaches, we show here that the most extensively studied species of Danionella is not D. translucida, but represents an undescribed species, D. cerebrum n. sp. that is externally almost identical to D. translucida, but differs trenchantly in several internal characters. Molecular analyses confirm the distinctiveness of D. cerebrum and D. translucida and suggest that the two species are not even sister taxa. Analysis of the evolution of sexual dimorphisms associated with the Weberian apparatus reveals significant increases in complexity from the simpler condition found in D. dracula, to most complex conditions in D. cerebrum, D. mirifica and D. translucida.