Recent studies have reported the existence of hippocampal “time cells,” neurons that fire at particular moments during periods when behavior and location are relatively constant. However, an ...alternative explanation of apparent time coding is that hippocampal neurons “path integrate” to encode the distance an animal has traveled. Here, we examined hippocampal neuronal firing patterns as rats ran in place on a treadmill, thus “clamping” behavior and location, while we varied the treadmill speed to distinguish time elapsed from distance traveled. Hippocampal neurons were strongly influenced by time and distance, and less so by minor variations in location. Furthermore, the activity of different neurons reflected integration over time and distance to varying extents, with most neurons strongly influenced by both factors and some significantly influenced by only time or distance. Thus, hippocampal neuronal networks captured both the organization of time and distance in a situation where these dimensions dominated an ongoing experience.
•Hippocampal neurons fire in sequences during treadmill running•Hippocampal neuronal activity reflects location, time, and distance
Kraus et al. report that, during stationary treadmill running, hippocampal neuronal activity reflects integration of both time elapsed and distance traveled, in addition other salient features of experience.
The spatial scale of grid cells may be provided by self-generated motion information or by external sensory information from environmental cues. To determine whether grid cell activity reflects ...distance traveled or elapsed time independent of external information, we recorded grid cells as animals ran in place on a treadmill. Grid cell activity was only weakly influenced by location, but most grid cells and other neurons recorded from the same electrodes strongly signaled a combination of distance and time, with some signaling only distance or time. Grid cells were more sharply tuned to time and distance than non-grid cells. Many grid cells exhibited multiple firing fields during treadmill running, parallel to the periodic firing fields observed in open fields, suggesting a common mode of information processing. These observations indicate that, in the absence of external dynamic cues, grid cells integrate self-generated distance and time information to encode a representation of experience.
•Time and distance coding by grid cells can be studied in rats running in place•In this task, grid cell activity reflects a combination of time and distance coding•Grid cells are more sharply tuned to time and distance than non-grid cells•Many grid cells exhibit multiple time and distance fields
Grid cells encode a periodic array of locations occupied as rats move through space. Kraus et al. show that, when cues about motion through locations are eliminated, grid cells integrate self-generated distance and time information that predominate in that experience.
Adipocyte cell culture is an important tool for mechanistic studies of energy metabolism. Many factors affect the differentiation of adipocytes in culture. Oil red O staining can be used to assess ...the degree of differentiation. However, the validity of this method for quantitative analysis has not yet been established. Here we show that a protocol with arbitrarily chosen parameters does not measure in the linear range and is not suitable for quantitative analysis (R
2
= 0.077, p = 0.382), and develop and validate an optimized protocol for quantitative oil red O staining of cultured adipocytes. 3T3-L1 preadipocytes and adipocytes are fixed with 4% formaldehyde and stained with 0.2% oil red O solution in 40% 2-propanol for 30 minutes. Dye is eluted with 2-propanol, and absorption of the eluate is measured photometrically at 510 nm. This optimized protocol achieves excellent correlation between defined amounts of differentiated adipocytes on constant-size culture plates and photometric absorption (R
2
= 0.972, p = 6.585E-14). The performance of the method is independent of the culture plates used. Thus, the optimized oil red O staining protocol can be universally employed to quantitatively assess adipocyte differentiation.
The absolute levels of 5‐hydroxymethylcytosine (hmC) and 5‐methylcytosine (mC) in human brain tissues at various ages were determined. Additionally, absolute levels of 5‐formylcytosine (fC) in adult ...individuals and cytosine modification levels in sorted neurons were quantified. These data were compared with age‐related fC, hmC, and mC levels in mouse brain samples. For hmC, an initial steady increase is observed, which levels off with age to a final steady‐state value of 1.2 % in human brain tissue. This level is nearly twice as high as in mouse cerebral cortex. In contrast, fC declines rapidly with age during early developmental stages, thus suggesting that while hmC is a stable epigenetic mark, fC is more likely an intermediate of active DNA demethylation during early brain development. The trends in global cytosine modification dynamics during the lifespan of an organism are conserved between humans and mice and show similar patterns in different organs.
Brain teaser: Age‐dependent global levels of 5‐methyl‐ (mC), 5‐hydroxymethyl‐ (hmC), and 5‐formylcytosine (fC) were quantified in human and mouse brain tissues. While the hmC content increases sharply with age to reach a high steady‐state level of 1.2 % in the adult human brain, fC levels rapidly decline during early developmental stages.
Parkinson’s disease (PD) is a slowly progressing neurodegenerative disorder that affects approximately seven million patients worldwide. Despite intensive research, the molecular mechanisms ...initiating and promoting PD are still unknown. However, it is assumed that environmental factors trigger PD. Recent research demonstrated that long noncoding RNAs (lncRNA) interfere in transcriptional and translational processes modulating gene expression reflecting environmental influences. Nevertheless, there is no systematic analysis available that investigates the impact of lncRNAs on PD. In the current study, we performed a comprehensive analysis on expression levels of 90 well-annotated lncRNAs in 30 brain specimens deriving from 20 PD patients and 10 controls as a preliminary report on the significance of lncRNAs in PD. Expression profiling of lncRNAs revealed that five lncRNAs are significantly differentially expressed in PD. While H19 upstream conserved 1 and 2 is significantly downregulated in PD, lincRNA-p21, Malat1, SNHG1, and TncRNA are significantly upregulated. An analysis on expression levels and PD stages revealed that the identified dysregulated lncRNA are altered already in early disease stage and that they precede the course of PD. In summary, this is the first comprehensive analysis on lncRNAs in PD revealing significantly altered lncRNAs. Additionally, we found that lncRNA dysregulations precede the course of the disease. Thus, the five newly identified lncRNAs may serve as potential new biomarkers appropriate even in early PD. They may be used in monitoring disease progression and they may serve as potential new targets for novel therapeutic approaches.
The response of larval aquatic insects to stressors such as metals is used to assess the ecological condition of streams worldwide. However, nearly all larval insects metamorphose from aquatic larvae ...to winged adults, and recent surveys indicate that adults may be a more sensitive indicator of stream metal toxicity than larvae. One hypothesis to explain this pattern is that insects exposed to elevated metal in their larval stages have a reduced ability to successfully complete metamorphosis. To test this hypothesis we exposed late-instar larvae of the mayfly, Centroptilum triangulifer, to an aqueous Zn gradient (32–476 μg/L) in the laboratory. After 6 days of exposure, when metamorphosis began, larval survival was unaffected by zinc. However, Zn reduced wingpad development at concentrations above 139 μg/L. In contrast, emergence of subimagos and imagos tended to decline with any increase in Zn. At Zn concentrations below 105 μg/L (hardness-adjusted aquatic life criterion), survival between the wingpad and subimago stages declined 5-fold across the Zn gradient. These results support the hypothesis that metamorphosis may be a survival bottleneck, particularly in contaminated streams. Thus, death during metamorphosis may be a key mechanism explaining how stream metal contamination can impact terrestrial communities by reducing aquatic insect emergence.
Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of ...cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues.
We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17.
Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.
The world's literature on traumatic brain injury (TBI) grows annually including new reports on epidemiologic findings from many regions. With the wide variety of reports emphasizing various factors ...it is useful to compile these findings, hence the objective of this report. Thus, we describe epidemiological factors from European studies largely published in the last 20 years.
The Medline was searched for TBI related articles from about 1980 to 2003 including terms such as "epidemiology", "head injury", "brain injury" and others. From the research reports identified, we checked references for additional relevant reports and from those reports we abstracted data on TBI incidence, severity, external cause, gender, mortality, prevalence, cost and related factors.
Twenty three European reports met inclusion criteria and included findings from national studies from Denmark, Sweden, Finland, Portugal, Germany, and from regions within Norway, Sweden, Italy, Switzerland, Spain, Denmark, Ireland, the U.K. and France. An aggregate hospitalized plus fatal TBI incidence rate of about 235 per 100,000 was derived. Prevalence rate data were not reported from any European country. An average mortality rate of about 15 per 100,000 and case fatality rate of about 11 per 100 were derived. The TBI severity ratio of hospitalized patients was about 22:1.5:1 for mild vs. moderate vs. severe cases, respectively. The percentages of TBI from external causes varied considerably and several reports reported an association of alcohol use with TBI. Outcome or disability findings were mixed and inconsistent.
It was difficult to reach a consensus on all epidemiological findings across the 23 published European studies because of critical differences in methods employed across the reports. We highly recommend the development of research guidelines to standardize definitional, case finding, and data reporting parameters to help establish a more precise description and hence utility of the epidemiology of TBI in Europe.
5‐Methylcytosine (5mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5‐Hydroxymethylcytosine (5hmC) is generated from 5mC by the action of the TET ...(Ten‐Eleven‐Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5mC. We have used immunohistochemistry (IHC) and isotope‐based liquid chromatography mass spectrometry (LC‐MS) to investigate the presence and distribution of 5hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5hmC positive cells in the cortex and 32.4% 5hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC‐MS also showed highest values in cortical areas (1.17% 5hmC/dG deoxyguanosine), in the cerebral WM we measured around 0.70% 5hmC/dG. 5hmC levels were related to tumor differentiation, ranging from lowest values of 0.078% 5hmC/dG in GBMs (WHO Grade IV) to 0.24% 5hmC/dG in WHO Grade II diffuse astrocytomas. 5hmC measurements were unrelated to 5mC values. We find that the number of 5hmC positive cells and the amount of 5hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia.
PDF
