Selective Vulnerabilities of N-methyl-D-aspartate (NMDA) Receptors During Brain Aging

N-methyl-D-aspartate (NMDA) receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within different brain regions. Spatial reference, passive avoidance, and working memory, as well as place field stability and expansion all involve NMDA receptors. Aged animals show deficiencies in these functions, as compared to young, and some studies have identified an association between age-associated changes in the expression of NMDA receptors and poor memory performance. A number of diet and drug interventions have shown potential for reversing or slowing the effects of aging on the NMDA receptor. On the other hand, there is mounting evidence that the NMDA receptors that remain within aged individuals are not always associated with good cognitive functioning. This may be due to a compensatory response of neurons to the decline in NMDA receptor expression or a change in the subunit composition of the remaining receptors. These studies suggest that developing treatments that are aimed at preventing or reversing the effects of aging on the NMDA receptor may aid in ameliorating the memory declines that are associated with aging. However, we need to be mindful of the possibility that there may also be negative consequences in aged individuals

Reducing expression of GluN1OXX subunit splice variants of the NMDA receptor interferes with spatial reference memory

The GluN1 subunit of the NMDA receptor shows age-related changes in its expression pattern, some of which correlate with spatial memory performance in mice. Aged C57BL/6 mice show an age-related increase in mRNA expression of GluN1 subunit splice variants that lack the N terminal splice cassette, GluN1ₒₓₓ (GluN1-a). This increase in expression is associated with good performance in reference and working memory tasks. The present study was undertaken to determine if GluN1ₒₓₓ splice variants are required for good performance in reference memory tasks in young mice. Mice were bilaterally injected with either siRNA specific for GluN1ₒₓₓ splice variants, control siRNA or vehicle alone into ventro-lateral orbital cortices. A fourth group of mice did not receive any injections. Starting five days post-injection, mice were tested for their performance in spatial reference memory, associative memory and cognitive flexibility tasks over 4 days in the Morris water maze. There was a 10 -19% reduction in mRNA expression for GluN1ₒₓₓ splice variants within the ventro-lateral orbital cortices in mice following GluN1ₒₓₓ siRNA treatment. Declines in performance within the first half of reference memory testing were seen in the mice receiving siRNA against the GluN1ₒₓₓ splice variants, as compared to the mice injected with control siRNA, vehicle and/or no treatment. These results suggest a role for the GluN1ₒₓₓ splice variants in orbital regions for early acquisition and/or consolidation of spatial reference memory.Keywords: NMDA receptor, siRNA, Memory, NR1, Splice variant, Zeta

Chronic PFOS exposures induce life stage-specific behavioral deficits in adult zebrafish and produce malformations in F1 offspring

Perfluorooctanesulphonicacid (PFOS) is an organic contaminant that is ubiquitous in the environment, wildlife, and humans. Few studies have assessed the effects of chronic PFOS exposure on central nervous system function in aquatic organisms. The present study defined the behavioral effects of varying life span chronic exposures to low dose PFOS in zebrafish. The zebrafish were treated with vehicle control or 0.5μM PFOS during 1-21, 21-120, or 1-120 day post fertilization (dpf). Chronic PFOS exposure impaired the adult zebrafish behavior mode under the tapping stimulus. The movement speed of 1-120 dpf exposed fish was significantly increased compared with control, while 1-21 and 21-120 dpf exposed groups were not severely affected. PFOS residues in F1 embryos derived from parental exposure during both the 1-120 and 21-120 dpf groups was significantly higher than control, and F1 embryos in these two groups showed obvious malformations, such as uninflated swim bladder (USB) and bent spine (BS). Larvae of the parental exposed to PFOS from 1-21 or 21-120 dpf elicited a higher swim rate than control in both the light and dark periods. Embryos derived from the 1-120 dpf group showed a statistically lower speed in the light period and a higher speed in the dark period as compared with control. Though there is little PFOS residue in 1-21 dpf group, the adverse behavioral effects on both adult and F1 larvae indicate that exposure during the first 21 dpf induce long-term neurobehavior toxicity. Our findings demonstrate that chronic exposure to low dose PFOS in different life stage adversely impacts adult behavior, subsequent offspring malformation, and larval behavior.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Society of Environmental Toxicology and Chemistry and can be found at: http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291552-8618.,Additional authors (Liu, Xiaojuan and Zhu, Guonian) appear and the author order is revised on the published version of this article.Keywords: perfluorooctanesulfonic acid, zebrafish embryo, chronic exposure, behavio

Probing R-parity violating models of neutrino mass at the Tevatron via top Squark decays

We have estimated the limiting branching ratio of the R-parity violating (RPV) decay of the lighter top squark, \tilde t_1 \ar l^+ d ($l=e$ or $\mu$ and d is a down type quark of any flavor), as a function of top squark mass(\MST) for an observable signal in the di-lepton plus di-jet channel at the Tevatron RUN-II experiment with 2 fb$^{-1}$ luminosity. Our simulations indicate that the lepton number violating nature of the underlying decay dynamics can be confirmed via the reconstruction of \MST. The above decay is interesting in the context of RPV models of neutrino mass where the RPV couplings ($\lambda'_{i3j}$) driving the above decay are constrained to be small (\lsim 10^{-3} - 10^{-4} ). If $\tilde t_1$ is the next lightest super particle - a theoretically well motivated scenario - then the RPV decay can naturally compete with the R-parity conserving (RPC) modes which also have suppressed widths. The model independent limiting BR can delineate the parameter space in specific supersymmetric models, where the dominating RPV decay is observable and predict the minimum magnitude of the RPV coupling that will be sensitive to Run-II data. We have found it to be in the same ballpark value required by models of neutrino mass, for a wide range of \MST. A comprehensive future strategy for linking top squark decays with models of neutrino mass is sketched.Comment: 28 pages, 14 Figure

Summary of the Activities of the Working Group I on High Energy and Collider Physics

This is a summary of the projects undertaken by the Working Group I on High Energy Collider Physics at the Eighth Workshop on High Energy Physics Phenomenology (WHEPP8) held at the Indian Institute of Technology, Mumbai, January 5-16, 2004. The topics covered are (i) Higgs searches (ii) supersymmetry searches (iii) extra dimensions and (iv) linear collider.Comment: summary of Working Group I at the Eighth Workshop on High Energy Physics Phenomenology (WHEPP8), I.I.T., Mumbai, January 5-16, 200

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Genetic engineering of sex chromosomes for batch cultivation of non-transgenic, sex-sorted males.

The field performance of Sterile Insect Technique (SIT) is improved by sex-sorting and releasing only sterile males. This can be accomplished by resource-intensive separation of males from females by morphology. Alternatively, sex-ratio biasing genetic constructs can be used to selectively remove one sex without the need for manual or automated sorting, but the resulting genetically engineered (GE) control agents would be subject to additional governmental regulation. Here we describe and demonstrate a genetic method for the batch production of non-GE males. This method could be applied to generate the heterogametic sex (XY, or WZ) in any organism with chromosomal sex determination. We observed up to 100% sex-selection with batch cultures of more than 103 individuals. Using a stringent transgene detection assay, we demonstrate the potential of mass production of transgene free males

Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish

Monosubstituted isopropylated triaryl phosphate (mITP) is a major component of Firemaster 550, an additive flame retardant mixture commonly used in polyurethane foams. Developmental toxicity studies in zebrafish established mITP as the most toxic component of FM 550, which causes pericardial edema and heart looping failure. Mechanistic studies showed that mITP is an aryl hydrocarbon receptor (AhR) ligand; however, the cardiotoxic effects of mITP were independent of the AhR. We performed comparative whole genome transcriptomics in wild-type and <i>ahr2</i>^{<i>hu3335</i>} zebrafish, which lack functional <i>ahr2</i>, to identify transcriptional signatures causally involved in the mechanism of mITP-induced cardiotoxicity. Regardless of <i>ahr2</i> status, mITP exposure resulted in decreased expression of transcripts related to the synthesis of all-<i>trans</i>-retinoic acid and a host of Hox genes. Clustered gene ontology enrichment analysis showed unique enrichment in biological processes related to xenobiotic metabolism and response to external stimuli in wild-type samples. Transcript enrichments overlapping both genotypes involved the retinoid metabolic process and sensory/visual perception biological processes. Examination of the gene–gene interaction network of the differentially expressed transcripts in both genetic backgrounds demonstrated a strong AhR interaction network specific to wild-type samples, with overlapping genes regulated by retinoic acid receptors (RARs). A transcriptome analysis of control <i>ahr2-</i>null zebrafish identified potential cross-talk among AhR, Nrf2, and Hif1α. Collectively, we confirmed that mITP is an AhR ligand and present evidence in support of our hypothesis that mITP’s developmental cardiotoxic effects are mediated by inhibition at the RAR level