Muscarinic receptor-dependent long term depression in the perirhinal cortex and recognition memory are impaired in the rTg4510 mouse model of tauopathy.

This is the final version of the article. Available from the publisher via the DOI in this record.Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L. We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy.SES was supported by a Medical Research Council studentship. JTB was an Alzheimer’s Research UK Senior Research Fellow. Eli Lilly & Co supplied the rTg4510 mice

Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells.

The evidence of a tight spatial interaction between mast cells (MCs) and B lymphocytes in secondary lymphoid organs, along with the data regarding the abundance of MCs in several B-cell lymphoproliferative disorders prompted us to investigate whether MCs could affect the proliferation and differentiation of B cells. To this aim, we performed coculture assays using mouse splenic B cells and bone marrow-derived MCs. Both nonsensitized and activated MCs proved able to induce a significant inhibition of cell death and an increase in proliferation of naive B cells. Such proliferation was further enhanced in activated B cells. This effect relied on cell-cell contact and MC-derived interleukin-6 (IL-6). Activated MCs could regulate CD40 surface expression on unstimulated B cells and the interaction between CD40 with CD40 ligand (CD40L) on MCs, together with MC-derived cytokines, was involved in the differentiation of B cells into CD138(+) plasma cells and in selective immunoglobulin A (IgA) secretion. These data were corroborated by in vivo evidence of infiltrating MCs in close contact with IgA-expressing plasma cells within inflamed tissues. In conclusion, we reported here a novel role for MCs in sustaining B-cell expansion and driving the development of IgA-oriented humoral immune responses

The effect of DEFRA guidance on greenhouse gas disclosure

This paper investigates the effect of the 2009 guidance of the Department for Environment, Food & Rural Affairs on greenhouse gas (GHG) disclosure. The sample comprises 215 companies from a population of London Stock Exchange FTSE 350 companies over four years (2008e 2011). To quantify GHG disclosure, a research index methodology is employed, with information derived from several GHG reporting frameworks. The econometric model is estimated using panel fixed effects. Our findings suggest that the publication of the 2009 guidance has had a significant effect on the level of GHG disclosure, and that corporate governance mechanisms (board size, director ownership, and ownership concentration) also affect the extent of GHG information disclosure. The results also indicate that companies increased their disclosures prior to the 2009 guidance in anticipation of its publication. These results have important implications for the government, suggesting that non-mandatory guidance could increase disclosure as much as do mandatory requirements

Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory

Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the potential to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically. Selective stimulation of glutamatergic neurons during the online maintenance of information enhanced associative recognition memory in normal animals. This cognitive enhancing effect was replicated by local infusions of the AMPAkine CX516, but not CX546, which differ in their effects on EPSPs. This suggests that enhancing the amplitude, but not the duration, of excitatory synaptic currents improves memory performance. Increasing glutamate release through infusions of the mGluR7 presynaptic receptor antagonist MMPIP had no effect on performance. SIGNIFICANCE STATEMENT These results provide new mechanistic information that could guide the targeting of future cognitive enhancers. Our work suggests that improved associative-recognition memory can be achieved by enhancing endogenous glutamatergic neuronal activity selectively using an optogenetic approach. We build on these observations to recapitulate this effect using drug treatments that enhance the amplitude of EPSPs; however, drugs that alter the duration of the EPSP or increase glutamate release lack efficacy. This suggests that both neural and temporal specificity are needed to achieve cognitive enhancement

The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms

To investigate the involvement of different types of glutamate receptors in recognition memory, selective antagonists of NMDA and kainate receptors were locally infused into the perirhinal cortex of the rat temporal lobe. Such infusion of a selective kainate receptor antagonist produced an unusual pattern of recognition memory impairment: amnesia after a short (20 min) but not a long (24 h) delay. In contrast, antagonism of perirhinal NMDA glutamate receptors by locally infused AP-5 (2-amino-5-phosphonopentanoic acid) impaired recognition memory after the long but not the short delay. For both drugs, impairment was found when the drug was present during acquisition but not when it was present during retrieval. Experiments in vitro indicate that selective antagonism of NMDA receptors containing NR2A subunits blocks perirhinal long-term potentiation (LTP), whereas antagonism of NMDA receptors containing NR2B subunits blocks long-term depression (LTD). However, recognition memory after a 24 h delay was impaired only when both an NR2A and an NR2B antagonist were infused together, not when either was infused separately. These results establish that kainate receptors have a role in recognition memory that is distinct from that of NMDA receptors, that there must be at least two independent underlying memory mechanisms in the infused region, that this region and no other is necessary for both short-term and long-term familiarity discrimination, and that perirhinal-dependent long-term recognition memory does not rely solely on processes used in NMDA-dependent LTP or LTD (although it might be independently supported by components of each type of process with one substituting for the other)

Multivariate Analyses to Improve Understanding of NAPL Pollutant Sources

Current site assessment techniques do not always generate adequate information regarding the presence, type, or distribution of nonaqueous phase liquids (NAPLs) at sites with ground water contamination. Without this information, however, the design of remediation methods is uncertain, often resulting in costly and/or failed attempts to minimize risks associated with the contamination. In this work, it is proposed that a thorough multivariate analysis of data from ground water sampling efforts could improve our overall understanding of these sites. Multivariate analyses can provide considerable insight into the contaminant source characteristics by elucidating correlations in ground water concentrations that identify recurring chemical patterns or “signatures.” These correlations are related to the type of NAPL and proximity to the contaminant source. Multivariate plots and a principal components analysis (PCA) are used to interpret ground water data from a manufactured gas plant site in Iowa contaminated with both gasoline and coal tar. Conclusions from these analyses regarding the distribution of NAPL contaminants were generally consistent with those derived from direct physical evidence of the NAPL sources. The multivariate analyses, however, provide an additional level of interpretation regarding the distribution of coal tar in the subsurface that was not possible with the standard evaluation techniques used during the remedial investigation (RI). Comparison of chemical signatures of ground water samples among wells identified two distinct regions of coal tar contamination, and suggests which wells are impacted by each source providing greater confidence in the location of the DNAPL sources.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72488/1/j.1745-6592.1997.tb01286.x.pd