Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer\u27s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures

Accounting students and communication apprehension: a study of Spanish and UK students

Accounting is about measuring and communicating. Accounting bodies and employers have expressed opinions, which have been supported by research results, advocating that greater emphasis is placed on the development of communication skills throughout the education and training of accountants. Consequently, an increasing number of accounting programmes now include communication skills as educational objectives or learning outcomes, and have integrated activities into the curriculum specifically to develop these skills. It is important to recognise that certain factors can severely restrict the development of communication skills; a major factor is communication apprehension. Research suggests that the existence of high levels of communication apprehension will make efforts to improve communication skills ineffective. Previous research findings indicate that accounting students have high levels of communication apprehension. This paper compares and contrasts the levels and profiles of communication apprehension exhibited by accounting students at the (UK University) and those at the (ESP University). The levels of communication apprehension are also compared with those of students from other disciplines at the same institutions. The results confirm the high levels of communication apprehension in European accounting students. There are notable differences between the two countries however in certain underlying factors.</p

Diffusional kurtosis imaging detects age-related grey matter changes in the normal mouse brain

Since the transition from young to aged adult during the normal aging process leads to changes in grey matter morphology, characterizing the age-related diffusion patterns in the rodent brain is important for interpreting and differentiating the changes associated with pathological process in rodents’ models of neurodegenerative diseases. Diffusional Kurtosis Imaging (DKI) quantifies the non-Gaussian behavior of water diffusion, contributing additional information beyond that provided by diffusion tensor imaging. Here we report that the DKI can characterize the age-related microstructural changes in the cortex and sub-cortical regions in the normal mouse brain

Diffusional kurtosis detects cortical demyelination in the cuprizone mouse model

The cuprizone mouse model is a well characterized animal model of demyelination. Recently, cortical demyelination has also been observed. Diffusion tensor imaging (DTI) studies have demonstrated the pathology of the corpus callosum (CC) in cuprizone mouse model, but no cortical diffusion changes have been reported. Diffusional Kurtosis Imaging (DKI) quantifies the non-Gaussian behavior of water diffusion, contributing additional information beyond that provided by DTI. Here we report, for the first time, DKI changes in the cortex of mice with demyelination induced by cuprizone, demonstrating the significant advantage of microstructural characterization using DKI, especially for abnormalities in grey matter

p75, but Not proNGF, Is Upregulated Following Status Epilepticus in Mice

ProNGF and p75 NTR are upregulated and induce cell death following status epilepticus (SE) in rats. However, less is known about the proneurotrophin response to SE in mice, a more genetically tractable species where mechanisms can be more readily dissected. We evaluated the temporal- and cell-specific induction of the proneurotrophins and their receptors, including p75 NTR , sortilin, and sorCS2, following mild SE induced with kainic acid (KA) or severe SE induced by pilocarpine. We found that mature NGF, p75 NTR , and proBDNF were upregulated following SE, while proNGF was not altered, indicating potential mechanistic differences between rats and mice. ProBDNF was localized to mossy fibers and microglia following SE. p75 NTR was transiently induced primarily in axons and axon terminals following SE, as well as in neuron and astrocyte cell bodies. ProBDNF and p75 NTR increased independently of cell death and their localization was different depending on the severity of SE. We also examined the expression of proneurotrophin co-receptors, sortilin and sorCS2. Following severe SE, sorCS2, but not sortilin, was elevated in neurons and astrocytes. These data indicate that important differences exist between rat and mouse in the proneurotrophin response following SE. Moreover, the proBDNF and p75 NTR increase after seizures in the absence of significant cell death suggests that proneurotrophin signaling may play other roles following SE

Presenilin Redistribution Associated with Aberrant Cholesterol Transport Enhances {beta}-Amyloid Production In Vivo

Epidemiology,in vitro, andin vivostudies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). We have examined the impact of aberrant intracellular cholesterol transport on the processing of the amyloid precursor protein (APP) in a mouse model of Niemann-Pick type C (NPC) disease. In the NPC mouse brain, cholesterol accumulates in late endosomes/lysosomes. This was associated with the accumulation of β-C-terminal fragments (CTFs) of APP, but the level of β-secretase and its activity were not affected. α-Secretase activity and secreted APPα generation were also not affected, suggesting CTFs increased because of decreased clearance. The level of presenilin-1 (PS-1) was unchanged, but γ-secretase activity was greatly enhanced, which correlated with an increase in Aβ40 and Aβ42 levels. These events were associated with abnormal distribution of PS-1 in the endosomal system. Our results show that aberrant cholesterol trafficking is associated with the potentiation of APP processing componentsin vivo, leading to an overall increase in Aβ levels.</jats:p