Prolonged Voluntary Running Negatively Affects Survival and Disease Prognosis of Male SOD1G93A Low-Copy Transgenic Mice

Amyotrophic Lateral Sclerosis (ALS) is a disease in which physical activity plays a controversial role. Epidemiological studies indicate an association between intense exercise and risk of developing ALS. To study the impact of physical activity on ALS, mouse models rely mostly on forced exercise. In this study we hypothesized that voluntary wheel running could represent a better model of the influence of exercise in the pathogenesis of ALS. We used an automated home-cage running-wheel system that enables individual monitoring of performance. To verify the effect of voluntary running on disease progression, prognosis and survival as well as motor functions, we challenged SOD1G93A low-copy male and female mice on one (1 RW, at age 24 weeks) or multiple (3 RW) running sessions at age 13, 18, and 24 weeks. In parallel we measured performance on Rotarod and Grip strength tests at different ages. Several parameters were analyzed through Principal Component Analysis in order to detect what indices correlate and may be useful for deeper understanding of the relation between exercise and disease development. We found mutant male mice more negatively affected than females by prolonged and repeated exercise. SOD1G93A low-copy male mice showed shorter survival, increased body weight loss and poorer disease prognosis when exposed to multiple running sessions. These findings could encourage the investigation of the pathogenetic mechanisms underlying the supposedly increased risk to develop ALS in humans engaged in specific and intense exercise activities

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

MicroRNA degradation by a conserved target RNA regulates animal behavior

International audiencemicroRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3′ UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3′ trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavio

Analytic information processing style in migraineurs

Despite great advances in pathophysiological facets of migraine that have been made during recent years, as of today, migraine etiology is still not completely understood; moreover, to date the relationship between psychological factors and this primary headache must be further elucidated. However, abnormal information processing, as measured by evoked and event-related potentials, has been considered a key feature in migraine pathogenesis. The aim of this work was to study the relationships between analytic/global style of information processing and migraine, hypothesizing an analytic style, as highlighted by our previous study on cluster headache. This study applied three cognitive style tests never previously used in the context of migraine: "Sternberg-Wagner Self-Assessment Inventory", the C. Cornoldi test series called AMOS, and Brain-Dominance Questionnaire. 280 migraneurs with and without aura were tested and matched with two control groups: healthy subjects and tension-type headache patients. Our results demonstrated a strong correlation between analytic information processing style and migraine, indicating a preference toward a visual sensory approach in migraine without aura, in line with known neuroelectrophysiological data. These findings may suggest a role for this specific cognitive behavior in migraine pathogenesis, leading us to further investigate the neuroelectrophysiological, neurobiological, and epigenetic correlates.Despite great advances in pathophysiological facets of migraine that have been made during recent years, as of today, migraine etiology is still not completely understood; moreover, to date the relationship between psychological factors and this primary headache must be further elucidated. However, abnormal information processing, as measured by evoked and event-related potentials, has been considered a key feature in migraine pathogenesis. The aim of this work was to study the relationships between analytic/global style of information processing and migraine, hypothesizing an analytic style, as highlighted by our previous study on cluster headache. This study applied three cognitive style tests never previously used in the context of migraine: "Sternberg-Wagner Self-Assessment Inventory", the C. Cornoldi test series called AMOS, and Brain-Dominance Questionnaire. 280 migraneurs with and without aura were tested and matched with two control groups: healthy subjects and tension-type he

Effects of acute and repeated daily exposure to hypergravity on spatial learning in mice

Studies in humans have revealed that exposure to altered gravity may lead to impairments in cognitive functions. The objective of this study was to test whether mice exposed to hypergravity using a centrifuge apparatus showed learning impairments in a spatial learning task. Mice rotating at 1G or at 2G acceleration gravity and non-rotating controls were tested for reactivity to a spatial change after either a single 1 h or five repeated 1 h daily rotations in the centrifuge. While no differences among groups were found in the performance after single exposure to altered gravity, 5 days of repeated exposures to 1 G or 2G gravity conditions significantly affected mouse ability to discriminate a new spatial arrangement. Additionally, this effect was stronger in the animals repeatedly exposed to 2G rather than to 1 G conditions. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Early motor deficits in mouse disease models are reliably uncovered using an automated home-cage wheel-running system: a cross-laboratory validation

Deficits in motor function are debilitating features in disorders affecting neurological, neuromuscular and musculoskeletal systems. Although these disorders can vary greatly with respect to age of onset, symptomatic presentation, rate of progression and severity, the study of these disease models in mice is confined to the use of a small number of tests, most commonly the rotarod test. To expand the repertoire of meaningful motor function tests in mice, we tested, optimised and validated an automated home-cage-based running-wheel system, incorporating a conventional wheel with evenly spaced rungs and a complex wheel with particular rungs absent. The system enables automated assessment of motor function without handler interference, which is desirable in longitudinal studies involving continuous monitoring of motor performance. In baseline studies at two test centres, consistently significant differences in performance on both wheels were detectable among four commonly used inbred strains. As further validation, we studied performance in mutant models of progressive neurodegenerative diseases – Huntington’s disease [TgN(HD82Gln)81Dbo; referred to as HD mice] and amyotrophic lateral sclerosis [Tg(SOD1G93A)dl1/GurJ; referred to as SOD1 mice] – and in a mutant strain with subtle gait abnormalities, C-Snap25Bdr/H (Blind-drunk, Bdr). In both models of progressive disease, as with the third mutant, we could reliably and consistently detect specific motor function deficits at ages far earlier than any previously recorded symptoms in vivo: 7–8 weeks for the HD mice and 12 weeks for the SOD1 mice. We also conducted longitudinal analysis of rotarod and grip strength performance, for which deficits were still not detectable at 12 weeks and 23 weeks, respectively. Several new parameters of motor behaviour were uncovered using principal component analysis, indicating that the wheel-running assay could record features of motor function that are independent of rotarod performance. This represents a powerful new method to detect motor deficits at pre-symptomatic stages in mouse disease models and should be considered as a valid tool to investigate the efficacy of therapeutic agents

Differences in visual information processing style between Idiopathic Generalized Epilepsy with and without photosensitivity

Recently, altered visual cortical processes i.e., lack of habituation to visual evoked potentials (VEP), has been highlighted in both photosensitive epilepsy and in a specific i.e., analytic mode of pro- cessing visual inputs. In this study we aimed at evaluating the relationship between photosensitivity (PS) and analytic style of processing visual information, in a sample of 30 patients with Idiopathic Generalized Epilepsy (IGE) and matched healthy controls. Methods: At our Epilepsy unit of the Sapienza University of Rome, we consecutively enrolled 15 patients with IGE with PSand matched them with 15 patients with IGE without PS and 15 Healthy Volunteers. All patients underwent EEG recording in basal conditions during hyperventilation (3 Min), and intermittent light stimulation. The most effective frequencies comprised from 12 to 16 Hz. The instruments used to gather psychological cognitive behavioral data, consisted of participation in two tests: the Sternberg-Wagner Self-Assessment Inventory and the Mariani Learning Style Questionnaire. Results: Compared to controls, both IGE groups show significantly higher scores for the analytic style (One-way ANOVA, F(2,44) = 110.3, p < 0.0001). Epilepsy groups thereby showed very distinctive cognitive styles as measured with the Sternberg test. In the visual style, scores of the photosensitive Individuals with IGE were significantly higher than the non-photosensitive individuals with IGE (p < 0.0001, Tukey’s post hoc test). Conclusions: An association between analytic style of processing visual information and PS in IGE has been shown. The common neurophysiological features between these two factors, suggest the possibility to evaluate this cognitive behavior as a potential target for nonpharmacological therapeutic strategies in photosensitive epilepsy

Circulating myomiRs in Muscle Denervation: From Surgical to ALS Pathological Condition

ALS is a fatal neurodegenerative disease that is associated with muscle atrophy, motoneuron degeneration and denervation. Different mechanisms have been proposed to explain the pathogenesis of the disease; in this context, microRNAs have been described as biomarkers and potential pathogenetic factors for ALS. MyomiRs are microRNAs produced by skeletal muscle, and they play an important role in tissue homeostasis; moreover, they can be released in blood circulation in pathological conditions, including ALS. However, the functional role of myomiRs in muscle denervation has not yet been fully clarified. In this study, we analyze the levels of two myomiRs, namely miR-206 and miR-133a, in skeletal muscle and blood samples of denervated mice, and we demonstrate that surgical denervation reduces the expression of both miR-206 and miR-133a, while miR-206 but not miR-133a is upregulated during the re-innervation process. Furthermore, we quantify the levels of miR-206 and miR-133a in serum samples of two ALS mouse models, characterized by different disease velocities, and we demonstrate a different modulation of circulating myomiRs during ALS disease, according to the velocity of disease progression. Moreover, taking into account surgical and pathological denervation, we describe a different response to increasing amounts of circulating miR-206, suggesting a hormetic effect of miR-206 in relation to changes in neuromuscular communication