Establishing operant conflict tests for the translational study of anxiety in mice

Rationale In conflict-based anxiety tests, rodents decide between actions with simultaneous rewarding and aversive outcomes. In humans, computerised operant conflict tests have identified response choice, latency, and vigour as distinct behavioural components. Animal operant conflict tests for measurement of these components would facilitate translational study. Objectives In C57BL/6 mice, two operant conflict tests for measurement of response choice, latency, and vigour were established, and effects of chlordiazepoxide (CDZ) thereon investigated. Methods Mice were moderately diet-restricted to increase sucrose reward salience. A 1-lever test required responding under medium-effort reward/threat conditions of variable ratio 2–10 resulting in sucrose at p = 0.7 and footshock at p = 0.3. A 2-lever test mandated a choice between low-effort reward/threat with a fixed-ratio (FR) 2 lever yielding sucrose at p = 0.7 and footshock at p = 0.3 versus high-effort reward/no threat with a FR 20 lever yielding sucrose at p = 1. Results In the 1-lever test, CDZ (7.5 or 15 mg/kg i.p.) reduced post-trial pause (response latency) following either sucrose or footshock and reduced inter-response interval (increased response vigour) after footshock. In the 2-lever test, mice favoured the FR2 lever and particularly at post-reward trials. CDZ increased choice of FR2 and FR20 responding after footshock, reduced response latency overall, and increased response vigour at the FR2 lever and after footshock specifically. Conclusions Mouse operant conflict tests, especially 2-lever choice, allow for the translational study of distinct anxiety components. CDZ influences each component by ameliorating the impact of both previous punishment and potential future punishment

Sledding injuries: is safety in this winter pastime overlooked? A three-year survey in South-Tyrol

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Sledding is a popular traditional pastime in northern countries. However it is only rarely thought as a potentially dangerous activity even though serious injuries and deaths do occur. The purpose of this study was to calculate the incidence, the severity and the pattern of sleddingrelated injuries in our area, in order to set up possible preventive measures. Results: In three consecutive winter seasons (Dec.–Apr.,2002–2005). 356 patients (182 males, 174 females, mean age 26.9 years, range 2 to 81) were referred directly to our ED after a sledding injury. One patient (male, age 21 years) was transferred from a community hospital and died on the following day. Two patients (males, age 47 and 28 years) were declared dead on the scene. In the majority of the cases the accident was due to a fall and collision with the ground or a standing object. The number of injuries showed a progressive increase during the observed seasons and all deadly accidents were observed in the last season. Injuries were divided into three severity classes: minor (ISS ≤ 3), intermediate (ISS ≥ 4 < 15), severe (ISS ≥ 15). Minor and intermediate injuries were equally distributed between males and females, whereas all severe and deadly accidents occurre

Novel alterations in corneal neuroimmune phenotypes in mice with central nervous system tauopathy

BACKGROUND: Tauopathy in the central nervous system (CNS) is a histopathological hallmark of frontotemporal dementia (FTD) and Alzheimer's disease (AD). Although AD is accompanied by various ocular changes, the effects of tauopathy on the integrity of the cornea, which is densely innervated by the peripheral nervous system and is populated by resident dendritic cells, is still unknown. The aim of this study was to investigate if neuroimmune interactions in the cornea are affected by CNS tauopathy. METHODS: Corneas from wild type (WT) and transgenic rTg4510 mice that express the P301L tau mutation were examined at 2, 6, 8, and 11 months. Clinical assessment of the anterior segment of the eye was performed using spectral domain optical coherence tomography. The density of the corneal epithelial sensory nerves and the number and field area of resident epithelial dendritic cells were assessed using immunofluorescence. The immunological activation state of corneal and splenic dendritic cells was examined using flow cytometry and compared between the two genotypes at 9 months of age. RESULTS: Compared to age-matched WT mice, rTg4510 mice had a significantly lower density of corneal nerve axons at both 8 and 11 months of age. Corneal nerves in rTg4510 mice also displayed a higher percentage of beaded nerve axons and a lower density of epithelial dendritic cells compared to WT mice. From 6 months of age, the size of the corneal dendritic cells was significantly smaller in rTg4510 compared to WT mice. Phenotypic characterization by flow cytometry demonstrated an activated state of dendritic cells (CD86+ and CD45+ CD11b+CD11c+) in the corneas of rTg4510 compared to WT mice, with no distinct changes in the spleen monocytes/dendritic cells. At 2 months of age, there were no significant differences in the neural or immune structures between the two genotypes. CONCLUSIONS: Corneal sensory nerves and epithelial dendritic cells were altered in the rTg4510 mouse model of tauopathy, with temporal changes observed with aging. The activation of corneal dendritic cells prior to the gradual loss of neighboring sensory nerves suggests an early involvement of corneal immune cells in tau-associated pathology originating in the CNS

Predictive ability of regression models. Part II: Selection of the best predictive PLS model

A procedure called GOLPE is suggested in order to detect those variables which increase the predictivity of PLS models. The procedure is based on evaluating the predictive power of a number of PLS models built by different combinations of variables selected according to a factorial design strategy. Examples are given of the efficiency of this variable selection procedure, which shows how these predictive PLS models are better than those obtained by all variables and better than the corresponding ordinary regression model

Separating Probability and Reversal Learning in a Novel Probabilistic Reversal Learning Task for Mice

The exploration/exploitation tradeoff – pursuing a known reward vs. sampling from lesser known options in the hope of finding a better payoff – is a fundamental aspect of learning and decision making. In humans, this has been studied using multi-armed bandit tasks. The same processes have also been studied using simplified probabilistic reversal learning (PRL) tasks with binary choices. Our investigations suggest that protocols previously used to explore PRL in mice may prove beyond their cognitive capacities, with animals performing at a no-better-than-chance level. We sought a novel probabilistic learning task to improve behavioral responding in mice, whilst allowing the investigation of the exploration/exploitation tradeoff in decision making. To achieve this, we developed a two-lever operant chamber task with levers corresponding to different probabilities (high/low) of receiving a saccharin reward, reversing the reward contingencies associated with levers once animals reached a threshold of 80% responding at the high rewarding lever. We found that, unlike in existing PRL tasks, mice are able to learn and behave near optimally with 80% high/20% low reward probabilities. Altering the reward contingencies towards equality showed that some mice displayed preference for the high rewarding lever with probabilities as close as 60% high/40% low. Additionally, we show that animal choice behavior can be effectively modelled using reinforcement learning (RL) models incorporating learning rates for positive and negative prediction error, a perseveration parameter, and a noise parameter. This new decision task, coupled with RL analyses, advances access to investigate the neuroscience of the exploration/exploitation tradeoff in decision making

A proposed method for generating high resolution current and future climate data for Passivhaus design

The sensitivity of low energy and passive solar buildings to their climatic context creates a requirement for accurate local climate data. This situation takes on increasing importance in the context of modelling Passivhaus buildings where the absence of conventional oversized heating and cooling systems implies a greater reliance upon fabric and system optimisation. Conversely, future climatic changes may also pose serious implications for super insulated buildings with inadequate solar shading. Currently, many widely used building performance simulation (BPS) tools still rely on very limited sources of climate data. The following research examines the need for regional and, in some cases, micro-regional climatic data when designing ultra-low energy Passivhaus buildings in the UK. The paper proposes a new methodology for generating this data in PHPP format. The data generated is compared to alternative sources, and the implications discussed in the context of three case studies examining a certified Passivhaus dwelling in a mountainous region of Wales as well as two locations, in close proximity, within London. If correctly implemented the use of such data should provide a more robust basis for future cost and performance optimisation in low energy and passive building design

Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care