APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.     

Tool-use learning in Tonkean macaques (Macaca tonkeana)

The transmission of tool use is a rare event in monkeys. Such an event arose in a group of semi-free-ranging Tonkean macaques (Macaca tonkeana) in which leaning a pole against the parks fence (branch leaning) appeared and spread to several males. This prompted us to test individual and social learning of this behavior in seven young males. In the first experiment, three males learned individually to obtain a food reward using a wooden pole as a climbing tool. They began using the pole to retrieve the reward only when they could alternatively experience acting on the object and reaching the target. In a second experiment, we first tested whether four other subjects could learn branch leaning after having observed a group-mate performing the task. Despite repeated opportunities to observe the demonstrator, they did not learn to use the pole as a tool. Hence we exposed the latter subjects to individual learning trials and they succeeded in the task. Tool use was not transmitted in the experimental situation, which contrasts with observations in the park. We can conclude that the subjects were not able to recognize the target as such. It is possible that they recognized it and learned the task individually when we alternated the opportunity to act upon the object and to reach the reward. This suggests that these macaques could then have associated the action they exercised upon the pole and the use of the pole as a means to reach the reward.     

Inferring the structure of latent class

Present optimization techniques in latent class analysis apply the expectation maximization algorithm or the Newton-Raphson algorithm for optimizing the parameter values of a prespecified model. These techniques can be used to find maximum likelihood estimates of the parameters, given the specified structure of the model, which is defined by the number of classes and, possibly, fixation and equality constraints. The model structure is usually chosen on theoretical grounds. A large variety of structurally different latent class models can be compared using goodness-of-fit indices of the chi-square family, Akaike’s information criterion, the Bayesian information criterion, and various other statistics. However, finding the optimal structure for a given goodness-of-fit index often requires a lengthy search in which all kinds of model structures are tested. Moreover, solutions may depend on the choice of initial values for the parameters. This article presents a new method by which one can simultaneously infer the model structure from the data and optimize the parameter values. The method consists of a genetic algorithm in which any goodness-of-fit index can be used as a fitness criterion. In a number of test cases in which data sets from the literature were used, it is shown that this method provides models that fit equally well as or better than the models suggested in the original articles.     

A blank look in reading: the effect of blank space on the identification of letters and words during reading

Two experiments investigated the effect of visual blank space on reading by varying the amount of interletter and interline blank space in prose passages. Increasing interletter blank spacing slowed the reading process overall, presumably because it disrupted the unitization of words and word identification, but it also improved the identification of the letters within words. By contrast, increasing interline blank spacing sped up the reading process overall, while also improving the identification of words and the letters within words, presumably because the extra spacing reduced the amount of visual information that was processed during reading. The latter finding supports the conclusion that information from surrounding lines of single-spaced text may interfere with reading.     

Every cloud has a silver lining: interpersonal and individual differences determinants of anger-related behaviors

Two studies examined the effect of status and liking of the anger target on anger behavior and individual differences in anger-related behavior. Participants recalled anger instances in which the anger target was of higher/equal/lower status and/or liked/ unfamiliar/disliked; subsequently, they indicated which behaviors they had displayed. In both studies, anger behaviors could be grouped into behaviors that imply approaching the target (anger-out, assertion, reconciliation) and behaviors that reflect avoidance/anger-in or social sharing. The results demonstrated that approach behaviors more likely occur toward lower status or liked targets; avoidance behaviors and social sharing more likely occur when the target is of higher status or disliked. On an individual differences level, an approach and an avoid/social sharing person class were identified. The findings suggest that anger may motivate prosocial behavior or social sharing, depending on the individual and type of relation with the target. Only few gender differences were found.     

Distance estimation in a dynamic simulated environment: a visual field dependence problem?

Egocentric distance estimation implies that the subject perceives his own location in the environment. In a simulated environment, subjects have to transpose perceptively their own observation point in order to assume their virtual body position. As only visual information specifies this position, their ability to perceive the camera viewpoint should be linked to the field dependence independence factor (FDI). Field-independent subjects underestimated the mid-distance between their own virtual body position and a far-located target; their bisection was located between the projective (2-D) and the simulated (3-D) mid-distance which indicates their difficulty in considering the in-depth simulated spatial references. High correlations between the vertical estimation in the rod-and-frame test and the egocentric-distance-estimation task (with shifted camera) suggest a similar perceptive process in both tasks. This result is confirmed by the better performances of the field-dependent subjects in this condition. In conclusion, we discuss the relationship between FDI and the sense of presence in virtual environments.     

Directed forgetting in working memory: age-related differences

This study explored the effects of ageing on working memory by means of the directed forgetting procedure designed by Reed (1970). Memory for a letter trigram was compared in conditions where it was either presented alone (single-item), or followed by a second trigram to be recalled (interference), or followed by a second trigram to be forgotten (directed forgetting). The results clearly indicated that elderly participants inhibited the no-longer-relevant information less efficiently (recall in the single-item condition - recall in the directed forgetting condition), as predicted by the model of Hasher and Zacks (1988). However, the results also demonstrated that sensitivity to interference (recall in the single-item condition - recall in the interference condition) increased in the condition in which no inhibition was directly required.     

Identifying environmental contributions to autism: provocative clues and false leads

The potential role of environmental factors in autism spectrum disorders (ASD) is an area of emerging interest within the public and scientific communities. The high degree of heritability of ASD suggests that environmental influences are likely to operate through their interaction with genetic susceptibility during vulnerable periods of development. Evaluation of the plausibility of specific neurotoxicants as etiological agents in ASD should be guided by toxicological principles, including dose-effect dependency and pharmacokinetic parameters. Clinical and epidemiological investigations require the use of sufficiently powered study designs with appropriate control groups and unbiased case ascertainment and exposure assessment. Although much of the existing data that have been used to implicate environmental agents in ASD are limited by methodological shortcomings, a number of efforts are underway that will allow more rigorous evaluation of the role of environmental exposures in the etiology and/or phenotypic expression of the disorder. Surveillance systems are now in place that will provide reliable prevalence estimates going forward in time. Anticipated discoveries in genetics, brain pathology, and the molecular/cellular basis of functional impairment in ASD are likely to provide new opportunities to explore environmental aspects of this disorder.     

Does imminent threat capture and hold attention?

According to models of attention and emotion, threat captures and holds attention. In behavioral tasks, robust evidence has been found for attentional holding but not for attentional capture by threat. An important explanation for the absence of attentional capture effects is that the visual stimuli used posed no genuine threat. The present study investigated whether visual cues that signal an aversive white noise can elicit attentional capture and holding effects. Cues presented in an attentional task were simultaneously provided with a threat value through an aversive conditioning procedure. Response latencies showed that threatening cues captured and held attention. These results support recent views on attention to threat, proposing that imminent threat captures attention in everyone.