How the Statistics of Sequential Presentation Influence the Learning of Structure

Recent work has shown that humans can learn or detect complex dependencies among variables. Even learning a simple dependency involves the identification of an underlying model and the learning of its parameters. This process represents learning a structured problem. We are interested in an empirical assessment of some of the factors that enable humans to learn such a dependency over time. More specifically, we look at how the statistics of the presentation of samples from a given structure influence learning. Participants engage in an experimental task where they are required to predict the timing of a target. At the outset, they are oblivious to the existence of a relationship between the position of a stimulus and the required temporal response to intercept it. Different groups of participants are either presented with a Random Walk where consecutive stimuli were correlated or with stimuli that were uncorrelated over time. We find that the structural relationship implicit in the task is only learned in the conditions where the stimuli are independently drawn. This leads us to believe that humans require rich and independent sampling to learn hidden structures among variables.     

How Fluorescent Tags Modify Oligomer Size Distributions of the Alzheimer Peptide

Within the complex aggregation process of amyloidogenic peptides into fibrils, early stages of aggregation play a central role and reveal fundamental properties of the underlying mechanism of aggregation. In particular, low-molecular-weight aggregates of the Alzheimer amyloid-β peptide (Aβ) have attracted increasing interest because of their role in cytotoxicity and neuronal apoptosis, typical of aggregation-related diseases. One of the main techniques used to characterize oligomeric stages is fluorescence spectroscopy. To this end, Aβ peptide chains are functionalized with fluorescent tags, often covalently bound to the disordered N-terminus region of the peptide, with the assumption that functionalization and presence of the fluorophore will not modify the process of self-assembly nor the final fibrillar structure. In this investigation, we systematically study the effects of four of the most commonly used fluorophores on the aggregation of Aβ (1–40). Time-resolved and single-molecule fluorescence spectroscopy have been chosen to monitor the oligomer populations at different fibrillation times, and transmission electron microscopy, atomic force microscopy and x-ray diffraction to investigate the structure of mature fibrils. Although the structures of the fibrils were only slightly affected by the fluorescent tags, the sizes of the detected oligomeric species varied significantly depending on the chosen fluorophore. In particular, we relate the presence of high-molecular-weight oligomers of Aβ (1–40) (as found for the fluorophores HiLyte 647 and Atto 655) to net-attractive, hydrophobic fluorophore-peptide interactions, which are weak in the case of HiLyte 488 and Atto 488. The latter leads for Aβ (1–40) to low-molecular-weight oligomers only, which is in contrast to Aβ (1–42). The disease-relevant peptide Aβ (1–42) displays high-molecular-weight oligomers even in the absence of significant attractive fluorophore-peptide interactions. Hence, our findings reveal the potentially high impact of the properties of fluorophores on transient aggregates, which needs to be included in the interpretation of experimental data of oligomers of fluorescently labeled peptides.     

New Episodic Learning Interferes with the Reconsolidation of Autobiographical Memories

It is commonly assumed that, with time, an initially labile memory is transformed into a permanent one via a process of consolidation. Yet, recent evidence indicates that memories can return to a fragile state again when reactivated, requiring a period of reconsolidation. In the study described here, we found that participants who memorized a story immediately after they had recalled neutral and emotional experiences from their past were impaired in their memory for the neutral (but not for the emotional) experiences one week later. The effect of learning the story depended critically on the preceding reactivation of the autobiographical memories since learning without reactivation had no effect. These results suggest that new learning impedes the reconsolidation of neutral autobiographical memories.     

Simple Growth Patterns Can Create Complex Trajectories for the Ontogeny of Constitutive Chemical Defences in Seaweeds

All of the theory and most of the data on the ecology and evolution of chemical defences derive from terrestrial plants, which have considerable capacity for internal movement of resources. In contrast, most macroalgae – seaweeds – have no or very limited capacity for resource translocation, meaning that trade-offs between growth and defence, for example, should be localised rather than systemic. This may change the predictions of chemical defence theories for seaweeds. We developed a model that mimicked the simple growth pattern of the red seaweed Asparagopsis armata which is composed of repeating clusters of somatic cells and cells which contain deterrent secondary chemicals (gland cells). To do this we created a distinct growth curve for the somatic cells and another for the gland cells using empirical data. The somatic growth function was linked to the growth function for defence via differential equations modelling, which effectively generated a trade-off between growth and defence as these neighbouring cells develop. By treating growth and defence as separate functions we were also able to model a trade-off in growth of 2–3% under most circumstances. However, we found contrasting evidence for this trade-off in the empirical relationships between growth and defence, depending on the light level under which the alga was cultured. After developing a model that incorporated both branching and cell division rates, we formally demonstrated that positive correlations between growth and defence are predicted in many circumstances and also that allocation costs, if they exist, will be constrained by the intrinsic growth patterns of the seaweed. Growth patterns could therefore explain contrasting evidence for cost of constitutive chemical defence in many studies, highlighting the need to consider the fundamental biology and ontogeny of organisms when assessing the allocation theories for defence.     

A Role for Calcium-Permeable AMPA Receptors in Synaptic Plasticity and Learning

A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca²⁺-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca²⁺-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca²⁺-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.     

Changes in Evoked Potentials Depending on Attention Level in Performance of Visual Tasks

Evoked potentials (EPs) in the parietal and temporal leads were recorded in 14 young subjects in response to successively administered right- and left-side simple visual symbols, squares and circles, during passive viewing and reactions to randomly presented target stimuli. Depending on task conditions and context, the stimuli were divided into four groups: (1) passively perceived stimuli, (2) irrelevant stimuli administered on the side opposite to the target, (3) irrelevant stimuli on the side of the target, and (4) target stimuli. The EPs were averaged over the groups. With an increase in the demands of attention from the first to the fourth groups of stimuli, a linear increase in activation, estimated by the total amplitude of the N1–P3 component, was observed in the parietal leads. The P3b component was mainly responsible for the growth of the EP amplitude. In the temporal leads, the activation was substantially weaker than in the parietal leads and displayed lower between-group differences. The results support the idea that the parietal cortex in humans is of primary importance in tasks involving visual attention and stimuli selection.     

Dopamine in Motor Cortex Is Necessary for Skill Learning and Synaptic Plasticity

Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill.     

Vesicular GABA Uptake Can Be Rate Limiting for Recovery of IPSCs from Synaptic Depression

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T-maze Forced Alternation and Left-right Discrimination Tasks for Assessing Working and Reference Memory in Mice

Forced alternation and left-right discrimination tasks using the T-maze have been widely used to assess working and reference memory, respectively, in rodents. In our laboratory, we evaluated the two types of memory in more than 30 strains of genetically engineered mice using the automated version of this apparatus. Here, we present the modified T-maze apparatus operated by a computer with a video-tracking system and our protocols in a movie format. The T-maze apparatus consists of runways partitioned off by sliding doors that can automatically open downward, each with a start box, a T-shaped alley, two boxes with automatic pellet dispensers at one side of the box, and two L-shaped alleys. Each L-shaped alley is connected to the start box so that mice can return to the start box, which excludes the effects of experimenter handling on mouse behavior. This apparatus also has an advantage that in vivo microdialysis, in vivo electrophysiology, and optogenetics techniques can be performed during T-maze performance because the doors are designed to go down into the floor. In this movie article, we describe T-maze tasks using the automated apparatus and the T-maze performance of α-CaMKII+/- mice, which are reported to show working memory deficits in the eight-arm radial maze task. Our data indicated that α-CaMKII+/- mice showed a working memory deficit, but no impairment of reference memory, and are consistent with previous findings using the eight-arm radial maze task, which supports the validity of our protocol. In addition, our data indicate that mutants tended to exhibit reversal learning deficits, suggesting that α-CaMKII deficiency causes reduced behavioral flexibility. Thus, the T-maze test using the modified automatic apparatus is useful for assessing working and reference memory and behavioral flexibility in mice.     

How to Create and Use Analogies Effectively in the Teaching of Science Concepts

Effective teaching is the art of getting information to the students' memory in an organized manner to facilitate later retrieval. Thanks to advances in cognitive science, one can talk of the science of teaching. A metaphor that captures the work of effective teachers is "teachers as knowledge engineers," which connotes that effective teachers understand the nature of knowledge and, by extrapolation, the nature of teaching and learning. When teachers take charge of knowledge, view it as a process, and understand how to work with it, they take charge of the knowledge-construction process and better help their students. This article discusses how science teachers use analogies as a means of organizing knowledge in their students' memory.     

Memory for Lectures: How Lecture Format Impacts the Learning Experience

The present study investigated what impact the presentation style of a classroom lecture has on memory, mind wandering, and the subjective factors of interest and motivation. We examined if having a professor lecturing live versus on video alters the learning experience of the students in the classroom. During the lectures, students were asked to report mind wandering and later complete a memory test. The lecture format was manipulated such that all the students received two lectures, one live and one a pre-recorded video. Results indicate that lecture format affected memory performance but not mind wandering, with enhanced memory in the live lectures. Additionally, students reported greater interest and motivation in the live lectures. Given that a single change to the classroom environment, professor presence, impacted memory performance, as well as motivation and interest, the present results have several key implications for technology-based integrations into higher education classrooms.     

How to Assess the Existence of Competing Strategies in Cognitive Tasks: A Primer on the Fixed-Point Property

When multiple strategies can be used to solve a type of problem, the observed response time distributions are often mixtures of multiple underlying base distributions each representing one of these strategies. For the case of two possible strategies, the observed response time distributions obey the fixed-point property. That is, there exists one reaction time that has the same probability of being observed irrespective of the actual mixture proportion of each strategy. In this paper we discuss how to compute this fixed-point, and how to statistically assess the probability that indeed the observed response times are generated by two competing strategies. Accompanying this paper is a free R package that can be used to compute and test the presence or absence of the fixed-point property in response time data, allowing for easy to use tests of strategic behavior.     

Replay of Episodic Memories in the Rat

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Fundamental Interventions: How Clinicians Can Address the Fundamental Causes of Disease

In order to enhance the “structural competency” of medicine—the capability of clinicians to address social and institutional determinants of their patients’ health—physicians need a theoretical lens to see how social conditions influence health and how they might address them. We consider one such theoretical lens, fundamental cause theory, and propose how it might contribute to a more structurally competent medical profession. We first describe fundamental cause theory and how it makes the social causes of disease and health visible. We then outline the sorts of “fundamental interventions” that physicians might make in order to address the fundamental causes.     

Mutant Telomeric Repeats in Yeast Can Disrupt the Negative Regulation of Recombination-Mediated Telomere Maintenance and Create an Alternative Lengthening of Telomeres-Like Phenotype

Some human cancers maintain telomeres using alternative lengthening of telomeres (ALT), a process thought to be due to recombination. In Kluyveromyces lactis mutants lacking telomerase, recombinational telomere elongation (RTE) is induced at short telomeres but is suppressed once telomeres are moderately elongated by RTE. Recent work has shown that certain telomere capping defects can trigger a different type of RTE that results in much more extensive telomere elongation that is reminiscent of human ALT cells. In this study, we generated telomeres composed of either of two types of mutant telomeric repeats, Acc and SnaB, that each alter the binding site for the telomeric protein Rap1. We show here that arrays of both types of mutant repeats present basally on a telomere were defective in negatively regulating telomere length in the presence of telomerase. Similarly, when each type of mutant repeat was spread to all chromosome ends in cells lacking telomerase, they led to the formation of telomeres produced by RTE that were much longer than those seen in cells with only wild-type telomeric repeats. The Acc repeats produced the more severe defect in both types of telomere maintenance, consistent with their more severe Rap1 binding defect. Curiously, although telomerase deletion mutants with telomeres composed of Acc repeats invariably showed extreme telomere elongation, they often also initially showed persistent very short telomeres with few or no Acc repeats. We suggest that these result from futile cycles of recombinational elongation and truncation of the Acc repeats from the telomeres. The presence of extensive 3′ overhangs at mutant telomeres suggests that Rap1 may normally be involved in controlling 5′ end degradation.