Genetic Controls Balancing Excitatory and Inhibitory Synaptogenesis in Neurodevelopmental Disorder Models

Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states

Temporal Requirements of the Fragile X Mental Retardation Protein in Modulating Circadian Clock Circuit Synaptic Architecture

Loss of fragile X mental retardation 1 (FMR1) gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP) is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLNvs), a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e.g. use-dependent pruning) occur, provided strong morphological rescue to reestablish normal sLNvs synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity

From Boring to Board Game: The Effect of a Serious Game on Key Learning Outcomes

Serious games incorporate learning objectives in the context of competitive games with rules. These types of games have been incorporated in education as well as therapeutic contexts. This study examined the effectiveness of a modification of the game “Snakes and Ladders,” for reviewing and learning qualitative research concepts. Using the Game-based Evaluation Model (GEM), the researchers also measured learning indicators such as interest and enjoyment, perceived competence, effort and importance, and value/usefulness. Thirty-eight Master of Occupational Therapy students completed a 25-question multiple choice pretest to measure knowledge of qualitative research concepts before playing the game. A 25-question multiple choice posttest was administered five days later to measure the students’ knowledge retention. A seven-point Likert-type Learning Indicators Questionnaire (LIQ) based on the Intrinsic Motivation Inventory was also administered following the posttest. A dependent t-test revealed a statistically significant increase in mean scores on the posttest [t(37) = 4.86, p \u3c .001; medium to large effect size (d = .79)]. All mean scores on the LIQ subscales were well above the median score of 3.5 on the 7-point scale. These results suggest that not only was the game effective for reviewing qualitative research concepts but that it also successfully incorporated motivational features that can influence learning in general. The particular game described in this study can be used with various content and incorporated in either an educational or therapeutic context

Social learning strategies and cooperative behaviour: Evidence of payoff bias, but not prestige or conformity, in a social dilemma game

Human cooperation, occurring without reciprocation and between unrelated individuals in large populations, represents an evolutionary puzzle. One potential explanation is that cooperative behaviour may be transmitted between individuals via social learning. Using an online social dilemma experiment, we find evidence that participants’ contributions were more consistent with payoff-biased transmission than prestige-biased transmission or conformity. We also found some evidence for lower cooperation (i) when exposed to social information about peer cooperation levels than without such information, and (ii) in the prisoners’ dilemma game compared to the snowdrift game. A simulation model established that the observed cooperation was more likely to be caused by participants’ general propensity to cooperate than by the effect of social learning strategies employed within the experiment, but that this cooperative propensity could be reduced through selection. Overall, our results support previous experimental evidence indicating the role of payoff-biased transmission in explaining cooperative behaviour, but we find that this effect was small and was overwhelmed by participants’ general propensity for cooperation

Does a peer model's task proficiency influence children's solution choice and innovation?

This work was supported by a Durham Doctoral Fellowship to L.A.W.The current study investigated whether 4- to 6-year-old children's task solution choice was influenced by the past proficiency of familiar peer models and the children's personal prior task experience. Peer past proficiency was established through behavioral assessments of interactions with novel tasks alongside peer and teacher predictions of each child's proficiency. Based on these assessments, one peer model with high past proficiency and one age-, sex-, dominance-, and popularity-matched peer model with lower past proficiency were trained to remove a capsule using alternative solutions from a three-solution artificial fruit task. Video demonstrations of the models were shown to children after they had either a personal successful interaction or no interaction with the task. In general, there was not a strong bias toward the high past-proficiency model, perhaps due to a motivation to acquire multiple methods and the salience of other transmission biases. However, there was some evidence of a model-based past-proficiency bias; when the high past-proficiency peer matched the participants' original solution, there was increased use of that solution, whereas if the high past-proficiency peer demonstrated an alternative solution, there was increased use of the alternative social solution and novel solutions. Thus, model proficiency influenced innovation.PostprintPeer reviewe

Teaching Macro Practice Through the Use of Experiential Instruction and Collaboration: A Formula to Create Sustainable Community Resources

While delivering an organizations and communities class to a cohort of students in an outlying rural area, a social work program explored ways to educate students effectively while simultaneously exploring and devising strategies to fill local gaps in community services. The project utilized evidence-based learning strategies focusing on experiential instruction and collaboration with local community agencies. Using aspects of the flipped classroom as well as service learning, the course was particularly interested in engaging with community stakeholders to identify issues arising from the realities of a rural service environment. Students identified a project, worked with community partners, and delivered recommendations at completion. The findings were then used to write a grant to assist with prisoner reentry into the community. This resulted in an award nearing $300,000 to bridge gaps in services. The grant funded two social work positions to provide strengths-based family centered case management, funds for community mentor/volunteer training, released prisoner group meetings aimed at improving released prisoner social and moral functioning, and funds aimed at transportation assistance. The article discusses all aspects of the project and provides an outline to assist social work educators to integrate similar projects into other programs. The project was completed in and is especially well suited for rural areas, where services, resources, and expertise are often lacking. The authors specifically discuss the challenges and strategies of completing a project of this type in a rural setting

The influence of task difficulty, social tolerance and model success on social learning in Barbary macaques

Despite playing a pivotal role in the inception of animal culture studies, macaque social learning is surprisingly understudied. Social learning is important to survival and influenced by dominance and affiliation in social animals. Individuals generally rely on social learning when individual learning is costly, and selectively use social learning strategies influencing what is learned and from whom. Here, we combined social learning experiments, using extractive foraging tasks, with network-based diffusion analysis (using various social relationships) to investigate the transmission of social information in free-ranging Barbary macaques. We also investigated the influence of task difficulty on reliance on social information and evidence for social learning strategies. Social learning was detected for the most difficult tasks only, with huddling relations outside task introductions, and observation networks during task introductions, predicting social transmission. For the most difficult task only, individuals appeared to employ a social learning strategy of copying the most successful demonstrator observed. Results indicate that high social tolerance represents social learning opportunities and influences social learning processes. The reliance of Barbary macaques on social learning, and cues of model-success supports the costly information hypothesis. Our study provides more statistical evidence to the previous claims indicative of culture in macaques

Testing differential use of payoff-biased social learning strategies in children and chimpanzees

Various non-human animal species have been shown to exhibit behavioural traditions. Importantly, this research has been guided by what we know of human culture, and the question of whether animal cultures may be homologous or analogous to our own culture. In this paper, we assess whether models of human cultural transmission are relevant to understanding biological fundamentals by investigating whether accounts of human payoff-biased social learning are relevant to chimpanzees (Pan troglodytes). We submitted 4- and 5-year-old children (N = 90) and captive chimpanzees (N = 69) to a token–reward exchange task. The results revealed different forms of payoff-biased learning across species and contexts. Specifically, following personal and social exposure to different tokens, children's exchange behaviour was consistent with proportional imitation, where choice is affected by both prior personally acquired and socially demonstrated token–reward information. However, when the socially derived information regarding token value was novel, children's behaviour was consistent with proportional observation; paying attention to socially derived information and ignoring their prior personal experience. By contrast, chimpanzees' token choice was governed by their own prior experience only, with no effect of social demonstration on token choice, conforming to proportional reservation. We also find evidence for individual- and group-level differences in behaviour in both species. Despite the difference in payoff strategies used, both chimpanzees and children adopted beneficial traits when available. However, the strategies of the children are expected to be the most beneficial in promoting flexible behaviour by enabling existing behaviours to be updated or replaced with new and often superior ones