Belli, E. | bioRxiv Science

bioRxiv2024

TNFα-driven Aβ aggregation, synaptic dysfunction and hypermetabolism in human iPSC-derived cortical neurons

Alzheimers disease (AD) patients exhibit an increased load of A{beta} aggregates in the brain parenchyma. The neurotoxic nature of these aggregates has been underscored by recent advances in therapies aimed at reducing their load. To make further progress towards the development of increasingly effective treatments, there is a still largely unmet need for reliable cell models that comprehensively recapitulate aggregate-driven AD pathology. Here, we report a robust and scalable pipeline for generating human iPSC-derived cortical neurons that display A{beta} aggregates in their axonal projections. This phenotype is caused by a repeated dosage of tumour necrosis factor-alpha (TNF) to simulate the chronic inflammatory environment characteristic of AD and enhanced in neurons carrying the Swedish mutation. In association with the increased A{beta} deposits in the cell bodies, this cell model exhibits other key hallmarks of AD, including structural alterations of synapses, electrophysiological asynchronous hyperactivity, and hypermetabolism. Overall, these results illustrate how repeated TNF treatment models central aspects of AD pathology, and provides a platform that could be used for facilitating the translation of potential drugs to clinical applications.

cell biology↗

bioRxiv2023

Hand preference predicts behavioral responses to threats in Barbary macaques

The structure and functioning of the brain are lateralized - the right hemisphere processes unexpected stimuli and controls spontaneous behavior, while the left deals with familiar stimuli and routine responses. Hemispheric dominance, the predisposition of an individual using one hemisphere over the other, may lead to behavioral differences; particularly, an individual may be programmed to act in a certain way concerning hemispheric dominance. Hand preference is a robust estimator of hemispheric dominance in primates, as each brain hemisphere controls the opposing side of the body. Studies have found links between hand preference and the exhibition of different behaviors in contexts such as exploring and manipulating objects. However, little is known about whether hand preference can predict behavioral variations in other ecologically relevant contexts like, for example, predation. We investigated the relationship between hand preference and the behavioral responses to two types of predator models in captive Barbary macaques (Macaca sylvanus) (n=22). Hand preference was determined by observing unimanual foraging, whereas focus and tension behaviors were quantified during experimental exposure to predator models. We found 91% of the macaques to be lateralized with no group-level bias. In contrast to their right-hand counterparts, individuals with a strong left-hand preference elicited frequent focus and tension behavior. Additionally, the behavioral response varied with predator type. We also found an interaction effect between hand preference and the predator type. Our study suggests that hand preference can reliably predict behavioral variations in the context of potential predation. While these results are consistent with the lateralized brain function, indicating lateralization as a potential neural mechanism of behavioral variation, the interaction effect between hand preference and predator type elucidates the importance of context-specificity when investigating laterality non-invasively. Future research on other non-human primates using the current framework may shed light on the evolution of laterality and underlying behavioral predispositions.

animal behavior and cognition↗