LEARNING AND MEMORY

"The zebrafish as a new vertebrate model for molecular and cellular mechanisms of learning and memory, including synaptic dysfunction in Alzheimer's disease"

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 Obiettivo del progetto (Objective)

'A majority of our most common neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, age-related dementia and multiple sclerosis, are manifested by memory loss and a reduced potential for learning. Additionally, a substantial portion of our population suffers from various forms of learning difficulties. Despite all the efforts to solve the mystery of learning and memory, we still do not have a complete cellular model of learning in a higher model organism. During my postdoc at UCLA, USA, I have developed a preparation to study learning of the rapid escape response in zebrafish (Danio Rerio). This model allows for genetic manipulations and behavioral memory testing, simultaneously with physiological recordings in vivo, in a way that has not yet been possible in any other model system. Using this model, I have been able to monitor changes in activity during the learning in the neurons that elicit the behavior. My experiments have also shown the importance of inhibitory regulation of the network during the learning. I will now use this model to study how molecular, cellular and network modifications underlie learning and memory. In parallel, I will investigate the usefulness of the model to study memory deficiencies induced by Alzheimer-associated proteins, such as A-beta. My goal is to establish the links between genes, molecular mechanisms, network function, and behavior of learning and memory, to help us understand both the normal and diseased brain.'

Introduzione (Teaser)

A European study used zebrafish as a model organism to study the key processes of learning and memory. Apart from providing invaluable knowledge on the pathophysiology of Alzheimer's disease (AD) this model could be further exploited for drug design.

Descrizione progetto (Article)

A considerable number of neurological disorders including AD, multiple sclerosis and Parkinson's disease manifest with learning disabilities and memory loss. However, we do not fully comprehend the molecular and cellular mechanisms of memory and learning.

Scientists on the EU-funded LEARNING AND MEMORY project proposed that for such investigations we need a suitable model organism. In this context, they used zebrafish (Danio rerio), a powerful model organism which combines genetic manipulations and behavioural memory testing. Using this model, they performed molecular and cellular analysis of the processes underlying learning and memory.

They focused on the learning of the startle response and localised the synaptic changes in the network underlying this particular behaviour. In parallel, they investigated memory deficiencies induced by AD-associated proteins, such as amyloid beta. To this end, they injected amyloid beta into the larval zebrafish and were able to show that learning is indeed blocked by amyloid beta. Similar results were obtained with the amyloid precursor protein (APP), which was seen to regulate zebrafish axonal outgrowth, synaptic formation and the startle response. Treatment with the commonly used AD medications showed an overall protection against memory impairments.

From a clinical perspective, the LEARNING AND MEMORY study used patient samples to identify gene variants and their association with disease development. Single nucleotide polymorphism analysis of the ARC gene in AD patients' unravelled one gene variant which reduced the risk of AD development.Project members demonstrated the potential of using zebrafish as a model organism to study basic learning and memory processes in both health and disease. This also opened up new avenues for utilising zebrafish as a future drug discovery tool.