The role of insulin signaling in memory formation: the larval Drosophila brain as a favorable model system

• Applicant: Dr. Annekathrin Widmann
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459524845

The neuronal processes underlying memory formation are highly complex and dynamic. For example, long-term memory (LTM) requires transient changes of intracellular signaling cascades that ultimately lead to de-novo protein synthesis. It has been shown in diverse species, including honeybees, fruit flies, sea slugs, mice and humans, that the transcription factor CREB is a universal cellular modulator for LTM formation by regulating the synthesis of synapse-associated proteins upon phosphorylation. However, there is growing evidence that LTM formation is more complex than initially assumed. Several studies in Drosophila have shown that a crucial factor in LTM formation is the metabolic state. Furthermore, our team has provided evidence that insulin signaling in Kenyon cells of the mushroom body plays a significant role for LTM. However, the exact modus operandi how insulin is involved in memory formation remains enigmatic. Does insulin merely increase the sugar uptake into neurons, thereby enhancing the energy available for the neuron? Or does insulin signaling activate dedicated downstream cascades that directly modulate memory formation, ultimately targeting transcription factors like CREB? To address these questions, we decided to use Drosophila larvae as an ideal model organism. Equipped with the advantage of a much smaller brain in terms of numbers of neurons than that of adult fruit flies, Drosophila larvae are still able to form different types of associative memories, including LTM. More importantly, the underlying cellular and molecular mechanisms are conserved between the developmental stages. In the current research project, we want to exploit the advantages of this model organism to analyze which components of the insulin transduction cascade are involved in gating LTM and what the exact cellular role of the actual metabolic state for LTM formation is. We will disentangle potential molecular candidates downstream of the insulin receptor by taking advantage of the abundant genetic tools that Drosophila offers, and will experimentally manipulate and quantify elements of the insulin transduction cascade. Moreover, we want to dissect which insulin-producing cells of the neuroendocrine system contribute LTM formation. Overall, our research project aims at providing a deeper understanding about how the metabolic state gates LTM formation at the molecular and cellular level. Given the fact that both the molecular underpinnings of memory formation and the insulin signaling cascades are highly conserved across the animal kingdom, our work will expand current knowledge of the modulatory function of insulin in memory formation in general. This is of relevance beyond fundamental research on Drosophila, and it might potentially stimulate research on mammalian brains, including that of humans.

• DFG Programme: Research Grants