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Genetic access to synaptic mechanisms of memory in the behaving animal - Axo-axonal synaptic integration in control of neurotransmitter release

Subject Area Cognitive, Systems and Behavioural Neurobiology
Molecular Biology and Physiology of Neurons and Glial Cells
Term from 2016 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 282979116
 
Final Report Year 2024

Final Report Abstract

This project set out to investigate how synaptic and network properties change at defined sites in a behavioural context in Drosophila. Starting from a focus on learning-induced synaptic plasticity at defined learning-relevant synapses in vivo, the scope of the project was broadened beyond learning and memory to understand sleep regulation. The initial questions aimed at understanding the molecular and physiological substrates of learning in vivo and how dopaminergic neurons shaped behaviour in the Drosophila learning and memory centre, the mushroom bodies. Contrary to the literature, which posited that learning-relevant plasticity mechanisms are expressed presynaptically in Drosophila, we uncovered a crucial plasticity pathway involving postsynaptic nicotinic acetylcholine receptors. Following training, nicotinic receptor subunits rearrange hierarchically downstream of dopaminergic signals leading to postsynaptic long-term depression. How receptor plasticity translates to long-term depression differs for defined synapses involved in storage of appetitive associative or non-associative familiarity memories respectively. On the presynaptic side this project expands our knowledge of in vivo signal integration downstream of the classical memory storage sites. We identified molecular interactions of presynaptic cholinergic receptors with the neurotransmitter release machinery at putative axo-axonal contacts. Indeed, the cholinergic receptors identified shaped behavioural responses following aversive learning. Moreover, this project uncovered a dendro-dendritic inhibition motif between dopaminergic neurons. This motif functions via a Dop2R receptor pathway and likely plays a role in terminating reward signals. Indeed, interfering with this inhibitory pathway resulted in animals overfeeding. Based on developed multi-unit optical recording strategies, we expanded this project beyond learning and reward signalling to sleep regulation in the central complex. We found that, based on glutamatergic NMDA receptor coincidence detection and nicotinic receptor input, single cells synchronized leading to local in vivo slow wave oscillations that are directly linked to consolidated uninterrupted sleep. Indeed, we found that excitatory and inhibitory networks synchronized over time under control of both homeostatic and circadian regulation. We found the temporal synchrony of networks to define how sensory information is transduced to downstream head-direction neurons, where excitatory and inhibitory input sites are localized in proximity along the dendrites. Finally, we identified t-type calcium channels that create arousal windows to render the described sensory filters breakable. This project has set the basis for understanding the interplay of synaptic and network parameters during memory storage and sleep need and now allows to study the interaction of both phenomena during acute decision making and post memory encoding. Moreover, it has set the stage to tackle the in vivo interplay of pre- and postsynaptic mechanisms during various neural processes.

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