Periodic Reporting for period 3 - EnergyMemo (Dynamic Interplay between Energy and Memory)
Reporting period: 2020-10-01 to 2022-03-31
The EnergyMemo project addresses the coupling between memory formation and brain energy metabolism, in the brain of the fruitfly Drosophila melanogaster. The metabolic syndrome, an emerging pathology linked to abnormal energy management by the body, is associated with an increased risk of diabetes, cardio vascular disease, but its impact on brain function remained under-investigated. Given the fast spreading of this syndrome, and given that the link between neurodegenerative diseases and defects in brain metabolism also appears increasingly clear, it is crucial to delineate the mechanisms by which the allocation and regulation of neuronal energy fluxes shape memorization abilites.
Using Drosophila for our studies gives access to a plethora of versatile genetically expressed tools to manipulate energy metabolism pathways in the course of memory formation, but also to monitor the use of energy by neurons and their neighbouring glial cells through fluorescence imaging experiments. In addition, previous work for our lab and others in the field provided a precise description of the neural networks involved in the encoding of memories over different time scales in the fly’s brain.
With this in hand, we developed research thematics at the interface of learning and memory and energy metabolism fields, which gives our team an original positioning within the international research landscape. Our objectives are to highlight timely regulations of energy supply to neurons is key to proper encoding of long-term memory, and to identify the network and molecular mechanisms that underlie those regulations, with a particular emphasis on neuron-glia interaction.
Using Drosophila for our studies gives access to a plethora of versatile genetically expressed tools to manipulate energy metabolism pathways in the course of memory formation, but also to monitor the use of energy by neurons and their neighbouring glial cells through fluorescence imaging experiments. In addition, previous work for our lab and others in the field provided a precise description of the neural networks involved in the encoding of memories over different time scales in the fly’s brain.
With this in hand, we developed research thematics at the interface of learning and memory and energy metabolism fields, which gives our team an original positioning within the international research landscape. Our objectives are to highlight timely regulations of energy supply to neurons is key to proper encoding of long-term memory, and to identify the network and molecular mechanisms that underlie those regulations, with a particular emphasis on neuron-glia interaction.
The starting point of our project was the discovery that dopamine input on the mushroom body, the brain area that integrates olfactory signals with salient stimuli of positive or negative valence, triggers an increase in pyruvate consumption by mitochondria in these neurons, which is necessary and sufficient to initiate the formation of long-term memory. Since then, an important part of our work consisted in identifying how this dopamine input circuit was controlled. First, we have identified a new pair of neurons that uses the serotonin neuromodulator to activate the energy-modulating dopamine input. We additionally showed that the phosphodiesterase-encoding gene dunce must is inhibited in these serotonergic neurons to allow for long-term memory encoding, thus establishing this gene as a so-called ‘memory checkpoint’ gene (Scheunemann et al., Neuron (2018)). Strikingly, we further found that this neuron is subjected to a post-mating regulation that enables dunce inhibition, which explained why virgin females could not properly form long-term memory (Scheunemann et al., Science Advances (2019)). Second, we also identified another GABA-ergic feedback circuit that allows the proper shaping over time of the activity of the energy-regulating dopamine neurons (Pavlowsky et al., Current Biology (2018)).
In parallel, we initiated our studies of neuron-glia interaction during long-term memory. We showed that a particular type of glial cells, that enwraps the neuronal cell bodies, is activated during memory formation, and we delineated the full molecular mechanism of the neuron-to-glia and glia-to-neuron metabolic dialogue (de Tredern et al., in preparation).
Finally, developing a pionneer expertise in the fluorescent imaging of energy metabolism fostered collaboration with the group of Irene Miguel-Aliaga, on a project focused on inter-organ communication in Drosophila. Using fluorescent sensors that we provided, this group showed that carbohydrate metabolism in the intestine is sexually dimorphic and that gut-derived citrate promotes food intake and sperm production (Hudry et al., Cell (2019)).
In parallel, we initiated our studies of neuron-glia interaction during long-term memory. We showed that a particular type of glial cells, that enwraps the neuronal cell bodies, is activated during memory formation, and we delineated the full molecular mechanism of the neuron-to-glia and glia-to-neuron metabolic dialogue (de Tredern et al., in preparation).
Finally, developing a pionneer expertise in the fluorescent imaging of energy metabolism fostered collaboration with the group of Irene Miguel-Aliaga, on a project focused on inter-organ communication in Drosophila. Using fluorescent sensors that we provided, this group showed that carbohydrate metabolism in the intestine is sexually dimorphic and that gut-derived citrate promotes food intake and sperm production (Hudry et al., Cell (2019)).
The most cutting-edge aspect of our project is the implementation of genetically-encoded fluorescent biosensors for the in vivo imaging of cellular metabolism. Many sensors already exist, but their usage has been mostly limited to ex-vivo or cell culture applications so far. Studies employing these sensors truly in vivo have remained scarce. We started by developing a protocol to measure mitochondrial metabolism in vivo using a pyruvate sensor. More recently we devised another method to measure cellular glucose consumption in neurons and glia. This approach is key to the success of our project and to decipher the metabolic regulations underlying memory We will pursue by developing additional approach to monitor other parameters or modalities of brain metabolism, such as ATP or lactate.
While our studies have been mostly focused on long-term memory so far, which is the most stable memory phase described in Drosophila, we expect in the remaining part of the project to also address the putative metabolic regulations that engage mushroom body neurons into the formation of other, less stable memory phases. We will also investigate the state-dependent alteration of memory ability under the angle of the modifications of neuron-glia interaction. At the end of the project we expect to get a comprehensive picture of metabolic plasticity occuring in the mushroom body, from learning to long-term memory formation.
While our studies have been mostly focused on long-term memory so far, which is the most stable memory phase described in Drosophila, we expect in the remaining part of the project to also address the putative metabolic regulations that engage mushroom body neurons into the formation of other, less stable memory phases. We will also investigate the state-dependent alteration of memory ability under the angle of the modifications of neuron-glia interaction. At the end of the project we expect to get a comprehensive picture of metabolic plasticity occuring in the mushroom body, from learning to long-term memory formation.