“Equipes FRM” awards – 2024

Congratulations to David Perrais, Naoya Takahashi and Pierre Trifilieff, “Equipes FRM” award winners.

David Perrais

Team: Trafic membranaire synaptique – IINS

Spatio-temporal control of catecholamine neuromodulation of hippocampal pyramidal cells: from mechanisms of neuromodulator release to receptor signaling and trafficking (SpaceNeuroModule)

Chemical neurotransmission has been classified into fast neurotransmission and neuromodulation. Fast chemical neurotransmission, used by a majority of neurons in the central nervous system, is spatially restricted, thanks to a tight spatial control of neurotransmitter release at the active zone, the presence of cognate post-synaptic receptors and powerful recapture systems. In contrast, neuromodulation arises from a small number of neurons mediating slow communication to widespread neuronal networks. The sparsity of neuromodulatory synapses and the absence of direct ionotropic receptor signaling hampered our ability to resolve neuromodulation mechanisms at the micrometer and millisecond scale. In the project SpaceNeuroModule, we will address this question at noradrenaline projections in the hippocampus. We will use state-of-the art synaptosome sorting, proteomics, correlative cryo light and electron tomography (cryoCLEM), receptor interactome profiling, live cell fluorescence imaging and electrophysiology in vitro and ex vivo. We have defined 2 work packages to address the release of neuromodulators and the activation of their receptors at pyramidal dendrites, which regulates attention related learning and stress-related behaviors. First, we will determine the organization and dynamics of noradrenaline release sites. Second, we will assess the spatio-temporal extent of beta-adrenergic signaling in post-synaptic compartments. This research program will enable the formulation of design principles for neuromodulatory systems which will be tested further in disease models.

Naoya Takahashi

Team: Neural Basis of Perception – IINS

Cortical mechanisms for tactile information processing during tool use

Tool-mediated tactile sensing is a crucial aspect of daily life. For instance, when using a fork, we can extract the food’s location and texture as if the fork were part of our body. Similarly, a blind person uses a cane to perceive their surroundings and accurately estimate object locations. The brain incorporates tools like forks or canes into the “body schema” – the internal representation of our own body and its surroundings, which can be expanded by tools. This schema is believed to be maintained and constantly updated in the frontoparietal cortical network, enabling the brain to interpret somatosensory information and create a coherent tactile experience and perception of the surrounding space. However, the specific neuronal processes involved are largely unexplored.

Given the unique nature of rodent whiskers, non-neuronal, extra-somatic elements, we propose using the mouse whisker system, as a new model to study neural mechanisms in tool-mediated object localization. Furthermore, our research takes a novel approach with “prosthetic whiskers,” artificial whiskers that substitute a mouse’s innate whiskers, offering a unique opportunity to examine neuronal processes in the context of “extrinsic” tool use in mice.

The proposed study aims to test the hypothesis that the layer 1 of the primary somatosensory cortex, receiving feedback from the frontoparietal network, integrates body schema and somatosensory information during tool use. Utilizing advanced imaging and genetic manipulation, we will delve into neuronal processes from subcellular to network levels, as mice employ innate or prosthetic whiskers for object localization. This research would revolutionize our understanding of the neurophysiological underpinnings of tactile processing during tool use.

Pierre Trifilieff

Team: Foodcircus – NutriNeuro

Contribution of lipid metabolism in the aetiology of psychiatric disorders: relevance of iPLA2β

Deficits in reward processing and executive functions belong to a common symptomatic frame across several psychiatric disorders such as schizophrenia, bipolar disorders and major depression, in relation with a dysfunction of mesocorticolimbic dopamine transmission. This suggests the existence of common pathogenic mechanisms underlying dopamine-related symptomatic dimensions. Converging evidence point to an alteration of polyunsaturated fatty acid (PUFA) metabolism that has been consistently described across psychiatric disorders. In accordance, we and others have demonstrated a unique vulnerability of dopamine transmission to decreased n-3 PUFA biostatus. However, the origin of n-3 PUFA deficiency in psychiatric disorders remains largely unclear, and the causal link with specific symptomatic dimensions remains to be established.

Herein, we will explore the impact of manipulations of the iPLA2β enzyme selectively in dopamine neurons, since iPLA2β is crucial for PUFA metabolism and polymorphisms in the gene coding for this enzyme are associated with the development of psychiatric symptoms. Using cutting-edge neuroscience techniques coupled with elaborated behavioral tasks in mice, we will identify how manipulations of iPLA2β impact reward-related behavioral dimensions, together with dopamine dynamics in the mesocorticolimbic pathway. In order to identify cellular and molecular targets, we will explore how manipulations of iPLA2β affect the translatome and synaptome of mesocorticolimbic projections. We will also assess to which extent n-3 PUFA supplementation alleviates behavioral alterations under manipulations of iPLA2β. This project will allow establishing causal relationship between activity of iPLA2β and behavioral dimensions relevant for the symptomatology of psychiatric disorders. Because PUFAs can be modified through dietary manipulation, such a project will pave the way for novel strategies to prevent or alleviate specific psychiatric symptoms.