Project Portugal 2030

Summary

Our main AIM is to provide mechanistic understanding on how brains process social information from the emotions of others (empathy), which will serve to guide novel therapeutic and diagnostic tools in the future. There is a current lack of understanding on how the brain processes appetitive social information, a fundamental process in our daily lives. With this ambitious project we aim to fill this gap, providing knowledge generated with novel conceptual and experimental approaches that go beyond the state of the art, with the goal to contribute to a better health for everyone. OBJECTIVES: 1.- DESCRIPTION OF EMOTIONAL TRANSFER OF POSITIVE EMOTIONS AT THE SINGLE CELL RESOLUTION IN THE VTA (Fig2A) Using high density electrophysiological recordings in DA photoidentified cells while animals are behaving in our social task, we will ask the existence of specific cluster of DA cells that respond to the emotions of others. Neural data will be aligned with behavior (DeepLabCut and KeyPoint-MoSeq) to identify the specific moments where these cells respond to specific actions of others. This rich data set will inform and guide the development of a theoretical model of the emotional transfer of reward, based in multi-agent reinforcement learning algorithms. 2.- DISSECTION OF THE ANATOMICAL CHARACTERISTICS OF THESE SOCIAL CELLS (Fig2B) We aim to perform a circuit-level anatomical characterization of these other-reward neurons. For this we will use st-Cal-Light (10), a new tool allowing to tag and manipulate neurons specifically engaged in a defined behavior, to have access to the neurons that specifically respond to other-reward cues. We will deliver blue light in the other-reward moments, and active cells will be tagged with GFP or opsins, depending on the WP. We will study where these other-reward tagged cells send their projections with whole-brain clearing methods. This data will help establish the multi-population model by constraining the connectivity structure. 3.- EVALUATION OF THE NECESSITY AND SUFFICIENCY OF THESE OTHER-REWARD CELLS IN GUIDING SOCIAL DECISIONS (Fig 3) Finally, we aim to assess the causal implication of other-reward neurons into social decision making. By using closed-loop optogenetics in circuit-specific manner in previously tagged other-reward neurons, we will unravel the functional role of this specific subpopulation in guiding decisions that have an impact on others (prosocial choices). These experiments will then be replicated in sillico to validate and further constrain the theory. Hence, we will prove the existence of other-reward neurons in the VTA coding specific social information from others and study how they modulate and are being modulated by ACC inputs/outputs by using a combination of neural tagging with high temporal/behavioral resolution, histology and optogenetics in socially behaving rats. Finally, we will assess the functional involvement of the VTA-ACC pathway in prosocial decision-making. To achieve all this, we will use state-of-the-art neuron tagging methods, circuit specific optogenetic manipulation, innovative and trial-based social behavioral tests, electrophysiology recordings and computational modelling. This ambitious project will push forward the frontiers of knowledge about the neural mechanisms underlying positive emotional contagion processes in social contexts and pave the way for the development of future circuit-based therapeutic approaches.