Circuit and synaptic plasticity mechanisms of approach and avoidance social behavior.

Informacje na temat projektu

SocialNAc

Identyfikator umowy o grant: 864552

DOI

10.3030/864552

Projekt został zamknięty

Data podpisania przez KE 9 Marca 2020

Data rozpoczęcia 1 Czerwca 2020

Data zakończenia 31 Maja 2025

Finansowanie w ramach

• EXCELLENT SCIENCE - European Research Council (ERC)

Koszt całkowity

€ 1 996 424,00

Wkład UE

€ 1 996 424,00

Koordynowany przez

UNIVERSITE DE GENEVE
Switzerland

Periodic Reporting for period 4 - SocialNAc (Circuit and synaptic plasticity mechanisms of approach and avoidance social behavior.)

Okres sprawozdawczy: 2024-12-01 do 2025-05-31

Podsumowanie kontekstu i ogólnych celów projektu

Social behavior is fundamental for survival and mental health. When the neural processes that support social interaction are disrupted, as in autism spectrum disorder, schizophrenia, or depression, individuals experience profound difficulties in daily life. Despite its importance, the neural mechanisms by which the brain encodes, recalls, and adapts social experiences remain poorly understood.
The project addresses this critical gap by investigating how distinct cortical and subcortical inputs to the ventral striatum (VS) encode the emotional and motivational value of social experiences. The ventral striatum acts as a key integrative hub for reward, emotion, and decision-making, yet how different afferent pathways contribute to specific aspects of social behavior has remained unclear.
The overall objectives are to:
Identify the circuit and synaptic mechanisms by which the AIC encodes the valence of social interactions through projections to the VS.
Determine the role of the BLA input to the VS in social threat learning and memory updating.
Elucidate the neuromodulatory interplay between serotonin and dopamine systems in regulating approach and avoidance behaviors.
Characterize the contribution of PFC projections to the VS in behavioral inhibition and social salience coding.
Integrate these circuit mechanisms into a unified model explaining how emotional valence, memory, and salience are represented in striatal networks to shape adaptive social behavior.
By revealing how these interconnected pathways contribute to social learning and motivation, the project provides a mechanistic foundation for understanding how their dysfunction leads to social withdrawal, apathy, or maladaptive behaviors in neuropsychiatric disorders.

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

We have made substantial progress in dissecting how distinct cortical and subcortical inputs to the NAc enable the encoding of social experiences and the selection between approach and avoidance behaviors. Our work has combined in vivo calcium imaging , optogenetics, patch-clamp electrophysiology, and machine learning–based analyses to link neuronal population activity, synaptic plasticity, and social decision-making.
Aim 1 – Synaptic mechanisms underlying social approach and avoidance behavior
We focused on the inputs from the AIC to the NAc to determine how social valence shapes synaptic transmission. Using behavioral analysis and ex vivo patch-clamp recordings, we found that distinct forms of synaptic plasticity are induced at AIC→NAc synapses depending on whether the preceding social experience was rewarding or aversive. These findings indicate that the valence of a social encounter determines specific synaptic modifications that guide future approach or avoidance behavior.
Aim 2 – Neural coding of social valence in the NAc
We investigated how neuronal activity in the NAc supports approach and avoidance of social stimuli. Using in vivo calcium imaging of D1 receptor–expressing medium spiny neurons (D1-MSNs), we observed robust activation during social interactions, independent of their valence. To identify the upstream drivers of this activity, we applied a neural activity–dependent labeling approach and found that neurons in the AIC are differentially engaged during prosocial and aggressive experiences. Using machine learning–based analyses of calcium dynamics, we demonstrated that the activity of D1-AIC neurons projecting to the NAc can accurately decode the valence of social contact. These results establish the AIC→NAc pathway as a key circuit for representing social valence.
Aim 3 – Sensory contributions to social approach behavior
We next examined how sensory cues contribute to social motivation. Using a three-chamber interaction assay, we demonstrated that olfactory cues play a critical role in driving approach behavior toward conspecifics. In vivo recordings from ventral tegmental area (VTA) dopamine neurons in freely moving mice revealed that complex social stimuli and isolated social odors elicit distinct patterns of activation. Moreover, in a four-choice task, mice consistently preferred complex social stimuli over decomposed sensory cues, highlighting the integrative nature of social reward processing.

Together, these studies have elucidated how the AIC, BLA, and PFC inputs to the NAc differentially contribute to social valence encoding, memory updating, and salience evaluation. Two manuscripts are under revision (Nature Neuroscience and Nature Communications), and one is in preparation. The results have been presented at international conferences and form the basis for future translational collaborations on social motivation and neuropsychiatric disorders.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

The project has advanced substantially beyond the original state of the art by revealing how distinct cortical and subcortical pathways to the ventral striatum encode the emotional, sensory, and motivational dimensions of social behavior. Through an integrated approach combining in vivo calcium imaging, optogenetics, electrophysiology, and AI-driven behavioral analysis, we have uncovered previously unknown circuit- and synapse-specific mechanisms that link social experience to adaptive behavior.

A first achievement was the demonstration that synapses from the AIC to the VS encode the valence of social interactions. We found that AIC projections display distinct patterns of activity and synaptic plasticity during rewarding versus aversive social experiences. This work represents a conceptual breakthrough in understanding how cortical information is transformed into motivationally relevant signals in the striatum. The study has been published as a preprint on bioRxiv —
Pedro Espinosa, Benoît Girard, Mattia Lucchini, Federica Campanelli, Valentina Tiriticco, Camilla Bellone
doi: https://doi.org/10.1101/2022.11.08.515650 — and is currently under revision at Nature Neuroscience.

A second line of work focused on the olfactory tubercle (OT) and its role in adaptive social behavior, revealing how this region integrates olfactory and emotional cues to guide social threat assessment and memory updating. We identified a previously unrecognized contribution of OT circuits in mediating the flexible expression of social avoidance and approach behaviors. This study has been published as a preprint on Research Square —
Camilla Bellone, Giulia Casarotto, Lorena Jourdain, Anastasia Gemelli
doi: https://doi.org/10.21203/rs.3.rs-5579784/v1 — and is currently under revision at Nature Communications.

In addition, a publication from the project has appeared in the European Journal of Neuroscience:
“Deconstructing the contribution of sensory cues in social approach”, which demonstrated that complex social stimuli engage motivational circuits differently from isolated sensory cues, highlighting the importance of multisensory integration in social approach behavior.

Collectively, these studies go well beyond the current state of the art by:
Providing the first mechanistic evidence that the AIC→VS pathway encodes social valence through distinct plasticity rules.
Demonstrating that olfactory tubercle circuits integrate sensory and emotional information to guide adaptive social behavior.
Establishing a technological pipeline combining miniscope imaging, automated behavioral tracking, and machine learning to decode social circuit dynamics.

We are now working on the preparation and submittion of a 4th manuscript about the role of PFC to VS in behavioral inhbition

Figure