Serotonin and Neurotensin Drive Opposing Social Behaviors

In a groundbreaking exploration of the neural underpinnings of social behavior, recent research has unveiled how two distinct neuromodulatory systems within a crucial hippocampal subregion drive opposite social valence responses. The ventral CA1 (vCA1) region of the hippocampus, previously recognized for its role in emotional and social memory, has now been shown to integrate signals from serotonin (5-HT) originating in the dorsal raphe (DR) and neurotensin (NT) emanating from the anterior paraventricular thalamus (aPVT). These two inputs encode antagonistic valence signals that decisively shape social preference and aversion, fundamentally advancing our understanding of the bio-neurological basis of social cognition.

The researchers used sophisticated optogenetic techniques to selectively manipulate serotonergic and neurotensinergic inputs into the vCA1 during controlled social interactions, revealing a pivotal role for these systems in encoding social valence. By expressing Cre-dependent channelrhodopsin-2 (ChR2) in DR 5-HT neurons of Sert-Cre mice and optically stimulating their terminals in the vCA1, they demonstrated that serotonin release during aggressive social encounters disrupted the typical preference for non-aggressive conspecifics. Crucially, this impairment of positive social valence was not simply a suppression but hinted at a complex interplay between concurrent neuromodulatory signals.

Intriguingly, neurotensin’s role emerged as an opposing force within this circuit. Although neurotensin continues to be released during aversive interactions, the simultaneous release of serotonin appeared to send contradictory signals, blurring valence encoding. Blocking neurotensin receptor 1A (NTR1-A) with the antagonist SR48692 shifted the balance favoring a positive social valence when 5-HT was concurrently released, effectively flipping the social preference. Conversely, administering the NTR1-A antagonist alone without serotonin release inhibited positive social valence, underscoring the intricate receptor-level integration of neuromodulatory signals.

The bi-directionality of these valence signals was further clarified by directly stimulating neurotensinergic projections from the aPVT to the vCA1 in NT-Cre mice. Under normal conditions with no optogenetic activation, mice exhibited a robust preference for positively valenced social partners. However, light-triggered release of neurotensin during rewarding social interactions impaired this preference, effectively inducing social aversion despite the inherently appetitive context. Here, blocking the 5-HT1B receptor with an antagonist reversed neurotensin’s aversive impact and restored positive social valence, confirming that these neuromodulators induce opposing valence signals within a coordinated neural framework.

This dual-opponent mechanism was further confirmed by behavioral assays designed to isolate valence association to individual social stimuli. When optogenetic activation of 5-HT inputs was paired with exposure to a neutral conspecific hidden under a cup, animals developed a strong preference for the previously light-paired mouse during memory recall. Parallel experiments replacing mice with inanimate objects revealed that novelty or non-social stimuli failed to acquire such valence through serotonin release, emphasizing the social specificity of this neuromodulatory encoding.

Conversely, pairing neurotensin release with a neutral social stimulus induced avoidance during subsequent testing, confirming that neurotensin serves as a critical mediator of negative social valence. The fact that neither serotonin nor neurotensin manipulations affected responses to objects highlights a selective encoding mechanism within the vCA1 that discriminates social salience from non-social novelty. This selective neuromodulation ensures precise attribution of valence that underlies nuanced social behaviors.

The implications of these findings extend beyond basic neuroscience into models of neuropsychiatric disorders characterized by social dysfunction. Notably, the team investigated heterozygous Shank3^Δ4-22+/− mice, a well-established model exhibiting social memory deficits relevant to autism spectrum disorder (ASD). Despite normal sociability, these mutants demonstrated impaired social memory that was not rescued by direct serotonin receptor agonism alone. However, temporally targeted activation of the 5-HT1B receptor during rewarding social interactions restored positive social valence to levels comparable to wild-type littermates, revealing a potential therapeutic avenue targeting discrete neuromodulatory pathways.

Electrophysiological recordings from vCA1 pyramidal neurons further elucidated the mechanism underpinning this rescue. Shank3 mutant neurons exhibited diminished excitability, reflected in reduced spike numbers in response to current injection. Bath application of the 5-HT1B receptor agonist reversed this hypoexcitability, providing a cellular correlate for the behavioral restoration observed. These convergent lines of evidence suggest that enhancing serotonergic modulation within the vCA1 could counteract synaptic disruptions linked to ASD-related social deficits.

The study’s meticulous combination of optogenetics, pharmacology, behavioral assays, and electrophysiology paints a comprehensive picture of how serotonin and neurotensin contort social valence computation and memory. Importantly, these findings reframe the vCA1 as a dynamic integration hub where opposing neuromodulatory signals converge to modulate social approach and avoidance. The balance between excitatory modulatory inputs fine-tunes social decision-making processes essential for adaptive interactions within complex environments.

Moreover, the discovery that simultaneous release of 5-HT and NT effectively nullifies both positive and negative valence suggests a neural mechanism by which conflicting social signals are resolved or suppressed. This could bear significance for understanding social ambiguity and the neural basis of social anxiety or indecision, where valence assignment is unclear or unstable. Further inquiry into this mechanism could unravel how social contexts shift the weighting of neuromodulatory influences.

Notably, the specificity of serotonin and neurotensin effects on social stimuli—but not on innate behaviors such as sexual activity or anxiety-like responses—highlights a neuromodulatory fine-tuning rather than a generalized arousal effect. This deduced selectivity argues for pathway-specific interventions that could modulate social behaviors without undesirable side effects affecting other motivational or physiological systems.

Taken together, this study pioneers a new conceptual framework in social neuroscience, delineating how antagonistic neuromodulatory systems map onto hippocampal circuits to encode social valence with precision. The ability to invert social preferences through targeted receptor manipulation opens the door to novel strategies for remediating social impairments in neurodevelopmental and psychiatric disorders. Future research may explore how environmental factors or genetic variations modulate this serotonergic-neurotensinergic axis, potentially revealing intricate layers of social brain plasticity.

As social behaviors represent a cornerstone of mammalian interaction and survival, insights into their molecular and circuit-level governance are poised to revolutionize both fundamental neuroscience and clinical therapeutics. This compelling example of neuromodulatory opposition within the vCA1 enriches our understanding of how social experiences are encoded, remembered, and behaviorally expressed.

Subject of Research: Neuromodulatory control of social valence in the ventral hippocampal CA1 region.

Article Title: Serotonin and neurotensin inputs in the vCA1 dictate opposing social valence.

Article References:
Zorab, J.M., Li, H., Awasthi, R. et al. Serotonin and neurotensin inputs in the vCA1 dictate opposing social valence. Nature (2025). https://doi.org/10.1038/s41586-025-08809-2

Image Credits: AI Generated

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