In a groundbreaking study published in Nature, researchers from Mount Sinai have unveiled the intricate neural circuitry that governs how the brain assigns emotional value—known as valence—to social encounters. This pioneering work sheds critical light on the mechanisms underlying both positive and negative impressions formed during social interactions, offering new avenues to understand and potentially treat neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. By focusing on the ventral CA1 region of the hippocampus, the team detailed how the nuanced interplay of two neuromodulators—serotonin and neurotensin—modulate social behavior via distinct receptor pathways.
Social valence, the brain’s capacity to distinguish beneficial or rewarding social stimuli from aversive or harmful ones, fundamentally shapes human behavior and social cognition. Prior to this study, despite its crucial role, the underlying cellular and molecular substrates remained largely enigmatic. Dr. Xiaoting Wu and colleagues addressed this gap by developing an innovative social cognitive paradigm designed to analyze mice behaviorally through controlled negative and positive social exposures, thereby illuminating the circuits responsible for valence assignment.
At the center of this neural circuitry lies the hippocampus, a region traditionally recognized for memory formation and spatial navigation but increasingly implicated in emotional processing. Within the hippocampus, the ventral CA1 (vCA1) subregion emerged as a vital hub where serotonin and neurotensin are differentially released to impart opposing valence signals. These neuromodulators act through their respective receptors: serotonin 1B receptor (5-HT1B) and neurotensin 1 receptor (NTSR1), each engaging distinct neuronal populations, thereby orchestrating either a positive or negative emotional imprint.
The experimental approach utilized involved exposing test mice to social encounters representative of negative stimuli—through interactions with aggressive conspecifics—and positive stimuli—via encounters with potential mates. By monitoring subsequent social preference behavior, the team observed that naive mice initially displayed no preference, but post-exposure developed clear behavioral biases. These biases were directly linked to neuronal activities modulated by serotonin and neurotensin receptor engagement, affirming the mechanistic role of these neuromodulators in assigning social valence.
One of the study’s most remarkable findings was the demonstration that activation of the serotonin 1B receptor could restore positive social valence in a mouse model of ASD, wherein social deficits are a hallmark feature. This revelation offers a highly promising therapeutic target, moving beyond symptomatic treatment toward addressing the neural circuitry deficits at a foundational level. In contrast, neurotensin signaling through the neurotensin 1 receptor was shown to promote the encoding of negative social valence, revealing a dualistic “neuromodulatory switch” mechanism that balances social approach and avoidance behaviors.
The discovery of this neuromodulatory switch highlights a fundamental principle in brain function: the continuous adaptation of social behavior based on prior social experiences and environmental context. This dynamic process involves integrating serotonergic and neurotensinergic influences within the ventral CA1 to modulate downstream circuits responsible for behavioral flexibility. Such insights deepen our understanding of social cognition’s neurobiological basis and illuminate how its dysregulation may contribute to developmental and psychiatric disorders.
Further technical investigations revealed that serotonin and neurotensin operate on distinct yet adjacent circuits within the vCA1, with their receptors expressed on separate neuronal subpopulations. Electrophysiological recordings and optogenetic manipulations underscored how serotoninergic activation enhanced excitatory synaptic transmission associated with positive social memories, whereas neurotensinergic signaling suppressed such activity, biasing toward aversive outcomes. These contrasting effects elucidate the cellular substrates whereby emotional valence is encoded and modified.
The implications of this research extend far beyond ASD, potentially transforming therapeutic strategies for a range of conditions involving social cognitive impairments, including schizophrenia and social anxiety disorders. By pharmacologically modulating the balance between serotonin 1B and neurotensin 1 receptor activation, it may be possible to recalibrate impaired social judgment and behavior, a prospect that represents a monumental leap in neuropsychiatric treatment development.
Moreover, the methodological innovation of the social cognitive paradigm itself presents a robust platform for future explorations. This framework allows for the dissection of complex social behaviors under controlled experimental conditions, facilitating the identification of novel molecular targets and the mapping of associated brain networks with unprecedented precision. As social cognition emerges as a critical domain in psychiatric research, such tools will prove invaluable.
Underlining the translational relevance, the study demonstrates that activation of the serotonin 1B receptor in the vCA1 region can effectively “flip” the emotional valence of social encounters in ASD models. This neuromodulatory control not only rescued social deficits but restored the natural preference for positive social stimuli, thereby reinstating normative social approach behaviors. These findings motivate the pursuit of selective receptor agonists or modulators as candidate therapeutics.
Mount Sinai’s research represents a milestone in our evolving understanding of the hippocampus as more than a memory center but a sophisticated processor of social affect and experience. The dual paths traced by serotonin and neurotensin expand the conceptual framework for valence processing to encompass neuromodulatory balance, opening new horizons for neuroscience aimed at deciphering the complexities of social brain function.
In conclusion, the elucidation of serotonin and neurotensin’s opposing actions within the ventral CA1 hippocampal region establishes a conceptual and mechanistic foundation for social valence processing. This discovery not only unravels a key neurobiological mystery but also propels the field toward innovative treatments for disorders characterized by social dysfunction. As society grapples with the increasing prevalence of neuropsychiatric conditions, such fundamental insights offer hope for more effective, targeted interventions that address the root causes of social cognitive impairments.
Subject of Research: Animals
Article Title: Serotonin and neurotensin inputs in the vCA1 dictate opposing social valence
News Publication Date: 30-Apr-2025
Web References:
Image Credits: Xiaoting Wu, PhD
Keywords:
Social research, Neuroreceptors, Serotonin, Autism, Social development, Serotonin receptor signaling, Mental health
