Oxytocin modulation of the insular cortex: implications for social cognition and neurodevelopmental disorders.

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

The current study aimed to explore the possible effect of stimulants on oxytocin (OT), a neuropeptide which regulates social behavior, as a mediator of the pro-social effect of methylphenidate (MPH) in children with attention deficit hyperactivity disorder (ADHD) compared to healthy controls (HCs). Utilizing a double-blind placebo-controlled design, we compared the performance of 50 children with ADHD and 40 HCs in "theory of mind" (ToM) tasks and examined the effect of a single dose of MPH/placebo on ToM and salivary OT levels in children with ADHD at baseline and following an interpersonal interaction. Children with ADHD displayed significantly poorer ToM performance; however, following MPH administration, their performance normalized and differences between children with ADHD and HC were no longer found. Salivary OT levels at baseline did not differ between children with ADHD and HCs. However, after a parent-child interaction, OT levels were significantly higher in the HC group compared to children with ADHD. Administration of MPH attenuated this difference such that after parent-child interaction differences in OT levels between children with ADHD and HC were no longer found. In the ADHD group, OT levels decreased from administration of placebo to the parent-child interaction. However, the administration of MPH to children with ADHD was associated with an increase in OT levels after the parent-child interaction. We conclude that OT might play a role as a mediator of social deficits in children with ADHD and that the reactivity of the OT system to social interaction in children with ADHD might be impaired. Stimulants may improve ToM and social functions in children with ADHD via its impact on the OT system. PRS: OT and Social Cognition in Children with ADHD: Impact of MPH.

Difficulties with social communication and interaction are a hallmark feature of autism spectrum disorder. These difficulties may be the result of problems with explicit social cognition (effortful and largely conscious processes) such as learning and recalling social norms or rules. Alternatively, social deficits may stem from problems with implicit social cognition (rapid and largely unconscious processes) such as the efficient integration of social information. The goal of this study was to determine how problems in explicit and implicit social cognition relate to social behavior in 34 youth with autism spectrum disorder. We measured aspects of implicit and explicit social cognition abilities in the laboratory using behavioral, cognitive, and brain (electrophysiological) measures. We then used those measures to predict "real-world" social behavior as reported by parents, clinicians, and independent observers. Results showed that overall better aspects of implicit and explicit social cognition predicted more competent social behavior. In addition, the ability to fluidly integrate social information (implicit social cognition) was more frequently related to competent social behavior that merely knowing what to do in social situations (explicit social cognition). These findings may help with the development of interventions focusing on improving social deficits.

In 2006, research on the neurotransmitter serotonin and its transporter protein (5‐HTT) in the synaptic gap celebrated a series of anniversaries. Forty‐five years earlier, presynaptic neurotransmitter uptake was discovered (Hertting & Axelrod, 1961). Two decades later, 5‐HTT was first linked to depression (Langer et al , 1981), shortly after its identification as a target of antidepressant drugs (Raisman et al , 1979). The sequence of the transporter gene from rats was published 10 years after that (Blakely et al , 1991), which initiated an avalanche of molecular genetic studies on the regulation of emotionality. This research culminated in two reports revealing an association between variations of the 5‐HTT gene ( 5‐HTT and SLC6A4 ) and anxiety‐related traits as well as depression (Collier et al , 1996; Lesch et al , 1996). Since then, clinical studies have further supported the link between variants of 5‐HTT and disorders in the regulation of emotion. Although modest effect sizes—typical of non‐Mendelian traits—polygenic patterns of inheritance, epistatic and epigenetic interactions, and heterogeneity between studies confounded the results, 5‐HTT comprises a model molecule for studying gene–environment interactions in cognitive and psychiatric neuroscience. The demonstration in rhesus macaques that stress early in life uniquely reinforces links between variations of 5‐HTT , behaviour and psychopathology seems to herald in a new era of behavioural genetics. Moreover, the discovery that 5‐HTT is a susceptibility gene for depression is a first step towards explaining the molecular dimensions of personality and behaviour, identifying physiological pathways that lead to other disorders of cognitive function and emotion, and analysing the interactive effects of genes and environment in the development of disease. On the heels of these results from behavioural genetics, novel approaches including neurophysiology, neuropsychology and functional neuroimaging, as well as the inclusion of other phenotypes (such as higher cognitive functions, communication skills, social competence and longevity), have …

The dorsal medial prefrontal cortex and basolateral amygdala exhibit social behavior-relevant neuronal oscillations, representing unified pathophysiological mechanisms underlying social behavioral deficits.

The dorsal medial prefrontal cortex and basolateral amygdala exhibit social behavior-relevant neuronal oscillations, representing unified pathophysiological mechanisms underlying social behavioral deficits.

Social neuroscience launched a novel multilevel (neural, hormonal, molecular and genetic) explanation of social cognition in psychiatry. In particular, the use of different levels of scientific inquiry assessing a) behavioral social cognition sensitivity to psychiatric impairment, b) neural networks engaged in social behaviors, c) the genetic underpinning of social phenomena, and d) the influence of the social environment on biological processes, have been outstandingly addressed by Cacioppo et al's paper 1. Neuroscientific progress suggests that the separation between psychiatry and neurology is counterproductive. Classical neurological conditions present a range of social cognition impairments that are often underrecognized and frequently undertreated. Social neuroscience has made important progress in elucidating the neurobiology of the social brain, but has not focused sufficiently on neurological disorders. Here we consider the implications of social neuroscience research for a specific neuropsychiatric condition, the behavioral variant of frontotemporal dementia (bvFTD). Moreover, we highlight the importance of social neuroscience for the cross-talk among psychiatry and neurology. BvFTD is a neurodegenerative disease whose initial symptoms are often confused with several psychiatric conditions. It is characterized by early decline in social interpersonal behavior, personality changes, and progressive deterioration in social functioning 2. Conventional neuropsychological assessment as well as clinical routine neuroimaging have been not been very useful for early diagnosis 2. The social neuroscience approach has raised new opportunities for research and translational applications in bvFTD. First, social cognition assessment in bvFTD has allowed the detection of early and subtle behavioral impairments, appearing even before imaging signatures of brain atrophy, or a clear decline in formal cognitive status 3. In particular, social cognition tasks that resemble everyday behavior seem to be a far more adequate assessment for this purpose 4. Social cognition assessment may soon become part of the clinical screening for bvFTD. Second, it has been proposed that models of social cognition associated with a degeneration of the fronto-insulo-temporal (social context network model) or fronto-insular (salience network) regions may explain the myriad of bvFTD social cognition impairments 2. For instance, Von Economo neurons are large spindle-shaped cells, abundant in the insular and anterior cingulate cortex. Among primates, these neurons have evolved only in hominids, and seem to be particularly vulnerable in neuropsychiatric conditions resulting in social cognition impairments. In bvFTD, a specific loss of these neurons within fronto-temporo-insular atrophy, at early stages, has been associated clinically with changes in empathy, social awareness, and other social cognition domains 5. Third, an important genetic component of bvFTD has been related with social cognition impairment. There are three main genes for bvFTD: MAPT, GRN, and C9ORF72. Patients with C9ORF72 mutations exhibit widespread frontotemporal atrophy, associated with psychiatric presentations as well as with social neglect 6. In a similar way, animal models and clinical studies of GRN have shown early social and emotional changes, without gross impairment in overall health 6. Fourth, the potential role of the social world, and its interaction with brain changes in bvFTD, deserves consideration. For instance, feeling lonely is associated with increased risk for dementia 7 and with a wish to hasten death in FTD 8. An inter-level social neuroscience approach combining the study of social behavior, neural networks, genetic influences, and the interactions between social behaviors and social cognition would help to provide a more in-depth understanding of bvFTD, as well as of the overlaps of this disorder with the symptomatology and social cognition impairments of several psychiatric conditions 9. A new form of cross-talk between psychiatry and neurology may thus be developed in the social neuroscience arena, spearheaded by work on bvFTD as perhaps the clearest example of the bridges between the two disciplines. Stimulating this cross-talk between neurological and psychiatric research seems to be one of the most promising roles for social neuroscience. Several neurological conditions with mental health manifestations (e.g., neurodegenerative conditions, prosopagnosia, tuberous sclerosis, and Angelman, Heller, Prader-Willi, Williams, Turner and Klinefelter syndromes) present impaired social functioning 10. Here, we have highlighted the multilevel social neuroscience approach to bvFTD, but the understanding of several other neurological conditions could benefit from this approach. Many social cognition domains (social emotions, decision making, theory of mind, empathy, moral cognition, and social norms) may be impacted differentially in various psychiatric and neurological conditions, and the differences in such parameters could be built into technologies for diagnosis and measurement of treatment efficacy. Psychiatrists and neurologists within this novel social neuroscience approach may be able to contribute a powerful multidisciplinary and transdisciplinary approach 11, that would be both clinically and theoretically relevant to major advances in contemporary neuropsychiatry.

The ability to detect, appraise, and respond to another's emotional state is essential to social affective behavior. This is mediated by a network of brain regions responsible for integrating external cues with internal states to orchestrate situationally appropriate behavioral responses. The basolateral amygdala (BLA) and the insular cortex are reciprocally connected regions involved in social cognition and prior work in male rats revealed their contributions to social affective behavior. We investigated the functional role of these regions in female rats in a social affective preference (SAP) test in which experimental rats approach stressed juvenile but avoid stressed adult conspecifics. In separate experiments, the BLA or the insula were inhibited by local infusion of muscimol (100ng/side in 0.5μL saline) or vehicle prior to SAP tests. In both regions, muscimol interfered with preference for the stressed juvenile and naive adult, indicating that these regions are necessary for appropriate social affective behavior. In male rats, SAP behavior requires insular oxytocin but there are noteworthy sex differences in the oxytocin receptor distribution in rats. Oxytocin (500nM) administered to the insula did not alter social behavior but oxytocin infusions to the BLA increased social interaction. In sum, female rats appear to use the same BLA and insula regions for social affective behavior but sex differences exist in contribution of oxytocin in the insula.

For social animals, social isolation is a potential threat to survival, and therefore can be considered innately aversive. Long-term social isolation induces a variety of social and affective deficits and has been used as a stress model in animal studies, with increasing insight into its underlying neural mechanisms. In contrast, short-term social isolation is known to elicit prosocial behaviors such as rebound social interactions, yet the neural basis of these adaptive responses remains poorly understood. Here, we investigated the effects of short-term social isolation on social and appetitive behaviors and examined the role of the insular cortex in modulating social preference in male mice. Three days of social isolation increased social contacts in a three-chamber social preference test. Additionally, socially isolated mice showed higher food intake in the home cage compared with the group-housed mice, and those exhibiting a higher social preference following social isolation also tended to consume more food during the isolation, postulating a potential correlation of social craving and food craving. Furthermore, chemogenetic suppression of the insular cortex during social isolation reduced rebound social interactions. We propose that the insular cortex modulates social valence by serving as an alert center for social deprivation. Our findings may help advance understanding of the neuronal mechanisms that underlie adaptive social and appetitive behaviors in response to social isolation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-025-01236-4.

Deficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a "common core" brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. This study aims to fill this knowledge gap. To determine the role of the anterior insula in social cognition, the authors manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and is involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. Multimodal analyses were conducted at the molecular, cellular, circuitry, and behavioral levels. At the molecular and cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. The authors also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, although not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts with the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus, where serotonergic neurons are projected to the anterior insula. Furthermore, the authors show that serotonin 5-HT2C receptor expressed in the anterior insula influences social novelty recognition. The anterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade but also remotely regulated by oxytocin via a long-range circuit mechanism.

The present study investigated the long-lasting effects of prenatal repeated restraint stress on social behavior and anxiety, as well as its repercussions on oxytocin (OT) and vasopressin (VP)-positive neurons of the paraventricular (PVN) and supraoptic (SON) nuclei from stressed pups in adulthood. Female Wistar rats were exposed to restraint stress in the last 7 days of pregnancy. At birth, pups were cross-fostered and assigned to the following groups: prenatally non-stressed offspring raised by prenatally non-stressed mothers (NS:NS), prenatally non-stressed offspring raised by prenatally stressed mothers (S:NS), prenatally stressed offspring raised by prenatally non-stressed mothers (NS:S), prenatally stressed offspring raised by prenatally stressed mothers (S:S). As adults, male prenatally stressed offspring raised both by stressed mothers (S:S group) and non-stressed ones (NS:S group) showed impaired social memory and interaction. In addition, when both adverse conditions coexisted (S:S group), increased anxiety-like behavior and aggressiveness was observed in association with a decrease in the number of OT-positive magnocellular neurons, VP-positive magnocellular and parvocellular neurons of the PVN. The NS:S group exhibited a reduction in the amount of VP-positive magnocellular neurons compared to the S:NS. Thus, the social behavior deficits observed in the S:S and NS:S groups may be only partially associated with these alterations to the peptidergic systems. No changes were shown in the OT and VP cellular composition of the SON nucleus. Nevertheless, it is clear that a special attention should be given to the gestational period, since stressful events during this time may be related to the emergence of behavioral impairments in adulthood.

Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model

Differences in social behaviours are common in young people with neurodevelopmental conditions (NDCs). Recent research challenges the long-standing hypothesis that difficulties in social cognition explain social behaviour differences. We examined how difficulties regulating one's behaviour, emotions and thoughts to adapt to environmental demands (i.e. dysregulation), alongside social cognition, explain social behaviours across neurodiverse young people. We analysed cross-sectional behavioural and cognitive data of 646 6- to 18-year-old typically developing young people and those with NDCs from the Province of Ontario Neurodevelopmental Network. Social behaviours and dysregulation were measured by the caregiver-reported Adaptive Behavior Assessment System Social domain and Child Behavior Checklist Dysregulation Profile, respectively. Social cognition was assessed by the Neuropsychological Assessment Affect-Recognition and Theory-of-Mind, Reading the Mind in the Eyes Test, and Sandbox continuous false-belief task scores. We split the sample into training (n = 324) and test (n = 322) sets. We investigated how social cognition and dysregulation explained social behaviours through principal component regression and hierarchical regression in the training set. We tested social cognition-by-dysregulation interactions, and whether dysregulation mediated the social cognition-social behaviours association. We assessed model fits in the test set. Two social cognition components adequately explained social behaviours (13.88%). Lower dysregulation further explained better social behaviours (β = -0.163, 95% CI -0.191 to -0.134). Social cognition-by-dysregulation interaction was non-significant (β = -0.001, 95% CI -0.023 to 0.021). Dysregulation partially mediated the social cognition-social behaviours association (total effect: 0.544, 95% CI 0.370-0.695). Findings were replicated in the test set. Self-regulation, beyond social cognition, substantially explains social behaviours across neurodiverse young people.

Administration of intranasal oxytocin has been found to improve social cognition in a number of brain conditions, including autism spectrum disorder and schizophrenia. Whether this approach is relevant in dementias is currently unknown, particularly in frontotemporal dementia, a younger-onset dementia characterized clinically by marked changes in social cognition and behavior and focal atrophy of the frontal and temporal lobes. This chapter provides an overview of the deficits in social cognition in frontotemporal dementia and reviews the emerging evidence of intranasal oxytocin administration as a potential treatment option for these deficits. Future research directions will also be discussed.

Empathy, the ability to vicariously experience and to understand the affect of other people, is fundamental for successful social-cognitive ability and behaviour. Empathy is thought to be a critical facilitator of prosocial behaviour and is disrupted in a number of psychiatric and neurological disorders. Research has begun to uncover the neural basis of such ‘vicarious experience’, which has been studied as a proxy measure of empathy. Together, these studies have identified portions of the insula and anterior cingulate cortex as critically involved. A key debate is whether overlapping or non-overlapping brain areas respond to personal and vicarious experience. This review will highlight emerging evidence for both types of brain response. Importantly, animal models have suggested that there are central divisions between the anterior cingulate gyrus and anterior cingulate sulcus that may be crucial for understanding social behaviour. Attention to this specific anatomy of vicarious processing could therefore help shed light on the functional profile of empathy. Studies in individuals with psychopathy and autism spectrum disorders have found that vicarious experience is atypical. However, the precise nature of these atypicalities is mixed. Understanding the mechanisms of vicarious experience can enhance our knowledge of the neural basis of empathy and, ultimately, help those with disorders of social cognition and behaviour.