Central serotonin is an important molecular pathway, involved in the regulation of social behavior and gray matter volume (GMV). In men with autism spectrum disorders (ASD), the serotonergic system and the GMV have been found disrupted. Here, we investigated the relation between serotonin, GMV, and social personality in men with typical development (TD) and in men with ASD. We combined anatomical magnetic resonance imaging, Positron emission tomography scan with 2′‐methoxyphenyl‐( N ‐2′‐pyridinyl)‐ p ‐18F‐fluoro‐benzamidoethylpiperazine radioligand and revised NEO personality inventory personality questionnaire to examine the association between serotonin 1A receptor (5‐HT 1A R) binding potential, GMV and social personality in 24 adult male TD subjects and 18 male men with ASD. In both groups, we found a positive correlation between 5‐HT 1A R binding potential and GMV in a region dependent manner. In the TD group, we observed a negative correlation between 5‐HT 1A R and GMV in the left and right posterior putamen. 5HT 1A R binding and GMV in the putamen further correlated with social personality scores in the TD group. None of these associations were found in men with ASD, although no differences were observed for 5‐HT 1A R concentration among the two groups. Our findings point to a deregulation of 5‐HT 1A R density in the striatum of men with ASD, a failure that might contribute to their social disturbances. Serotonin is suspected to be involved in the pathophysiology of autism. We provide evidence for a role of serotonin 1A receptor in social behavior through a specific regulation of GMV in the putamen region in neurotypical subjects but not in men with autism. This suggests a potential impairment of the serotonergic system in men with autism which may contribute to patients' social disturbances. Our findings suggest further investigation on the role of serotonin 1A receptor and its activity in the striatum to regulate social behavior. Autism Res 2020, 13 : 1843‐1855. © 2020 International Society for Autism Research and Wiley Periodicals LLC Lay Summary Serotonin is suspected to be involved in the pathophysiology of autism. We provide evidence for a role of serotonin 1A receptor in social behavior through a specific regulation of gray matter volume in the putamen region in neurotypical subjects but not in men with autism. This suggests a potential impairment of the serotonergic system in men with autism which may contribute to patients' social disturbances. Our findings suggest further investigation on the role of serotonin 1A receptor and its activity in the striatum to regulate social behavior.

Oxytocin (OT), a neuropeptide involved in affiliation has been shown to enhance social skills in patients with autism spectrum disorders (ASD). Nevertheless, OT improvements seem ephemeral. Animal research has demonstrated OT action on serotonin (5-HT), an interaction that we also found in the healthy human brain. Whether such synaptic interplay also occurs in ASD patients is unknown. To address this issue, we mapped the effects of intranasal OT on 5-HT in 18 patients with ASD and 24 healthy controls (HC) in a double blind, placebo controlled, within subject PET-scan experiment. Each participant underwent two scans: baseline and spray (OT or placebo). Using the radiotracer [18 F]MPPF, marking the 5-HT 1A receptor (5-HT1AR), we measured MPPF-Binding Potential (BP) as an index of OT-induced serotonin functional modulation. At baseline ASD patients did not differ from controls for 5-HT1AR concentration and distribution. However, while OT significantly increased MPPF BP in several brain regions of HC, no changes were observed in the ASD group. Serotonin serum concentration analysis corroborated these results. Our findings suggest a disturbed OT-serotonin interaction in autism. This may limit the potential benefits of OT in these patients and open the ways to investigate combined OT-serotonin treatments.

Oxytocin (OT) concentration in the blood is considered to be a marker of its action in the brain. However, two problems have emerged when measuring OT level in the blood. First, it is unclear whether different methods of assessment lead to similar OT values. Second, it is unclear if plasma OT concentrations is informative on what OT does in the brain. To clarify these issues, we collected cerebrospinal fluid (CSF) from the brain ventricle of 25 patients during surgery to compare with plasma OT after simultaneous blood withdrawal. Additionally, we collected 12 CSF and blood samples from non-human primates while awake or under anaesthesia. We used four methods to assay OT concentrations: Commercial EIA with/without extraction, laboratory developed EIA with filtration and RIA with extraction. Three of these methods showed a positive correlation between plasma and CSF OT, suggesting a link between plasma and central OT, at least under specific testing conditions. However, none of the methods correlated to each other. Our results show major disagreements among methods used here to measure peripheral and brain OT and therefore they call for more caution when plasma OT is taken as a marker of central OT.

Autism spectrum disorder (ASD) includes a family of neurodevelopmental disorders with very early onset that affect many aspects of behavior and cognition. In particular, it refers to a set of deficiencies concerning three major domains: social functioning, communication, and stereotyped behavior. Given the importance of the ability to interact with others in daily life, social functioning impairment in ASD has received much attention from different research domains and is considered a core characteristic of this pathology. Understanding how autism affects social functioning development at both behavioral and neural level is crucial for the conception of effective and early interventions to improve social and communicative skills in individuals suffering from this pathology. In this chapter we will focus on the several and different aspects of social functioning impairments in ASD by reviewing the literature on this topic. We will then discuss the important role of the natural hormone oxytocin in social behavior and its therapeutic potential for autism. (C) 2015 S. Karger AG, Basel

Significance Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. Here we show that these chemical messengers interact in areas of the human brain important for the regulation of emotion-based behavior. By highlighting the role of OXT in the regulation of 5-HT signaling, our findings can lead to novel therapeutic strategies for mental disorders such as social anxiety, depression, and autism.

Interagir avec autrui est crucial pour notre survie. Differentes etudes ont mis en evidence le role de l'ocytocine (OT) dans la sociabilite et l'affiliation. La premiere partie de notre travail montre qu'il y a un lien entre la concentration d'ocytocine plasmatique et l'ocytocine centrale et que les deux sont correlees au niveau d'extraversion des individus. L'OT plasmatique correle aussi au volume de l'amygdale et de l'hippocampe, deux regions cerebrales importantes pour le comportement social. Nous montrons egalement que l'administration d'OT entraine une modification (augmentation) de la perception subjective de la sociabilite. L'ensemble de ces resultats suggere que l'OT constitue un biomarqueur de la personnalite sociale et pourrait servir au diagnostic de pathologies sociales comme l'Autisme. Nous avons etudie le fonctionnement central de l'OT et particulierement son interaction avec la serotonine (5-HT), impliquee elle aussi dans la regulation du comportement social. Avec la Tomographie par Emission de Positon (TEP) et grâce a un radioligand ([18-F]MPPF) specifique des recepteurs 5-HT1A de la 5-HT nous montrons que l'administration d'OT entraine, chez le sujet sain une augmentation du potentiel de liaison (BP) du MPPF traduisant une modification de l'activite de la 5 HT au niveau du raphe, de l'amygdale/hippocampe, de l'insula et du cortex orbitofrontal, regions cles pour le traitement du comportement social. Les patients Asperger demontrent une diminution du MPPF BP par rapport aux controles au niveau de ces memes regions, difference qui s'annule par la prise d'OT. Ces resultats confirment le potentiel therapeutique de l'OT et ouvrent de nouvelles pistes de recherche visant a integrer la relation entre les neurotransmetteurs dans les futurs traitements. L'ensemble de ce travail place l'ocytocine au coeur de la physiologie du comportement social et suggere son utilisation tant au niveau du diagnostic que de la prise en charge de l'Autisme

Oxytocin has a fundamental role in social behavior. In humans, supporting evidence shows that oxytocin enhances people's ability to trust or affiliate with others. A key question is whether differences in plasma oxytocin concentration in humans are related to people's differences in their social traits of personality and if such differences are reflected in the structural organization of brain areas responsive to the action of this hormone. We examined the correlation between oxytocin plasma levels and personality traits in 30 healthy subjects, tested with the Inventory revised neuroticism-extroversion-openness personality inventory (NEO-PI-R). By using the voxel-based morphometry technique, we also investigated changes in gray matter volume as a function of the plasma oxytocin level and NEO-PI-R scores. A positive correlation was found between plasma oxytocin and extraversion scores, a dimension that captures social affiliative tendencies. Moreover, we found an inverse correlation between plasma oxytocin and the volume of the right amygdala and the right hippocampus, 2 brain areas implicated in fear and anxiety. Finally, we showed that the amygdala-hippocampal complex correlate negatively with extraversion scores. Our findings provide evidence for a neural mechanism linking physiological oxytocin's variability and structural variation of brain regions relevant for emotion regulation to individual differences in affiliative personality traits.