Michihiro TORITSUKA

Oxytocin has been implicated in regulating social behaviour and emotional responses; however, the underlying neural circuits remain incompletely understood. Neurons expressing oxytocin receptors (OTRs) in the paraventricular thalamus (PVT) are emerging as a potential modulator of these processes. In this study, we investigated the specific role of OTR-expressing PVT neurons in sociability and fear-related behaviours. Using chemogenetic approaches, we found that bidirectional manipulation of these neurons significantly modulated social behaviour and fear extinction in mice. Inhibition of OTR-expressing PVT neurons impaired sociability and fear extinction, whereas activation selectively enhanced early extinction learning without affecting sociability. Electrophysiological analyses revealed that oxytocin increases tonic firing in PVT neurons, suggesting a mechanism for heightened excitability. In contrast, manipulation of OTR-expressing neurons in the medial prefrontal cortex had no effect on sociability. In a complementary human dataset, salivary oxytocin levels were modestly associated with thalamic microstructure and autism spectrum disorder trait severity. Although the experimental paradigms differed across species, these findings collectively suggest that OTR-expressing PVT neurons may contribute to social and emotional behaviours through circuit-specific mechanisms. These findings may have implications for psychiatric conditions such as autism spectrum disorder and anxiety. Future translational studies should explore the therapeutic potential of targeting oxytocin-related PVT function to treat social and fear-related deficits. Overall, these findings advance our understanding of the role of oxytocin in brain function and its relevance to mental health.

BACKGROUND: Self-esteem is a critical factor in the psychological adjustment of children and adolescents, yet little is known about how autistic traits and parenting styles interact to relate self-worth in individuals with autism spectrum disorder (ASD). Understanding these relationships may provide important insights for family-based interventions. METHODS: We conducted a cross-sectional study of 76 participants (ASD: n = 40; typically developing [TD]: n = 36). Autistic traits were assessed using the Japanese version of the Autism-Spectrum Quotient (AQ-J), parenting attitudes were evaluated with the Parental Nurturance and Parenting Scale (PNPS), and self-esteem was measured using the Rosenberg Self-Esteem Scale (RSES). In the ASD group, clinician-rated autism symptom severity was additionally assessed using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). Associations among autistic traits, parenting attitudes, and self-esteem were examined using multiple linear regression and partial correlation analyses. RESULTS: Children and adolescents with ASD exhibited significantly lower self-esteem than their TD peers (RSES: ASD < TD, p < 0.01). In the combined sample, higher AQ-J scores were independently associated with lower self-esteem (β ≈ -0.48, p < 0.01). Within the ASD group, negative parenting attitudes were linked to lower self-esteem (β = -0.36, p = 0.02), whereas positive parenting attitudes showed a non-significant trend toward higher self-esteem (β = 0.20, p = 0.17). Conversely, clinician-rated autism symptom severity assessed by the ADOS-2 was not associated with self-esteem (β = 0.06, p = 0.72). Overall, parenting attitudes were more closely related to self-esteem than clinician-rated symptom severity in the ASD group. CONCLUSION: These findings underscore the relevance of parenting contexts in relation to self-esteem among youth with ASD. Although autistic traits were associated with greater vulnerability in self-esteem, supportive parenting attitudes were associated with more favorable self-esteem outcomes. Together, the results suggest that parenting-related factors may be important considerations when addressing psychological well-being in autistic children and adolescents.

AIM: This study aimed to explore the relationship between self-esteem and tumor necrotic factor-alpha (TNF-α) expression in individuals with autism spectrum disorder (ASD). Self-esteem was assessed using the Contingencies of Self-Worth (CSW) scale, with a focus on external and internal contingencies, and TNF-α expression was measured, given its association with both ASD pathophysiology and self-esteem in prior studies. METHODS: We enrolled 51 high-functioning individuals with ASD and 34 typically developed (TD) individuals. Self-esteem was assessed using the Japanese version of the CSW scale, which evaluates seven domains, and the Personal Sense of Power. TNF-α expression in plasma was quantified via ELISA. Correlations of CSW scores and the Personal Sense of Power with TNF-α levels were analyzed using multiple regression models adjusted for confounding factors such as age, sex, education level, and autistic symptoms. RESULTS: In ASD individuals, TNF-α expression was significantly negatively correlated with the external CSW domain of others' approval and showed a trend toward negative correlations with appearance and relationship harmony. These correlations were not observed in the TD individuals. Likewise, the Personal Sense of Power within family settings showed a trend toward positive correlations with TNF-α expression in ASD individuals, but not in TD individuals. DISCUSSION: This study highlights the implication of TNF-α levels in the self-esteem of ASD individuals, particularly in interpersonal relationships. Lower TNF-α expression was associated with higher self-esteem in social contexts, independent of the severity of autistic symptoms. These findings suggest a biological link between inflammatory pathways and self-esteem in ASD, contributing to a deeper understanding of the interplay between immune function and psychological well-being in this population.

Sensory issues are common in autism spectrum disorders (ASD) and can significantly affect daily living. The phenomena of gating and habituation of event-related potentials (ERPs) to repetitive stimuli have been suggested as potential biomarkers reflecting atypical sensory processing in ASD. Sensory hypersensitivity and anxiety are closely related in ASD, and habituation to emotionally evocative stimuli may serve as a more sensitive biomarker for sensory hypersensitivity symptoms. However, previous studies have primarily used tonal stimuli, and there has been little investigation into whether habituation to emotionally evocative sounds is impaired in ASD patients. In this study, we compared the degree of habituation of the P1-N1 peak-to-peak amplitude in response to repeated tones and fearful vocalizations between control and ASD groups. Contrary to expectations, no significant difference was observed for fearful vocalizations between the groups, while ASD patients showed significantly reduced habituation to tonal sounds in the left parieto-occipital region. Furthermore, we found a significant correlation between the degree of habituation to tonal sounds in the left parieto-occipital region and sensory hypersensitivity symptoms in ASD patients, and similar abnormalities in BTBR mice, an animal model of ASD. These results suggest that habituation to tonal sounds, rather than emotionally evocative stimuli, may serve as a translational biomarker reflecting sensory hypersensitivity symptoms.

Dendritic spine abnormalities are believed to be one of the critical etiologies of autism spectrum disorder (ASD). Over the past decade, the importance of microglia in brain development, particularly in synaptic elimination, has become evident. Thus, microglial abnormalities may lead to synaptic dysfunction, which may underlie the pathogenesis of ASD. Several human studies have demonstrated aberrant microglial activation in the brains of individuals with ASD, and studies in animal models of ASD have also shown a relationship between microglial dysfunction and synaptic abnormalities. However, there are very few methods available to directly assess whether phagocytosis by human microglia is abnormal. Microglia are tissue-resident macrophages with phenotypic similarities to monocyte-derived macrophages, both of which consistently exhibit pathological phenotypes in individuals with ASD. Therefore, in this study, we examined the phagocytosis capacity of human macrophages derived from peripheral blood monocytes. These macrophages were polarized into two types: those induced by granulocyte-macrophage colony-stimulating factor (GM-CSF MΦ, traditionally referred to as "M1 MΦ") and those induced by macrophage colony-stimulating factor (M-CSF MΦ, traditionally referred to as "M2 MΦ"). Synaptosomes purified from human induced pluripotent stem cell-derived neuron were used to assess phagocytosis capacity. Our results revealed that M-CSF MΦ exhibited higher phagocytosis capacity compared to GM-CSF MΦ, whereas ASD-M-CSF MΦ showed a marked impairment in phagocytosis. Additionally, we found a positive correlation between phagocytosis capacity and cluster of differentiation 209 expression. This research contributes to a deeper understanding of the pathobiology of ASD and offers new insights into potential therapeutic targets for the disorder.