Oxytocin Neurons Uncover the Brain Mechanism Linking Sociality and Anxiety

Key Points This study revealed that neurons in the paraventricular nucleus of the thalamus (PVT) expressing oxytocin receptors are involved in social behavior and the extinction of fear memory, through an integrated analysis of mouse experiments and human clinical data. Using chemogenetic manipulation, the researchers demonstrated that these cells regulate both the promotion and inhibition of social behavior and fear memory extinction. Furthermore, associations were confirmed between salivary oxytocin levels, thalamic microstructure, and symptoms of Autism Spectrum Disorder (ASD). Overview A research group led by Director Kazuhiko Yamamuro and Assistant Professor Masanobu Ikehara (Department of Psychiatry, Nara Medical University) has clarified the brain mechanism linking sociality and anxiety through oxytocin neurons, using both mouse and human subjects. In this study, multi-faceted analyses were conducted on mice and humans to elucidate the function of neurons expressing oxytocin receptors (OTR), which are thought to be involved in social behavior and fear responses. First, selective chemogenetic manipulation of OTR-expressing PVT neurons in mice showed that inhibiting their activity reduced sociality and impaired fear memory extinction, while activating them promoted the early extinction of fear memory. In contrast, manipulating OTR-expressing neurons in the prefrontal cortex had no effect on sociality or fear responses. Furthermore, electrophysiological analysis revealed that oxytocin administration biases the firing pattern of PVT neurons toward persistent firing, thereby increasing excitability. In the human study, the relationship between salivary oxytocin levels and brain structure was examined in adolescents, including those with ASD. The results showed that salivary oxytocin levels were significantly associated with the Neurite Density Index (NDI) of the thalamus, and that NDI was also associated with the severity of ASD symptoms (particularly difficulty with attention switching and communication). This suggests that peripheral oxytocin levels may be linked to sociality and anxiety via thalamic structure. These findings indicate that OTR-expressing PVT neurons play a central role in regulating sociality and fear, highlighting their potential for understanding the pathology of psychiatric disorders and as new therapeutic targets. By integrating mouse experiments and human clinical data, this study presents the circuit-specific role of oxytocin and provides insights that expand the possibilities for therapeutic interventions for ASD and anxiety disorders. Background Sociality and anxiety significantly impact mental health. Difficulty enjoying interactions with others or experiencing intense anxiety and fear can lead to isolation and stress, resulting in mental health issues. In psychiatric disorders such as ASD, anxiety disorders, and depression, a decline in sociality and difficulty in controlling fear often occur simultaneously, and how these two are linked in the brain has been a long-standing question. Oxytocin is considered a key factor. Beyond its role in childbirth and lactation, it provides a sense of security and trust, earning it the nickname "the love hormone." While oxytocin administration is known to improve interpersonal relationships in some individuals with ASD, it is not effective for everyone, and the mechanism behind this variability remained unknown. The PVT is a region of particular interest in the brain. It is known to be involved in stress and anxiety, as well as social behavior, learning, and reward, suggesting it may serve as a hub linking sociality and anxiety/fear. However, the function of the oxytocin receptor-expressing neurons within it had not been sufficiently studied. In this study, researchers used mice to chemogenetically manipulate these neurons to investigate their impact on sociality and fear memory extinction. Additionally, as a clinical study, they analyzed the relationship between salivary oxytocin levels and brain structure in humans to examine the link to ASD symptoms. This study aimed to approach the mechanism by which oxytocin neurons link sociality and anxiety by combining animal experiments with human research.