Brain-wide input and output wiring diagram of oxytocin neurons and its function in claustrum-endopiriform complex

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Abstract Social behavior reflects highly complex, multimodal, internal/external stimuli integration and is critical to the survival of many animals, including humans. Impaired social behavior has been implicated in many different mental disorders. Despite its importance, we know relatively little about underlying neural circuit mechanisms to generate context appropriate social behavioral response. Oxytocin (OT) is a neuropeptide that plays an essential role in regulating social behavior. Genetic mutations that affect OT signaling have been heavily implicated in brain disorders with social behavioral impairments such as autism spectrum disorder. OT neurons predominately located in the hypothalamus receive input from the sensory system and other brain regions to integrate both external stimuli and internal information. In turn, hypothalamic OT neurons release OT to the bloodstream via the pituitary to affect body metabolism and provide central projection to other brain regions. To support OT function, OT receptor (OTR) is highly expressed in socially important brain areas. Particularly, OT signaling via OTR in different brain regions is known to increase social information processing while suppressing background noise to achieve circuit specific neural modulation. Despite prominent roles of OT signaling during social behavior, precise neuroanatomical connectivity and circuit specific effects of OT signaling remain unclear. Here, we propose to study the detailed anatomical organization of hypothalamic OT neurons and to investigate its function in a novel mouse brain area. It has been technically challenging to image and analyze microscopic structures (e.g., axons) throughout the entire mammalian brain. To overcome this barrier, we previously developed a novel method that combines serial two-photon tomography (STPT) imaging of whole mouse brains at cellular resolution with viral and genetic tools to achieve quantitative input and output maps of cell type specific populations. Using this approach, we will examine topographically segregated output (Aim1) and input (Aim2) maps of hypothalamic OT neurons and will develop web visualization platform to display high-resolution images for further analysis. Moreover, we will investigate OT signaling function in the claustrum-endopiriform complex to guide normal social behavior based on our preliminary results (Aim3). We believe these studies will establish a much-needed detailed anatomical wiring diagram of OT neurons and will provide a foundation to elucidate the neural circuit basis of mature social behavior in health and disease.