Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in rats

Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA). Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which is not activating the related vasopressin V1a receptor. CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes. These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.社交行为改变是多种神经发育障碍与神经精神疾病的典型特征，然而此类功能异常背后的神经底物仍未得到充分阐明。越来越多的证据表明，前额叶皮层（prefrontal cortex, PFC）是调控社交行为的关键脑区之一。基于这一认知，本研究旨在构建一种转化型社交环路功能异常大鼠模型——慢性前额叶皮层激活模型（chronic PFC activation model, CPA）。本研究采用化学遗传学设计受体hM3Dq，对大鼠前额叶皮层进行为期10天的慢性激活，并对长期前额叶皮层过度激活的行为学与电生理特征进行了评估。为验证该模型对长期药理学干预的敏感性，并确认其转化潜力，本研究采用新型高选择性催产素受体（oxytocin receptor, OXTR）激动剂RO6958375对大鼠进行处理，该激动剂不会激活与之同源的血管加压素V1a受体。CPA模型大鼠在三箱社交行为实验中表现出社交能力减退，同时通过急性脑片电生理记录发现，其前额叶皮层内神经元兴奋性与突触传递功能均伴随下降。在CPA模型造模后，采用低剂量新型OXTR激动剂进行亚慢性给药，可干预前额叶皮层环路功能异常、社交行为异常以及特异性转录组变化的发生。上述结果表明，持续性前额叶皮层过度激活可改变脑环路特征与社交行为，且该效应可通过选择性激活OXTR进行调控；同时，本模型可用于解析药物研发中亲社会性治疗手段的环路招募机制。