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. Three groups of rats (N=4 for each group) with or without repeated chemogenetic activation of the PFC over 10 days and subsequent repeated treatment with an oxytocin receptor agonist or vehicle for 7 days

社交行为改变是多种神经发育及神经精神疾病的标志性特征，但此类功能异常的潜在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。基于这一理念，本研究旨在构建社交环路功能异常的转化性大鼠模型——慢性前额叶皮层激活模型（chronic PFC activation model, CPA）。研究采用化学遗传学设计受体hM3Dq，在10天内诱导前额叶皮层的慢性激活，并评估了前额叶皮层长期过度激活的行为与电生理特征。为验证该模型在更长时间尺度下对药理学干预的敏感性，并确认其转化潜力，研究团队使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——该激动剂不会激活相关的血管加压素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降低，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均伴随下降。在CPA模型构建完成后，以低剂量给予该新型OXTR激动剂进行亚慢性处理，可干扰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出现。上述结果表明，持续性前额叶皮层过度激活可改变环路特性与社交行为，且该效应可通过选择性激活OXTR进行调控；同时，该模型可用于探究药物研发中亲社会治疗的环路招募机制。本实验共纳入三组大鼠（每组n=4），分别接受以下处理：10天重复化学遗传学前额叶皮层激活并后续7天重复催产素受体激动剂给药、10天重复化学遗传学前额叶皮层激活并后续7天重复溶剂对照给药，以及无前额叶皮层激活并后续7天重复溶剂对照给药。