下丘脑-丘脑室旁核-伏隔核（或杏仁核）神经通路催产素系统活化改善精神分裂症社会认知缺陷的机制研究

Social cognition deficits are the core symptoms of schizophrenia (SZ). Oxytocin (OT) regulates the development of central nervous system and closely relates to the disease courses of SZ spectrum disorders, although intranasal administration of OT improves social cognition deficits of SZ patients significantly, the exact mechanism is not clear. As the relay of all kinds of sensory signals transmission, PVT receives the projections of peptides nerve fibres, such as OT from hypothalamus, and project to accumbens nucleus (NAcc) and amygdala (AMG) to regulate their function activity, involving in the regulation of social cognition, emotion and addiction. Considering the projections of PVT to NAcc and AMG overlap in part with dopamine (DA) projections from other brain regions, we postulate that the OT system in HYP - PVT pathway may integrate OT/DA ergic social cognition network in NAcc and AMG to regulate the function of prelimbic cortex and improve social cognition deficits in SZ patients. In this study, employing the development model of SZ mice induced by MK-801 administration in perinatal period and postweaning social isolation, we will try to determine the impact of the activation of OT system on the function of social cognition- associated pathway both in vivo and in vitro, hoping to illuminate the mechanism of how the activation of OT system improves social cognition deficits of SZ patients. Our study will provide theoretical and experimental basis for the developing new antipsychotic drugs.

社会认知缺陷是精神分裂症(SZ)的核心症状。催产素(OT)参与中枢神经系统发育调控，与SZ的疾病进程密切相关，鼻内吸入OT可显著改善SZ患者的社会认知缺陷，其机制未明。丘脑室旁核(PVT)是各类感觉信号传输的中继站，接受来自下丘脑(HYP)的OT等肽类神经支配，并向伏隔核(NAcc)和杏仁核(AMG)发出纤维投射，调节二者的功能活动，参与社会认知和行为调控。PVT肽能纤维投射与其他脑区的DA投射在NAcc和AMG汇聚重叠，推测HYP-PVT通路的OT系统可能通过整合NAcc和AMG的OT/DA能社会认知网络活动，改善SZ社会认知缺陷。本研究拟用围产期MK-801干预和社会隔离诱导的SZ发育小鼠模型，在活体、组织、突触及分子水平，研究大脑OT系统活化对上述神经通路功能活动的影响，以求阐明大脑OT系统活化改善SZ社会认知缺陷的机制，为研发靶向中枢OT系统的新型抗精神病药物提供理论和实验依据。

社会认知缺陷是精神分裂症(Schizophrenia, SZ) 的核心症状。催产素(Oxytocin, OXT)参与中枢神经系统发育调控，与SZ的疾病进程密切相关，鼻内吸入OT可显著改善SZ患者的社会认知缺陷。OT可能通过整合NAcc和AMG的OT/DA能社会认知网络活动，进而改善SZ社会认知缺陷，其机制尚不明确。..主要研究内容：（1）验证慢性鼻内吸入OXT治疗和抗精神病药物利培酮(Risperidone)治疗改善MK-801和PWSI诱导的SZ小鼠模型的社交行为及疗效的性别差异。（2）OXT治疗对MK-801或PWSI诱导的SZ模型小鼠社交行为相关神经核团功能及OXT信号通路蛋白基因的表达影响。（3）首发精神分裂症(first-episode schizophrenia, FES）患者外周血OXT系统相关蛋白基因的表达变化及其临床意义。（4）FES患者外周血淋巴细胞GSK3β、PICK1、GR-1B和GRIA1等基因的表达变化及其临床意义。（5）定向注射腺相关病毒(AAV)下调OXT(IRES-Cre)模型小鼠下丘脑室旁核(PVN) OXT基因表达，观察模型小鼠的社会行为变化并检测OXT相关信号通路表达情况。..重要研究结果和关键数据：（1）OXT和Risperidone治疗使MK-801诱导的SZ模型小鼠的社会接触时间延长，对陌生鼠的识别指数升高。（2）利培酮治疗增加SZ发育模型小鼠的社会交往时间和非攻击性行为百分比，此效应存在性别差异。（3）FES患者存在OXT系统功能紊乱。FES患者外周血血浆OXT浓度、血清OXT、OXTR浓度、AVP和CD38mRNA表达水平较健康对照组(HC组)显著降低，外周血淋巴细胞OXT和OXTRmRNA表达水平较HC组显著升高，上述指标在各组内无性别差异。（4）FES患者的PICK1和NKCC1mRNA表达水平明显低于HC组，NEFL基因水平明显高于HC组；PICK1和NEFLmRNA表达水平存在性别差异。SZ患者存在HPA轴功能紊乱，而CSZ患者较FES患者更为严重；FES患者存在GRIA1、SMURF1和TOP1基因的表达异常，这些指标或可成为FES早期诊断和疗效评估的血清标志物。