Oxytocin在社交响应及免疫调节中的协同作用及机制研究

Dynamic distribution of lymphocyte in meninges and choroid plexus play important roles in cross-talk between central nerves system and immunologic system. In this process, interferon -γ (IFN-γ) serve as the key molecule to refine the regulation. Neuropsychiatric disease characterized by the social defeat, such as autism frequently accompanied the aberrant distribution of lymphocyte in meninges and choroid plexus and abnormal secretion of IFN-γ. Previous study indicated oxytocin play the synergistic regulation on social behavior and immunoreaction through the specific neural circuit, endocrine and paracrine pathway. Our preliminary study indicated that social defeat accompanied the changes of IFN-γ in meninges and choroid plexus and microglial activation in PVN of hypothalamus. Simultaneously, oxytocin fluctuation is obvious in different social paradigm. Nevertheless, it is still unknown whether the fluctuation of oxytocin induced by social cues affect the distribution of lymphocyte in meninges and choroid plexus and generation of IFN-γ. Whether oxytocin synergistically regulated the social behavior and immunoreaction through IFN-γ signals originated from the meninges and choroid plexus. In this proposes, DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) technology was used to control the oxytocinergic neurons in PVN. Cytometry by time of flight technology was used to identify the subset of lymphocyte in meninges and choroid plexus. The aim of this study focused on the effects of oxytocin on distribution of lymphocyte in meninges and choroid plexus under the different social paradigm. Furthermore, IFN-γ-KO mice were used to explore the roles of IFN-γ signals in immunoregulation and social defeat. This study will present the theoretical foundation and therapeutic target through immunotherapy on mental disorders.

脑膜、脉络丛淋巴细胞动态分布是中枢和外周免疫对话的关键，IFN-γ是其中的关键调节分子。以自闭症为代表的一类社交障碍相关的神经精神疾病常伴随脑膜及脉络丛淋巴细胞亚群分布变化及IFN-γ分泌异常。OT(催产素）通过特定神经环路及内分泌、旁分泌途径调节社交行为和免疫反应。我们前期研究结果发现不同行为范式诱导的社交障碍常伴随脑膜及脉络丛IFN-γ水平的改变、OT水平波动及下丘脑PVN区小胶质细胞活化，但不清楚社交线索诱导的OT水平改变是否影响脑膜及脉络丛淋巴细胞亚群分布及IFN-γ分泌，是否通过此途径发挥神经-免疫协同调节作用。本研究利用化学遗传技术操纵下丘脑PVN区OT神经元，利用质谱流式技术检测脑膜及脉络丛淋巴细胞亚群分布，探索在不同社交行为范式下，OT神经元状态对脑膜及脉络丛淋巴细胞亚群分布的影响，结合IFN-γ基因敲除，研究IFN-γ的调节作用，揭示OT在社交响应和免疫调节中的协同机制。

催产素（OT）是由室旁核和视上核分泌的9肽激素。催产素受体（OTR）在社会行为调节相关的多个脑区有表达，同时在免疫细胞上也发现了催产素受体，表明催产素不但参与社会行为调节，也参与免疫调节。OT具有诱导型表达的特点，但不清楚早期社交环境变化对成年后社会行为模式有何影响，对脑内OT-OTR系统的重塑发挥何种作用。社交压力诱导的社交行为改变、OT-OTR改变与外周免疫之间的关联如何。我们研究结果发现出生后连续17天母子分离导致子鼠成年后社交障碍，社交识别能力下降，杏仁核及海马区OT-OTR系统发生变化，树突分支形式改变。丰富环境下饲养3个月，对母子分离诱导的社交障碍及社交认知有改善作用。早期母子分离导致PVN区神经元树突棘密度在早期大量增加，在成年后显著减少，树突棘的这一改变和该区域小胶质细胞的形态与活化的关系不大。早期母子分离降低成年小鼠外周血白细胞、中性粒细胞、淋巴细胞数量，增加了脑膜、脉络丛CD8+阳性细胞数量，降低了海马的BDNF表达水平，增加了下丘脑OT表达水平。急性社交压力导致小鼠出现社交障碍，表现为社交恐惧和社交退缩，血清IFN-γ水平升高，脾脏淋巴细胞、外周血淋巴细胞及脉络丛组织中IFN-γ转录水平同步升高。脾脏切除小鼠对社交压力刺激的敏感性下降，焦虑样反应减少。急性社交压力导致OT水平下降，但脾脏切除小鼠社交压力刺激对OT水平无影响。社交压力导致BDNF及IGF2水平在海马减少，但在前额皮层增加。IFN-γ-/-小鼠表现出社交障碍，IFN-γ-/-小鼠PFC区CREB水平升高，BDNF水平下降，海马区BDNF及IGF2水平均下降，下丘脑OT及CRH表达水平下降；同时可见下丘脑PVN核团内OT阳性神经元数目减少，β-gal 阳性细胞数量增加。以上结果表明不同时期，不同类型的社交压力导致的OT-OTR系统改变不同，对免疫系统的影响也存在差别，免疫调节关键分子INF-γ对PVN区OT神经元的发育有影响。该结果对理解社会行为和免疫调控的协同进化有帮助，对自闭症的免疫治疗提供了新思路。