【作者】 刘玲；

【导师】 徐晗；

【作者基本信息】 浙江大学 ， 神经生物学， 2020， 博士

【摘要】 社会交互是一种在许多物种中均存在的复杂行为,从简单低等的单细胞微生物到我们复杂的人类中均可观察到,对微生物和动物的生存和繁衍都至关重要。社会交互行为异常与自闭症、精神分裂症、抑郁症和社交焦虑障碍等精神类疾病密切相关。因此,了解社会交互行为的神经机制对揭示社交障碍发病机制具有重要意义。研究表明内侧前额叶皮层(medial prefrontal cortex,m PFC)在社会交互行为中起着重要作用,皮层兴奋与抑制的失衡可引起社交功能受损,升高皮层抑制降低了社会交互行为。皮层抑制是由不同类型中间神经元所介导,不同类型抑制性神经元在形态、分子标记、电生理特性和突触连接等方面具有高度多样性,这提示不同类型抑制性神经元在处理信息方面可能发挥不同的作用。在社会交互行为中不同类型抑制性神经元的功能,特别是不同类型中间神经元在实时社会交互行为中是如何反应以及哪种类型神经元的活动对于维持正常的社会交互行为是必要并不清楚。我们采用在体多通道记录的方法对上述问题进行了探究,发现在社会交互行为中m PFC大多数锥体神经元的发放活动不变,仅有少量的神经元的活动增强或者降低。光遗传学标记的方法可以在在体条件下精确地识别特定类型神经元的反应,因此我们分析了m PFC中表达小清蛋白(parvalbumin,PV)和生长抑素(somatostatin,SST)的中间神经元在社会交互行为中的活动情况。具体来讲,在社会交互行为中,PV神经元活动和gamma能量显著升高,而SST神经元活动无变化。采用药理遗传学抑制PV神经元的活动显著降低了gamma能量并且损害小鼠的社会交互行为,抑制SST神经元的活动对gamma能量和小鼠的社会交互行为无影响。然而,有意思的是,采用光遗传学的方法以gamma频率同步化激活PV或者SST神经元均能显著升高gamma能量并产生pro-social的效应。这些结果揭示不同类型抑制性神经元之间的功能差异,并提示低频gamma在社会交往行为中的重要性。此外,我们还发现SST神经元可能可以作为常见社交障碍精神类疾病的治疗靶点。更多还原

【Abstract】 Social interaction is a complex behavior essential for many species and is observed in species as simple as single-celled microorganisms to species as complex as humans and is vital to the survival and reproduction of microorganisms and animals.Social dysfunction is strongly associated with autism,schizophrenia,depression,and social anxiety disorder in clinical.Therefore,understanding the neural mechanism of social interaction behavior is of great significance to reveal the pathogenesis of social disorder.Previous studies have found that the medial prefrontal cortex(m PFC)plays a crucial role in social behavior.A disturbed excitatory and inhibitory balance in the cortex has shown to induce social dysfunction.Increasing the inhibitive effect of cortex reduces the time of social interaction.Cortical inhibition mediated by diverse GABAergic interneurons,which have high diversity in morphology,molecular markers,electrophysiological characteristics and synaptic connections.These studies suggest that different types of inhibitory neurons may play different roles in processing information.The functional contributions of different IN subtypes remain unknown.In particular,it is unclear how distinct interneuron subtypes behave during real-time interactions and what kind of activities they generated are important for appropriate social interactions.We use in vivo multi-channel recording,immunohistochemistry,pharmacogenetic and optogenetics to explore the above questions,found distinct activity patterns and manipulation effects of two major populations of prefrontal INs,parvalbumin(PV)and somatostatin(SST)INs in mice social interaction.Specifically,social interaction closely correlated with spiking of PV but not SST INs and selectively increased low gamma but not high gamma rhythms.Furthermore,pharmacogenetic inactivation of PV instead of SST INs decreased low gamma power and impaired sociability.However,interestingly,optogenetic synchronization of either PV or SST INs at low gamma frequency produced pro-social effects,whereas high gamma frequency stimulation of PV INs enhances high gamma rhythms but had no effect.These results reveal distinct roles of PV and SST INs in social interaction with a critical dependence on low-gamma rhythms.Moreover,except for PV INs,SST INs could serve as therapeutic targets for social improvement in major neuropsychiatric disorders.These results reveal a functional differentiation among IN subtypes and suggest the importance of low gamma rhythms in social interaction behavior.Furthermore,our findings underscore previously unrecognized potential of SST INs as therapeutic targets for social impairments commonly observed in major neuropsychiatric disorders.更多还原