应激和奖励对内侧苍白球抑制诱导大鼠自残行为调控的神经机理

Self-Injurious Behavior (SIB), which is defined as intended self-destructive behavior, often conmorbids with several psychological disorders such as depression, autism, schizophrenia etc. However, the underlying mechanism is not clear yet. SIB could be examined passively in previous animal models induced by social isolation, brain lesion, chronic drug treatment or genetic mutation. We found that inhibition of internal globus pallidus (GPi) of fear conditioned rat could induce SIB when the rat underwent retrieval of this fear memory. Our preliminary experiment and previous data suggested that stress system and reward system could involve in modulation of SIB induced by GPi inhibition. But how these systems interact with each other to modulate the behavior is not clear yet. We hypothesized that stress and reward could act on synaptic modification and neural network activity in the Prefontal cortex （PFC）, neucleus accumbence (NAc) and amygdale to modulate SIB. In this project, we will explore whether stress and reward could modulate SIB, whether emotion related neural circuits involve in SIB, how synaptic modification and neural network activity in these nucleuses change during SIB, whether modulation of synaptic transmission and neural network activity could modulate SIB. The project could help us to understand the neural mechanism underlying SIB and provide clues for treatment of psychological disorders related to SIB.

自残行为是一种蓄意伤害自身躯体的行为，往往是多种精神类疾病的并发症。但其发作的神经机理并不清楚。以往研究利用社会隔离，脑区损伤、长期药物作用或者基因突变等手段建立的动物模型中只能被动观测自残的发生。我们首次建立了事件相关的脑区特异性的大鼠自残模型，在经历条件性恐惧的大鼠提取恐惧记忆的同时抑制其基底神经节中内侧苍白球活动可以诱导大鼠自残。以前的研究结果和我们前期实验提示应激和奖励系统可能参与自残的调控。我们推测皮质酮和多巴胺可能通过调节前额叶、伏隔核和杏仁核的突触功能和神经元网络活动进而调控自残行为的发生。本项目将探索应激和奖励是否对自残有调控作用，是否通过情感相关环路起作用，这些脑区在自残中突触功能和神经网络活动是如何改变，调控这些脑区突触传递和神经活动是否能够调控自残行为。通过本研究我们探索皮质酮和多巴胺调控自残行为的神经机理，为相关精神疾病的发病原理和治疗提供线索。

自残行为是一种蓄意伤害自身躯体的行为，往往是多种精神类疾病的并发症。但其发作的神经机理并不清楚。以往研究利用社会隔离，脑区损伤、长期药物作用或者基因突变等手段建立的动物模型中只能被动观测自残的发生。我们首次建立了事件相关的脑区特异性（脚间核，EP）的大鼠自残模型。本项目利用该模型探索应激和奖励是否对自残有调控作用，是否通过情感相关环路起作用，这些脑区在自残中突触功能和神经网络活动是如何改变，调控这些脑区突触传递和神经活动是否能够调控自残行为。.通过研究发现：1）应激和奖励参与对自残行为的调控。自残行为伴随着皮质酮的升高，而阻断皮质酮升高可以降低自残的发生率。特异性地调整LHb-RMTg-VTA通路的活动可以调节自残行为的发生。但是NAc的shell不论是增强还是抑制其活动，自残行为发生率增加 。2）利用示踪技术和c-fos表达探索了自残行为时全脑各个脑区的活动，初步筛选出一批脑区可能参与自残行为。进一步实验发现VTA，NAc，mPFC中突触GluR1 表达及磷酸化水平下降，而LHb和AMG中则上调。上述脑区在自残行为中其发放相对功率谱有显著改变，而mPFC和VTA/NAc/AMG活动的藕联性下降。3）抑制EP损伤了条件恐惧，而LHb中D1R和D2R对条件恐惧及焦虑有调控作用。.通过本研究我们建立了脑区特异性的自残动物模型，探索自残行为调控的神经机理，为相关精神疾病的发病原理和治疗提供线索。