Active and passive coping strategies: the periaqueductal grey to cerebellar link

从生存的角度来看，如果出现威胁，痛苦或可怕的事件，动物必须产生适当的行为反应。中脑导水管周围灰质（PAG）在调节合适的“应对策略”中起着关键作用，涉及心血管调节、感觉调节和运动输出的综合阵列。积极应对；对抗行为（对外部刺激的反应性增加）与PAG背外侧/外侧（dl/l）细胞柱的激活有关，而被动应对(例如：静止（对外部刺激反应性降低）与腹侧PAG （vl）细胞柱的激活有关。我们对PAG的这些不同的列是如何连接到运动系统以引起这些不同的防御反应的理解上的一个主要空白。PAG的功能柱对输入（并可以修改）运动电路的感觉信号的调节是否不同，这也是未知的。我们提出的工作计划将建立在实验的基础上，在这些实验中，我们已经表明，vlPAG投射到小脑前结构，可以唤起小脑的活动，也可以有力地控制进入这个主要的大脑中心的感觉信号，这个主要的大脑中心与运动控制密切相关。小脑是一个高度模块化的结构，因此在与主动和被动应对相关的一系列行为中，有足够的不同途径参与其中。因此，我们将把注意力集中在PAG与小脑回路的联系上。我们的主要目标是：1)绘制连接PAG不同功能柱与小脑和小脑前结构的神经连接链；2)直接测试小脑功能与pag相关运动输出之间的因果关系；3)研究PAG各功能柱在控制感觉信息进入不同小脑模块中的作用。为了理解完整动物的不同行为是如何由神经元网络支撑的，我们将在系统分析层面使用解剖学、药理学、电生理学和行为技术的综合力量。将这些不同的方法联系起来，将极大地提高我们对以下方式的理解：(1)PAG的不同功能柱在运动控制的重要途径中调节不同行为意义的感觉信号的传递（无害的和有害的）；(2)PAG引发与主动和被动应对相关的不同运动反应的神经回路的结构和功能。特别是，如果小脑的特定模块是神经回路的重要组成部分，PAG的单个功能柱通过这些模块引发特定的运动反应，那么这些模块的失活应该导致运动反应的改变。大鼠和猫的PAG不同功能柱所引发的防御行为非常相似，我们在大鼠身上的试点工作表明，PAG与小脑蚓内模块之间的联系可能是该电路的重要组成部分。小脑的结构和连接模式，特别是蚯蚓，在哺乳动物物种中是高度保守的。因此，我们使用大鼠作为实验模型的结果应该具有普遍的适用性。由于PAG对感觉信号的调节是一个依赖于行为状态的动态过程，我们的实验计划还将包括研究PAG参与的两种特征明确的行为情况发展过程中这种控制的变化：(i)慢性疼痛状态的获得；（二）厌恶（恐惧）反应的获得。总的来说，这些实验将揭示对生存至关重要的行为反应背后的基本神经回路的结构和动态功能。

From the perspective of survival, if a threatening, painful or fearful event arises it is imperative that an animal generates the appropriate behavioural response. The midbrain periaqueductal grey (PAG) plays a key role in mediating suitable 'coping strategies', involving an integrated array of cardiovascular adjustments, sensory regulation and motor output. Active coping (eg.confrontational behaviours with increased responsiveness to external stimuli) is associated with activation of a column of cells in the dorsolateral/lateral (dl/l) PAG, whilst passive coping (eg. quiescence with reduced responsiveness to external stimuli) is associated with activation of a column of cells in the ventrolateral (vl) PAG. A major gap in our understanding concerns how these different columns of the PAG are connected to the motor system to elicit these distinct defensive responses. It is also unknown if the functional columns of the PAG differ in their regulation of sensory signals that feed into (and can modify) motor circuits. The proposed plan of work will build on experiments in which we have shown that vlPAG projects to pre-cerebellar structures, can evoke activity in the cerebellum, and can also powerfully control access of sensory signals to this major brain centre critically involved in movement control. The cerebellum is a highly modular structure so there is ample scope for different pathways to be involved in the range of behaviours associated with active and passive coping. We will therefore focus attention on PAG links to cerebellar circuits. Our key aims are to: 1) chart the chain of neural connections that link the different functional columns of the PAG to the cerebellum and pre-cerebellar structures; 2) test directly for a causal link between cerebellar function and PAG-related motor output; and 3) study the role of individual functional columns of the PAG in controlling access of sensory information to different cerebellar modules. Choice of techniques To understand how distinct behaviours are underpinned by neuronal networks in the intact animal we will use the combined power of anatomical, pharmacological, electrophysiological and behavioural techniques at the systems level of analysis. Linking these different methods should greatly improve our understanding of the way (i) different functional columns of the PAG regulate transmission of sensory signals of different behavioural significance (non-noxious versus noxious) in pathways important for movement control and (ii) the structure and function of neural circuits through which PAG elicits different motor responses associated with active versus passive coping. In particular, if specific modules of the cerebellum are an essential part of the neural circuitry by which individual functional columns of the PAG elicit particular motor responses, then inactivation of these modules should lead to an altered motor response. Choice of experimental model The defensive behaviours elicited by different functional columns of the PAG are very similar in rat and cat, and our pilot work in rats suggests that a link between the PAG and modules in the cerebellar vermis may be an important component of this circuitry. Cerebellar architecture and patterns of connectivity, especially of the vermis are highly conserved across mammalian species. Our results using rats as an experimental model should therefore have general applicability. Since regulation of sensory signals by the PAG is a dynamic process dependent on behavioural state our programme of experiments will also include study of the changes in such control during development of two well characterized behavioural situations in which the PAG is involved: (i) the acquisition of a chronic pain state; and (ii) the acquisition of an aversive (fear) response. Overall, these experiments will therefore reveal the structure and dynamic function of the basic neural circuitry underlying behavioural responses critical to survival.