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

从生存的角度来看，如果发生威胁、痛苦或恐惧的事件，动物必须产生适当的行为反应。中脑导水管周围灰质(PAG)在调节适当的“应对策略”方面起着关键作用，它涉及一系列完整的心血管调节、感觉调节和运动输出。主动应对(如对抗性行为，对外界刺激的反应增强)与背外侧/外侧(dl/L)PAG中一列细胞的激活有关，而被动应对(例如。对外界刺激反应减弱的静止)与腹外侧部(VL)PAG中的一列细胞的激活有关。我们理解中的一个主要差距是关于PAG的这些不同部分是如何连接到运动系统以引发这些不同的防御反应的。同样未知的是，PAG的功能柱是否在它们对馈入(并可以修改)马达回路的感觉信号的调节方面存在差异。拟议的工作计划将建立在实验的基础上，在这些实验中，我们已经证明vlPAG投射到小脑前结构，可以唤起小脑的活动，也可以强有力地控制感觉信号到达这个关键参与运动控制的主要大脑中心。小脑是一个高度模块化的结构，因此有足够的空间让不同的路径参与到与主动和被动应对相关的一系列行为中。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)绘制将PAG的不同功能柱连接到小脑和小脑前结构的神经连接链；2)直接测试小脑功能和PAG相关运动输出之间的因果联系；以及3)研究PAG的各个功能柱在控制感觉信息进入不同小脑模块中的作用。为了了解完整动物的神经网络如何支持不同的行为，我们将在系统层面上使用解剖学、药理学、电生理学和行为学技术的组合力量。将这些不同的方法联系起来应该会极大地提高我们对以下方式的理解：(I)PAG的不同功能柱调节对运动控制至关重要的通路中不同行为意义的感觉信号(非伤害性或伤害性)的传递，以及(Ii)PAG引起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的各个功能柱通过该回路引发特定的运动反应，那么这些模块的失活应该会导致运动反应的改变。实验模型的选择PAG的不同功能柱在大鼠和猫身上引起的防御行为非常相似，我们在大鼠身上的实验工作表明，PAG与小脑蛔部模块之间的联系可能是这一环路的重要组成部分。在哺乳动物物种中，小脑的结构和连接模式，特别是蚯蚓的连接模式是高度保守的。因此，我们以大鼠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研究PAG参与的两种典型行为情景的发展过程中这种控制的变化：(I)获得慢性疼痛状态；(Ii)获得厌恶(恐惧)反应。总体而言，这些实验将因此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.