Role of the cerebellum in survival circuits activated by fear.

我们对大脑神经网络障碍如何导致情绪障碍的了解有限，许多患者(动物和人类)对现有治疗方法反应不佳。对构成动物“生存回路”的神经网络的基础研究将提供必要的信息，为开发新的治疗策略提供信息。有两种类型的生存回路会对厌恶或恐惧的事件产生防御性反应。一种是天生的、硬连线的无条件反应，另一种是条件性反应，是由经验修正的生存回路活动的结果。两者都协调对情绪状态、心血管活动的调整，并产生适当的动作，如打架、逃跑或僵住。这些活动的总和构成了一种防御性反应。所涉及的神经网络可以比作邮政服务，它‘知道’邮寄的是什么，以及它需要去哪里，以便适当的信息通知必要的结果。我们理解中的一个主要差距是，这种邮政服务如何与大脑的运动系统接触，以引发对恐惧事件的独特和行为适当的无条件和条件性防御反应。马达系统是否能反馈和改变生存回路中的活动也是未知的。我们的目标是提供对解剖学的新见解--它定义了“邮寄地址”；生理--决定了正在传递的“信息”的性质；以及行为--信息产生的影响。小脑是大脑中最大的运动控制器，一个新兴的概念是，它在这个邮政系统中扮演着关键角色。最近，我们已经证明，由无条件和条件性恐惧事件诱发的大鼠的防御性冰冻行为依赖于完整的小脑回路。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通路参与到对生存至关重要的防御反应范围内。我们将专注于小脑与中央生存回路的关键组成部分的相互作用，即中脑导水管周围灰质和杏仁核。我们的主要目标是：(I)绘制连接小脑与大脑生存网络的神经连接链；(Ii)直接测试小脑功能与与生存回路相关的无条件和条件性防御反应之间的因果联系。我们将在系统分析水平上使用解剖学、电生理和行为技术的综合力量，以提高对涉及动物生存的大脑回路的结构和功能的理解。如果小脑的特定区域(模块)是神经网络的重要组成部分，生存回路通过这些区域引发防御反应的特定方面，那么这些不同区域的实验失活应该会导致情绪、运动和/或心血管反应的改变。实验模型的选择：小脑和生存网络的结构和连接模式在哺乳动物物种中高度保守，包括人类。然而，老鼠是实验动物的首选，因为我们对基本神经解剖学和生理学的了解在这个物种中是最完整的。重要的是，我们的实验将包括研究神经网络在行为情景中的相互作用，这些情景已经在老鼠身上得到了最彻底的特征，即：无条件和有条件的行为，对暴露在厌恶或可怕的刺激下的反应，例如捕食者(猫)的气味和厌恶的脚电击。我们的结果应该揭示关于大脑电路结构和信息编码如何引起对动物福利和生存如此关键的明确行为反应的一般规则。

Our understanding of how disturbances in neural networks in the brain result in emotional disorders is limited, and many patients (animal and human) don't respond well to existing treatments. Fundamental research into the neural networks that underlie 'survival circuits' in animals will provide essential information that will inform the development of new therapeutic strategies. There are two types of survival circuits that produce defensive responses to aversive or fearful events. One generates an UNCONDITIONED response, innate and hard wired, the other a CONDITIONED response, the result of activity in survival circuits modified by experience. Both co-ordinate adjustments to emotional state, cardiovascular activity and generate appropriate actions such as fight, flight or freezing. The sum of these activities constitutes a defensive response.The neural networks involved can be likened to a postal service that 'knows' what's being posted and where it needs to go in order that the appropriate information informs the necessary outcome. A major gap in our understanding concerns how this postal service engages with motor systems of the brain to elicit distinct and behaviourally appropriate unconditioned and conditioned defensive responses to fearful events. It is also unknown if the motor system can feed back and modify activity in survival circuits.We aim to provide new insights into the ANATOMY - which defines the 'postal address'; the PHYSIOLOGY - which determines the nature of the 'message' being transmitted; and the BEHAVIOUR- the effect the message has. The cerebellum is the largest motor controller in the brain and an emerging concept is that it plays a key role in this postal system. Recently we have shown that defensive freezing behaviour in rats, evoked by unconditioned and conditioned fearful events, is dependent on intact cerebellar circuitry. The cerebellum is a highly modular structure, so there is ample scope for different pathways to be involved in the range of defensive responses essential for survival. We will focus on cerebellar interactions with key components of central survival circuits, namely the midbrain periaqueductal grey and the amygdala. Our key objectives are to:(i) chart the chain of neural connections that link the cerebellum with the brain survival network;(ii) test directly for a causal link between cerebellar function and survival circuit-related unconditioned and conditioned defensive responses.We will use the combined power of anatomical, electrophysiological and behavioural techniques at the systems level of analysis to improve understanding of the structure and function of brain circuits involved in animal survival. If specific regions of the cerebellum (modules) are an essential part of the neural network by which survival circuits elicit particular aspects of a defensive response, then experimental inactivation of these different regions should lead to an altered emotional, motor and/or cardiovascular response. Choice of experimental model: cerebellar and survival network architecture and patterns of connectivity are highly conserved across mammalian species, including human. However, rats are the experimental animal of choice because our understanding of the basic neuroanatomy and physiology is most complete in this species. Importantly, our experiments will include study of neural network interactions during behavioural situations that have been most thoroughly characterized in rats, namely: unconditioned and conditioned behaviours in response to exposure to an aversive or fearful stimulus e.g. predator (cat) odour and aversive footshock.Our results should reveal general rules as to how brain circuit structure and information coding give rise to the well-defined behavioural responses that are so critical to animal welfare and survival.