Role of the cerebellum in survival circuits activated by fear.

小脑在恐惧激活的生存回路中的作用。

• 批准号: BB/M019616/1
• 负责人: Richard Apps
• 金额: $ 78.17万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM019616%2F1
• 关键词: Role; cerebellum; survival; circuits; activated

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.

我们对大脑神经网络的干扰如何导致情绪障碍的理解是有限的，许多患者（动物和人类）对现有的治疗反应不佳。对动物“生存回路”背后的神经网络的基础研究将提供必要的信息，为新的治疗策略的发展提供信息。有两种类型的生存回路对厌恶或恐惧的事件产生防御反应。一种产生无条件的反应，天生的和硬连线的，另一种是条件反应，由经验修改的生存回路的活动的结果。两者都协调调整情绪状态，心血管活动，并产生适当的行动，如战斗，飞行或冻结。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”要发布什么以及它需要去哪里，以便适当的信息通知必要的结果。我们理解的一个主要差距是，这种邮政服务如何与大脑的运动系统相结合，以引发对恐惧事件的不同的、行为上适当的无条件和有条件的防御反应。运动系统是否能够反馈和修改生存回路中的活动也是未知的。我们的目标是提供新的见解解剖学-定义“邮政地址”;生理学-决定“信息”被传递的性质;和行为-信息的影响。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起着关键作用。最近，我们已经表明，防御冻结行为大鼠，诱发的无条件和条件的恐惧事件，是依赖于完整的小脑电路。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生存所必需的防御反应。我们将集中在小脑的相互作用与中央生存电路的关键组成部分，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生存回路相关的无条件和条件防御反应之间的因果关系。我们将在系统水平上使用解剖学，电生理学和行为学技术的综合力量，以提高对动物生存所涉及的脑回路结构和功能的理解。如果小脑的特定区域（模块）是神经网络的重要组成部分，生存回路通过它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：小脑和生存网络结构和连接模式在包括人类在内的哺乳动物物种中高度保守。然而，大鼠是首选的实验动物，因为我们对基本神经解剖学和生理学的理解在这个物种中是最完整的。重要的是，我们的实验将包括在大鼠中最彻底表征的行为情况下神经网络相互作用的研究，即：无条件和条件的行为反应暴露于一个厌恶或可怕的刺激，如捕食者（猫）的气味和厌恶的脚震。我们的研究结果应该揭示一般规则，大脑回路结构和信息编码如何引起良好的-对动物福利和生存至关重要的行为反应。

项目成果

Top down control of spinal sensorimotor circuits essential for survival.

• DOI: 10.1113/jp273360
• 发表时间: 2017-07-01
• 期刊: The Journal of physiology
• 作者: Koutsikou S;Apps R;Lumb BM
• 通讯作者: Lumb BM

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats.

• DOI: 10.7554/elife.65156
• 发表时间: 2021-02-08
• 期刊: eLife
• 影响因子: 7.7
• 作者: Drake RA;Steel KA;Apps R;Lumb BM;Pickering AE
• 通讯作者: Pickering AE

The cerebellum and fear extinction: evidence from rodent and human studies.

• DOI: 10.3389/fnsys.2023.1166166
• 发表时间: 2023
• 期刊: FRONTIERS IN SYSTEMS NEUROSCIENCE
• 影响因子: 3
• 作者: Doubliez, Alice;Nio, Enzo;Senovilla-Sanz, Fernando;Spatharioti, Vasiliki;Apps, Richard;Timmann, Dagmar;Lawrenson, Charlotte L.
• 通讯作者: Lawrenson, Charlotte L.

Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.

• DOI: 10.7554/elife.76278
• 发表时间: 2022-03-15
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lawrenson C;Paci E;Pickford J;Drake RAR;Lumb BM;Apps R
• 通讯作者: Apps R

Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper [corrected].

• DOI: 10.1007/s12311-018-0952-3
• 发表时间: 2018-10
• 期刊: Cerebellum (London, England)
• 作者: Apps R;Hawkes R;Aoki S;Bengtsson F;Brown AM;Chen G;Ebner TJ;Isope P;Jörntell H;Lackey EP;Lawrenson C;Lumb B;Schonewille M;Sillitoe RV;Spaeth L;Sugihara I;Valera A;Voogd J;Wylie DR;Ruigrok TJH
• 通讯作者: Ruigrok TJH