Sex Differences in Chronic Pain; A Role for Noradrenaline in Cognitive Flexibility

慢性疼痛的性别差异；

• 批准号: 2895005
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2895005
• 关键词: Sex; Differences; Chronic; Pain; Role

Chronic pain is increasingly viewed as a disorder of the brain in which impairment of executive functions like cognition, emotional regulation and adaptive behaviour are central to disease development. Noradrenaline signalling from the Locus Coerelus (LC) to the frontal cortex is important for cortical function in tasks that require flexibility in response to changing rules and conditions. Previous work from our lab implicates LC to frontal cortex noradrenaline signalling (10.7554/eLife.29808) and loss of cortical control (10.7554/eLife.65156) in the development of chronic pain in rats. Additionally, that LC to frontal cortex NA signalling plays a critical role in cognitive flexibility (10.1371/journal.pcbi.1006267). We now wish to bring these concepts together to understand how noradrenaline signalling in the frontal cortex alters cortical output to regulate flexible behaviour, and whether maladaptation of this process underpins the vulnerability to develop chronic pain. The project will utilise experimental techniques that are well developed in our laboratory for the monitoring (electrophysiology, fibre photometry) and manipulation (opto- / chemo-genetics) of specific neuronal populations in behaving animals. The first aim is to investigate how levels of frontal cortex noradrenergic signalling effect behavioural flexibility in uninjured animals during cognitive tasks (e.g. reversal learning, virtual competitor) and/or acutely stressful events. By selectively controlling LC to frontal cortex inputs we can determine its causal contribution to decision making and behaviour. These experiments will reveal the relationship between NA neurotransmission, cortical neuronal activity, and flexibility of behaviour. The second aim is to understand how these characteristics in healthy animals can then predict the likelihood of developing chronic pain following injury. By relating findings from aims 1 and 2 we will determine how cognitive flexibility in health predicts features of chronic pain in male and females. By relating this to noradrenergic signalling we will identify neuronal pathway, receptors and mechanism that may form therapeutic targets for chronic pain, mental health and neuropsychiatric conditions.

慢性疼痛越来越被视为大脑疾病，在这种疾病中，诸如认知，情绪调节和适应性行为之类的执行功能受损是疾病发展的核心。从基因座（LC）到额叶皮层的去甲肾上腺素信号传导对于需要灵活性以应对变化的规则和条件而需要灵活性的任务中的皮质功能很重要。我们实验室的先前工作暗示了LC到额叶皮质去甲肾上腺素信号传导（10.7554/Elife.29808）和皮层对照的丧失（10.7554/Elife.65156）在大鼠慢性疼痛的发展中。此外，该LC到正面皮层NA信号在认知灵活性中起着至关重要的作用（10.1371/journal.pcbi.1006267）。现在，我们希望将这些概念聚集在一起，以了解额叶皮质中的去甲肾上腺素信号传导如何改变皮质输出以调节柔性行为，以及该过程的不良适应是否构成了发展慢性疼痛的脆弱性。该项目将利用我们实验室中发达的实验技术，用于监测（电生理学，纤维光度法）和对行为动物中特定神经元种群的操作（光学 - /化学基因）。第一个目的是研究在认知任务（例如逆转学习，虚拟竞争者）和/或严重压力的事件中，额叶皮层甲状腺素能信号传导的水平如何影响未受伤的动物的行为灵活性。通过选择性控制LC到额叶皮层输入，我们可以确定其对决策和行为的因果关系。这些实验将揭示NA神经传递，皮质神经元活性和行为灵活性之间的关系。第二个目的是了解健康动物中的这些特征如何预测受伤后慢性疼痛的可能性。通过将AIM 1和2的发现联系起来，我们将确定健康中的认知灵活性如何预测男性和女性的慢性疼痛特征。通过将其与去甲肾上腺素能信号传导联系起来，我们将确定可能构成慢性疼痛，心理健康和神经精神疾病的治疗靶点的神经元途径，受体和机制。