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

慢性疼痛越来越多地被视为一种大脑疾病，其中认知，情绪调节和适应行为等执行功能的损害是疾病发展的核心。去甲肾上腺素信号从蓝斑（LC）到额叶皮层是重要的皮质功能的任务，需要灵活性，以应对不断变化的规则和条件。我们实验室以前的工作涉及LC额叶皮质去甲肾上腺素信号（10.7554/eLife.29808）和皮质控制的丧失（10.7554/eLife.65156）在大鼠慢性疼痛的发展。此外，LC至额叶皮质NA信号传导在认知灵活性中起着关键作用（10.1371/journal.pcbi.1006267）。我们现在希望将这些概念结合起来，以了解额叶皮层中的去甲肾上腺素信号如何改变皮层输出以调节灵活的行为，以及这一过程的适应不良是否会导致慢性疼痛的发生。该项目将利用我们实验室开发的实验技术，用于监测（电生理学，纤维光度学）和操纵（光/化学遗传学）行为动物的特定神经元群体。第一个目的是研究额叶皮质去甲肾上腺素能信号传导水平如何影响未受伤动物在认知任务（如逆转学习，虚拟竞争对手）和/或急性应激事件中的行为灵活性。通过选择性地控制LC到额叶皮层的输入，我们可以确定它对决策和行为的因果贡献。这些实验将揭示NA神经传递、皮层神经元活动和行为灵活性之间的关系。第二个目的是了解健康动物的这些特征如何预测受伤后发生慢性疼痛的可能性。通过将目标1和目标2的发现联系起来，我们将确定健康认知灵活性如何预测男性和女性慢性疼痛的特征。通过将其与去甲肾上腺素能信号传导联系起来，我们将确定可能形成慢性疼痛、精神健康和神经精神疾病治疗靶点的神经元通路、受体和机制。

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.