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

慢性疼痛越来越被视为一种脑部疾病，认知、情绪调节和适应行为等执行功能受损是疾病发展的核心。在需要灵活应对不断变化的规则和条件的任务中，从Coerelus(LC)到额叶皮质的去甲肾上腺素信号对皮质功能非常重要。我们实验室以前的工作涉及LC到额叶皮质去甲肾上腺素信号(10.7554/eLife.29808)和皮质控制丧失(10.7554/eLife.65156)在大鼠慢性疼痛的发展中。此外，LC到额叶皮质NA的信号在认知灵活性中起着关键作用(10.1371/Journal al.pcbi.1006267)。我们现在希望将这些概念结合在一起，以了解额叶皮质中的去甲肾上腺素信号如何改变皮质输出以调节灵活的行为，以及这一过程的不适应是否会巩固发展慢性疼痛的脆弱性。该项目将利用我们实验室开发的实验技术来监测(电生理学、纤维光度学)和操纵(光/化学遗传学)行为动物中的特定神经元群体。第一个目的是研究额叶皮质去甲肾上腺素能信号的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对额叶皮质的输入，我们可以确定其对决策和行为的因果贡献。这些实验将揭示NA神经传递、皮质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。通过联系目标1和目标2的发现，我们将确定健康中的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联系起来，我们将确定可能形成慢性疼痛、心理健康和神经精神疾病治疗靶点的神经元途径、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.