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

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.