Determining the brain basis of heart rate variability during extinction of learned fear and avoidance

Anxiety disorders are the most common psychiatric diseases and have become even more common since the Covid-19 pandemic began. These disorders are characterised by excessive fear and avoidance, heightened body arousal, and abnormal brain function in processing and responding to threat. Although treatments are available, medicines can be ineffective and have unwanted side effects, while psychological therapies can have limited or temporary effects that lead to relapse. Anxiety disorders are an enormous social and economic burden that require new treatment approaches. To do this we need to better understand how the healthy brain controls the appropriate expression of threat-related behaviours and arousal states. Academic and industry researchers study the brain basis of threat learning and defensive behaviours in rodents to gain insight into anxiety disorders and potential treatment targets. This research is clinically relevant because rodent defensive behaviours map on well to fear and avoidance, while the brain networks involved are similar in humans. Threat learning is also studied in the same way in rodents and humans, where a harmless cue becomes threatening through its association with an aversive stimulus to cause fear and avoidance. Repeated cue exposure results in extinction, which is new learning that can reduce fear and avoidance. Extinction has important clinical relevance as the basis of exposure therapies for treating anxiety disorders. However, fear and avoidance can persist or return after therapy, highlighting the need for further research on the brain networks controlling extinction. Lagging behind is our understanding of the relationship between different anxiety-related behaviours and arousal states, how extinction affects this arousal, and the brain networks involved. Human studies support measuring heart rate variability (HRV), the natural variation in timing between successive heart beats, as a marker of arousal. This has clinical relevance since HRV is decreased in anxiety disorders and extinction of fear is associated with increased HRV. Human studies also show overlap in the brain networks involved in HRV and extinction. Rodent studies combining brain manipulations with HRV and behavioural measures to investigate the brain networks controlling arousal during extinction of fear and avoidance have huge potential for understanding disturbed behaviour-body interactions in anxiety disorders. We aim to determine the brain basis of HRV during extinction of learned fear and avoidance in rats to improve the clinical relevance of rodent studies on threat learning and defensive behaviours. In Objective 1 we will characterise HRV during fear, avoidance, and their extinction. We will also validate a new non-invasive method for measuring HRV during behavioural testing. In Objectives 2-3 we will use cutting-edge methods to turn on or off a relevant brain area (Objective 2) or brain circuit (Objective 3) to determine how they control HRV during extinction of fear and avoidance. We will also map the different cell types and connections involved in this brain circuit (Objective 3). Understanding how the healthy brain controls arousal associated with extinction of fear and avoidance will lead to new insights on behavioural and bodily disturbances in anxiety disorders, along with their responses to psychological treatment. Mapping the cell types in the brain networks involved will also identify promising treatment targets for future drug development. This is highly relevant to various BBSRC priorities (Integrated understanding of health, Understanding the rules of life, Bioscience discovery) and the UK government’s life sciences vision (Mental health challenges and missions).