Noradrenergic circuits in heights avoidance: an ethological, translatable threat behavior

PROJECT SUMMARY / ABSTRACT Despite its centrality in anxiety- and trauma-related disorders, the avoidance of danger in the environment requires new paradigms. Using the RDoC framework, the mental health field has sought to define circuit- behavior relationships that may underlie psychiatric disorders. A central challenge in this process has been the difficulty in identify clear links between threat computation and neural circuits. A further threat has been that even when such links are apparent, as in predator avoidance, the translatability of these behavioral models across species has been limited. Threat computation plays a central role in the genesis of anxiety- and trauma- related disorders, yet we do not have a clear behavioral paradigm that enables us to precisely control the perception of survival danger in the same way in mice and humans. Here, we propose to develop a novel quantitative circuit neuroscience platform for studying the fear of heights. Exposure to high places induces common patterns of peripheral arousal, avoidance, and distress across species yet has been limited in its study in mice. Since physical height is experience through the visual system, it can be precisely manipulated to induce artificial changes in threat perception that can influence behavior. Most importantly, the exposure to heights is a stimulus which induces a threat of death across species. Thus, we propose to establish a controllable model of aversion to visual heights as a new paradigm in the translational circuit neuroscience of anxiety. In order to do so, we will combine chemogenetics, fiber photometry, computational modeling of behavior, and a virtual reality system to demonstrate the role of norepinephrine circuits in the fear of heights. This comprehensive program is based on substantial preliminary data demonstrating that norepinephrine neurons in the locus coeruleus are activated by elevation. Furthermore, we will demonstrate the potential of the visual fear of heights paradigm by manipulating the perceived distance from the ground in real time, thus enabling unprecedented insights into the online computation of threat that is not possible with other fear-related paradigms. Once established, this behavioral model will facilitate inference into circuit mechanisms of innate threat that can for the first time be compared in both mice and humans.