The role of serotonin in escape responses and learned adaptation to the looming stimulus

Animal survival depends on effective predator avoidance mechanisms. However, an innately threatening stimulus may prove non-threatening, allowing the animal to ignore it over time. Such adaptation is exemplified by the learned suppression of escape (LSE) paradigm, in which animals adapt to repeated threatening stimuli. Neuromodulation, and more specifically serotonin modulation has been implicated in the expression and modulation of defensive responses. However, its role in the LSE remains unknown. Recently, we observed an upregulation of the serotonin biosynthesis pathway in the dorsal periaqueductal gray (dPAG, the region known to initiate escape responses) that coincided with a decreased baseline escape response in a mouse model of intellectual disability, Setd5. To test the causality of whether increased serotonergic levels influence escape response adaptation, we performed pharmacological perturbations and tested the electrophysiological properties of dPAG neurons in vitro. In parallel, we tested the behavioral effects in the LSE paradigm. Interestingly, pharmacologically increasing serotonin levels globally lead to slower, less vigorous responses to threatening stimuli without affecting LSE. Conversely, global depletion of serotonin did not affect escape behavior but impaired LSE. These results indicate a short time scale and a long timescale effect for serotonin. On short time scales, it regulates the expression of escape responses, while on longer time scales it is affecting adaptive responses to repeated threat exposure. Currently, we are investigating how serotonin exerts a short-term impact on escape responses and long-term influence on adaptive reactions by targeting diverse serotonergic receptors in the dPAG.