Stress Accelerates Defensive Responses to Looming in Mice and Involves a Locus Coeruleus-Superior Colliculus Projection

Abstract

Defensive responses to threatening stimuli are crucial to the survival of species. While expression of these responses is considered to be instinctive and unconditional, their magnitude may be affected by environmental and internal factors. The neural circuits underlying this modulation are still largely unknown. In mice, looming-evoked defensive responses are mediated by the superior colliculus (SC), a subcortical sensorimotor integration center. We found that repeated stress caused an anxiety-like state in mice and accelerated defensive responses to looming. Stress also induced c-fos activation in locus coeruleus (LC) tyrosine hydroxylase (TH)⁺ neurons and modified adrenergic receptor expression in SC, suggesting a possible Th::LC-SC projection that may be involved in the accelerated defensive responses. Indeed, both anterograde and retrograde neural tracing confirmed the anatomical Th::LC-SC projection and that the SC-projecting TH⁺ neurons in LC were activated by repeated stress. Optogenetic stimulation of either LC TH⁺ neurons or the Th::LC-SC fibers also caused anxiety-like behaviors and accelerated defensive responses to looming. Meanwhile, chemogenetic inhibition of LC TH⁺ neurons and the infusion of an adrenergic receptor antagonist in SC abolished the enhanced looming defensive responses after repeated stress, confirming the necessity of this pathway. These findings suggest that the Th::LC-SC pathway plays a key role in the sophisticated adjustments of defensive behaviors induced by changes in physiological states.

Keywords: anxiety; defensive circuitry; fear; flight; locus coeruleus; looming; modulation; norepinephrine; stress; superior colliculus.