Repetitive stress decreases norepinephrine's dynamic range in the auditory cortex

Norepinephrine (NE) is a key neuromodulator in the brain with a wide range of functions. It regulates arousal, attention, and the brain's response to stress, enhancing alertness and prioritizing relevant stimuli. In the auditory domain, NE modulates neural processing and plasticity in the auditory cortex by adjusting excitatory-inhibitory balance, tuning curves, and signal-to-noise ratio. However, stress adds a layer of complexity to NE's cortical influence. Although acute stress can transiently boost locus coeruleus's activity and NE release, the effect of repeated stress on NE dynamics in the auditory cortex remains unclear. Using chronic two-photon imaging of the genetically encoded NE sensor GRAB_NE1m in head-fixed mice, we show that repetitive stress strongly attenuates NE responses to high-intensity sounds in the auditory cortex, with continued decline as the stressor becomes chronic. Additionally, repetitive stress disrupts normal habituation within each session: mice no longer exhibit the typical decrease in NE activation following repeated presentations of a loud stimulus. Our findings demonstrate that repetitive stress narrows the dynamic range and adaptability of the noradrenergic system in the auditory cortex, markedly reducing NE responses to intense sounds and eliminating the expected within-session habituation. By demonstrating that prolonged stress compromises NE dynamics in the auditory cortex, our results provide mechanistic insights into how repetitive stress could degrade auditory processing and potentially exacerbate hypervigilance or anxiety-like states.