Neuromodulatory Mechanisms Underlying Contrast Gain Control in Mouse Auditory Cortex

Neural adaptation enables the brain to efficiently process sensory signals despite large changes in background noise. Previous studies have established that recent background spectro- or spatio-temporal statistics scale neural responses to sensory stimuli via a canonical normalization computation, which is conserved among species and sensory domains. In the auditory pathway, one major form of normalization, termed contrast gain control, presents as decreasing instantaneous firing-rate gain, the slope of the neural input-output relationship, with increasing variability of background sound levels (contrast) across time and frequency. Despite this gain rescaling, mean firing-rates in auditory cortex become invariant to sound level contrast, termed contrast invariance. The underlying neuromodulatory mechanisms of these two phenomena remain unknown. To study these mechanisms in male and female mice, we used a 2-photon calcium imaging preparation in layer 2/3 neurons of primary auditory cortex (A1), along with pharmacological and genetic KO approaches. We found that neuromodulatory cortical synaptic zinc signaling is necessary for contrast gain control but not contrast invariance in mouse A1. When sound levels in the acoustic environment become more variable across time and frequency, the brain decreases response gain to maintain dynamic range and thus stimulus discriminability. This gain adaptation accounts for changes in perceptual judgments in humans and mice; however, the underlying neuromodulatory mechanisms remain poorly understood. Here, we report context-dependent neuromodulatory effects of synaptic zinc that are necessary for contrast gain control in A1. Understanding context-specific neuromodulatory mechanisms, such as contrast gain control, provides insight into A1 cortical mechanisms of adaptation and also into fundamental aspects of perceptual changes that rely on gain modulation, such as attention.