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.

SIGNIFICANCE STATEMENT 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.

尽管背景噪音发生巨大变化，神经适应使大脑能够有效地处理感觉信号。先前的研究已经证实，最近的背景光谱或时空统计通过规范标准化计算来衡量神经对感觉刺激的反应，该计算在物种和感觉领域之间是保守的。在听觉通路中，归一化的一种主要形式，称为对比度增益控制，表现为瞬时放电率增益（神经输入-输出关系的斜率）降低，背景声级（对比度）随时间和频率的变化而增加。尽管增益重新调整，听觉皮层的平均放电率对于声级对比度变得不变，称为对比度不变性。这两种现象的潜在神经调节机制仍然未知。为了研究雄性和雌性小鼠的这些机制，我们在初级听觉皮层 (A1) 的 2/3 层神经元中使用了 2 光子钙成像制剂，以及药理学和遗传 KO 方法。我们发现神经调节皮层突触锌信号传导对于对比度增益控制是必需的，但对于小鼠 A1 的对比度不变性不是必需的。

意义陈述当声学环境中的声级随时间和频率变化变得更大时，大脑会降低响应增益以维持动态范围，从而维持刺激辨别能力。这种增益适应解释了人类和小鼠知觉判断的变化。然而，人们对潜在的神经调节机制仍然知之甚少。在这里，我们报告了突触锌的上下文依赖性神经调节作用，这对于 A1 中的对比度增益控制是必需的。了解特定环境的神经调节机制（例如对比度增益控制）可以深入了解 A1 皮质适应机制，以及依赖于增益调节的知觉变化的基本方面（例如注意力）。