The Spatial and Temporal Scale of Neuromodulation in Mouse Sensory Cortex

神经调质乙酰胆碱（ACh）和去甲肾上腺素（NE）与神经元的功能有关。 一种激活的大脑皮层状态，其特征是皮层反应的可靠性增加 外部刺激和增强的行为任务表现。一个尚未解决的关键问题是 这些神经调质发挥作用的空间和时间尺度。新方法 直接记录局部乙酰胆碱和去甲肾上腺素的含量，同时记录神经元的活动， 小鼠中的种群为回答这个问题提供了可能性。在第一组实验中 我们将检验激活状态的神经信号在大脑皮层中可能不同的假设 这是由于时刻到时刻的神经调节剂可用性的空间不均匀性。在第二 我们将通过一系列实验来验证小鼠可以募集神经调质的假设 独立于听觉和视觉皮层，以增强多模态注意力的表现 任务鉴于这些系统的破坏是各种人类疾病的关键特征， 包括阿尔茨海默病，多动症，自闭症谱系障碍，了解 健康动物中神经调质活性的基线变异性对于鉴别 在不同的疾病状态下可能发生的神经调质效应的微妙变化， 用于评估治疗的效果。从神经科学家的角度来看， 理解群体活动中刺激的编码，神经调质的影响出现 不依赖于刺激的噪音增加了感官反应的可变性。了解 ACh和NE效应的时空分辨率将使这些效应的建模成为可能， 状态变量塑造了皮层群体的反应。ACh对大脑皮层的影响 和NE的释放与在小鼠中记录的注意力的神经相关性惊人地相似， 人类和灵长类动物虽然老鼠不太可能具有精细的空间或特征注意力， 就像人类一样，理解这两种神经调质在小鼠体内的时空动力学， 将是一个重要的一步，分离他们对注意力机制的影响， 一般来说。清楚地了解这两种影响的相对时间过程， 神经调质对皮层加工的影响将为未来的研究提供重要的限制。 细胞和电路机制背后的影响。

The neuromodulators acetylcholine (ACh) and norepinephrine (NE) are associated with an activated cortical brain state characterized by an increase in the reliability of cortical responses to external stimuli and enhanced performance on behavioral tasks. A key unresolved question is the spatial and temporal scale at which these neuromodulators exert their effects. New methods to directly record the local availability of ACh and NE simultaneously with the activity of neural populations in mice opens up the possibility to answer this question. In a first set of experiments we will test the hypothesis that neural signatures of the activated state may vary across cortex due to spatial inhomogeneities in moment-to-moment neuromodulator availability. In a second set of experiments we will test the hypothesis that mice can recruit neuromodulators independently to auditory and visual cortex to enhance performance on a multimodal attention task. Given that disruption of these systems is a key feature of a variety of human diseases including Alzheimer’s disease, ADHD, and Autism Spectrum Disorders, understanding the baseline variability in neuromodulator activity in healthy animals will be critical for identifying subtle changes in the effects of neuromodulators that may occur in different disease states and for evaluating the efficacy of treatments. From the perspective of neuroscientists attempting to understand the encoding of stimuli in population activity, the effects of neuromodulators appear as stimulus-independent noise that adds variability to sensory responses. Understanding the spatiotemporal resolution of the effects of ACh and NE will enable modeling of these effects as state variables shaping the response of cortical populations. The cortical effects of both ACh and NE release in mice are strikingly similar to neural correlates of attention recorded in humans and primates. While it is unlikely that mice have fine-grained spatial or feature attention like humans, understanding the spatiotemporal dynamics of these two neuromodulators in mice will be a significant step towards dissociating their influence on attentional mechanisms more generally. Having a clear understanding of the relative time course of the influence of these two neuromodulators on cortical processing will provide important constraints for future studies of the cellular and circuit mechanisms underlying their effects.