Synaptic basis of perceptual learning in primary auditory cortex

项目摘要 大脑有非凡的能力来改变对经验的反应。这种可塑性对于 学习和记忆，是听觉皮质的一个重要特征，尤其对于学习意义重大 用于诸如语音的感觉信号，用于诸如人工耳蜗的设备的使用，以及用于在短时间后的恢复- 耳聋一词。这些变化被认为主要发生在突触，即信息处理的基本单位 和可塑性。长期突触可塑性需要感觉体验和神经调节的激活 将行为背景传递给局部皮质回路的系统。然而，人们对这种相互作用知之甚少。 在体内突触输入和神经调节剂释放之间的关系，使得将知觉联系起来具有挑战性 学习听觉皮质或其他脑区的可塑性。最近，我们开发了一种测量方法 数小时的突触改变的动态，加上成像技术使我们能够监测相同的 细胞在训练期间的天数，直接监测和操纵行为小鼠的活动。这些方法 允许仔细检查调制、皮质可塑性和听觉知觉学习之间的联系。 具体地说，我们将研究听觉知觉训练如何激活胆碱能与去甲肾上腺素能 调制系统。这两个调节器主要参与对行为的选择性注意- 重要的刺激、一般的唤醒和学习。然而，它们之间可能存在重要的功能差异 系统在训练的不同阶段何时活跃，或胆碱能和 去甲肾上腺素能对听觉神经元进行语境信息处理的调制。本提案描述了一种 一系列成像、记录、光遗传学和行为学实验，将比较和对比效果 蓝斑激活和去甲肾上腺素释放与基底核激活和去甲肾上腺素释放的关系 胆碱能对行为小鼠初级听觉皮质的调节作用。许多研究都强调了 在清醒的动物行为过程中记录的重要性，我们将首先检查如何兴奋的合奏 而抑制神经元在整个训练过程中都受到学习的影响，因为动物从幼稚和 表现不佳，到在我们使用过的听觉检测和识别任务中有可靠的表现 在实验室呆了好几年。接下来，我们确定胆碱能和去甲肾上腺素能调节何时以及如何影响行为 和神经反应。最后，我们将对调制神经元进行第一次直接测量。 回答，询问这些系统是如何被与任务相关的变量激活的，比如与奖励有关的声音。 总而言之，我们在这里使用活体记录和成像方法来询问行为训练是如何进行的 并改变去甲肾上腺素和胆碱能系统，共同影响听觉皮质处理和 持之以恒地提高行为小鼠的听觉感知能力。

Project Summary The brain has the remarkable capability to change in response to experience. This plasticity is essential for learning and memory, and is an important feature of the auditory cortex, especially for learning the significance of sensory signals such as speech, for the use of devices such as cochlear implants, and for recovery after short- term deafness. These changes are thought to occur primarily at synapses, basic units of information processing and plasticity. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems which convey behavioral context to local cortical circuits. However, little is known about the interactions between synaptic inputs and release of neuromodulators in vivo, making it challenging to relate perceptual learning to plasticity in the auditory cortex or other brain areas. Recently we developed an approach to measuring dynamics of synaptic modifications for hours, coupled with imaging techniques enabling us to monitor the same cells over days during training, directly monitoring and manipulating activity in behaving mice. These approaches allow for a close examination of links between modulation, cortical plasticity and auditory perceptual learning. Specifically, we will study how auditory perceptual training activates the cholinergic vs noradrenergic modulatory systems. These two modulators are principally involved in selective attention towards behaviorally- important stimuli, general arousal, and learning. However, there may be important functional differences in these systems in terms of when they are active during different phases of training or consequences of cholinergic and noradrenergic modulation on auditory neurons for contextual information processing. This proposal describes a series of imaging, recording, optogenetic, and behavioral experiments that will compare and contrast the effects of locus coeruleus activation and norepinephrine release vs the effects of nucleus basalis activation and cholinergic modulation on the primary auditory cortex of behaving mice. Many studies have highlighted the importance of recording in awake animals during behavior, and we will first examine how ensembles of excitatory and inhibitory neurons are affected by learning over the entire duration of training, as animals go from naïve and poor performers, to having reliable performance on an auditory detection and recognition task we have used in the lab for years. Next, we determine when and how cholinergic and noradrenergic modulation affect behavioral and neural responses. Finally, we will make some of the first direct measurements of modulatory neuron responses, asking how these systems are activated by task-relevant variables such as sounds linked to reward. In summary, here we use in vivo recording and imaging methods to ask how behavioral training engages and modifies noradrenergic and cholinergic systems, to collectively affect auditory cortical processing and persistently improve auditory perceptual abilities in behaving mice.