Function of 5HT3aR Cortical Interneurons for Auditory Perception and Learning

项目摘要 皮质抑制细胞在调节神经回路中的信息处理和突触可塑性方面起着关键作用。 这种可塑性对学习和记忆是必不可少的，也是听觉皮质的一个重要特征，尤其是 以了解语音等感官信号的重要性。长期突触可塑性需要感觉 体验和激活神经调节系统，如胆碱能基底核，它传递 与局部大脑皮层回路有关的行为背景。然而，关于皮质中间神经元是如何参与的，我们知之甚少。 在这些机制中，或者如果不同类型的抑制细胞对发育或成体可塑性有不同的作用。 最近，我们开发了一种方法来测量长时相兴奋性和抑制性突触修改。 活体数小时至数周。这些实验表明，在经历声音之前，大脑皮层抑制 最初与激励不匹配，但在经历或培训后与激励变得“平衡”。 [这些实验现在使我们能够构建一个新的框架来理解5HT3aR的作用 和非5HT3aR皮层中间神经元在小鼠的听觉行为中，用一系列的行为，成像， 并与更大的协作式PPG结构集成在一起记录实验。我们假设有 这些细胞类型在它们对听觉行为的相对贡献方面的重要功能差异 (目标1)、胆碱能调节(目标2)、皮质微回路组织和可塑性(目标3)。具体来说， 在目标1中，我们将首先检查特定皮质中间神经元亚型的行为相关性，因为最初是幼稚的 小鼠被训练来执行我们在实验室中使用了多年的听觉检测和识别任务。我们问 感觉体验和行为训练如何招募这些细胞类型并自然形成兴奋性和 抑制电路元件，采用全细胞记录结合双光子钙成像直接测量 体内的刺激和各种特定细胞类型的抑制来源。在目标2中，我们检查这些细胞类型是否 受胆碱能调节的不同影响，可能是由于对乙酰胆碱或特异性胆碱的不同敏感性 胆碱能传入大脑皮层。最后，在目标3中，我们将在大脑皮层切片中进行录音，以 记录不同类型的皮质中间神经元是如何突触连接和修饰的，以适应电路操作。] 总之，在这里，我们将使用体内和体外的电生理学、成像学和光遗传学来询问如何 不同的皮质中间神经元(5HT3aR和非5HT3aR)控制感觉加工和可塑性。两个核心 这些研究的概念涉及长期突触可塑性，被认为是学习的主要神经关联 和记忆，以及兴奋-抑制平衡--抑制电路对兴奋的精确调节。这些 人们认为，在大量神经疾病和精神健康障碍中，这一过程会受到干扰， 强调迫切需要对行为过程中的皮质组织和功能进行更完整的描述。

Project Summary Cortical inhibitory cells are critical for regulating information processing and synaptic plasticity in neural circuits. 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. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems such as the cholinergic nucleus basalis, which conveys behavioral context to local cortical circuits. However, little is known about how cortical interneurons are involved in these mechanisms, or if different inhibitory cell types have different roles for developmental or adult plasticity. Recently we developed an approach to measure long-term excitatory and inhibitory synaptic modifications in vivo over hours to weeks. These experiments revealed that prior to experience with sounds, cortical inhibition was initially mismatched with excitation, but becomes `balanced' with excitation after experience or training. [These experiments now allow us to construct a new framework for understanding the roles of 5HT3aR and non-5HT3aR cortical interneurons during auditory behavior in mice, with a series of behavioral, imaging, and recording experiments integrated with the larger collaborative PPG structure. We hypothesize that there are important functional differences in these cell types, in terms of their relative contributions to auditory behavior (Aim 1), cholinergic modulation (Aim 2), and cortical microcircuit organization and plasticity (Aim 3). Specifically, in Aim 1 we will first examine the behavioral relevance of specific cortical interneuron subtypes, as initially-naive mice are trained to perform an auditory detection and recognition task we have used in the lab for years. We ask how sensory experience and behavioral training might recruit these cell types and naturally shape excitatory and inhibitory circuit elements, using whole-cell recordings combined with 2-photon Ca2+ imaging to directly measure excitation and various cell-type-specific sources of inhibition in vivo. In Aim 2 we examine if these cell types are differentially affected by cholinergic modulation, perhaps due to differential sensitivity to acetylcholine or specific wiring of cholinergic input into cortex. Finally, in Aim 3 we will make recordings in cortical brain slices, to document how different cortical interneuron types are synaptically connected and modified for circuit operation.] In summary, here we will use in vivo and in vitro electrophysiology, imaging, and optogenetics to ask how different cortical interneurons (5HT3aR vs non-5HT3aR) govern sensory processing and plasticity. The two core concepts of these studies involve long-term synaptic plasticity, believed to be a major neural correlate of learning and memory, and excitatory-inhibitory balance- the precise regulation of excitation by inhibitory circuits. These processes are believed to be disrupted in a large number of neurological conditions and mental health disorders, highlighting an urgent need for a more complete description of cortical organization and function during behavior.