Function of 5HT3aR Cortical Interneurons for Auditory Perception and Learning

项目摘要 皮层抑制细胞对神经回路中的信息处理和突触可塑性的调节至关重要。 这种可塑性对学习和记忆至关重要，是听觉皮层的重要特征， 来学习感觉信号的重要性，比如语言。长期突触可塑性需要感觉 经验和激活的神经调节系统，如胆碱能基底核，这传达了 行为背景与局部皮层回路的联系然而，对于皮层中间神经元如何参与， 在这些机制中，或者不同的抑制细胞类型是否对发育或成年可塑性具有不同的作用。 最近，我们开发了一种方法来测量长期兴奋性和抑制性突触修饰， 在几个小时到几周的时间内。这些实验表明，在经历声音之前， 最初与兴奋不匹配，但在经历或训练后与兴奋“平衡”。 [这些实验现在使我们能够构建一个新的框架来理解5 HT 3aR的作用。 和非5-HT 3aR皮质中间神经元在小鼠听觉行为过程中的作用， 以及与更大的协作PPG结构集成的记录实验。我们假设 这些细胞类型的重要功能差异，就其对听觉行为的相对贡献而言， (Aim 1），胆碱能调制（目标2），和皮层微电路组织和可塑性（目标3）。具体地说， 在目标1中，我们将首先检查特定皮层中间神经元亚型的行为相关性，如初始幼稚型， 老鼠被训练来执行我们在实验室中使用多年的听觉检测和识别任务。我们要求 感觉体验和行为训练如何招募这些细胞类型，并自然地塑造兴奋性和 抑制电路元件，使用全细胞记录结合双光子Ca 2+成像直接测量 激发和体内抑制的各种细胞类型特异性来源。在目标2中，我们检查这些细胞类型是否是 不同的影响胆碱能调制，也许是由于不同的敏感性乙酰胆碱或特定的 将胆碱能输入连接到皮层。最后，在目标3中，我们将记录大脑皮层切片， 记录不同的皮层中间神经元类型如何突触连接和修改电路操作。 总之，在这里，我们将使用体内和体外电生理学，成像和光遗传学来询问如何 不同的皮质中间神经元（5 HT 3aR与非5 HT 3aR）支配感觉处理和可塑性。两大核心 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相关物 和记忆，以及兴奋-抑制平衡-抑制回路对兴奋的精确调节。这些 据信在大量神经病症和精神健康障碍中， 强调迫切需要一个更完整的描述皮层组织和功能在行为。

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.