Inhibitory Network Dynamics Supporting Hippocampal Spatial Representations

项目摘要 海马体是哺乳动物的大脑结构，对各种认知功能至关重要，包括 空间导航和情景记忆。海马区CA1区，输出节点 海马体，由相对同质的兴奋性锥体细胞群组成 以及数量较少但种类繁多的GABA能中间神经元(INS)。值得注意的是，个人 CA1区锥体细胞可整合数千个兴奋性和抑制性突触 具体响应外部环境的各种特征的输入(“特征选择性”)。 特征选择性的一个突出例子是特定于位置的射击率的增加 当动物在其环境中穿行时，锥体细胞表现为(“定位细胞”)。尽管放置单元格 可能提供了海马体的认知功能和活动之间的联系 单个细胞的模式，负责它们形成的电路级机制，以及 稳定性仍是未知数。特别是，目前仍不清楚INS是否会影响Place细胞 动力学，因为缺乏关于分子定义的在体内的活动模式的信息 INS和INS与锥体细胞之间的突触连接仍难以建立 活着。这项建议的目标是描述主要IN亚型在体内的动力学特征 突触后CA1PC的群体水平及其与空间调谐活动的关系 在空间导航和学习过程中。在目标1中，我将执行基于AOD的双光子泛函 羟基磷灰石后成像细胞的钙成像及分子生物学特性研究 免疫组织化学研究亚型中主要CA1的集体动态 在行为过程中。在目标2中，我将把这些技术与单细胞启动的单突触相结合， 逆行病毒示踪以确定功能动力学之间的关系 突触前INS与突触后CA1PC空间调谐活动的形成和稳定性 在空间导航和学习过程中。这些实验将使我们更好地理解 支持海马区空间表征以指导行为的局部抑制动力学。

Project Abstract The hippocampus is a mammalian brain structure critical for various cognitive functions, including spatial navigation and episodic memory. Hippocampal area CA1, the output node of the hippocampus, is composed of a relatively homogenous population of excitatory pyramidal cells and a smaller, yet diverse, population of GABAergic interneurons (INs). Remarkably, individual pyramidal cells in CA1 (CA1PCs) can integrate thousands of excitatory and inhibitory synaptic inputs to respond specifically to various features of the external environment (“feature selectivity”). One prominent example of feature selectivity is the location-specific increases in firing rate that pyramidal cells exhibit (“place cells”) as an animal traverses its environment. Although place cells might provide the link between the cognitive functions of the hippocampus and the activity patterns of individual cells, the circuit-level mechanisms responsible for their formation and stability remain unknown. In particular, it remains unknown whether INs influence place cell dynamics, as there is a lack of information about the in vivo activity patterns of molecularly-defined INs and synaptic connectivity between INs and pyramidal cells remains difficult to establish in vivo. The goal of this proposal is to characterize the in vivo dynamics of the major IN subtypes at the population level and their relationship to the spatially tuned activity of postsynaptic CA1PCs during spatial navigation and learning. In Aim 1, I will perform AOD-based two-photon functional calcium imaging and retrospective molecular characterization of the imaged cells with post-hoc immunohistochemistry to characterize the collective dynamics of the major CA1 IN subtypes during behavior. In Aim 2, I will combine these techniques with single-cell-initiated monosynaptic, retrograde viral tracing to determine the relationship between the functional dynamics of presynaptic INs and the formation and stability of spatially tuned activity in postsynaptic CA1PCs during spatial navigation and learning. These experiments will lead to a better understanding of the local inhibitory dynamics that support hippocampal spatial representations to guide behavior.