Inhibitory Network Dynamics Supporting Hippocampal Spatial Representations

项目摘要 海马体是哺乳动物大脑中的一种结构，对各种认知功能至关重要，包括 空间导航和情景记忆。海马CA1区， 海马由相对同质的兴奋性锥体细胞群组成 和一个较小但多样的GABA能中间神经元（IN）群体。值得注意的是， CA1区锥体细胞（CA1PCs）可以整合数千个兴奋性和抑制性突触， 输入以具体地响应外部环境的各种特征（“特征选择性”）。 特征选择性的一个突出例子是特定于位置的发射率的增加， 当动物穿越它的环境时，锥体细胞展示（“位置细胞”）。虽然定位细胞 可能提供了海马体认知功能和活动之间的联系， 单个细胞的模式，负责其形成的电路水平机制， 稳定性仍然未知。特别是，尚不清楚是否IN影响位置细胞 动力学，因为缺乏关于分子定义的药物的体内活性模式的信息， 神经元和神经元与锥体细胞之间的突触连接仍然很难建立， vivo.本提案的目标是表征主要IN亚型的体内动力学， 群体水平及其与突触后CA1PCs空间调谐活性的关系 在空间导航和学习中。在目标1中，我将执行基于AOD的双光子泛函 钙成像和回顾性分子表征的成像细胞与事后 免疫组化以表征主要CA1 IN亚型的集体动力学 在行为上。在目标2中，我将联合收割机这些技术与单细胞启动的单突触， 逆行病毒追踪，以确定功能动力学之间的关系， 突触前INs与突触后CA1PCs空间调谐活动的形成和稳定性 在空间导航和学习中。这些实验将使我们更好地了解 支持海马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.