Optogenetic disruption of the multi-synaptic pathway to CA1 during hippocampal oscillations

 描述（由申请人提供）：大脑的海马回路被认为负责情景记忆的存储和回忆。在这个回路中，活动至少通过两条不同的途径传播。包括输入到CA1神经元，神经活动直接从内嗅皮层的第III层到达，或者通过涉及递归连接的CA3区域的多突触链到达。许多重要的实验和理论研究都针对这些途径中的每一个在CA1可观察到的神经活动的作用和影响，但由于各种限制，导致了不完整的，往往是相互矛盾的观点。在这个项目中，我们的目标是解开这两个输入途径的突触后效应区域CA1通过执行光遗传失活的区域CA3锥体神经元在大鼠海马在一组特定的体内网络状态，同时记录大规模的神经元活动在CA3和CA1。我们的工作假设是，通过CA3的多突触通路代表了输入到CA1的主要来源，因此在振荡活动的关键阶段应该有显着的突触后效应。我们将测试这一假设在一些具体的目标，以确定和表征的影响，分别在θ，γ，和尖锐波涟漪振荡，在麻醉大鼠（目的1a和1b），在行为中的延迟交替任务（目的2），并将这些与行为的影响在空间交替任务（目的3）的性能。海马CA1区神经元在theta、gamma和涟漪振荡过程中的放电模式被广泛认为在海马的记忆功能中起着关键作用。因此，我们期望这项工作将在两个方面提供重大进展：我们对海马多突触通路的作用的理解，以及我们对θ和γ振荡的不同阶段的输入的收敛如何使海马的功能受益的理解。

 DESCRIPTION (provided by applicant): The hippocampal circuit of the brain is considered to be responsible for storage and recall of episodic memory. Within this circuit, activity propagates through at least two distinct pathways. Comprising the input to CA1 neurons, neural activity arrives either directly from layer III of the entorhinal cortex, or through a multi-synaptic chain involving the recurrently connected CA3 region. A number of important experimental and theoretical studies have targeted the role and effect of each of these pathways on neural activity observable at CA1 but, due to various limitations, have resulted in incomplete and often contradictory viewpoints. In this project, we aim to untangle the postsynaptic effect of these two input pathways to region CA1 by performing optogenetic inactivation of region CA3 pyramidal neurons in the rat hippocampus during a specific set of in vivo network states while recording large-scale neuronal activity in CA3 and CA1. Our working hypothesis is that the multi-synaptic pathway through CA3 represents a major source of input to CA1 and as such should have a significant postsynaptic effect during key phases of oscillatory activity. We will test this hypothesis in a number of specific aims to determine and characterize the effect of region CA3 on CA1 activity separately during theta, gamma, and sharp-wave ripple oscillations, in urethane-anesthetized rats (Aims 1a and 1b), during behavior in a delayed alternation task (Aim 2), and to correlate these with behavioral effects on performance in a spatial alternation task (Aim 3). The neuronal firing patterns of CA1 neurons during theta, gamma and ripple oscillations are widely considered to play critical roles in serving the mnemonic function of the hippocampus. Thus, we expect that this work will provide a major advance forward on two fronts: in our understanding of the role of the hippocampal multi-synaptic pathway and in our understanding of how the convergence of input at different phases of theta and gamma oscillations subserves the functions of the hippocampus.