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

 描述(申请人提供)：大脑的海马体回路被认为负责存储和回忆情景记忆。在这个回路中，活动通过至少两条不同的路径传播。由CA1神经元的输入组成，神经活动直接来自内嗅皮层的第三层，或通过涉及反复连接的CA3区的多突触链到达。许多重要的实验和理论研究都针对这些通路在CA1可观察到的神经活动中的作用和效果，但由于各种限制，导致了不完整的观点，往往是相互矛盾的。在这个项目中，我们的目标是通过在一组特定的活体网络状态下对大鼠海马区CA3区锥体神经元进行光遗传灭活，同时记录CA3和CA1区的大规模神经元活动，来解开这两条通往CA1区的输入通路的突触后效应。我们的工作假设是，通过CA3的多突触通路是CA1的主要输入来源，因此在振荡活动的关键阶段应该具有显着的突触后效应。我们将在一些特定的目标上测试这一假说，以确定和表征CA3区域分别在theta、Gamma和锐波涟漪振荡期间、在乌拉坦麻醉的大鼠中(目标1a和1b)、在延迟交替任务中的行为(目标2)中对CA1活性的影响，并将这些与空间交替任务中的行为影响相关联(目标3)。CA1神经元在theta、Gamma和涟漪振荡过程中的神经元放电模式被广泛认为在服务于海马区的助记功能中起着关键作用。因此，我们预计这项工作将在两个方面取得重大进展：在我们理解海马体多突触通路的作用方面，以及在我们理解在不同阶段的theta和Gamma振荡的输入如何融合辅助海马体的功能方面。

 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.