Neural Pathways Modulating Memory Consolidation

 描述(申请人提供)：先前对大脑中多个记忆系统的研究很难阐明影响不同类型学习的巩固和突触可塑性的特定神经连接。目前的建议将利用光遗传操作连接大鼠不同大脑区域的特定路径，在大鼠经历了不同类型的学习后立即进行。具体地说，这一建议将建立在杏仁基底外侧核(BLA)影响许多不同类型学习的巩固的证据基础上，包括空间/背景、情绪和线索反应学习，而其他区域涉及更离散形式的学习的记忆。更多的证据表明，BLA通过调节这些其他脑区的突触可塑性来影响巩固，包括调节活性调节的细胞骨架相关蛋白(Arc)，这已被证明介导了BLA对记忆巩固的一些影响。基于这些先前的发现，本研究将探讨在不同类型的学习后，不同的BLA投射到海马体和尾状核不同部分是如何调节记忆巩固和下游脑区Arc表达的。后续实验将确定增加的Arc表达是否对记忆调制是必要的。为此，目前的建议将利用不同学习任务后立即在特定BLA投射中的光遗传控制来直接检查每个目的：1)候选路径如何影响特定类型学习的巩固；2)这些路径如何影响下游区域的Arc表达，以及Arc表达是否对记忆调节是必要的。目标1将确定BLA投射到海马结构的不同部分如何影响在修改的情境恐惧条件反射任务中情境与足部电击学习的巩固和Arc表达。目标2将确定BLA投射到部分海马结构和尾状核如何影响空间与线索反应学习的巩固和Arc表达。在这两个目标中，将在相关训练后立即对每个候选途径给予光遗传刺激/抑制，以确定其在影响巩固中的作用。此外，每个目标都将检查这种光遗传操作是否改变不同下游结构中的Arc表达，以及降低这些区域的Arc水平是否阻止了光遗传操作的记忆调制效应，提供了一组关键的补充实验，这些实验将改进我们的模型，以了解BLA如何影响其他区域的记忆和可塑性相关蛋白质，如Arc。这些研究的发现将第一次为从大脑BLA到其他大脑区域的特定路径如何影响记忆巩固和突触可塑性提供知识。此外，这些实验将为理解大脑中潜在的巩固过程中的功能联系提供第一步。

 DESCRIPTION (provided by applicant): Prior studies examining multiple memory systems in the brain have had great difficulty elucidating the specific neural connections that influence the consolidation and synaptic plasticity for different kinds of learning. The present proposal will utilize optogenetic manipulations of specific pathways connecting different brain regions in rats immediately after the rats have undergone different kinds of learning. Specifically, this proposal will build upon the evidence that the basolateral amygdala (BLA) influences consolidation for many different kinds of learning, including spatial/contextual, emotional, and cued-response learning, whereas other regions are involved in memory for more discrete forms of learning. Additional evidence indicates that the BLA influences consolidation through regulation of synaptic plasticity in these other brain regions, including modulation of activity-regulated cytoskeletal-associated protein (Arc), which has been shown to mediate some of the BLA's effects on memory consolidation. Based on these prior findings, the present studies will investigate how distinct BLA projections to different parts of the hippocampus and caudate modulate memory consolidation and Arc expression in downstream brain regions following different kinds of learning. Follow-up experiments will determine whether the increased Arc expression is necessary for the memory modulation. To do so, the current proposal will utilize optogenetic control of activity in specific BLA projections immediately after different learning tasks to directly examine in each Aim: 1) how the candidate pathways influence consolidation for the specific type of learning and 2) how the pathways influence Arc expression in downstream regions and whether the Arc expression is necessary for the memory modulation. Aim 1 will determine how BLA projections to different parts of the hippocampal formation influence consolidation and Arc expression for the context vs. footshock learning in a modified contextual fear conditioning task. Aim 2 will determine how BLA projections to part of the hippocampal formation and the caudate influence consolidation and Arc expression for spatial vs. cued-response learning. In both aims, optogenetic stimulation/inhibition will be given to each candidate pathway immediately after the relevant training to determine its role in influencing consolidation. Moreover, each aim will examine whether such optogenetic manipulations alter Arc expression in different downstream structures and whether reducing Arc levels in those regions prevents the memory-modulating effects of the optogenetic manipulations, providing a critical complementary set of experiments that will improve our model for understanding how the BLA influences memory and plasticity-related proteins such as Arc in other regions. The findings from these studies will provide, for the first time, knowledge for how the specific pathways from the BLA to other brain regions influence memory consolidation and synaptic plasticity. Moreover, these experiments will provide a first step to creating an understanding of the functional connections within the brain underlying consolidation processes.