Neural Pathways Modulating Memory Consolidation

 描述（由申请人提供）：先前的研究检查大脑中的多个记忆系统，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。目前的提议将利用在大鼠经历不同类型的学习后立即连接大鼠不同脑区的特定通路的光遗传学操作。具体来说，这个提议将建立在以下证据的基础上：基底外侧杏仁核（BLA）影响许多不同类型学习的巩固，包括空间/上下文，情感和线索反应学习，而其他区域则参与更多离散形式学习的记忆。其他证据表明，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内相关蛋白（Arc），这已被证明介导了BLA对记忆巩固的一些影响。基于这些先前的研究结果，本研究将探讨不同的BLA预测海马和尾状核的不同部分如何调节记忆巩固和Arc在不同类型的学习后下游脑区的表达。后续实验将确定Arc表达的增加是否是记忆调制所必需的。为此，本提案将在不同的学习任务之后立即利用特定BLA投射中的活性的光遗传学控制，以直接检查每个目标：1）候选途径如何影响特定类型学习的巩固和2）途径如何影响下游区域中的Arc表达以及Arc表达是否是记忆调节所必需的。目的1将确定BLA预测海马结构的不同部分如何影响巩固和Arc表达的背景与footshock学习在一个修改的背景恐惧条件反射任务。目的2将确定BLA投射到海马结构和尾状核的一部分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，在相关训练后立即对每个候选途径进行光遗传学刺激/抑制，以确定其在影响巩固中的作用。此外，每个目标将检查这种光遗传学操作是否会改变不同下游结构中的Arc表达，以及降低这些区域中的Arc水平是否会阻止光遗传学操作的记忆调节作用，提供一组关键的互补实验，这些实验将改善我们的模型，以了解BLA如何影响记忆和可塑性相关蛋白，如其他区域中的Arc。这些研究的结果将首次提供从BLA到其他大脑区域的特定通路如何影响记忆巩固和突触可塑性的知识。此外，这些实验将提供第一步，以建立一个理解的功能连接在大脑内的巩固过程。

 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.