Optogenetic modulation of memory consolidation for footshock-based learning

描述（由申请人提供）：了解记忆巩固的神经生物学对于开发记忆相关疾病（如创伤后应激障碍和恐惧症）的治疗至关重要。大量的证据表明，基底外侧杏仁核（BLA）与各种前脑结构的相互作用，影响巩固不同类型的学习，但以前的工作一直无法检查特定的通路BLA在不同类型的学习记忆巩固的作用。光遗传学的最新发展现在能够以优异的时间和空间精度对结构进行光学控制，以及它们向传出区域的投射。这项研究的长期目标是利用光遗传学研究记忆巩固过程中的神经回路，特别是连接结构的投射。目前的R21将开发光遗传学在记忆巩固研究中的应用，作为未来研究更大神经回路的基础。在本实验中，基底外侧杏仁核（BLA）将被病毒转导以表达去极化阳离子通道通道视紫红质-2（ChETA）或超极化外向质子泵古视紫红质-3（ArchT）。因为视蛋白沿整个细胞膜（包括轴突）沿着表达，所以也可以向结构（例如接受BLA输入以控制该特定途径的丘脑核（NA））提供照明。在本实验中，大鼠将被训练在一个修改的上下文恐惧条件（CFC）任务，分离的上下文学习和脚电击学习。因此，目前的建议将使用对BLA的光遗传学控制及其对NA的投射来确定这些神经回路如何影响不同类型学习的巩固。目的1将研究BLA的光遗传学控制如何影响改良CFC任务中足电击与背景学习的巩固。在目标1中，我们将在训练后立即使用各种不同的照明参数来刺激（通过ChETA表达）或抑制（通过ArchT表达）BLA活性。目的1的发现将提供关于BLA神经元活动的光遗传学控制如何影响记忆巩固的关键知识。目标2将研究如何光学控制的BLA的预测NA（壳与核心）影响巩固的背景与脚电击学习。目的2将利用光遗传学的能力，通过照射NA壳或核中表达视蛋白的BLA纤维来控制特定的投射途径。这些研究结果将回答以前棘手的问题，从BLA的NAshell和核心的途径，在巩固CFC学习的不同方面（上下文与footshock）。总之，这些实验将为光遗传学应用于理解记忆巩固中涉及的神经回路提供关键基础，并回答有关不同类型学习巩固期间从BLA到NA回路的主要问题。 公共卫生相关性：公共卫生相关性：受情绪影响的学习和记忆障碍，如创伤后应激障碍和恐惧症，仍然是我们社会的严重关切。这项拟议中的研究将调查调节这种学习过程背后的记忆巩固的神经回路，为未来研究记忆障碍的治疗方法奠定基础。

DESCRIPTION (provided by applicant): Understanding the neurobiology of memory consolidation is crucial to the development of treatments for memory-related disorders, such as post-traumatic stress disorder and phobias. Considerable evidence indicates that the basolateral amygdala (BLA) interacts with a variety of forebrain structures to influence the consolidation for different types of learning, but previous work has been unable to examine the roles of specific pathways from the BLA in the memory consolidation for distinct types of learning. The recent development of optogenetics now enables optical control over structures, as well as their projections to efferent regions, with excellent temporal and spatial precision. Th long-term objective of the proposed research is to use optogenetics to investigate the neural circuitry, and especially the projections connecting structures, during memory consolidation. The present R21 will develop the use of optogenetics in the study of memory consolidation as a foundation for future research investigating larger neural circuits. In the present experiments, the basolateral amygdala (BLA) will be virally transduced to express the depolarizing cation channel channelrhodopsin-2 (ChETA) or the hyperpolarizing outward proton pump archaerhodopsin-3 (ArchT). Because the opsins are expressed along the entire cell membrane, including the axons, illumination can also be provided to structures, such as the nucleus accumbens (NA), that receive BLA input to control that specific pathway. In the present experiments, rats will be trained in a modified contextual fear conditioning (CFC) task that separates the context learning from the footshock learning. Thus, the current proposal will use optogenetic control over the BLA and its projections to the NA to determine how these neural circuits influence consolidation for different kinds of learning. Aim 1 will investigate how optogenetic control of the BLA influences the consolidation of the footshock vs. context learning in the modified CFC task. In Aim 1, we will use a variety of different illumination parameters to stimulate (via ChETA expression) or inhibit (via ArchT expression) BLA activity immediately after training. Aim 1's findings will provide critical knowledge about how optogenetic control of BLA glutamatergic neuron activity influences memory consolidation. Aim 2 will examine how optical control over the BLA's projections to the NA (shell vs. core) influences the consolidation of context vs. footshock learning. Aim 2 will take advantage of the ability of optogenetics to control specific projection pathways by illuminating opsin-expressing BLA fibers in the NAshell or core. These findings will answer previously intractable questions about the pathways from the BLA to the NAshell and core during the consolidation of different aspects (context vs. footshock) of CFC learning. Together, these experiments will provide a critical foundation in the application of optogenetics to the understanding of the neural circuits involved in memory consolidation and answer major questions regarding the circuits from the BLA to the NA during consolidation for different types of learning. PUBLIC HEALTH RELEVANCE: Public health relevance: Disorders of emotionally influenced learning and memory, such as post-traumatic stress disorder and phobias, remain serious concerns in our society. The proposed research will investigate the neural circuitry modulating memory consolidation underlying such learning processes, laying the foundation for future research into treatments for memory disorders.