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发展记忆相关疾病的治疗至关重要，如创伤后应激障碍和恐惧症。大量证据表明，基底外侧杏仁核（BLA）与多种前脑结构相互作用，影响不同类型学习的巩固，但以前的工作无法检查来自BLA的特定途径在不同类型学习的记忆巩固中的作用。光遗传学的最新发展现在使光学控制结构，以及它们的投射到传出区域，具有优异的时间和空间精度。该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。本研究将发展光遗传学在记忆巩固研究中的应用，为未来研究更大的神经回路奠定基础。在本实验中，基底外侧杏仁核（BLA）将被病毒转导表达去极化阳离子通道通道视紫红质-2 （ChETA）或超极化向外质子泵视紫红质-3 （ArchT）。由于视蛋白沿包括轴突在内的整个细胞膜表达，因此也可以向接收BLA输入以控制特定途径的伏隔核（NA）等结构提供照明。在本实验中，大鼠将在一个改良的情境恐惧条件反射（CFC）任务中进行训练，该任务将情境学习与脚震学习分开。因此，目前的建议将利用光遗传学控制BLA及其对NA的预测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将研究光遗传控制BLA如何影响修改CFC任务中足部冲击与情境学习的巩固。在Aim 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。Aim 1的研究结果将提供关于光遗传控制BLA谷氨酸神经元活动如何影响记忆巩固的关键知识。目的2将研究视觉控制BLA对NA的投射（壳与核）如何影响情境与脚震学习的巩固。Aim 2将利用光遗传学的能力，通过照亮纳什维尔或核心中表达视蛋白的BLA纤维来控制特定的投射途径。这些发现将回答以前难以解决的问题，即在CFC学习的不同方面（情境与足部冲击）巩固过程中，从BLA到NAshell和核心的途径。综上所述，这些实验将为光遗传学应用于记忆巩固的神经回路的理解提供重要的基础，并回答关于不同类型学习在巩固过程中从BLA到NA的回路的主要问题。

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.