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治疗与记忆相关的障碍至关重要，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，但以前的工作一直无法研究BLA的特定通路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使人们能够以极高的时间和空间精度对结构及其向传出区域的投影进行光学控制。这项拟议研究的长期目标是利用光遗传学来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将发展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，杏仁基底外侧核(BLA)将被病毒转导以表达去极化阳离子通道视紫红质-2(Cheta)或超极化外向质子泵古紫质-3(ARCHT)。由于视蛋白沿着包括轴突在内的整个细胞膜表达，因此也可以向结构提供照明，例如伏隔核(NA)，这些结构接受BLA输入来控制这一特定途径。在本实验中，大鼠将接受一种改进的情境恐惧条件反射(CFC)任务的训练，该任务将情境学习与脚底电击学习分开。因此，目前的提议将使用光遗传控制BLA及其向NA的投射，以确定这些神经回路如何影响不同类型学习的巩固。目标1将调查BLA的光遗传控制如何影响在修改的CFC任务中脚电与背景学习的巩固。在目标1中，我们将在训练结束后立即使用各种不同的光照参数来刺激(通过Cheta表达)或抑制(通过ARCHT表达)BLA活性。目的1‘S的发现将为光遗传控制BLA谷氨酸能神经元活动如何影响记忆巩固提供关键知识。目标2将研究对BLA到NA(贝壳与核心)的投影的光学控制如何影响背景与脚震学习的巩固。目标2将利用光遗传学的能力，通过照亮NA壳或核中表达视蛋白的BLA纤维来控制特定的投射路径。这些发现将回答以前关于在巩固氟氯化碳学习的不同方面(背景与足迹)期间从BLA到NAShell和核心的路径的棘手问题。总之，这些实验将为应用光遗传学来理解记忆巩固所涉及的神经回路提供关键的基础，并回答关于不同类型学习巩固过程中从BLA到NA的回路的主要问题。 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。这项拟议的研究将研究这种学习过程背后的神经回路调节记忆巩固，为未来治疗记忆障碍的研究奠定基础。

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.