Involvement of the Retrosplenial Cortex in Distinct Aspects of Fear Memory

压后皮质参与恐惧记忆的不同方面

• 批准号: 10012772
• 负责人: Sydney Trask
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012772
• 关键词: Amygdaloid structure; Animals; Anterior; Aversive Stimulus; Behavior; Behavioral; Brain; Brain region; Cells; Cues; Data; Disease; Dissociation; Distress; Environment; Event; Exposure to; Freezing; Fright; Generalized Anxiety Disorder; Goals; Gold; Hippocampus (Brain); Human; Impairment; Injections; Knowledge; Laboratories; Lead; Learning; Lesion; Literature; Measures; Memory; Methods; Molecular; National Research Service Awards; Neurons; Performance; Phase; Play; Post-Traumatic Stress Disorders; Procedures; Process; Research; Retrieval; Rodent; Role; Shock; Stimulus; Structure; Symptoms; System; Techniques; Testing; Therapeutic Intervention; Time; Training; Variant; Work; base; conditioned fear; conditioning; experimental study; fear memory; memory encoding; memory recall; memory retrieval; molecular marker; neuropsychiatric disorder; optogenetics; relating to nervous system; response; targeted treatment

PROJECT ABSTRACT The ability to form aversive memories (e.g., connecting stimuli in the environment with the negative events they predict) is crucial to survival and is well-conserved across species. Alterations in this system, however, can lead to maladaptive or inappropriate fear responding outside of situations in which a fear response is warranted. This “generalized” fear response, in which fearful behavior is expressed outside of the context or environment in which it was acquired, is a hallmark symptom of several human neuropsychiatric disorders like post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The inability to appropriately use context to guide fear responding is a common process that, when treated, could target symptomology underlying several disorders, most of which cause significant distress to the afflicted. Most research on the encoding and retrieval of contextual processing in fear memory has focused on subcortical regions like the hippocampus and the amygdala. Recent data has begun to suggest a critical role for the retrosplenial cortex (RSC) in the acquisition and expression of these memories. Previous work has primarily used spatially and temporally imprecise manipulations of the RSC, making it difficult to understand the exact role of this relatively large structure in encoding and retrieval of both the event-related (i.e., “what”) and context-related (i.e., “where”) aspects of aversive memory. The overarching hypothesis of this proposal is that the anterior region of the RSC (i.e., the aRSC) is important for encoding of the event-related aspects of memory (the “what” memory) and that the posterior region (i.e., the pRSC) independently and dissociably encodes the context-related information (that “where” memory). In Specific Aim 1, we will examine differential contributions of aRSC and pRSC to the to the independent formation of event-related and contextual memory, and their subsequent association, via a modified form of contextual fear conditioning. In Specific Aim 2, we will examine the contributions of both regions to the retrieval of event-related and contextual memory, using both contextual fear conditioning and trace fear conditioning (a type of cued fear conditioning that is crucially dependent on the RSC). In all studies, neurons in either aRSC or pRSC will be optogenetically silenced, a technique that allows for unprecedented spatial and temporal precision. This temporary and reversible inactivation will allow for examination of the type of information processed within the RSC, as well as for the discrete roles of the RSC during aversive event-related and contextual memory formation. By investigating the neural substrates that support these forms of learning, this work could identify a new target in treating disorders in which the learning controlled by the RSC is likely dysregulated.

项目摘要 形成厌恶记忆的能力（例如，将环境中的刺激与负面事件联系起来， 预测）对生存至关重要，并且在物种中保存良好。然而，这一系统的改变可能导致 适应不良或不适当的恐惧反应的情况下，其中一个恐惧反应是必要的。这 “广义”恐惧反应，其中恐惧行为在上下文或环境之外表达， 它是后天获得的，是几种人类神经精神疾病的标志性症状， 应激障碍（PTSD）和广泛性焦虑症（GAD）。无法适当地使用上下文来 引导恐惧反应是一个常见的过程，当治疗时，可以针对几个潜在的神经病学， 疾病，其中大多数会给患者带来巨大的痛苦。大多数关于编码和检索的研究 恐惧记忆的背景处理集中在皮层下区域，如海马体和大脑皮层。 杏仁核最近的数据已经开始表明压后皮质（RSC）在获得中的关键作用。 这些记忆的表达。以前的工作主要使用空间和时间上不精确的 操纵的RSC，使其难以理解这个相对较大的结构， 事件相关的编码和检索（即，“什么”）和上下文相关（即，“where”）的各个方面 厌恶性记忆该提议的首要假设是RSC的前部区域（即，的 aRSC）对于记忆的事件相关方面（“什么”记忆）的编码是重要的， 后部区域（即，pRSC）独立地和可分离地编码上下文相关信息（其 “where”记忆）。在具体目标1中，我们将研究aRSC和pRSC对 事件相关和上下文记忆的独立形成，以及它们随后的关联，通过修改后的 一种情境恐惧条件反射在具体目标2中，我们将研究这两个地区对 使用情境恐惧条件反射和痕迹恐惧来检索事件相关记忆和情境记忆 条件反射（一种关键依赖于RSC的线索恐惧条件反射）。在所有研究中， aRSC或pRSC将被光遗传学沉默，这是一种允许前所未有的空间和生物学效应的技术。 时间精度这种暂时和可逆的失活将允许检查信息类型 在RSC内处理，以及在与厌恶事件相关的 情境记忆的形成通过研究支持这些学习形式的神经基质， 这项工作可以确定一个新的目标，在治疗疾病，其中学习控制的RSC是可能的， 失调