Involvement of the Retrosplenial Cortex in Distinct Aspects of Fear Memory

项目摘要 形成厌恶记忆的能力(例如，将环境中的刺激与它们的负面事件联系起来 预测)对生存至关重要，并在物种间得到很好的保护。然而，这个系统中的变化可能会导致 适应不良或不适当的恐惧反应，在需要恐惧反应的情况下做出反应。这 “广义的”恐惧反应，恐惧行为表现在背景或环境之外 它是后天获得的，是几种人类神经精神障碍的标志性症状，比如创伤后 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，当接受治疗时，可以针对几个潜在的症状 疾病，其中大多数会给受难者带来巨大的痛苦。关于编码和检索的研究最多 关于恐惧记忆中的语境处理的研究主要集中在皮质下区域，如海马体和 杏仁核。最近的数据表明，脾后皮质(RSC)在习得中起着关键作用。 以及这些记忆的表达。以前的工作主要是使用空间和时间上的不精确 RSC的操纵，使得很难理解这个相对较大的结构在 对以下两个方面进行编码和检索：与事件相关的(即“什么”)和与上下文相关的(即“在哪里”)方面 厌恶的记忆。这一建议的首要假设是RSC的前区(即 ARSC)对于对记忆中与事件相关的方面(“什么”记忆)进行编码是很重要的 后区(即，PRSC)独立且分离地编码与上下文相关的信息(即 “WHERE”记忆)。在具体目标1中，我们将研究aRSC和PRSC对 事件相关记忆和语境记忆的独立形成，以及它们随后的关联 情境恐惧条件反射的形式。在具体目标2中，我们将审查这两个区域对 事件相关记忆和背景记忆的提取，使用背景恐惧条件反射和痕迹恐惧 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，神经元在 ARSC或PRSC都将被光遗传沉默，这项技术允许前所未有的空间和 时间精确度。这种临时的和可逆的失活将允许检查信息类型 在RSC内处理，以及RSC在厌恶事件相关和 语境记忆的形成。通过研究支持这些学习形式的神经底物，这一点 这项工作可以确定治疗学习障碍的新靶点，在这些障碍中，学习很可能由RSC控制 监管不力。

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.