Functional Neurobiology of the Retrosplenial Cortex During Associative Learning

描述（由申请人提供）：大多数事件发生在充满视觉、听觉、触觉和嗅觉刺激的环境中。动物必须吸收大量的信息来学习重要的、与行为相关的事件。复杂或构形联想学习是指需要在不同的、同时呈现的刺激之间形成相互关系的学习。这种类型的学习通常被认为发生在大脑的皮质-海马体网络中，但是编码这种基本学习形式的特定途径和区域尚未得到解决。本研究的主要假设是，脾后皮层及其与鼻后皮层的连接对构形联想学习至关重要。总之，这些目标旨在研究神经活动，功能电路和RSP对行为的具体贡献。目的1的实验提出了一个问题：RSP是学习的主动中介吗？在情境恐惧条件反射（一种构型联想学习形式）后，将测量大鼠RSP中的神经元激活。行为诱导的神经活动将通过量化即时早期基因Arc（活性相关细胞骨架蛋白）的亚区域特异性表达来评估，该基因已被证明在突触可塑性中发挥着重要作用。这些研究有可能证明，在联想学习过程中，RSP是一种感官信息的中介，而不仅仅是一种管道。具体目标2侧重于了解动物在学习时，RSP的哪些子区域与其他“认知”大脑区域进行交流。在这些研究中，逆行追踪将与即时早期基因表达相结合，以确定在厌恶恐惧条件反射后最显著激活的RSP通路。在目标3中，消极模式任务，即配置学习的示范测试，将被用来明确检验RSP对于涉及处理多个同时呈现的刺激的联想学习是必要的这一假设。这一建议解决了关于RSP认知的神经基础的基本问题，RSP是一个与阿尔茨海默病和精神分裂症等病理状况密切相关的大脑区域。阐明健康大脑中与学习有关的神经通路可能被证明对确定可能在认知功能的神经退行性和心理障碍中受影响最大的目标区域特别有用。

DESCRIPTION (provided by applicant): Most events occur in environments that are rich with visual, auditory, tactile and olfactory stimuli. Animals must assimilate vast amounts of information to learn about important, behaviorally relevant events. Complex or configural associative learning is that which requires the formation of inter-relationships among different, simultaneously presented stimuli. This type of learning has traditionally been considered to occur within cortico-hippocampal networks in the brain, but the particular pathways and regions that encode this essential form of learning are unresolved. The overarching hypothesis of this research is that the retrosplenial cortex (RSP) and its connections with the postrhinal cortex are critical for configural associative learning. Together, these aims are designed to investigate the neural activity, functional circuitry and specific contribution of RSP to behavior. The experiments in Aim 1 pose the question: Is RSP an active mediator of learning? Neuronal activation in RSP will be measured in rats following contextual fear conditioning (a form of configural associative learning). Behaviorally-induced neural activity will be assessed by quantifying the sub-region specific expression of the immediate early gene, Arc (activity related cytoskeletal protein), which has been shown to play a prominent role in synaptic plasticity. These studies have the potential to establish that RSP is a mediator, rather than simply a conduit, of sensory information during associative learning. Specific Aim 2 is focused on understanding which subregions of RSP communicate with other "cognitive" brain regions when an animal is learning. For these studies, retrograde tracing will be combined with immediate early gene expression to identify RSP pathways that are most prominently activated following aversive fear conditioning. In aim 3, the negative patterning task, which is the demonstrative test of configural learning, will be employed to explicitly test the hypothesis that RSP is necessary for associative learning that involves the processing of multiple, simultaneously presented stimuli. This proposal addresses basic questions about the neural basis of cognition in RSP, a brain region that is closely associated with pathological conditions such as Alzheimer's disease and Schizophrenia. Elucidating the neural pathways involved in learning in healthy brains could prove to be especially useful in identifying target regions that may be most affected in neurodegenerative and psychological disorders of cognitive function. PUBLIC HEALTH RELEVANCE: This project has the potential to produce critical new insights about the neural organization underlying learning and memory. By investigating a brain region (the retrosplenial cortex) that is known to be compromised in human disorders such as Alzheimer's disease and schizophrenia, this work may eventually lead to the development of novel therapies and treatments for some of the most pervasive human disorders.