GABA-A Receptor Pharmacology of Neural Coding in Hippocampal Place Cells

项目摘要/摘要 对疾病的治疗，如形成新记忆的能力不足和空间记忆受损，对老年人来说是一个特别重要的主要未满足的医学需求，而正常衰老的动物模型为潜在的治疗方法提供了一个窗口。对啮齿动物衰老的研究表明，海马体的结构和功能发生了变化，海马体是记忆编码和检索的关键结构，与记忆缺陷相关。本申请中描述的研究建立在以下现象的基础上：动物S的物理位置是由海马体锥体细胞(HPC)编码的，因此HPC的放电频率与物理空间中的位置相关。这种神经元被称为定位细胞。衰老引起的空间记忆损伤(ASMI)的特点是：(1)在依赖海马体的空间学习和记忆任务中表现不佳；(2)在进入新环境时，位置场的重新映射存在缺陷。地点场被认为代表了环境认知地图的元素，或者是在情节记忆中发生重大事件的地点的表示。这项拟议的研究旨在了解成年和ASMI大鼠中伴随位置场表征的网络机制，这些机制可能通过药物和遗传方法来调节，以提高认知能力。A5GABA{A}受体主要位于海马区，它们的基因缺失或药物抑制增强了啮齿动物模型的学习和记忆。令我们震惊的是，ASMI大鼠表现出海马区含a5亚单位的γ-氨基丁酸A型受体(a5GABA{A}R)mRNA表达减少，同时CA3锥体神经元显著活跃，这增加了年龄诱导的适应性变化等可能是观察到的认知损害的基础。在这一应用中，长期植入的多单位高密度电极将被用来测量(1)系统地给药TB21007，一种更喜欢作为认知增强剂的a5GABA{A}R在正常成年大鼠中的作用；(2)双侧给药AAV2病毒载体，它调节A5亚单位水平对HPC发作率的影响，并在清醒的、行为自由的正常成年和ASMI大鼠中放置场重新映射。这些实验将确定a5GABA{A}Rs是否以不同方式改变CA1和CA3亚区的HPC发射率，以及与年龄相关的神经活动变化是否影响海马区特定的位置场表征(反映在它们进行模式分离和完成的能力上)。此外，我们将测试a5GABAAR偏好的负调制子和调节a5亚单位水平的特定AAV2病毒载体是否能提高成年和/或ASMI动物的认知能力。这些研究将开始位置场重新映射的分子解剖，有助于更深入地了解HPC活动在年龄相关性认知下降中的作用，并为建立系统水平的方法来评估治疗与正常衰老相关的认知障碍的药物策略提供基础。

Project Summary/Abstract The treatment of disorders such as deficiencies in the ability to form new memories and impaired spatial memory presents a major unmet medical need of particular importance to aged individuals, and animal models for normal aging offer a window on potential therapeutic approaches. Studies of aging in rodents have revealed that structural and functional changes occur in the hippocampus, a structure critical for the encoding and retrieval of memory, that correlate with memory deficits. The research described in this application builds upon the phenomenon that the animal¿s physical location is encoded by hippocampal pyramidal cells (HPCs), such that firing rates for HPCs correlate with location in physical space. Such neurons are referred to as place cells. Aging induced spatial memory impairments (ASMI) are characterized by (1) poor performance during hippocampus-dependent spatial learning and memory tasks, and (2) deficits in remapping of place fields upon introduction into a novel environment. Place fields are thought to represent elements of a cognitive map of the environment or representations of places where significant events occur within episodic memories. The proposed research is aimed at understanding the network mechanisms that accompany place field representations in adult and ASMI rats that may be modulated via pharmacological and genetic methods to enhance cognitive performance. a5GABA{A}Rs are located primarily in the hippocampus and their genetic deletion or pharmacological inhibition enhances learning and memory in rodent models. We were struck by the observation that ASMI rats exhibit a reduction in a5 subunit-containing y-aminobutyric acid type A receptor (a5GABA{A}R) mRNA expression in the hippocampus along with significant hyperactivity of CA3 pyramidal neurons, raising the possibility that age-induced adaptive changes such as these may underlie the observed cognitive impairments. In this application chronically implanted multi-unit high density electrodes will be used to measure the effects of (1) systemically administered TB21007, an a5GABA{A}R preferring negative modulator that acts as a cognitive enhancer in normal adult rat, and (2) bilaterally administered AAV2 viral vectors that regulate a5 subunit levels on HPC firing rates and place field remapping in awake, freely behaving normal adult and ASMI rats. These experiments will determine whether a5GABA{A}Rs differentially alter HPC firing rates in the CA1 and CA3 subregions and whether age-related changes in neural activity affect hippocampal-specific place field representations (as reflected in their ability to carry out pattern separation and completion). In addition, we will test whether an a5GABAAR-preferring negative modulator and specific AAV2 viral vectors that regulate a5 subunit levels enhance cognitive performance in adult and/or ASMI animals. These studies will begin a molecular dissection of place field remapping, contribute to a deeper understanding of the role of HPC activity in age-related cognitive decline, and provide the basis for establishing a systems-level approach to evaluate pharmacological strategies for treatment of cognitive deficits associated with normal aging.