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

描述（由申请人提供）：疾病（如形成新记忆的能力缺陷和空间记忆受损）的治疗对老年人来说是一个特别重要的主要未满足的医疗需求，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。对啮齿类动物衰老的研究表明，海马体发生了结构和功能变化，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动物的物理位置由海马锥体细胞（HPC）编码的现象上，使得HPC的放电速率与物理空间中的位置相关。这种神经元被称为位置细胞。衰老诱导的空间记忆障碍（ASMI）的特征在于（1）在依赖于校园的空间学习和记忆任务中表现不佳，以及（2）在引入新环境后重新映射位置场的缺陷。地点场被认为代表了环境认知图的元素，或者是情景记忆中发生重大事件的地点的表征。拟议的研究旨在了解伴随成年和ASMI大鼠位置场表征的网络机制，这些机制可能通过药理学和遗传学方法进行调节，以提高认知能力。5GABAAR主要位于海马中，并且它们的遗传缺失或药理学抑制增强啮齿动物模型中的学习和记忆。我们被ASMI大鼠海马沿着CA 3锥体神经元显著过度活跃的5亚基氨基丁酸A型受体（5 GABAAR）mRNA表达减少的观察结果所震惊，这提高了年龄诱导的适应性变化（如这些）可能是观察到的认知障碍的基础的可能性。在本申请中，将使用长期植入的多单元高密度电极来测量（1）全身施用的TB 21007（一种在正常成年大鼠中充当认知增强剂的5GABAAR偏好负调节剂）和（2）双侧施用的AAV 2病毒载体的作用，所述AAV 2病毒载体调节HPC放电速率上的5个亚基水平并在清醒时进行场重映射，行为自由的正常成年大鼠和ASMI大鼠。这些实验将确定是否5GABAAR差异改变HPC的放电率在CA 1和CA 3的子区域，以及是否年龄相关的神经活动的变化影响特定的位置场表征（反映在他们的能力，进行模式分离和完成）。此外，我们将测试是否5GABAAR偏好负调节剂和特定的AAV 2病毒载体，调节5个亚基水平，提高成年和/或ASMI动物的认知能力。这些研究将开始的分子解剖的地方字段重新映射，有助于更深入地了解HPC活动的作用，在年龄相关的认知功能下降，并提供了基础，建立一个系统水平的方法来评估与正常老化相关的认知功能障碍的治疗的药理学策略。 公共卫生相关性：在美国，2006年有3730万65岁或以上的人，约占美国人的八分之一，到2030年，这一群体预计将增长到人口的20%。衰老伴随着记忆力的下降，这种损害与海马体功能的变化有关，海马体是人类和动物记忆的重要大脑区域。这项培训计划中提出的工作是首批在多个研究领域培训博士生的工作之一，这将使她作为一名年轻的独立科学家能够采用尖端技术并将其应用于一起，以揭示与正常衰老相关的认知缺陷治疗策略的分子基质。

DESCRIPTION (provided by applicant): 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. 5GABAARs 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 5 subunit-containing -aminobutyric acid type A receptor (5GABAAR) 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 5GABAAR preferring negative modulator that acts as a cognitive enhancer in normal adult rat, and (2) bilaterally administered AAV2 viral vectors that regulate 5 subunit levels on HPC firing rates and place field remapping in awake, freely behaving normal adult and ASMI rats. These experiments will determine whether 5GABAARs 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 5GABAAR-preferring negative modulator and specific AAV2 viral vectors that regulate 5 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. PUBLIC HEALTH RELEVANCE: In the United States, there were 37.3 million people 65 years or older in 2006, representing about one in every eight Americans, and by 2030 this group is expected to grow to become 20% of the population. Aging is accompanied by a decline in memory and this impairment has been associated with changes in the function of the hippocampus, a brain region important for memory in humans and animals. The work put forth in this training program is one of the first of its kind to train a doctoral student in multiple research domains that will enable her as a young independent scientist to take cutting edge technologies and apply them together to uncover the molecular substrate for a therapeutic strategy for cognitive deficits associated with normal aging.