Cytokines, Synapses, Neural Circuits and Cognition

描述（由申请人提供）：一个中心的心理健康问题是更好地了解感染，创伤和衰老相关疾病期间大脑中产生的细胞因子如何影响认知过程。通常，通过急性或慢性细胞因子暴露导致认知损害的潜在分子和细胞变化在很大程度上未被探索。现有文献提供的证据表明：（i）免疫激发或单一细胞因子可损害行为表现，以及（ii）细胞因子治疗在分子/细胞水平上影响神经功能和可塑性。然而，有一个显着的差距，在分子/细胞水平的认知障碍，在行为水平上的信息连接的精氨酸介导的变化。我们的初步数据显示，在用特定细胞因子组合处理的皮层神经元培养物中，涉及突触功能和学习记忆的多个基因发生了显著改变。此外，直接将这些细胞因子池注入大鼠的大脑中会导致空间水迷宫任务中的行为表现缺陷。从我们的初步发现，和其他人的工作，我们提出了一般的假设：不同的细胞因子池差异影响与突触功能和神经传递相关的基因的表达。这些扰动，更具体地说，改变海马体能信号传导平衡的那些扰动，在信息处理期间改变海马体中的神经元回路动力学，这导致认知障碍。在我们的假设框架内，我们提出了具体的目标，以解决以下问题，不同的细胞因子池如何差异影响：（1）在不同阶段的学习和记忆的表现，（2）海马神经回路活动的学习和记忆的各个阶段，（3）海马RNA表达谱，表达和特定突触蛋白的定位。特别重要的是，所提出的实验将代表第一个系统的方法，跨行为，神经回路和分子/细胞水平连接细胞因子对认知的影响。在目前的文献中，有许多研究解决了细胞因子如何影响行为或细胞因子如何影响神经功能的问题，但没有一个包括所有三个水平。作为整合分子/细胞机制与行为输出所需的中间地带，了解细胞因子如何改变海马回路的网络特性至关重要。目前，文献中普遍缺乏这种水平的分析。通过整合从单个实验中的行为，神经回路和分子/细胞水平产生的数据，我们提案的具体目标将导致细胞因子如何改变神经元功能的全面自上而下的观点的发展，这反过来又影响大脑功能。公共卫生相关性：细胞因子在大脑中产生以响应许多损伤，包括病毒和细菌感染、局部缺血、心理应激和其他脑创伤。此外，已知细胞因子可不利地影响认知过程，例如学习和记忆。拟议的实验将系统地研究脑细胞因子对学习和记忆的影响，脑神经元网络的活动，以及神经元基因表达的变化。从这些研究中获得的信息可能有助于治疗神经创伤和损伤后的记忆功能，以及阿尔茨海默病等慢性疾病。

DESCRIPTION (provided by applicant): A central mental health issue is to better understand how cytokines produced in the brain during infection, trauma, and aging-related diseases, impact cognitive processes. Generally, the underlying molecular and cellular changes that lead to cognitive impairment by either acute or chronic cytokine exposure are largely unexplored. Current literature provides evidence that (i) behavioral performance can be impaired by administration of an immune challenge or a single cytokine, and that (ii) cytokine treatment impacts neural function and plasticity at the molecular/cellular level. However, there is a significant gap in information linking cytokine-mediated changes at the molecular/cellular level with cognitive impairment at the behavioral level. Our preliminary data shows that multiple genes involved with synaptic function and learning and memory are significantly altered in cortical neuron cultures treated with specific cytokine combinations. Additionally, direct infusion of these cytokine pools into the hippocampi of rats caused behavioral performance deficits in the spatial water maze task. From our preliminary findings, and the work of others, we propose the general hypothesis: Distinct cytokine pools differentially influence expression of genes associated with synaptic function and neurotransmission. These perturbations, and more specifically those altering the balance of glutamatergic signaling, modify neuronal circuit dynamics in the hippocampus during information processing, which results in cognitive impairment. Within the framework of our hypothesis we propose specific aims to address the following questions of how distinct cytokine pools differentially impact: (1) performance in distinct stages of learning and memory, (2) hippocampal neural circuit activity across stages of learning and memory, and (3) hippocampal RNA expression profiles, and expression and localization of specific synaptic proteins. Of particular importance is that the proposed experiments would represent the first systematic approach towards linking the impact of cytokines on cognition across behavioral, neural circuit, and molecular/cellular levels. Within the current literature, there are many studies that address the question of how cytokines impact behavior or how cytokines impact neural function, but none that encompass all three levels. As the middle ground needed to integrate molecular/cellular mechanisms with behavioral output, it is critical to understand how cytokines alter network properties of hippocampal circuits. At present, this level of analysis is generally absent from the literature. By integrating data generated from behavioral, neural circuit, and molecular/cellular levels from within single experiments, the Specific Aims of our proposal will lead to the development of a comprehensive top-down view of a how cytokines alter neuronal functions, which in turn impact brain function. PUBLIC HEALTH RELEVANCE: Cytokines are produced in the brain in response to a number of insults, including viral and bacterial infection, ischemia, psychological stress, and other brain traumas. Moreover, it is known that cytokines can adversely affect cognitive process, such as learning and memory. The proposed experiments will systematically examine the impact of brain cytokines on learning and memory, the activity of brain neuronal networks, and on changes in neuronal gene expression. Information obtained from these studies may prove useful for treatments to improve memory functions following neural trauma and injury, as well as in chronic diseases such as Alzheimer's Disease.