Cytokines, Synapses, Neural Circuits and Cognition

描述（由申请人提供）：一个核心的心理健康问题是更好地理解在感染、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。一般来说，由于急性或慢性细胞因子暴露导致认知障碍的潜在分子和细胞变化在很大程度上尚未被探索。目前的文献提供的证据表明：(1)行为表现可因免疫挑战或单一细胞因子的施用而受损，(2)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，在分子/细胞水平上细胞因子介导的变化与行为水平上的认知障碍之间的信息联系还存在很大的空白。我们的初步数据显示，在特定细胞因子组合处理的皮层神经元培养中，涉及突触功能和学习记忆的多个基因显着改变。此外，将这些细胞因子池直接注入大鼠海马会导致空间水迷宫任务中的行为表现缺陷。根据我们的初步发现和其他人的工作，我们提出了一般假设：不同的细胞因子池对突触功能和神经传递相关基因的表达有不同的影响。这些干扰，特别是那些改变谷氨酸能信号平衡的干扰，改变了海马信息处理过程中的神经元回路动力学，从而导致认知障碍。在我们的假设框架内，我们提出了具体的目标来解决以下问题，即不同的细胞因子池如何不同地影响：(1)学习和记忆不同阶段的表现，(2)学习和记忆不同阶段的海马神经回路活动，以及(3)海马RNA表达谱，以及特定突触蛋白的表达和定位。特别重要的是，所提出的实验将代表第一个将细胞因子对认知的影响跨行为、神经回路和分子/细胞水平联系起来的系统方法。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，但没有一个涵盖所有三个层面。由于中间立场需要将分子/细胞机制与行为输出相结合，因此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，这一层面的分析在文献中普遍缺失。通过整合单个实验中从行为、神经回路和分子/细胞水平产生的数据，我们提议的具体目标将导致对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，从而影响大脑功能。公共卫生相关性：细胞因子在大脑中产生是对一系列损伤的反应，包括病毒和细菌感染、缺血、心理压力和其他脑创伤。此外，众所周知，细胞因子会对认知过程产生不利影响，如学习和记忆。该实验将系统地研究脑细胞因子对学习和记忆、脑神经网络活动以及神经元基因表达变化的影响。从这些研究中获得的信息可能对改善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的治疗有用。

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.