Modulation of memory encoding by the blood-brain barrier

情绪强烈地影响着人类和动物的学习和记忆等认知过程。然而，绝大多数的行为研究都是以神经元为中心的，然而，越来越多的证据表明，其他生物系统的参与还有待探索。我的NSERC研究项目的主要研究目标是了解外周免疫系统如何与脑神经血管系统相互作用，以修改涉及记忆过程的神经元回路。我建议结合我在大脑和膜的可塑性、记忆形成和情绪反应方面开发的专业知识来破译其中涉及的机制。血脑屏障(BBB)代表了大脑和外周免疫信号之间的终极边界。尽管如此，我们对循环炎症介质在正常情况下如何影响血脑屏障、脑细胞回路以及最终在不同环境中的行为知之甚少。情感体验可以是消极的，也可以是积极的，例如，如果它分别与恐惧或奖励有关。大脑是一个免疫特权部位，外周免疫细胞和促炎细胞因子等介体接触它的途径非常有限。然而，我们发现，消极的情绪体验会导致血脑屏障通透性的改变和促进炎症信号渗透的紧密连接蛋白的丢失。我们的初步数据显示，细胞因子水平与主要促进剂超家族结构域包含2a(Mfsd2a)的表达显著相关，Mfsd2a是一种对血脑屏障形成和完整性至关重要的膜运输蛋白。这些发现为这一提议提供了基础，并提出了关于内皮运输机制在外周免疫信号渗透中所起的作用，以及情绪驱动的免疫反应、血脑屏障完整性和积极或消极记忆形成之间的潜在联系的问题。为了解决这些基本问题，我们将把行为评估与形态和功能研究结合起来。对于我们的第一个短期目标，我们建议评估情绪驱动的记忆形成如何影响血液细胞因子谱、血脑屏障形态和分子特性。对于第二个短期目标，我们建议操纵与血脑屏障完整性和运输有关的基因的表达，并确定它如何影响记忆形成和细胞因子向大脑的渗透。血脑屏障的位置非常合适，可以将外周免疫信号传递给邻近的神经胶质细胞和神经元，影响它们的生物学行为，最终影响情绪价格和记忆过程。我们的研究计划旨在了解神经血管适应和免疫反应如何影响行为编码，以及这些系统是否可以被操纵以促进积极偏见和正常记忆的形成。申请的资金将促进与认知相关的基本方面的知识，并使下一代科学家接触到动态的研究环境和尖端技术。

Emotions strongly influence cognitive processes such as learning and memory in humans and animals. The vast majority of behavioral studies are neuron-centric however accumulating evidence suggest involvement of other biological systems yet to explore. The main research goal of my NSERC research program is to understand how the peripheral immune system interacts with the brain neurovasculature to modify neuronal circuits involved in memory processes. I propose to combine the expertise I developed in brain and membrane plasticity, memory formation and emotional response to decipher the mechanisms involved. The blood-brain barrier (BBB) represents the ultimate frontier between the brain and peripheral immune signals. Still, we know very little on how circulating inflammatory mediators influence the BBB, brain cell circuits and ultimately behaviors in different environmental context under normal conditions. Emotional experience can have a negative or positive valence, for example if it is associated with fear or reward, respectively. The brain is an immunologically privileged site and peripheral immune cells and mediators such as proinflammatory cytokines have a very limited access to it. However, we showed that negative emotional experience induces changes in BBB permeability and loss of tight junction proteins promoting infiltration of inflammatory signals. Our preliminary data revealed significant correlations between levels of cytokines and expression of Major facilitator super family domain containing 2a (Mfsd2a), a membrane transport protein critical for BBB formation and integrity. These findings provide a basis to this proposal and raises questions about the role played by endothelium transport mechanisms in infiltration of peripheral immune signals and a potential link between emotion-driven immune responses, BBB integrity and formation of positive or negative memories. To tackle these fundamental questions, we will combine behavioral assessments to morphological and functional studies. For our first short-term objective we propose to evaluate how emotion-driven memory formation affects blood cytokine profile, BBB morphology and molecular properties. For the second short-term objective we propose to manipulate expression of genes involved in BBB integrity and transport and determine how it affects memory formation and cytokine infiltration into the brain. The BBB is perfectly located to carry on peripheral immune signals to neighboring glial cells and neurons affecting their biology and ultimately emotional valence and memory processes. Our research program will aim to understand how neurovascular adaptations and immune responses affect behavioral encoding and if these systems can be manipulated to promote positive bias and normal memory formation. Requested funds will advance knowledge of fundamental aspects related to cognition and expose the next generation of scientists to a dynamic research environment and cutting-edge technologies.