Modulation of memory encoding by the blood-brain barrier

情绪强烈地影响人类和动物的认知过程，如学习和记忆。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研究计划的主要研究目标是了解外周免疫系统如何与大脑神经血管相互作用，以修改参与记忆过程的神经元回路。我打算联合收割机结合我在大脑和膜可塑性、记忆形成和情感反应方面的专业知识来破译其中的机制。血脑屏障（BBB）代表了大脑和外周免疫信号之间的最终边界。尽管如此，我们对循环炎症介质如何影响BBB，脑细胞回路以及在正常条件下不同环境背景下的最终行为知之甚少。 情绪体验可以有消极或积极的效价，例如，如果它分别与恐惧或奖励有关。大脑是一个免疫特权的网站和外周免疫细胞和介质，如促炎细胞因子有一个非常有限的访问it.However，我们发现，负面的情绪体验诱导BBB通透性的变化和紧密连接蛋白的损失，促进炎症信号的浸润。我们的初步数据显示细胞因子水平与主要易化剂超家族结构域2a（Mfsd2a）表达之间存在显著相关性，Mfsd2a是一种对BBB形成和完整性至关重要的膜转运蛋白。这些发现为这一提议提供了基础，并提出了关于内皮转运机制在外周免疫信号渗透中所起作用的问题，以及情绪驱动的免疫反应，BBB完整性和积极或消极记忆形成之间的潜在联系。为了解决这些基本问题，我们将联合收割机行为评估与形态和功能研究相结合。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，我们建议操纵参与BBB完整性和运输的基因的表达，并确定它如何影响记忆形成和细胞因子浸润到大脑中。 血脑屏障的位置非常适合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，并最终影响情绪效价和记忆过程。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的偏见和正常的记忆形成。所申请的资金将促进与认知有关的基本方面的知识，并使下一代科学家接触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.