Neuronal-Glial Dialogue and Cognition

描述（由申请人提供）：Fractalkine是一种由健康神经元组成表达的趋化因子，已被确定为一种新的神经免疫调节蛋白，其功能是向小胶质细胞发送警报信号，并抑制炎症条件下的小胶质细胞活性。这种对话的中断可能会引发小胶质细胞功能表型的更剧烈变化。与许多其他趋化因子相比，fractalkine仅结合一种受体（CX3CR1）。对几种不涉及血脑屏障损害的病理过程的评估（因此不需要外周白细胞的大规模进入）表明，通过CX3CR1受体的信号传导减少了神经元损伤。也有研究表明，fractalkine通过减少IL-1的产生来控制小胶质细胞毒性的程度。和TNFa。在本应用中提出的具体假设是，神经元衍生的fractalkine和表达CX3CR1的小胶质细胞之间的串扰中断导致小胶质细胞过度激活，将细胞因子谱从M2/替代状态推向M1/经典状态，IL-1¿？？是导致CX3CR1/fractalkine信号中断对认知功能产生有害影响的关键分子之一。我们发表的数据支持了我们的工作假设，我们首次表明，老年大脑中可溶性fractalkine蛋白水平下降，这可能是随着年龄增长而被破坏的关键因素之一，从而导致先天免疫系统过度激活。我们进一步证明，给予老年大鼠fractalkine可增加齿状回亚颗粒区内源性神经元祖细胞的增殖，而在年轻大鼠中阻断CX3CR1的功能可减少亚颗粒区神经元祖细胞的增殖。此外，我们有新的初步数据显示，在非病理条件下，CX3CR1-/-小鼠以神经发生减少的形式降低突触可塑性，最近这些小鼠表现出LTP减少和认知功能缺陷。据我们所知，除了我们直接调查FKN对老年大鼠学习和记忆的作用外，没有其他研究的数据。我们假设衰老会导致CX3CR1/fractalkine信号的中断，从而引发IL-1水平的增加。这种积极的反馈循环导致神经炎症，并导致认知受损。在这里，我们将通过追求以下两个特定目的来验证这一假设：1)CX3CR1缺陷（CX3CR1-/-）小鼠的小胶质细胞功能障碍和IL-1水平升高导致认知功能障碍；2) Fractalkine/CX3CR1信号的损伤调节海马依赖的年龄相关记忆缺陷。我们在这里的贡献有望是详细了解老年大脑中FKN/CX3CR1信号缺陷如何导致认知功能下降。

DESCRIPTION (provided by applicant): Fractalkine, is a chemokine expressed constitutively by healthy neurons and it has been identified as a novel neuroimmune regulatory protein, whose function is to send alert signals to microglia, and inhibit microglia activity under inflammatory conditions. Disruption of this dialogue could trigger more drastic changes in the functional phenotype of microglia. In contrast to many other chemokines, fractalkine binds to only one receptor (CX3CR1). Evaluation of several pathological processes that did not involve blood brain barrier compromise (and therefore did not entail large scale entry of peripheral leukocytes) showed that signaling through the CX3CR1 receptor reduced neuronal damage. It has also been shown that fractalkine controls the degree of microglia toxicity by attenuating the production of IL-1¿?and TNFa. The specific hypothesis addressed in this application is that a disruption in the crosstalk between neuronally-derived fractalkine and microglial cell expressed CX3CR1 leads to microglia overactivation by pushing the cytokine profile away from a M2/alternative state towards the M1/classical state, and that IL-1¿??is one of the key molecules responsible for the deleterious effect of disruption of CX3CR1/fractalkine signaling on cognitive function. Our working hypothesis is supported by our published data in which we show for the first time that there is a decrease in soluble fractalkine protein levels in the aged brain and this may be one of the key players that is disrupted with age, thereby leading to overactivation of the innate immune system. We have further demonstrated that administering fractalkine to aged rats increases proliferation of endogenous neuronal progenitors in the subgranular zone of the dentate gyrus, while blocking the function of CX3CR1 in young rats decreases neuronal progenitor cell proliferation in the subgranular zone. In addition we have new preliminary data showing that CX3CR1-/- mice in non-pathological conditions have reduced synaptic plasticity in the form of decreased neurogenesis and most recently that these mice show reduced LTP and deficits in cognitive function. To the best of our knowledge, there are no data from studies other than ours directly investigating the role of FKN on learning and memory in aged rats. We hypothesize that aging leads to a disruption in CX3CR1/fractalkine signaling, which triggers an increase in IL-1¿ levels. This positive feedback loop leads to neuroinflammation and contributes to impaired cognition. Here, we will test this hypothesis by pursuing the following two specific aims: 1) Microglial dysfunction in CX3CR1-deficient (CX3CR1-/-) mice and increased levels of IL-1¿ lead to functional impairment in cognitive function; 2) Impairment in Fractalkine/CX3CR1 signaling modulates hippocampal-dependent age-related memory deficits. Our contribution here is expected to be a detailed understanding of how FKN/CX3CR1 signaling defect in the aged brain leads to a decline in cognitive function.