Neuroinflammation, Inflammatory Challenge, and Memory

描述（由申请人提供）： 该提案旨在了解衰老过程中导致认知能力下降的一些因素。它的动机是一种新的假设，即衰老是一种敏感或引发神经胶质细胞的脆弱性因素，从而导致与年龄相关的夸大的脑促炎细胞因子（PIC）对某些挑战的反应。正是这种敏感的PIC反应及其“下游”产物被假设为老年人（和动物）对通常与细菌感染，手术和压力相关的认知功能障碍的脆弱性的核心。该假说基于以下发现：1）在对感染或损伤的反应中，外周免疫细胞释放PIC，如白细胞介素-1 β。2)PIC可以向大脑发出信号并诱导大脑中PIC的合成和释放，主要是通过神经胶质细胞。3)大脑中的PIC，特别是海马体中的ILI β，可以干扰记忆巩固，也许还有其他认知过程。因此，如果衰老使神经胶质细胞敏感，那么老年人的大脑PIC对挑战的反应应该是夸大的，从而损害记忆形成。第一个目标是询问老年大鼠是否更容易受到与免疫系统激活和诱导海马PIC的其他事件（外周感染，手术和社会压力）相关的记忆障碍的影响。第二个目标是询问胶质细胞激活，脑PIC和PIC的下游产物，特别是脑源性神经营养因子（BDNF）的减少是否是这些挑战产生的年龄相关记忆障碍的原因。第三个目标调查是否是已知的防止年龄相关的神经胶质启动，即饮食限制（DR）的操作，将防止与年龄相关的夸大大脑PIC反应和挑战诱导的记忆障碍。

DESCRIPTION (provided by applicant): This proposal is directed at understanding some of the factors that contribute to cognitive decline during aging. It is motivated by the novel hypothesis that aging is a vulnerability factor that sensitizes or primes glial cells, thereby resulting in an age-related exaggerated brain proinflammatory cytokine (PIC) response to certain challenges. It is this sensitized PIC response, and its "downstream" products that are hypothesized to be at the core of the aged humans' (& animals') vulnerability to cognitive dysfunctions often associated with bacterial infection, surgery, and stress. The hypothesis rests on the following findings: 1) In response to infection or injury, immune cells in the periphery release PICs such as interleukin-1beta. 2) PICs can signal the brain and induce the synthesis and release of PICs in the brain, primarily by glial cells. 3) PICs in the brain, particularly ILI beta in the hippocampus, can interfere with memory consolidation, and perhaps other cognitive processes Thus, if aging sensitizes glial cells, then there should be exaggerated brain PIC responses to challenge in the aged, and a resultant impairment in memory formation. The first Aim asks whether the aged rat is more vulnerable to memory impairments associated with immune system activation and other events that induce hippocampal PICs (peripheral infection, surgery, and social stress). The second Aim asks whether glial activation, brain PICs, and downstream products of PICs, particularly reductions in brain derived neurotrophic factor (BDNF) are responsible for the age-related memory impairments produced by these challenges. The third Aim investigates whether a manipulation that is known prevent age-related glial priming, namely dietary restriction (DR), will prevent age-related exaggeration of brain PIC responses and challenge-induced memory impairments.