Neuron-microglia interactions during gamma-frequency oscillations

背景：痴呆如阿尔茨海默病（AD）与脑巨噬细胞（小胶质细胞）介导的大量神经炎症有关。目前，关于这种炎症反应是神经退行性疾病的致病因素还是试图修复由其他病理特征引起的损伤的代偿机制存在激烈的争论。最近的一项研究表明，在海马和视觉皮层中连续诱导γ频率网络振荡能够减少进行性淀粉样变性的各种转基因小鼠模型中的淀粉样病变;这一结果似乎是通过激活小胶质细胞发生的。这一非常令人惊讶和有趣的发现表明，我们小组和其他人在这种转基因小鼠中观察到的伽马振荡缺陷实际上可能在病理学中起着致病作用。也就是说，自然发生的生理伽马频率振荡可能在调节A-β和/或tau病理的表达中起作用;当这些被痴呆相关的突触功能障碍破坏时，通常调节这些病理的伽马诱导的神经免疫系统发生故障。在这种情况下，根据本论文，A-β和/或tau矿床被允许蓬勃发展。实验设计：在这个项目中，学生将联合收割机电生理技术与体外和体内成像相结合，以建立这种形式的振荡驱动的神经元-小胶质细胞相互作用的细胞机制。我们将使用已建立的转基因小胶质细胞报告小鼠系，在脑切片中持续的γ振荡过程中观察小胶质细胞。有几种这样的品系可用，包括MacGreen和CX 3CR 1 +/GFP小鼠品系，两者都在小胶质细胞中表达eGPF，后者可在布里斯托获得。学生还将利用小鼠品系表达Cre重组酶在小胶质细胞特异性的方式。使用Cre-Lox系统，我们可以使用这些小鼠在小胶质细胞中表达荧光Ca 2+报告基因，以检查γ频率振荡期间小胶质细胞中的Ca 2+动力学。这些系统将使我们能够检查参与伽马诱导的小胶质细胞激活的神经递质和生化途径。学生还将应用尖端的体内成像设施，可在埃克塞特和布里斯托探索视觉诱发伽马振荡和小胶质细胞形态之间的相互作用在一个完整的系统。最后，学生将结合联合收割机在体外和体内的方法，在这里概述了调查神经元-小胶质细胞相互作用的动态响应痴呆相关的病理，如β淀粉样蛋白。结果：该项目将提供一个机制框架，支持这种新的和疾病相关的神经元-小胶质细胞相互作用的形式。

Background:Dementias such as Alzheimer's disease (AD) are associated with substantial levels of neuroinflammation mediated by the macrophages of the brain, microglia. There is a current and lively debate on whether this inflammatory response is a causative factor in neurodegenerative disease or a compensatory mechanism attempting to repair damage caused by other pathological features. A recent study has suggested that continuous induction of gamma frequency network oscillations in the hippocampus and visual cortex is capable of reducing amyloid pathologies in various transgenic mouse models of progressive amyloidosis; an outcome that appears to occur via activation of microglia. This highly surprising and intriguing finding suggests that deficits in gamma oscillations observed by our group and others in such transgenic mice, may actually play a causative role in pathology. To wit, naturally occurring physiological gamma frequency oscillations may play a role in regulating the expression of A-beta and/or tau pathologies; and when these are disrupted by dementia-related synaptic dysfunction, the gamma-induced neuroimmunological systems which normally regulate these pathologies malfunction. Under these circumstances, according to this thesis, A-beta and/or tau deposits are allowed to flourish. Experimental design: In this project, the student will combine electrophysiological techniques with in vitro and in vivo imaging to establish the cellular mechanisms underlying this form of oscillation driven neuron-microglia interaction. We will use established transgenic microglia reporter mice lines to visualise microglia during ongoing gamma oscillations in brain slices. There are several such lines available including the MacGreen and CX3CR1+/GFP mice lines, both of which expresses eGPF in microglia and the latter of which is available in Bristol. The student will also make use of mouse lines expressing Cre recombinase in a microglia specific manner. Using the Cre-Lox system, we can use these mice to express florescent Ca2+ reporters in microglia to examine Ca2+ dynamics in microglia during gamma frequency oscillations. These systems will allow us to examine the neurotransmitter and biochemical pathways involved in gamma-induced microglial activation. The student will also apply cutting edge in vivo imaging facilities available in both Exeter and Bristol to explore the interplay between visually evoked gamma oscillations and microglial morphology in an intact system. Finally, the student will combine the in vitro and in vivo approaches outlined here to investigate the dynamics of neuron-microglia interactions in response to dementia related pathology, such as beta amyloid. Outcome:This project will provide a mechanistic framework underpinning this novel and disease-relevant form of neuron-microglia interaction.