Selective neuronal silencing to study cognitive decline in Alzheimer's disease

我们对神经退行性疾病的了解目前由于缺乏确凿的证据而受到阻碍 患者症状和潜在神经病理之间的神经生物学联系。至 为了取得进展，我们不仅必须确定关键的生化变化，而且必须确定这些变化是如何改变的 引起神经症状的特定回路的功能。我试图理解为什么 阿尔茨海默病(AD)的早期症状是由特定回路的损伤引起的，以及 进一步的功能障碍会导致这种疾病的最终衰落。我要用一种新方法 在转基因小鼠中选择性神经元沉默的研究 阿尔茨海默病中受损的神经元回路失活。我的博士后实验室已经开发出一种 通过产生超极化对伊维菌素产生特异性反应的新型氯离子通道 这会导致选择性的、可逆的神经元活动抑制。我将利用我的专业知识 转基因技术创造了一种伊维菌素通道有条件地 在Cre重组酶控制下表达。将这只小鼠与表达Cre的动物交配 选定的神经元群体将允许这些细胞用全身伊维菌素沉默。我的 目标是探索成年出生的海马神经元的功能，因为这一群体严重 在AD的小鼠模型中减少。我将研究这些细胞在学习和学习中的作用 通过在获取、巩固和回忆的关键时刻选择性地使他们保持沉默来记忆 新的信息。其他研究将解决沉默对迁徙的影响， 这些成体细胞的形态和存活情况。我的长期计划是研究 使病程后期受损的其他回路沉默对行为的影响 理解在多个领域活动减少如何导致渐进性认知 AD的衰退。在这个过程中，我将产生一只用于选择性神经元的转基因小鼠 沉默，这将对神经科学界广泛有用。

Our understanding of neurodegenerative diseases is currently hindered by lack of a firm neurobiological link between the patient's symptoms and the underlying neuropathology. To advance, we must identify not only key biochemical changes, but also how these changes alter the function of specific circuits to cause neurological symptoms. I seek to understand how impairment of particular circuits initiates early symptoms of Alzheimer's disease (AD), and how addition of further dysfunction leads to the disease's ultimate decline. I will apply a new method of selective neuronal silencing in transgenic mice to examine the behavioral impact of inactivating neuronal circuits damaged in AD. My postdoctoral laboratory has developed a novel chloride channel that responds specifically to ivermectin by producing hyperpolarization that results in selective, reversible suppression of neuronal activity. I will use my expertise in transgenic technology to create a mouse in which the ivermectin channel is conditionally expressed under control of Cre recombinase. Mating this mouse to animals expressing Cre in selected neuronal populations will allow those cells to be silenced with systemic ivermectin. My goal is to explore the function of adult-born hippocampal neurons, as this population is severely diminished in mouse models for AD. I will examine the role of these cells in learning and memory by selectively silencing them at critical times in the acquisition, consolidation, and recall of new information. Additional studies will address the effect of silencing on the migration, morphology, and survival of these adult-born cells. My long-term plans are to examine the behavioral impact of silencing other circuits damaged later in the course of disease to understand how diminished activity in multiple domains results in the progressive cognitive decline of AD. In the process, I will generate a transgenic mouse for selective neuronal silencing that will be broadly useful to the neuroscience community.