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

我们对神经退行性疾病的理解目前受到缺乏一个坚定的 患者症状和潜在神经病理学之间的神经生物学联系。到 为了取得进展，我们不仅必须确定关键的生物化学变化，而且还必须确定这些变化如何改变 引起神经症状的特定回路的功能。我想知道 特定回路的损伤会引发阿尔茨海默病（AD）的早期症状，以及如何 进一步的功能障碍导致疾病的最终衰退。我将采用一种新的方法 在转基因小鼠中进行选择性神经元沉默，以检查 使AD中受损的神经元回路失活。我的博士后实验室开发了一种 通过产生超极化特异性响应伊维菌素的新型氯离子通道 导致选择性的可逆的神经元活动抑制。我会用我的专业知识 转基因技术来产生小鼠，其中伊维菌素通道被条件性地 在Cre重组酶的控制下表达。将这只小鼠与表达Cre的动物交配， 选择的神经元群体将允许那些细胞被全身性伊维菌素沉默。我 目的是探索成年海马神经元的功能，因为这一群体是严重的， 在AD小鼠模型中减少。我将研究这些细胞在学习和 在获得、巩固和回忆的关键时刻， 新的信息。更多的研究将解决沉默对迁移的影响， 形态和这些成体细胞的存活。我的长期计划是检查 在疾病过程中，沉默其他受损回路的行为影响， 了解多个领域的活动减少如何导致渐进性认知障碍 AD的下降。在这个过程中，我将产生一个转基因小鼠， 沉默，这将是广泛有用的神经科学界。

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.