A systems approach to long-term in vivo homeostatic control of neural activity

在整个生命过程中，大脑都面临着保持其稳定性的挑战，同时也要有足够的灵活性来应对环境变化，并做出存储记忆所需的修改。在面对这些挑战时，将大脑功能维持在某个设定值附近的过程被称为体内平衡。体内平衡调节神经元的电活动，可能对终身健康和健康衰老特别重要。需要将神经元的活动维持在最佳范围内。如果神经元活动过多或过少，神经元就会受损或信息丢失。体内平衡缺陷被认为在一系列脑部疾病中起着关键作用，这些疾病是制药和生物技术行业的目标。然而，我们对稳定成人大脑神经活动的基本细胞或分子机制知之甚少。我们提出了一种新的方法来建立介导成人大脑稳态的基本细胞和分子机制。我们的方法使用我们最近开发的分子工具来专门操纵成年小鼠大脑中已识别的神经元群的活动。有了这些工具，我们可以增加或减少神经元活动，然后直接测量将关键神经元功能恢复到先前设定点的稳态反应。我们将把重点放在一个叫做齿状回（DG）的大脑区域，它对空间记忆很重要，并与年龄相关的记忆丧失有关。这是一个很好的模型，因为它具有明确的解剖和生理特性。我们的初步数据表明，齿状回中的神经元能够自稳态地适应导致其活动增加或减少的操作。我们现在建议使用这种新方法来识别对成人大脑内稳态重要的分子，并了解其潜在机制。我们将使用我们的新分子工具来诱导成年小鼠DG神经元的稳态反应。然后，我们将使用电生理记录来测量已经发生的功能变化，使神经活动恢复到之前的设定值。这些实验将确定神经元是否通过改变它们彼此之间的交流或改变它们处理传入信息的方式来自我补偿它们活动水平的变化。我们将开发计算模型来协调来自不同实验的数据，并为进一步的实验做出可测试的预测。使用基因表达谱技术，我们将确定哪些基因在稳态反应中变得或多或少活跃。然后，我们将研究这些基因如何促进与体内平衡相关的细胞变化。通过将基因表达、细胞变化和神经元活动的计算模型联系起来，我们的目标是预测体内平衡对大脑回路功能的影响，并最终影响认知过程和行为。本研究所建立的模型和实验结果将在多个领域具有一定的价值和应用价值。1)通过建立基因之间的基本联系，神经元之间的交流和神经稳态，该研究将为了解神经元在健康大脑中的功能提供重要的见解。这将为进一步研究特定基因如何影响大脑功能奠定基础。2)本研究结果将为研究体内平衡在衰老和疾病中的作用奠定基础。确定支持体内平衡的细胞变化将为药物发现提供潜在的靶点，我们改变成年神经元兴奋性的方法将为药物测试和验证提供有用的模型。3)我们建立的计算模型将使制药或生物技术公司开发的潜在治疗策略的干实验室测试成为可能。

Throughout life the brain is faced with the challenge of maintaining its stability, while also being sufficiently flexible to respond to environmental changes and to make modifications required for storage of memories. The process of maintaining brain functions near some set point in the face of these challenges is called homeostasis. Homeostasis regulates the electrical activity of neurons and is likely to be exceptionally important for life-long health and for healthy aging. It is required to maintain a neuron's activity within an optimal range. If neurons have too much or too little activity, neurons will be damaged or information will be lost. Deficits in homeostasis are believed to play critical roles in a spectrum of brain disorders that are targets for pharmaceutical and biotechnology industries. Yet, we know very little about the basic cellular or molecular mechanisms that stabilize neural activity in the adult brain. We propose a new approach to establish fundamental cellular and molecular mechanisms that mediate homeostasis in the adult brain. Our approach uses molecular tools that we have recently developed to specifically manipulate activity of identified populations of neurons in the brains of adult mice. With these tools we can either increase or reduce neuronal activity and then directly measure homeostatic responses that return key neuronal functions to previous set points. We will focus on a brain area called the dentate gyrus (DG), which is important for spatial memory and is implicated in age-related memory loss. This is a good model as it has well defined anatomical and physiological properties. Our preliminary data demonstrate that neurons in the dentate gyrus homeostatically adapt to manipulations that cause their activity to be increased or reduced. We now propose to use this new approach to to identify molecules that are important for homeostasis in the adult brain and to understand the underlying mechanisms. We will use our new molecular tools to induce homeostatic responses in neurons in the DG of adult mice. We will then use electrophysiological recordings to measure the functional changes that have occurred to return neural activity to its previous set point. These experiments will determine if neurons compensate homeostatically for changes in their activity levels by altering their communication with each other or by changing the way they process incoming information. We will develop computational models to reconcile data from different experiments and to make testable predictions for further experiments. Using gene expression profiling technology we will identify which genes have become more or less active during the homeostatic response. We will then examine how these genes contribute to the cellular changes that are associated with homeostasis. By linking gene expression, cellular changes and computational models of neuronal activity, we aim to predict the impact of homeostasis on the function of circuits in the brain and ultimately on cognitive processes and behaviour. The models and experimental results generated by this study will be of benefit and application in several areas. 1) By establishing basic links between genes, communication between neurons and neural homeostasis, the study will provide important insight into how neurons function in the healthy brain. It will form a basis for further investigations of how specific genes influence brain function. 2) The results of the study will give a foundation for investigation of the roles of homeostasis during aging and in disease. Identification of cellular changes underpinning homeostasis will provide potential targets for drug discovery and our approach to altering excitability in adult neurons will provide a useful model for drug testing and validation. 3) The computational models that we build will enable dry lab testing of potential therapeutic strategies in development by pharmaceutical or biotechnology companies.