Selective neuronal silencing to study hippocampal neurogenesis in depression

描述（由申请人提供）：近十分之一的12岁以上的美国人服用抗抑郁药物，但我们对其疾病的神经基础或恢复机制知之甚少。最近的研究表明，一些与学习和记忆有关的细胞过程也可能是抑郁症的基础，这导致了一种理论，即抑郁症源于有利于“学习”抑郁状态的神经元可塑性的变化。海马体对新记忆的形成至关重要，它在学习和记忆中的作用是由一群独特的神经元支持的，这些神经元在成人生活中不断产生和替换。当这些成年出生的神经元融入局部网络时，它们对刺激表现出更强的可塑性，并且在学习过程中比现有的海马神经元更有可能被纳入神经回路。我们认为，这些成年海马神经元的可塑性增强也有助于抑郁症等病理状况，但同样可以在抗抑郁治疗期间帮助恢复。为了支持这一观点，最近的实验表明，成人神经发生的丧失阻止了慢性压力后社会回避的发生，相反，减弱了对抗抑郁药物（如百忧解）的行为反应。测试成人神经发生在抑郁症和康复中的作用最常用的方法是杀死分裂的祖细胞。不幸的是，这产生了一个人为的环境来研究结果，因为大脑是高度可塑的，可以适应一个神经元群的损失。一个更好的解决方案是让成年的神经元正常整合，然后强烈地阻止它们参与局部回路。我们已经开发了一种新的转基因小鼠模型，在这种模型中，我们可以特异性地、可逆地沉默任何一群神经元的活动，这些神经元可以通过选择性启动子在基因上定义。我们提供了显示新模型特征的初步数据，并描述了优化成年出生海马神经元选择性沉默系统所需的下一步。然后，我们提出了使用新的消声器系统的实验来验证两个假设-第一，成年出生的功能可塑性

DESCRIPTION (provided by applicant): Nearly 1 in 10 Americans over 12 years of age takes antidepressant medication, yet we know little about the neural basis for their disorder or the mechanism of their recovery. Recent work suggests that some of the cellular processes involved in learning and memory may also underlie depression, leading to the theory that depression arises from changes in neuronal plasticity that favor "learning" of the depressed state. The hippocampus is essential for the formation of new memories and its role in learning and memory is supported by a unique population of neurons that are constantly generated and replaced during adult life. As these adult- born neurons become integrated into the local network, they show increased plasticity to stimulation and are more likely to be incorporated into neural circuits during learning than existing hippocampal neurons. We believe that enhanced plasticity of these adult-born hippocampal neurons also contributes to pathological conditions such as depression, yet can likewise aid recovery during antidepressant treatment. Supporting this idea, recent experiments suggest that loss of adult neurogenesis prevents the onset of social avoidance following chronic stress, and conversely, blunts the behavioral response to antidepressant medications such as Prozac. The most common means of testing the role of adult neurogenesis in depression and recovery is to kill the dividing progenitors. Unfortunately, this produces an artificial setting in which to study the outcome, as the brain is highly plastic ad may accommodate for the loss of one neuronal population with another. A better solution would allow the adult-born neurons to integrate normally and then acutely prevent them from participating in the local circuit. We have developed a novel transgenic mouse model in which we can specifically and reversibly silence the activity of any population of neurons that can be genetically defined with a selective promoter. We provide preliminary data showing characterization of the new model and describe the next steps needed to optimize the system for selective silencing of adult-born hippocampal neurons. We then propose experiments using the new silencer system to test two hypotheses - first that the functional plasticity of adult-born neurons is necessary to induce the depressed state during chronic stress, and second that activity within these neurons is also necessary to recover from the depressed state during antidepressant treatment. We will test these hypotheses by suppressing activity in adult-born neurons during exposure to chronic stress, and during antidepressant treatment following induction of the depressed state. Our strategy will allow us to examine the function of adult-born neurons without destroying them, with the goal of more precisely defining the relationship between neurogenesis, depression, and therapeutic recovery.