Selective neuronal silencing to study hippocampal neurogenesis in depression

描述（由申请人提供）：12岁以上的美国人中有近十分之一服用抗抑郁药物，但我们对他们的疾病或恢复机制的神经基础知之甚少。最近的研究表明，一些参与学习和记忆的细胞过程也可能是抑郁症的基础，导致抑郁症的理论，即抑郁症源于神经元可塑性的变化，有利于“学习”抑郁状态。海马体对于新记忆的形成是必不可少的，它在学习和记忆中的作用是由一群独特的神经元支持的，这些神经元在成年后不断产生和替换。随着这些成年出生的神经元逐渐融入局部网络，它们对刺激表现出增强的可塑性，并且比现有的海马神经元更有可能在学习过程中融入神经回路。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条件，但同样可以帮助抗抑郁药治疗期间的恢复。支持这一观点，最近的实验表明，成年神经发生的丧失可以防止慢性压力后社交回避的发生，相反，会减弱对百忧解等抗抑郁药物的行为反应。 测试成年神经发生在抑郁症和恢复中的作用的最常见方法是杀死分裂的祖细胞。不幸的是，这产生了一个研究结果的人工环境，因为大脑是高度可塑的，可以适应一个神经元群体与另一个神经元群体的损失。一个更好的解决方案是让成年人出生的神经元正常整合，然后迅速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，在该模型中，我们可以特异性地和可逆地沉默任何神经元群体的活性，这些神经元群体可以用选择性启动子进行遗传定义。我们提供了初步的数据显示新模型的特征，并描述了下一步需要优化系统的成年出生的海马神经元的选择性沉默。然后，我们提出了使用新的消音器系统来测试两个假设的实验-首先，成年人出生的功能可塑性 神经元内的活性对于在慢性应激期间诱导抑郁状态是必需的，并且第二，这些神经元内的活性对于在抗抑郁剂治疗期间从抑郁状态恢复也是必需的。我们将测试这些假设，通过抑制活动，在成年出生的神经元暴露于慢性压力，并在抗抑郁药治疗后诱导抑郁状态。我们的策略将使我们能够在不破坏成年神经元的情况下检查它们的功能，目的是更精确地定义神经发生，抑郁症和治疗恢复之间的关系。

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.