Selective neuronal silencing to study hippocampal neurogenesis in depression

描述(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，但我们对他们的障碍的神经基础或他们恢复的机制知之甚少。最近的研究表明，参与学习和记忆的一些细胞过程也可能是抑郁症的基础，这导致了一种理论，即抑郁症是由于神经元可塑性的变化而产生的，这种变化有利于抑郁状态的“学习”。海马体对于形成新的记忆是必不可少的，它在学习和记忆中的作用是由一组独特的神经元支持的，这些神经元在成年后不断地产生和替换。随着这些成年出生的神经元融入局部网络，它们对刺激的可塑性增强，在学习过程中比现有的海马神经元更有可能被合并到神经回路中。我们认为，这些成年出生的海马神经元的可塑性增强也有助于抑郁症等病理情况的发生，但同样有助于抗抑郁药物治疗期间的恢复。支持这一观点的是，最近的实验表明，成年神经发生的丧失可以防止慢性应激后社交回避的发生，反过来，也会削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康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性的，可能会适应一个神经元群体与另一个神经元群体的丧失。一种更好的解决方案是允许成年出生的神经元正常整合，然后强烈阻止它们参与局部回路。我们开发了一种新的转基因小鼠模型，在该模型中，我们可以特异性和可逆地沉默任何一组神经元的活动，这些神经元可以通过选择性启动子在基因上定义。我们提供的初步数据显示了新模型的特征，并描述了优化选择性沉默成年出生的海马神经元的系统所需的下一步步骤。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-第一，成人出生时的功能可塑性 在慢性应激期间，神经元是诱导抑郁状态所必需的，其次，在抗抑郁药物治疗期间，这些神经元内的活动也是从抑郁状态恢复所必需的。我们将通过在慢性应激期间以及在抑郁状态诱导后的抗抑郁治疗期间抑制成年出生神经元的活动来检验这些假说。我们的策略将使我们能够在不破坏成年出生的神经元的情况下检查它们的功能，目标是更准确地定义神经发生、抑郁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.