Regulated Genetics Studies of Memory Formation

描述(申请人提供)：许多精神疾病会导致情绪、知觉和记忆的改变。大脑的活动如何导致准确的感知和记忆回忆是神经科学中一个关键的基本问题，一直难以直接解决。在这项资助中，我们在小鼠身上开发了一种方法，允许根据神经元对自然环境刺激或学习范式的反应活动来改变神经元的基因。我们用它来引入hM3Dq DREADD受体或通道视紫红质(CHEF)的变体，以允许化学或用光对标记的神经元进行电刺激。通过这种方式，我们可以直接刺激对行为动物的刺激而自然激活的神经元集合，以研究产生感知或记忆所需的参数。在初步研究中，我们表明，解剖上分散的、内部产生的神经活动可以整合到新的记忆中。这与新记忆不会形成从头开始，而是与学习时可能活跃的预先存在的图式或相关的内部表征整合在一起的观点是一致的。使用CHEF，我们发现光刺激脾后皮质中的神经元，这些神经元在恐惧条件作用下自然激活，可以产生冰冻的反应。这表明，我们正在通过人工刺激正确的神经元模式来直接招募记忆痕迹的一个组成部分。我们将扩展这些研究，以探索在巩固和再巩固过程中，控制神经活动整合到新的和现有的记忆中的参数。此外，我们将使用局部刺激来直接测试最优条件 (神经元数量、放电频率)是招募记忆回忆所需的。这些研究将首次直接测试神经活动的空间和时间模式在感知和记忆生成中的作用。产生的数据应该会促进我们对精神障碍的理解，并有助于建立动物模型来测试治疗方法。

DESCRIPTION (provided by applicant): Many psychiatric illnesses lead to alterations in mood, perception and memory. How activity in the brain leads to accurate perception and memory recall is a critical basic question in neuroscience that has been difficult to address directly. In this grant we develop an approach in mice that allows the genetic alteration of neurons based on their activity in response to a natural environmental stimulus or learning paradigm. We use this to introduce either the hM3Dq DREADD receptor or a variant of channelrhodopsin (ChEF) to allow the electrical stimulation of the labeled neurons either chemically or with light. In this way we can directly stimulate the ensemble of neurons activated naturally in response to a stimulus in the behaving animal to investigate the parameters required to produce a perception or memory. In preliminary studies we show that anatomically dispersed, and internally generated neural activity can be integrated into new memory. This is consistent with the idea that new memory does not form de novo but integrates with pre-existing schemas or relevant internal representations that may be active at the time of learning. Using ChEF we found that light stimulation of neurons in the retrosplenial cortex that were activated naturally with fear conditioning could produce a freezing response. This suggests that we are directly recruiting a component of the memory trace through the artificial stimulation of the correct pattern of neurons. We will extend these studies to investigate the parameters that control the integration of neural activity into new and existing memories during consolidation and reconsolidation. In addition, we will use local stimulation to directly test the optimal conditions (number of neurons, firing frequency) required for recruiting memory recall. These studies will provide the first direct test of the role of spatial and temporal patterns of neural activity in th generation of perceptions and memories. The data generated should advance our understanding of psychiatric disorders and aid in the creation of animal models in which to test treatments.