Regulated Genetics Studies of Memory Formation

描述（由申请人提供）：许多精神疾病导致情绪，感知和记忆的改变。大脑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。在这项研究中，我们开发了一种小鼠方法，允许神经元根据其对自然环境刺激或学习范式的反应而进行遗传改变。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，我们可以直接刺激行为动物中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，我们发现解剖学上分散的，内部产生的神经活动可以整合到新的记忆中。这与新记忆不会重新形成，而是与先前存在的图式或相关的内部表征整合在一起的想法是一致的，这些图式或内部表征可能在学习时是活跃的。使用ChEF，我们发现，光刺激压后皮质中的神经元，这些神经元在恐惧条件反射下自然激活，可以产生冻结反应。这表明，我们通过人工刺激正确的神经元模式，直接招募了记忆痕迹的一部分。我们将扩展这些研究，以调查在巩固和重新巩固期间控制神经活动整合到新的和现有记忆中的参数。此外，我们将使用局部刺激直接测试最佳条件 （神经元数量，放电频率）所需的招募记忆回忆。这些研究将首次直接检验神经活动的空间和时间模式在知觉和记忆产生中的作用。所产生的数据应该会促进我们对精神疾病的理解，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.