Regulated Genetics Studies of Memory Formation

记忆形成的调控遗传学研究

• 批准号: 8610354
• 负责人: MARK R MAYFORD
• 金额: $ 42.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610354
• 关键词: Address; Animal Model; Animals; Area; Behavior Control; Behavioral; Brain; Cells; Complex; Cues; Data; Disease; Doxycycline; Electric Stimulation; Freezing; Frequencies; Fright; Generations; Genetic; Goals; Grant; Hippocampus (Brain); Label; Lead; Learning; Ligands; Light; Memory; Mental disorders; Moods; Mus; Mutation; Neurons; Neurosciences; Neurosciences Research; Output; Pattern; Perception; Production; Recruitment Activity; Relative (related person); Research Design; Role; Sensory; Specificity; Staging; Stimulus; Structure; Testing; Time; Training; Transgenes; Update; Variant; base; behavior test; conditioned fear; experience; insight; memory recall; neural patterning; neural stimulation; neuromechanism; novel; promoter; public health relevance; receptor; relating to nervous system; response; sensory stimulus

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.

描述（由申请人提供）：许多精神病疾病会导致情绪，感知和记忆的改变。大脑中的活动如何导致准确的感知和记忆回忆是神经科学中很难直接解决的关键基本问题。在这笔赠款中，我们开发了一种方法，在小鼠中，可以根据自然环境刺激或学习范式来基于神经元的活性来改变遗传。我们使用它来引入HM3DQ Dreadd受体或ChannelRhopopsin（Chef）的变体，以使标记的神经元的电刺激化学或光线刺激。通过这种方式，我们可以直接刺激自然激活的神经元的集合，以响应行为动物中的刺激，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，可以将解剖学分散和内部产生的神经活动整合到新的记忆中。这与以下想法一致：新记忆不会从头形成新的，而是与先前存在的模式或相关的内部表示形式集成在一起，这些模式可能在学习时可能活动。使用厨师，我们发现，在恐惧条件下自然激活的脾后皮质中神经元的光刺激可能会产生冰冻反应。这表明我们通过人工刺激神经元的正确模式直接募集了记忆迹线的组成部分。我们将扩展这些研究，以研究控制神经活动与整合和重新溶解过程中新的和现有记忆的参数。此外，我们将使用局部刺激直接测试最佳条件 （神经元的数量，发射频率）招募记忆召回所需的所需。这些研究将对神经活动的空间和时间模式的作用进行首次直接检验，在感知和记忆的产生中。产生的数据应提高我们对精神疾病的理解，并有助于创建用于测试治疗的动物模型。