Regulated Genetics Studies of Memory Formation

描述（由申请人提供）：记忆功能的损害可以从正常衰老引起的中度不方便的良性遗忘到与阿尔茨海默病相关的毁灭性丧失。此外，正常记忆机制的改变被认为是抑郁症和创伤后应激障碍等精神疾病的基础，并可能导致成瘾复发。该基金使用动物模型来确定记忆形成的细胞和分子机制。我们使用一种基因技术，允许我们将基因引入大脑的特定部位，并在学习或记忆提取的不同时间打开或关闭它们。例如，在一项研究中，我们观察了与发育异常和严重认知障碍相关的人类遗传疾病（鲁宾斯坦·泰比综合征）的小鼠模型。我们提出的一个问题是，在成人中发现的认知缺陷是由于大脑发育缺陷还是由于成人大脑中异常的基因功能。通过仅在成人中诱导基因损伤，我们可以证明它会严重地产生学习和记忆缺陷，而这些缺陷可以通过关闭缺陷基因来逆转。我们还表明，在这种小鼠模型中，使用针对生化缺陷的药物可以逆转行为缺陷。我们将这种方法应用于神经元中被认为是记忆基础的许多不同的细胞信号通路。我们还使用遗传方法来分析记忆的解剖结构。通过这种方法，我们希望能够识别出产生特定记忆的单个神经元。我们用它来解决这样的问题：“在学习过程中激活的神经元在回忆过程中重新激活了吗？”和“随着时间的推移，记忆的巩固，神经元激活的模式会改变吗？”通过研究记忆背后的特定细胞回路，我们希望更容易地识别潜在的细胞和分子机制。这项资助研究学习和记忆的机制，从学习如何激活脑细胞到细胞中哪些基因和分子对记忆的形成很重要。我们在老鼠身上做这些研究，因为它们在基因和大脑结构方面都与人类惊人地相似。记忆是大脑功能的一个基本要素，在许多疾病状态下都会发生改变，从阿尔茨海默氏症等衰老性退行性疾病到精神分裂症和创伤后应激障碍等精神疾病。我们研究的其中一种基因是老鼠的类似基因，这种基因会在人类中产生某种形式的智力迟钝。

DESCRIPTION (provided by applicant): Impairments in memory function can range from the moderately inconvenient benign forgetfulness with normal aging to the devastating losses associated with Alzheimer's disease. In addition, alterations in the mechanisms that underlie normal memory are thought to underlie psychiatric disorders such as depression and post-traumatic stress disorder and may contribute to relapse in addiction. This grant uses animal models to identify the cellular and molecular mechanisms of memory formation. We use a genetic technique that allows us to introduce genes into specific parts of the brain and to turn them on or off at different times either during learning or during memory retrieval. For example, in one study we looked at a mouse model of a human genetic disorder (Rubenstein Taybi Syndrome) associated with both developmental abnormalities and severe cognitive impairment. One question that we addressed was whether the cognitive defects found in adults were due a defect in brain development or due to abnormal gene function in the adult brain. By inducing the genetic lesion only in the adult we could show that it produced learning and memory defects acutely and that these defects could be reversed by turning off the defective gene. We also showed that the behavioral defects could be reversed in this mouse model with a drug that targeted the biochemical defect. We apply this approach to a number of different cellular signaling pathways in neurons that are thought to underlie memory. We also use a genetic approach to analyze the anatomical structure of memory. Using this approach we hope to identify the individual neurons that contribute specific memories. We use this to address questions such as: "Are the neurons activated during learning reactivated during recall?" and "Does the pattern of neuronal activation change as memories consolidate over time?" By studying the specific cellular circuits that underlie memory we hope to more readily identify the underlying cellular and molecular mechanisms. PUBLIC HEALTH RELEVANCE This grant examines the mechanisms of learning and memory, from how brain cells are activated with learning to what genes and molecules in the cells are important for the formation of memories. We do these studies in mice because they are surprisingly similar to humans both genetically and in terms of brain structure. Memory is a basic element of brain function that is altered in many disease states from the degenerative diseases of aging like Alzheimer's to psychiatric disorders such as schizophrenia and post-traumatic stress disorder. One of the genes we work on is the mouse analogue of a gene that produces a form of mental retardation in humans.