CREB and Memory Allocation in the Basolateral Amygdala

CREB ​​和基底外侧杏仁核的内存分配

• 批准号: 8318850
• 负责人: Thomas W Rogerson
• 金额: $ 2.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-13 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318850
• 关键词: Action Potentials; Affect; Amygdaloid structure; Anxiety; Attention; Auditory; Behavioral; Cells; Complement; Cyclic AMP-Responsive DNA-Binding Protein; Disease; Emotional; Fright; Herpes Simplex Infections; Laboratories; Lead; Light; Memory; Molecular; Mus; Neurons; Neurosciences; Post-Traumatic Stress Disorders; Probability; Process; Public Health; Recruitment Activity; Research; Retrieval; Rhodopsin; Role; Synapses; System; Techniques; Testing; Training; Viral Vector; abstracting; conditioned fear; emotional trauma; insight; memory retrieval; neuronal excitability; optogenetics; research study; therapy development; transcription factor

Project Summary/Abstract While the molecular and cellular mechanisms underlying the acquisition, consolidation, reconsolidation and retrieval of memory have attracted a considerable amount of attention in neuroscience, very little is known about memory allocation, the process that determines which neurons in a network store a given memory. Results from our laboratory have suggested that the transcription factor CREB (cAMP-response element binding protein) has a role in memory allocation in the basolateral amygdala (BLA); increasing the levels of CREB in a subset of neurons of the BLA increased the probability that these neurons were engaged in an auditory-fear memory. More recently, we and others used cell-inactivation techniques to confirm that BLA neurons with higher levels of CREB are preferentially recruited during memory formation. Additionally, we demonstrated that BLA neurons with higher CREB levels are more excitable than other neurons, a finding that provides a potential explanation for why they are especially selected during auditory-fear conditioning. Importantly, we found that increases in synaptic strength thought to be critical for memory are larger in CREB-over expressing neurons, suggesting that these neurons hold a disproportionately large component of the auditory-fear memory trace. Here, I propose to extend and complement these studies with state-of-the-art optogenetic approaches that allow for the activation of specific neurons in the BLA. The specific aims are: 1-To test the hypothesis that CREB has a key role in memory allocation. I propose to use Herpes Simplex Viral (HSV) vectors that can manipulate CREB levels in 15-20% of BLA neurons, and Channel Rhodopsin 2 (ChR2) that allows for the specific activation of these neurons. My hypothesis predicts that activating BLA neurons with higher CREB levels in trained mice will lead to a behavioral manifestation of the memory, while activating a similar number of neurons with normal CREB levels will not. My very preliminary findings suggest that it is possible to activate an auditory-fear memory with this approach. 2-To examine the hypothesis that increases in excitability are key to memory allocation in the BLA. I propose to manipulate excitability in specific BLA neurons with bi-stable Channel Rhodopsin 2 (ChR2-C128S) delivered with HSV vectors. Unlike the ChR2, light-activation of ChR2-C128S does not necessarily trigger action potentials and instead increases the depolarization of these neurons, thus increasing their excitability. The experiments described in this aim provide an independent test for the hypothesis that CREB affects memory allocation by increasing neuronal excitability. The research proposed here will not only advance our understanding of CREB's role in memory allocation, it will also provide insights into how emotional memories are stored in the amygdala. These insights will aid in the development of treatments for disorders thought to be caused by abnormal emotional memory storage and retrieval in the amygdala, including posttraumatic stress disorder (PTSD).

项目摘要/摘要 而巩固的基础的分子和细胞机制， 重新整合和回收记忆吸引了很多关注 神经科学，关于记忆分配的知之甚少，该过程决定了哪个 网络中的神经元存储给定内存。我们实验室的结果表明 转录因子CREB（CAMP响应元件结合蛋白）在记忆分配中起作用 在基底外侧杏仁核（BLA）中；在BLA的神经元子集中增加CREB的水平 增加了这些神经元参与听觉刺激记忆的可能性。更多的 最近，我们和其他人使用细胞灭活技术来确认具有较高的BLA神经元 在记忆形成期间优先募集CREB的水平。此外，我们证明了 CREB水平较高的BLA神经元比其他神经元更兴奋，这一发现是 提供了一个潜在的解释，说明为什么在听觉刺激下特别选择它们。 重要的是，我们发现认为对记忆至关重要的突触力量的增加很大 在表达神经元的Creb-over中，这表明这些神经元具有不成比例的大 听觉折磨内存跟踪的组成部分。在这里，我建议扩展和补充这些 使用最先进的光遗传学方法的研究，可以激活特定神经元 bla。具体目的是： 1-检验CREB在记忆分配中具有关键作用的假设。我建议使用 单纯疱疹病毒（HSV）载体可以在15-20％的BLA神经元中操纵CREB水平，并且 通道Rhodopsin 2（CHR2），允许这些神经元的特定激活。我的假设 预测，在训练有素的小鼠中激活具有较高CREB水平的BLA神经元将导致行为 记忆的表现，同时激活具有正常CREB水平的类似数量的神经元 不会。我的初步发现表明可以激活听觉恐惧记忆 使用这种方法。 2探讨兴奋性增加的假设是记忆分配的关键 bla。我建议用双稳定通道Rhopopsin 2在特定的BLA神经元中操纵兴奋性2 （CHR2-C128）用HSV矢量传递。与CHR2不同，CHR2-C128的光激活确实 不一定触发动作电位，而是增加了这些神经元的去极化， 从而提高了他们的兴奋性。此目标中描述的实验提供了独立的测试 关于CREB通过增加神经元兴奋性影响记忆分配的假设。 这里提出的研究不仅会促进我们对Creb在 记忆分配，它还将提供有关情感记忆如何存储在 杏仁核。这些见解将有助于开发被认为是引起的疾病的治疗方法 通过异常的情绪记忆存储和杏仁核的检索，包括创伤后压力 障碍（PTSD）。