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: 8153871
• 负责人: Thomas W Rogerson
• 金额: $ 3.28万
• 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 2013-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8153871
• 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; conditioned fear; emotional trauma; insight; memory retrieval; neuronal excitability; public health relevance; research study; therapy development; transcription factor

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: Traumatic situations often lead to the formation of fear memories that can be debilitating, causing inappropriate fear and anxiety and, in severe cases, posttraumatic stress disorder. This study will elucidate memory mechanisms that could ultimately lead to the development of treatments for the excessive fear and anxiety associated with of emotional trauma.

描述（由申请人提供）：虽然对记忆的获取，巩固，重新溶解和检索的基础的分子和细胞机制吸引了神经科学的大量关注，但对记忆分配的了解很少，但对确定网络中的哪些神经元存储给定记忆的过程知之甚少。我们实验室的结果表明，转录因子CREB（CAMP响应元件结合蛋白）在基底外侧杏仁核（BLA）的记忆分配中起作用；在BLA神经元的一部分中增加CREB的水平增加了这些神经元参与听觉恐惧记忆的可能性。最近，我们和其他人使用细胞灭活技术来确认在记忆形成过程中优先募集具有较高creb的BLA神经元。此外，我们证明了具有较高CREB水平的BLA神经元比其他神经元更令人兴奋，这一发现提供了潜在的解释，以说明为什么在听觉恐惧调节过程中特别选择它们。重要的是，我们发现，在表达神经元的Creb-Over中，认为对记忆至关重要的突触强度的增加表明这些神经元具有听觉触觉记忆迹线的不成比例的大部分。在这里，我建议通过最先进的光遗传学方法扩展和补充这些研究，以使BLA中特定的神经元激活。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，该载体可以在15-20％的BLA神经元中操纵CREB水平，以及通道Rhodopsin 2（ChR2），以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神经元将导致记忆的行为表现，而激活具有正常CREB水平的类似数量的神经元不会。我的初步发现表明，可以通过这种方法激活听觉恐惧记忆。 2要检查兴奋性增加的假设是BLA中记忆分配的关键。我建议用带有HSV载体传递的双稳定通道2（CHR2-C128）在特定的BLA神经元中操纵兴奋性。与CHR2不同，CHR2-C128的光激活不一定触发动作电位，而是增加了这些神经元的去极化，从而增加了它们的兴奋性。此目标中描述的实验为CREB通过增加神经元兴奋性影响记忆分配的假设提供了独立的检验。 这里提出的研究不仅将提高我们对Creb在记忆分配中的作用的理解，还将提供有关杏仁核如何存储情感记忆的见解。这些见解将有助于开发因情绪记忆的异常存储和杏仁核（包括创伤后应激障碍（PTSD））而引起的疾病治疗方法。 公共卫生相关性：创伤状况通常会导致恐惧记忆的形成，这些记忆可能使人衰弱，导致不适当的恐惧和焦虑，并在严重的情况下发生创伤后应激障碍。这项研究将阐明记忆机制，最终可能导致对与情绪创伤相关的过度恐惧和焦虑的治疗发展。