Memory allocation in the hippocampus

描述(申请人提供)：大量研究已经证明了CREB在记忆巩固中的重要性。然而，最近的发现表明，CREB在内存分配中也扮演着关键角色。增加CREB的水平会增加杏仁核中特定神经元被招募到记忆痕迹中的可能性，而降低CREB的水平则会产生相反的效果。先前的结果还表明，CREB通过改变神经元的兴奋性来影响记忆分配，由此高水平的CREB增加了杏仁核神经元的内在兴奋性，从而使这些细胞偏向于被包括在记忆踪迹中。虽然有令人信服的证据表明CREB和神经元的兴奋性对杏仁核的记忆分配很重要，但尚不清楚这些原理是否适用于其他对记忆重要的大脑区域，如海马体。我建议通过操纵带有病毒CREB的CA1神经元的亚群来直接检验这一假设，以查看其表征是否偏向于CREB增加的神经元。此外，我将分别使用Western印迹分析和全细胞贴片记录来研究获得上下文记忆后CA1区CREB激活和神经元兴奋性的时间动力学。最后，我将研究转基因TetTag小鼠对两个记忆的共同分配，它可以在两个不同的时间点标记激活的神经元。我的预测是如果 CREB偏向于记忆分配，然后由一个海马体依赖的记忆诱导的CREB激活增加，应该会偏向将第二个记忆分配给许多被招募来存储第一个记忆的相同神经元。我们之前对杏仁外侧核的研究开创了记忆分配领域的先河。虽然这一领域一直非常令人兴奋，但它仅限于杏仁核，要使这一领域向前发展，我们必须能够 将我们的发现推广到其他大脑结构和记忆类型。这些拟议研究的结果将使我们更好地了解内存分配过程如何影响信息的整合和存储。有了这些知识，我们可以更好地开发有针对性的治疗记忆障碍的方法，包括阿尔茨海默病？S病，因为我们已经知道在这一人群中存在CREB介导的异常基因调控。 公共卫生相关性：阿尔茨海默病(AD)是老龄化人口中最常见的痴呆症形式，记忆障碍是主要的定义特征。有强有力的证据表明，这些患者大脑中CREB的调节异常，这可能与记忆丧失有关。这些拟议研究的结果将使我们更好地了解CREB如何影响信息的整合和存储。有了这些知识，我们可以更好地开发针对记忆障碍的有针对性的治疗方法，包括阿尔茨海默病。

DESCRIPTION (provided by applicant): Numerous studies have demonstrated the importance of CREB in memory consolidation. However, recent findings suggest that CREB also plays a key role in memory allocation. Increasing the levels of CREB increases the probability that a given neuron in the amygdala will be recruited into a memory trace, while decreasing the levels of CREB has the opposite effect. Previous results also suggest that CREB affects memory allocation by altering neuronal excitability, whereby high levels of CREB increases the intrinsic excitability of neurons in the amygdala which biases these cells towards being included in the memory trace. While there is convincing evidence that CREB and neuronal excitability are important for memory allocation in the amygdala, it is unclear whether these principles generalize to other brain regions important for memory, such as the hippocampus. I propose to directly test this hypothesis by manipulating a subpopulation of CA1 neurons with viral CREB to see if the representation is biased towards those neurons with increased CREB. Additionally, I will examine the temporal dynamics of CREB activation and neuronal excitability in CA1 following acquisition of a context memory using Western blot analysis and whole cell patch recording, respectively. Lastly, I will examine the co-allocation of two memories with transgenic TetTag mice, which can label activated neurons at 2 different time points. My prediction is that if CREB biases memory allocation, then increased CREB activation induced by one hippocampus-dependent memory should bias the allocation of a second memory to many of the same neurons recruited to store the first memory. Our previous studies in the lateral amygdala pioneered the field of memory allocation. While this field has been very exciting, it has been exclusively limited to the amygdala and for this field to move forward, it is essential that we can generalize our findings to other brains structures and memory types. The results from these proposed studies will give us a better idea of how memory allocation processes affect the integration and storage of information. With this knowledge, we can better develop targeted treatments for memory disorders, including Alzheimer¿s disease, as we already know there is aberrant CREB-mediated gene regulation in this population. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common form of dementia in the aging population and memory impairment is the principle defining feature. There is strong evidence that these patients have an aberrant regulation of CREB in the brain, which could be related to the memory loss. The results from these proposed studies will give us a better idea of how CREB affects the integration and storage of information. With this knowledge, we can better develop targeted treatments for memory disorders, including Alzheimer's disease.