The maintenance of fear memories in the amygdala

描述（由申请人提供）：巴甫洛夫恐惧条件反射已被证明是研究恐惧学习和记忆的细胞机制的有用模型。在理解支持这种学习形式的神经机制方面已经取得了相当大的进展，但对于面对蛋白质周转时恐惧记忆如何持续知之甚少。杏仁核被认为对恐惧记忆的获取和储存至关重要，但这在细胞水平上是如何发生的还没有得到充分的回答。最近的研究表明，蛋白激酶mzeta （PKM6）在学习后变得持续活跃，并可能支持长期记忆维持的突触活动。这项提案的工作旨在探索几个关于恐惧记忆如何在杏仁核中维持的问题。我们将测试PKM6抑制后的记忆缺陷是否是永久性的，以及杏仁核依赖的恐惧记忆是否依赖于PKM6的活动，而与记忆的年龄无关。我们还将验证一个假设，即杏仁核中恐惧记忆的维持是由含有1-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的GluR2的运输所支持的，该受体被认为是由PKM6控制的。最后，我们将使用慢病毒载体来确定参与最初获得恐惧记忆的神经元是否与使用PKM6维持记忆的细胞相同。这项研究的长期目标是更好地理解记忆是如何储存在大脑中的这一基本问题。这项提议中的工作对于全面理解各种器质性失忆症和精神病理学是如何发展和持续的可能非常有用。

DESCRIPTION (provided by applicant): Pavlovian fear conditioning has proved to be a useful model for the study of the cellular mechanisms of fear learning and memory. Considerable progress has been made in understanding the neural mechanisms that support this form of learning, but very little is known about how fear memories persist in the face of protein turnover. The amygdala is thought to be critical to the acquisition and storage of fear memory, but how this occurs at the cellular level has yet to have been fully answered. Recent studies suggest that protein kinase M zeta (PKM6) becomes persistently active following learning and may support synaptic activity underlying the maintenance of long-term memories. The work in this proposal is designed to explore several questions about how fear memories are maintained in the amygdala. We will test if the deficits in memory following PKM6 inhibition are permanent and if amygdala-dependent fear memories rely on PKM6 activity regardless of the age of the memory. We will also test the hypothesis that the maintenance of fear memory in the amygdala is supported by the trafficking of GluR2 containing 1-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors, which is thought to be controlled by PKM6. Finally, we will use lentiviral vectors to determine if neurons that are involved in the initial acquisition of fear memory are the same cells that use PKM6 to maintain the memory. The long-term goal of the work in this proposal is to reach a better understanding of the fundamental issue of how memories are stored in the brain. The work in this proposal is potentially very useful in coming to a full understanding of how various organic amnesias and psychopathologies develop and persist.