Towards a critical test of the synaptic plasticity and memory hypothesis

记忆是如何储存在大脑中的尚不清楚。优势突触可塑性和记忆(SPM) 假说认为，记忆是通过学习所引起的功能改变来储存的 神经元的突触被激活来编码学习体验。这预示着永久性的 记忆擦除是由于分子突触可塑性维持的学习后抑制引起的 持久存储长期记忆所必需的机制。事实上，擦除各种 记忆已被证明是由颅内ZIP管理。ZIP抑制非典型肺炎细胞的激酶活性 PKcs、pkmζ和pkcι/λ，这两种基因都可以在获得记忆后持续上调。PKMζ 对于野生型晚期LTP维持既是必要的也是充分的，并且当PKMζ基因PrkcZ缺失时， PKCι/λ弥补了PKMζ的丢失，成为维持晚期LTP所必需的。脑内蛋白原激活蛋白C 操作会擦除各种长期记忆，但不是全部，为基础记忆提供关键支持 SPM假说。然而，因为操作通常起作用，影响可能不参与的细胞 对于记忆存储，选择性地去增强与记忆相关的细胞子集中的突触是至关重要的 批判性地检验SPM假说。事实上，其他人利用了记忆形成需要蛋白质这一事实 来挑战SPM假说。他们证明了学习后的光基因刺激 情境恐惧记忆激活的海马神经元亚群足以表达记忆，即使在 一种导致失忆的蛋白质合成区块。然而，这些研究并没有对SPM进行批判性测试 假说是因为既没有海马体功能，也没有最常见的N-甲基-D-天冬氨酸受体 海马区(NMDAR)和依赖于PKC的LTP对于情景恐惧记忆是必需的， 在其他实验性问题中。我们建议对SPM假说进行批判性检验：1)长期 主动位置回避记忆，足以诱导持久的海马区突触增强，以及 依赖于海马PKMζ，两者至少持续30天；2)神经元的光遗传激活，即 足以表达回避记忆；以及3)在基因上针对 与内存相关的单元子集。我们将以光基因的方式激活一个“足够记忆”的子集 被分配来编码和回忆特定位置记忆的海马神经元，在擦除 记忆和相关的突触可塑性通过对相同细胞的PKC操作。我们将在之后进行评估 记忆相关细胞的擦除、光发生激活表达了神经中的空间信息 放电和表达记忆的条件性回避行为。如果光遗传激活 导致记忆表达，SPM假说将需要修改，至少就它所涉及的而言 APKC依赖的突触可塑性和主动位置回避记忆。

How memory is stored in the brain is unknown. The dominant synaptic plasticity and memory (SPM) hypothesis asserts that memory is stored by functional modifications induced by learning at a subset of the synapses of the neurons that are activated to encode the learning experience. This predicts permanent memory erasure is caused by post-learning inhibition of a molecular synaptic plasticity maintenence mechanism that is necessary for persistent storage of the long-term memory. Indeed, erasure of a variety of memories has been demonstrated by intracranial ZIP administration. ZIP inhibits the kinase activity of atypical PKCs, PKMζ and PKCι/λ, both of which can be persistently upregulated following memory acquisition. PKMζ is both necessary and sufficient for wildtype late-LTP maintenance, and when the PKMζ gene Prkcz is deleted, PKCι/λ compensates for the loss of PKMζ, becoming necessary for maintaining late-LTP. Intracranial aPKC manipulations erase a variety of long-term memories, but not all, providing crucial support for the foundational SPM hypothesis. However, because the manipulations act generally, affecting cells that may not participate in the memory storage, it is crucial to selectively depotentiate synapses in a memory-associated subset of cells to critically test the SPM hypothesis. Indeed, others have used the fact that memory formation requires protein synthesis to challenge the SPM hypothesis. They demonstrated that post-learning optogenetic stimulation of a context-fear memory-activated subset of hippocampal neurons is sufficient to express the memory, even after an amnesia-producing block of protein synthesis. However, these studies did not critically test the SPM hypothesis because neither hippocampus function, nor the most common N-Methyl-D-Aspartate receptor (NMDAR)- and aPKC-dependent form of LTP in the hippocampus are necessary for context-fear memory, amongst other experimental issues. We propose to critically test the SPM hypothesis using 1) a long-term active place avoidance memory that is sufficient to induce persistent hippocampal synaptic potentiation, and depends on hippocampus PKMζ, both for at least 30 days; 2) optogenetic activation of neurons that is sufficient to express the avoidance memory; and 3) aPKC manipulations that are genetically targeted to the memory-associated subset of cells. We will optogenetically activate a “sufficient-for-memory” subset of the hippocampal neurons that are allocated to encode and recall a specific place memory, after erasing the memory and associated synaptic plasticity by aPKC manipulation of the same cells. We will evaluate if after erasure, optogenetic activation of the memory-associated cells expresses the spatial information in neural discharge and the conditioned avoidance behavior that express the memory. If the optogenetic activation causes memory expression, the SPM hypothesis will require modification, at least as far as it it concerns aPKC-dependent synaptic plasticity and active place avoidance memory.