Towards a critical test of the synaptic plasticity and memory hypothesis

对突触可塑性和记忆假说进行关键测试

• 批准号: 10681918
• 负责人: ANDRE ANTONIO FENTON
• 金额: $ 67.59万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681918
• 关键词: Affect; Amnesia; Animals; Anisomycin; Behavior; Behavioral; Brain; Cartoons; Cells; Chemosensitization; Code; Collection; Compensation; Dendritic Spines; Discipline; Electrophysiology (science); Genes; Genetic; Genetic Recombination; Hippocampus; Homosynaptic Depression; Label; Learning; Light; Maintenance; Measures; Memory; Modification; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Oranges; Outcome; Periodicals; Phosphotransferases; Physiological; Population; Prevention; Protein Biosynthesis; Protein Kinase M; Retrograde amnesia; Role; Role Concepts; Structure; Synapses; Synaptic plasticity; Technology; Testing; Text; Tracer; Uncertainty; Vertebral column; avoidance behavior; behavior test; conditioned fear; conditioning; density; educational atmosphere; experience; falls; fear memory; genetic manipulation; information processing; long term memory; memory acquisition; memory encoding; molecular marker; neural; neural stimulation; optogenetics; pharmacologic; preservation; prevent; response; timeline

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.

记忆如何存储在大脑中尚不清楚。主导突触可塑性和记忆（SPM） 假设断言，记忆是通过学习的一个子集引起的功能修改来存储的。 被激活以编码学习体验的神经元突触。这预示着永久 记忆擦除是由学习后抑制分子突触可塑性维持引起的 长期记忆持久存储所必需的机制。确实，各种删除 记忆已通过颅内 ZIP 给药得到证实。 ZIP 抑制非典型激酶活性 PKC、PKMz 和 PKCι/λ，这两者在记忆获取后都可以持续上调。 PKMz 对于野生型晚期 LTP 维持来说既必要又充分，并且当 PKM z 基因 Prkcz 被删除时， PKCι/λ 补偿 PKM z 的损失，成为维持晚期 LTP 所必需的。颅内aPKC 操纵消除了各种长期记忆，但不是全部，为基础记忆提供了重要支持 SPM 假设。然而，由于这些操作通常会影响那些可能不参与的细胞 在记忆存储中，选择性地削弱与记忆相关的细胞子集中的突触以 批判性地检验 SPM 假设。事实上，其他人已经利用了记忆形成需要蛋白质这一事实 综合挑战 SPM 假设。他们证明了学习后光遗传学刺激 情境恐惧记忆激活的海马神经元子集足以表达记忆，即使在 产生失忆症的蛋白质合成区块。然而，这些研究并没有严格测试 SPM 假设是因为海马体和最常见的 N-甲基-D-天冬氨酸受体都没有功能 海马体中 (NMDAR) 和 aPKC 依赖的 LTP 形式对于情境恐惧记忆是必需的， 除其他实验问题外。我们建议使用以下方法严格检验 SPM 假设：1) 长期 足以诱导持续海马突触增强的活跃地点回避记忆，以及 取决于海马 PKM z，两者都至少 30 天； 2）神经元的光遗传学激活 足以表达回避记忆； 3) 基因靶向的 aPKC 操作 与记忆相关的细胞子集。我们将通过光遗传学激活一个“足以记忆”的子集 海马神经元被分配来编码和回忆特定的位置记忆，在擦除之后 通过 aPKC 对相同细胞的操作来控制记忆和相关的突触可塑性。我们将评估之后是否 记忆相关细胞的擦除、光遗传学激活表达神经中的空间信息 放电和表达记忆的条件性回避行为。如果光遗传学激活 导致记忆表达，SPM 假设需要修改，至少就其所涉及的而言 aPKC 依赖性突触可塑性和活跃地点回避记忆。