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.

记忆在大脑中的存储方式尚不清楚。主要的突触可塑性和记忆（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。 被激活以编码学习经验的神经元突触这预示着永久性。 记忆擦除是由学习后抑制分子突触可塑性维持引起的 事实上，这种机制是持久存储长期记忆所必需的，可以擦除各种内容。 颅内 ZIP 给药已证明 ZIP 可抑制非典型的激酶活性。 PKC、PKM z 和 PKCι/λ，两者在记忆获取后都可以持续上调。 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。 操纵会抹去各种长期记忆，但不是全部，为基础记忆提供了关键支持。 然而，SPM 假设由于操作的作用是普遍的，因此影响了可能不参与的细胞。 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 事实上，其他人已经利用了记忆形成需要蛋白质这一事实。 他们证明了学习后的光遗传学刺激。 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 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， 在其他实验问题中，我们建议使用 1) 长期来严格检验 SPM 假设。 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）针对基因的 aPKC 操作 我们将通过光遗传学激活“足够记忆”的细胞子集。 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 我们将评估通过 aPKC 操作相同细胞的记忆和相关突触可塑性。 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。