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.

记忆是如何储存在大脑中的还不清楚。突触可塑性和记忆（SPM） 这一假说断言，记忆是通过在大脑的一个子集上学习引起的功能改变来储存的。 神经元的突触被激活以编码学习经验。这预示着永久性的 记忆擦除是由一种分子突触可塑性维持的学习后抑制引起的 这是持久存储长期记忆所必需的机制。的确，各种各样的 记忆已通过颅内ZIP给药得到证实。ZIP抑制了非典型的 PKC、PKM β和PKC 1/λ，这两者都可以在记忆获得后持续上调。PKM系列 是野生型晚期LTP维持的必要和充分条件，当PKM β基因Prkcz缺失时， PKCι/λ补偿PKM β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，为基础记忆提供了关键支持。 SPM假说然而，由于这些操作通常会影响可能不参与细胞凋亡的细胞， 在记忆储存的过程中，选择性地使记忆相关细胞亚群中的突触去电位是至关重要的， 严格检验SPM假说。事实上，其他人已经使用了记忆形成需要蛋白质的事实， 挑战SPM假说。他们证明，学习后的光遗传学刺激， 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 蛋白质合成的一个导致失忆的障碍然而，这些研究并没有严格测试SPM 这一假设是因为海马体功能和最常见的N-甲基-D-天冬氨酸受体 海马中的NMDAR和aPKC依赖性LTP形式对于情境恐惧记忆是必需的， 以及其他实验性问题。我们建议严格测试SPM假设使用1）长期 足以诱导持续海马突触增强的主动位置回避记忆，以及 依赖于海马PKM β，两者至少30天; 2）神经元的光遗传学激活， 足以表达回避记忆;和3）aPKC操纵，其在遗传上靶向于 与记忆相关的细胞子集。我们将通过光遗传学激活一个“记忆顺从性”亚群， 海马神经元被分配来编码和回忆特定的位置记忆，在擦除 记忆和相关的突触可塑性通过aPKC操纵相同的细胞。我们将评估之后， 擦除，记忆相关细胞的光遗传学激活表达神经元中的空间信息。 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，至少就其所关注的而言。 aPKC依赖的突触可塑性和主动位置回避记忆。