Molecular mechanisms of memory maintenance and dysfunction in neural circuits

记忆维持和神经回路功能障碍的分子机制

• 批准号: 10372932
• 负责人: ANDRE ANTONIO FENTON
• 金额: $ 69.39万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372932
• 关键词: Affect; Age-associated memory impairment; Alzheimer' s Disease; Amygdaloid structure; Animal Model; Anterior; Autopsy; Biological Models; Bipolar Depression; Bipolar Disorder; Brain; Brain Diseases; Brain region; Cells; Chronic; Cognitive; Corpus striatum structure; Disease; Dorsal; Functional disorder; Hippocampus (Brain); Human; Human Genetics; Impaired cognition; Individual; Insula of Reil; Knockout Mice; Learning; Long-Term Potentiation; Maintenance; Mediating; Memory; Mental disorders; Modeling; Molecular; Mood Disorders; Mus; Neurons; Neuropathy; Neurosciences; Nucleus Accumbens; Pathologic; Phase; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Protein Isoforms; Role; Signal Transduction; Spinal Cord; Symptoms; Synapses; Synaptic Transmission; Testing; Tissues; addiction; age related; antagonist; brain dysfunction; chronic neuropathic pain; conditional knockout; conditioning; genetic linkage; inhibitor; long term memory; nervous system disorder; neural circuit; nonhuman primate; novel; overexpression; persistent symptom; post-traumatic stress; relating to nervous system; spatial memory

How molecular mechanisms modify neuronal networks to maintain long-term memory is a fundamental question in neuroscience, with relevance for disorders of persistent, memory-like dysfunction of brain circuits. Atypical PKCs (aPKC), the persistently active isoform PKMζ and PKCι/λ, are core molecules maintaining late- phase synaptic long-term potentiation (LTP) and several forms of long-term memory. Unlike most PKCs that are active only briefly after stimulation, aPKCs have persistent actions. After strong synaptic stimulation, PKMζ increases by new synthesis, and the persistent increase in the autonomously active isoform enhances synaptic transmission during LTP maintenance and lasts for days to weeks during long-term memory storage. The other aPKC, PKCι/λ, can also maintain LTP and long-term memory, as revealed by PKMζ-knockout (KO) mice. Inhibitors of aPKC disrupt memory even weeks after it is formed and ameliorate persistent symptoms of PTSD, addiction, and chronic neuropathic pain in specific brain circuits in animal models. Conversely, overexpressing PKMζ enhances long-term memory and alleviates persistent deficits in disorders in which decreased PKMζ is implicated. Thus, understanding how aPKCs contribute to maintaining memory by sustaining representations of memory in brain circuits will provide fundamental information to assess their roles in pathological memory. Therefore, our Specific Aims are: Aim 1: Is there a hierarchy of PKCs in memory maintenance that store representations differently in networks of neurons? Spatial memory representations depend on the discharge of hippocampus place cell ensembles. We will examine if the properties of hippocampus place cell ensemble representations of spatial memories differ when maintained by PKMζ or PKCι/λ, and if other PKCs can also maintain spatial memory. Aim 2: How are spatial memory-related place cell ensemble representations modified when memory is erased by inhibiting individual PKCs in wild-type and PKMζ- KO mice? Using novel isoform-selective antagonists and conditional KO (cKO) mice, we will test the necessity of aPKC-mediated enhanced synaptic connectivity for representing spatial memory by examining whether reversing this connectivity concurrently erases memory and destabilizes memory-related place cell ensemble representations. Aim 3: Does persistently increased synthesis of PKMζ maintain very long-term memory? Strong conditioning produces increases in PKMζ in the hippocampus that last a month. We will use PKMζ-antisense and PKMζ-cKOs to determine if these persistent increases are due to persistent increased synthesis and/or decreased degradation. To test sufficiency of PKMζ for maintaining memory and memory- related representations of space, we will use overexpression of PKMζ that prolongs long-term memory to examine if increased PKMζ synthesis also perpetuates memory-related place cell ensemble representations. Our aims will elucidate the persistent molecular mechanisms maintaining long-term memories, causally test their role in memory persistence, and so establish a basis for understanding disorders of pathological memory.

分子机制如何改变神经元网络以维持长期记忆是一个基本的问题 神经科学中的问题，与持续性的、记忆样的大脑回路功能障碍有关。 非典型PKC(APKC)是一种持续活跃的亚型PKMζ和PKCι/λ，是维持晚期免疫功能的核心分子。 相突触长时程增强(LTP)和几种形式的长时记忆。与大多数PKC不同的是 仅在刺激后短暂激活，APKC有持续的作用。强突触刺激后，PKMζ 通过新的合成增加，自主活性异构体的持续增加增强突触 在LTP维护期间传输，在长期内存存储期间持续数天至数周。另一个 PKC，即PKCι/λ，也能维持长时程增强和长时记忆，这是由PKMζ基因敲除(KO)小鼠揭示的。 蛋白激酶C抑制剂甚至在形成几周后就会扰乱记忆，并改善创伤后应激障碍的持续性症状， 在动物模型中，成瘾和特定脑回路的慢性神经病理性疼痛。相反，过度表达 PKMζ增强长期记忆并缓解PKMζ降低的疾病的持续性缺陷 牵连其中。因此，了解APKC如何通过维持表征来帮助维持记忆 大脑回路中记忆的研究将提供基本信息，以评估它们在病理性记忆中的作用。 因此，我们的具体目标是：目标1：在内存维护中是否存在一个层次结构的PKC 在神经元网络中以不同的方式存储表征？空间内存表示形式取决于 海马区细胞群放电。我们将检查海马体的特性是否将细胞 当由PKMζ或PKCι/λ维护时，空间记忆的集合表示不同，并且如果其他PKC 也可以保持空间记忆。目标2：空间记忆相关的位置细胞集合是如何形成的 通过抑制野生型和PKMζ中的单个PKC来修改记忆被擦除时的表征- Ko老鼠？我们将使用新的异构体选择性拮抗剂和条件性KO(CKO)小鼠来验证这种必要性 通过检测APKC介导的增强突触连接来表征空间记忆 颠倒这种连接会同时擦除记忆并破坏与记忆相关的位置单元集合的稳定性 申述。目的3：持续增加的PKMζ合成能维持很长时间吗？ 记忆？强烈的条件反射会导致海马体中PKMζ的增加，这种增加持续一个月。我们将使用 PKMζ-反义和pKMζ-cKO以确定这些持续增加是否是由于持续增加 合成和/或减少降解。为了测试pkmζ维护内存和内存的充分性- 相关的空间表征，我们将使用PKMζ的过度表达来延长长时记忆 检查增加的PKMζ合成是否也使记忆相关的位置细胞集合表征永久化。 我们的目标是阐明维持长期记忆的持久分子机制，因果检验 它们在记忆持久性中的作用，从而为理解病理性记忆障碍奠定了基础。