Molecular mechanisms of memory maintenance and dysfunction in neural circuits

分子机制如何修改神经元网络以维持长期记忆是一个基本的 这是神经科学中的一个问题，与脑回路的持续性记忆样功能障碍有关。 非典型蛋白激酶C（aPKC），即持续活性的PKM β和PKC 1/λ亚型，是维持晚期细胞凋亡的核心分子。 突触长时程增强（LTP）和几种形式的长期记忆。与大多数PKC不同， aPKCs在刺激后仅短暂激活，但具有持续的作用。在强烈的突触刺激后，PKM 通过新的合成增加，并且自主活性亚型的持续增加增强突触 在LTP维持期间，它可以持续传输，并在长期记忆存储期间持续数天至数周。另 如PKM β-敲除（KO）小鼠所揭示的，aPKC（PKC 1/λ）也可以维持LTP和长期记忆。 aPKC的抑制剂甚至在记忆形成后数周就会破坏记忆，并改善PTSD的持续症状， 成瘾和慢性神经病理性疼痛在特定的脑回路的动物模型。相反，过度表达 PKM β增强长期记忆，并减轻PKM β减少的疾病中的持续性缺陷。 牵连因此，了解aPKCs如何通过维持表征来维持记忆， 大脑回路中的记忆将提供基本信息，以评估它们在病理记忆中的作用。 因此，我们的具体目标是：目标1：在内存维护中是否存在PKC的层次结构， 在神经元网络中以不同的方式存储表征？空间记忆表征取决于 海马定位细胞群放电。我们将研究海马定位细胞的特性是否 空间记忆的总体表征在由PKM λ或PKCι/λ维持时不同，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如何 当记忆被擦除时，通过抑制野生型和PKM中的单个PKC来修饰表达。 KO小鼠？使用新型亚型选择性拮抗剂和条件性KO（cKO）小鼠，我们将测试 aPKC介导的增强的突触连接，通过检查是否 逆转这种连接性同时会消除记忆并使与记忆相关的位置细胞集合不稳定 表示。目的3：持续增加的PKM合成是否能维持很长时间 记忆？强烈的条件反射会导致海马体中PKM的增加，持续一个月。我们将使用 PKM β-反义和PKM β-cKO，以确定这些持续性增加是否是由于持续性增加 合成和/或降低的降解。为了测试PKM存储器是否足以维持存储器和存储器- 相关的空间表征，我们将使用过度表达的PKM神经元，它可以增强长期记忆， 检查增加PKM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。

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.