The role of heterosynaptic plasticity in achieving stable yet adaptable memory st

描述(申请人提供)：新大脑皮层中的每个神经元都从数千个其他神经元接收数千个突触。只激活其中的一部分，几十到数百个，就可以激发细胞的激发，并在特定条件下诱导可塑性。输入特有的联想可塑性被认为是学习和记忆的突触机制。然而，正如新的学习总是在现有记忆的背景下进行一样，突触的可塑性总是在现有突触权重分布的背景下诱导的。为了理解神经元如何在保留现有信息的同时实现新的学习，我们需要知道特定突触组的可塑性诱导如何与现有的突触重量模式相互作用。因此，了解控制异突触可塑性的规则是至关重要的，即在可塑性诱导过程中不活跃的突触的变化。我们的建议就是针对这个问题提出的。使用啮齿动物新皮质的体外切片，我们将记录主要类型的新皮质神经元的兴奋性突触后电位：来自第2/3层和第5层的锥体，来自第4层的棘细胞和抑制性中间神经元。我们将研究这些细胞的可塑性变化，这些变化是由细胞内的破伤化--短的去极化脉冲的爆发，在没有突触前活动的突触后神经元中激起体内类似的放电模式。我们将问，不同类型的突触是如何诱导异突触可塑性的(目标1)，它如何与时间重合(配对)或传入破伤风诱导的可塑性相互作用，以及为什么它会导致混合效应：增强、抑制或不改变(目标2)。我们将在主要类型的新皮质神经元的详细模型中实施上述实验中得出的规则。利用这些模型，我们将检验在活体神经元典型的输入活动模式中以及在多次应用可塑性诱导方案期间突触重量及其分布的变化(目标3)。这种实验和理论相结合的方法将使我们能够实现该提议的长期目标：了解单个神经元如何在保留现有记忆痕迹的同时结合学习新知识的能力，以及异突触可塑性如何帮助解决这一困境。这一新知识将刺激对影响人类学习和记忆以前学习的信息的紊乱机制的研究和理解。国家学习障碍中心估计，5%的美国人口或1500万人受到学习障碍的影响。300万中小学生因学习障碍而得到特殊帮助。学习障碍的研究和新疗法的开发将提高受影响人群的生活质量，并从医疗保健中带来经济利益。 公共卫生相关性：国家学习障碍中心估计，5%的美国人口，即1500万人，受到学习障碍的影响。这个项目的目标是了解神经元如何在保存旧记忆的同时实现新的学习。这一新知识将促进对人类学习和记忆障碍机制的研究和理解，以及新诊断工具和治疗方法的开发。

DESCRIPTION (provided by applicant): Every neuron in the neocortex receives thousands of synapses from thousands of other neurons. Activation of only a portion of them, dozens to hundreds, may evoke cell firing and under certain conditions induce plasticity. Input-specific associative plasticity is believed to be the synaptic mechanism of learning and memory. However, just as new learning always takes place on a background of existing memories, so synaptic plasticity is always induced on a background of existing distribution of synaptic weights. To understand how neurons achieve new learning while preserving existing information, we need to know, how the induction of plasticity at a specific group of synapses interacts with the existing pattern of synaptic weights. It is crucial, therefore, to understand the rules that govern heterosynaptic plasticity i.e. changes at synapses which were not active during plasticity induction. Our proposal is aimed at this question. Using in vitro slices of rodent neocortex, we will record excitatory postsynaptic potentials in major types of neocortical neurons: pyramids from layer 2/3 and 5, spiny cells from layer 4 and inhibitory interneurons. We will study plastic changes, induced in these cells by intracellular tetanization - bursts of short depolarizing pulses that evoke in vivo-like firing patterns in the postsynaptic neuron without presynaptic activity. We will ask, how heterosynaptic plasticity is induced at different types of synapses (Aim 1), how it interacts with plasticity induced by temporal coincidence (pairing) or afferent tetanization, and why it leads to mixed effects: potentiation, depression or no change (Aim 2). We will implement the rules derived in the above experiments in detailed models of major types of neocortical neurons. With these models we will examine changes of synaptic weights and their distribution during patterns of input activity typical for neurons in vivo and during multiple applications of plasticity induction protocols (Aim 3). This combined experimental and theoretical approach will allow us to achieve the long-term goal of the proposal: to understand how single neurons combine the ability for learning new while retaining existing memory traces, and how heterosynaptic plasticity helps to resolve this dilemma. This new knowledge will stimulate research and understanding of mechanisms of disorders that affect learning new and remembering previously learned information by humans. The National Center for Learning Disabilities estimates that five percent of the United States population or fifteen million people are affected by learning disorders. Three million school students receive special help because of learning disabilities. Research of learning disorders and development of new therapies will improve the quality of life of the affected people and bring economic benefits from healthcare. PUBLIC HEALTH RELEVANCE: The National Center for Learning Disabilities estimates that five percent of the United States population, or fifteen million people are affected by learning disorders. The goal of this project is to understand how neurons achieve new learning while preserving the old memories. This new knowledge will stimulate research and understanding of mechanisms of disorders of learning and remembering in humans and development of new diagnostic tools and therapies.