The Role of Heterosynaptic Plasticity in Achieving Stable Yet Adaptable Memory

描述（由申请人提供）：新皮层中的每个神经元接收来自数千个其他神经元的数千个突触。激活其中的一部分，几十到几百个，可能会引起细胞放电，并在某些条件下诱导可塑性。输入特异性联想可塑性被认为是学习记忆的突触机制。然而，正如新的学习总是发生在现有的记忆的背景下，所以突触可塑性总是在突触权重的现有分布的背景下诱导。为了理解神经元如何在保持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突触权重的现有模式相互作用。 因此，理解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。使用啮齿动物新皮层的体外切片，我们将记录主要类型的新皮层神经元的兴奋性突触后电位：金字塔从层2/3和5，多刺细胞从层4和抑制性中间神经元。我们将研究可塑性变化，在这些细胞中诱导细胞内强直-短去极化脉冲的爆发，在体内诱发突触后神经元的放电模式，而没有突触前活动。我们会问，异突触可塑性是如何在不同类型的突触中被诱导的（目标1），它是如何与由时间重合（配对）或传入强直化诱导的可塑性相互作用的，以及为什么它会导致混合效应：增强、抑制或无变化（目标2）。我们将在主要类型的新皮层神经元的详细模型中实现上述实验中得出的规则。通过这些模型，我们将研究突触权重的变化及其在体内神经元典型的输入活动模式和可塑性诱导方案（目的3）的多次应用过程中的分布。 这种实验和理论相结合的方法将使我们能够实现该提案的长期目标：了解单个神经元联合收割机如何在保留现有记忆痕迹的同时结合学习新事物的能力，以及异突触可塑性如何帮助解决这一困境。这一新知识将促进研究和理解影响人类学习新知识和记忆以前所学信息的障碍机制。国家学习障碍中心估计，美国人口的5%或一千五百万人受到学习障碍的影响。300万在校学生因学习障碍而得到特别帮助。对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效益。

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.