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其他数千个神经元的数千个突触。只要激活其中的一部分，几十到几百个，就可能引起细胞放电，并在一定条件下诱发可塑性。输入特异性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已有记忆的背景下发生一样，突触可塑性也总是在已有突触权重分布的背景下产生的。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是如何与现有的突触权重模式相互作用的。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发生变化。我们的建议就是针对这个问题的。利用啮齿动物新皮层体外切片，我们将记录主要类型的新皮层神经元：2/3层和5层锥体，4层棘细胞和抑制性中间神经元的兴奋性突触后电位。我们将研究由细胞内破伤风引起的可塑性变化——短去极化脉冲的爆发，在突触后神经元中引起体内样的放电模式，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上被诱导的（目标1），它是如何与时间巧合（配对）或传入破伤风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、抑制或没有变化（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施上述实验得出的规则。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输入活动模式和多种可塑性诱导协议应用期间的分布（目的3）。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新知识和记忆先前所学信息的障碍机制的研究和理解。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。三百万在校学生因为学习障碍而接受特殊帮助。学习障碍的研究和新疗法的开发将提高患者的生活质量，并带来医疗保健的经济效益。

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.