The effects of thalamoamygdalar synaptic potentiation on learning performance

描述(由申请人提供)：长时程增强(LTP)被广泛认为是对记忆轨迹进行编码和存储的机制(1-15)。马丁和他的同事提出的突触可塑性和记忆假说认为，依赖活动的突触可塑性是在记忆形成过程中在适当的突触处诱导的，对于观察到可塑性的大脑区域所介导的记忆类型的信息存储来说，这既是必要的，也是充分的。有大量证据表明，突触可塑性对学习和记忆是必要的，但没有令人信服的证据支持充分性的概念(14)。虽然许多研究表明，某些类型的学习可以阻断LTP在相关大脑区域(10-13，15-20)的作用，但LTP还没有被证明阻碍学习。到目前为止，技术上的限制阻碍了LTP阻断学习的令人信服的演示，因为使用电极进行破伤风可能会产生直接和间接的全电路影响。随着最近Deisseroth实验室(我将在那里工作)和其他小组在活体(21-23)中使用的ChannelRhotopin2(ChR2)的出现和应用，现在可以有选择地将LTP诱导到被认为对联想学习重要的特定突触子集。我推测，通过使用ChR2选择性地在丘脑-杏仁核通路中诱导LTP，首先将阻断线索-结果关联的获得，但随后将增强这一通路的基础能力，从而增强联想学习的能力。我将首先(特定目标1)开发一种新的方法，使用ChR2在特定的突触子集中诱导LTP，然后(特定目标2)测试这些大鼠在ChR2-LTP诱导后的不同时间点的学习能力，以检验这一假设。这些实验将使我们能够得出关于神经生理变化的时间进程的结论，这些变化介导了记忆的形成和存储

DESCRIPTION (provided by applicant): Long-term potentiation (LTP) is widely assumed to be the mechanism by which memory traces are encoded and stored (1-15). From Martin and colleagues, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." There is a great deal of evidence demonstrating that synaptic plasticity is necessary for learning and memory, but there is no convincing evidence supporting the notion of sufficiency (14). While numerous studies have shown that certain types of learning can occlude LTP in relevant brain regions (10-13,15-20), LTP has yet to be proven to occlude learning. Until now, technological limitations have precluded a convincing demonstration of LTP occlusion of learning, as delivering a tetanus with an electrode may have direct and indirect circuit-wide repercussions. With the recent advent and application of ChannelRhodopsin2 (ChR2) used in vivo (21-23) by the Deisseroth laboratory, where I will be working, and other groups, the tools are now available to selectively induce LTP into a specific subset of synapses thought to be important for associative learning. I hypothesize that selectively inducing LTP in the thalamo- amygdala pathway by using ChR2 will first occlude acquisition of a cue-outcome association, but will subsequently enhance the basal capacity of this pathway to be potentiated, thereby enhancing the aptitude for associative learning. I will test this hypothesis by first (Specific Aim 1) developing a novel method of inducing LTP in a specific subset of synapses using ChR2, and then by (Specific Aim 2) testing the learning ability of these rats at various time points after ChR2-LTP induction. These experiments will allow us to draw conclusions about the time course of the neurophysiological changes that mediate memory formation and storage with confidence