The effects of thalamoamygdalar synaptic potentiation on learning performance

描述（由申请人提供）：长期增强（LTP）被广泛认为是记忆痕迹编码和存储的机制（1-15）。马丁和他的同事提出的突触可塑性和记忆假说认为，“在记忆形成过程中，活动依赖的突触可塑性是在适当的突触上产生的，对于记忆类型的信息存储来说，这既是必要的，也是充分的，而这种记忆类型是由观察到可塑性的大脑区域介导的。”有大量证据表明突触可塑性对于学习和记忆是必要的，但没有令人信服的证据支持充足性的概念（14）。虽然大量研究表明，某些类型的学习可以在相关的大脑区域阻塞LTP(10-13,15-20)，但LTP尚未被证明会阻塞学习。到目前为止，技术限制已经排除了LTP阻断学习的令人信服的证明，因为用电极传递破伤风可能会产生直接和间接的全回路影响。随着desserth实验室（我将在那里工作）和其他小组最近在体内使用的ChannelRhodopsin2 （ChR2）的出现和应用，现在可以使用这些工具选择性地诱导LTP进入被认为对联想学习很重要的特定突触亚群。我假设，通过使用ChR2选择性地诱导丘脑-杏仁核通路中的LTP将首先阻断线索-结果关联的获得，但随后将增强该通路的基础能力，从而增强联想学习的能力。我将首先通过（Specific Aim 1）开发一种使用ChR2在特定突触子集中诱导LTP的新方法来验证这一假设，然后通过（Specific Aim 2）测试这些大鼠在ChR2-LTP诱导后不同时间点的学习能力。这些实验将使我们有把握地得出介导记忆形成和储存的神经生理变化的时间过程的结论

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