The effects of thalamoamygdalar synaptic potentiation on learning performance

描述（由申请人提供）：长时程增强（LTP）被广泛认为是编码和存储记忆痕迹的机制（1-15）。马丁和他的同事们提出的突触可塑性和记忆假说指出：“活动依赖性突触可塑性是在记忆形成过程中在适当的突触处被诱导的，并且对于由观察到可塑性的大脑区域介导的记忆类型的信息存储来说是必要的和足够的。“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。虽然许多研究表明，某些类型的学习可以阻塞相关大脑区域的LTP（10- 13，15 -20），但LTP尚未被证明会阻塞学习。到目前为止，由于技术限制，无法令人信服地证明LTP阻塞了学习，因为用电极进行破伤风可能会产生直接和间接的电路范围的影响。随着最近Deisseroth实验室（我将在那里工作）和其他小组在体内使用的ChR 2（ChR 2）的出现和应用，现在可以选择性地将LTP诱导到被认为对联想学习很重要的特定突触子集中。我假设，通过使用ChR 2选择性地诱导丘脑-杏仁核通路中的LTP将首先阻塞线索-结果关联的获取，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（具体目标1）开发一种使用ChR 2在特定突触子集中诱导LTP的新方法，然后（具体目标2）在ChR 2-LTP诱导后的不同时间点测试这些大鼠的学习能力，以验证这一假设。这些实验将使我们能够得出结论的时间进程的神经生理学的变化，介导记忆的形成和储存的信心

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