Investigations on pre- and postsynaptic plasticity

在发现长时程增强（LTP）近五十年后，无数研究突触效能的长时程增加和减少（LTD）的研究已经发表。多年来，突触可塑性和记忆（SPM）假说已经出现，指出突触改变是记忆形成和学习的基础，因为突触可塑性的关键参与者的药理学或遗传操作影响了行为测试中的记忆表现。此外，突触的长期调节与突触数量和形态的变化密切相关。学习后发现树突棘或钮扣的数量增加。总之，有充分的证据表明突触可塑性和突触形态与学习和记忆的形成有关。然而，突触变化与学习或记忆阶段之间的直接联系是具有挑战性的，因为1)缺乏能够在不影响基础神经传递的情况下特异性阻断突触可塑性的工具；2)研究行为动物突触变化的复杂性。除了理解突触功能及其与神经元网络和行为的关系的基本重要性之外，这些关系与人类健康有关，因为突触可塑性受损和突触丢失与各种神经退行性疾病有关。我的博士研究重点是在分子和网络水平上研究突触在学习、记忆和行为中的作用。我的博士研究可以分为两个主要部分：1)我的目标是研究突触前机制，因为它们与突触后机制相比尚不完善，但在学习和记忆中发挥着同样重要的作用。这包括表征preNMDAR在突触前和Schaffer-collateral突触末端的激活机制。2)我的目标是开发一种基于纤维的微创脑深部成像系统。有了这项技术，我们将能够在最小收缩的情况下直接观察到行为动物的突触变化。

Nearly five decades after the inital discovery of long-term potentiation (LTP), innumerable studies investigating long-lasting increases and decreases (LTD) in synaptic efficacy have been published. Over the years, the synaptic plasticity and memory (SPM) hypothesis has emerged stating that synaptic alterations underly memory formation and learning since pharmacological or genetic manipulation of key players in synaptic plasticity affected memory performance in behavioural tests. Moreover, long-term modulations at synapses, have been closely linked to changes in synapse number and morphology. Increased numbers of dendritic spines or boutons have been detected following learning. In summary, there is profound evidence that synaptic plasticity and synapse morphology correlate with learning and memory formation.However, a direct link between synaptic changes and phases of learning or memory is challenging to establish due to1) a lack of tools that can specifically block synaptic plasticity without affecting basal neurotransmission and2) the complexity of studying synaptic alterations in behaving animals.Beyond the fundamental importance of understanding synaptic function and how it is related to neuronal network and behaviour, these relationships are of relevance to human health because impaired synaptic plasticity and synapse loss has been associated with a variety of neurodegenerative diseases.My DPhil research focusses on investigating the role of synapses in learning, memory and behaviour on the molecular as well as the network level.My DPhil research can be divided in two major parts:1) I aim to investigate presynaptic mechanisms since they are poorly established compared to their postsynaptic counterparts but play just as an important role in learning and memory. This includes to characterize the mechanisms of preNMDAR activation at the presynaptic and terminals of Schaffer-collateral synapses.2) I aim to develop a fiber-based system for minimally invasive deep-brain imaging in vivo. With this technique, we will be able to directly observe synaptic changes in the behaving animal with minimal constriction.