Regulation of hippocampal spike-timing dependent plasticity by endogenous sources of dopamine and BDNF: synergy or distinct mechanisms?

不受损害的学习和记忆过程对一个人的正常行为很重要。因此，神经学家对了解与记忆相关的大脑功能很感兴趣。为了了解大脑是如何工作的，科学家们把重点放在学习和记忆所涉及的细胞过程上。记忆的细胞印记被认为是由神经元突触效能的长期变化形成的，这种变化要么被称为长期突触增强(LTP)，要么被称为长期抑制(LTD)，原因是神经元之间的突触传递减少。为了防止大脑的普遍过度兴奋或过度抑郁，额外的代偿性稳态可塑性机制被用于保持大脑处于有益的活动模式。海马体(髋部)，特别是CA1区是中央大脑区域或参与学习和记忆过程的区域。在我们的拨款申请中，我们将研究生理上高度相关的脉冲时序依赖可塑性(STDP)协议在髋关节突触可塑性中的作用。我们将重点放在已被证明发生在体内情况下的STDP范例，并将精确地确定神经调节剂，如脑源性神经营养因子(BDNF)或多巴胺(DA)如何影响这种类型的海马突触可塑性。我们的实验将确定不同的刺激模式是否参与了不同的信号级联和随后的表达机制。为此，我们将应用药理学和光遗传学方法，并通过电生理记录读出由此对突触可塑性的影响。此外，我们的项目关注神经调节作用的时间限制，我们询问神经调节剂是否在LTP或LTD期间的特定时间点起作用。平行实验将解决代偿性稳态可塑性机制的作用。既然已经知道髋部不同的亚区参与不同的记忆功能，我们将研究STDP和神经调节作用的地区差异。这些实验将通过解决仍然悬而未决的问题来总结，即多巴胺是如何传递到髋部的，以及腹侧被盖区是否是海马多巴胺的实际来源。在我们实验的最后部分，我们将在CA3-CA1锥体神经元的配对记录中确认关于DA和BDNF依赖的STDP调节的关键发现。通过拟议的实验，我们将收集有关神经调节功能和体内可能的区域差异的信息，如髋关节的突触可塑性。有了这些数据，我们应该能够更好地理解不同的信号级联是如何独立或协同作用形成记忆痕迹的。此外，我们的结果将为我们深入了解有助于学习和记忆过程的活动依赖增强和抑郁现象的多种方式。

Unimpaired learning and memory processes are important for a normal behavior of an individual. Neuroscientists are therefore interested in understanding memory related brain functions. To understand how the brain works, scientist focus on cellular processes involved in learning and memory. Cellular engrams of memory are thought to be formed by long-term changes in synaptic efficacy of neurons, which are called either long-term potentiation (LTP) in case of a long-lasting increase of synaptic transmission or long-term depression (LTD) resulting from decreased synaptic transmission between neurons. In order to prevent a general over-excitation or over-depression of the brain, additional compensatory homeostatic plasticity mechanisms are engaged to keep the brain in a beneficial mode of activity. The hippocampus (HIP) and especially the CA1 region are central brain regions or areas involved in learning and memory processes. In our grant application, we will study the role of physiologically highly relevant spike timing-dependent plasticity (STDP) protocols in synaptic plasticity in the HIP. We focus on STDP paradigms which have been shown to occur in in vivo situations and will pinpoint how neuromodulators like brain-derived neurotrophic factor (BDNF) or dopamine (DA) influence this type of hippocampal synaptic plasticity. Our experiments will determine whether different stimulation patterns engage distinct signaling cascades and subsequent expression mechanisms. To this aim we will apply pharmacological and optogenetic approaches and read out the resulting effects on synaptic plasticity with electrophysiological recordings. Furthermore our project is focused on the time constrains of neuromodulatory actions and we ask whether neuromodulators act at certain, specific time points during LTP or LTD. Parallel experiments will address the role of compensatory homeostatic plasticity mechanisms. Since it is known that different sub-regions of the HIP are involved in different memory functions, we will study regional differences in efficacy of STDP and neuromodulation. The experiments will be rounded up by solving the still open question how DA is delivered to the HIP and whether the ventral tegmental area is the actual source of hippocampal DA. In the last part of our experiments we will confirm key findings on the DA and BDNF-dependent regulation of STDP also in paired recordings of unitarily connected CA3-CA1 pyramidal neurons.With the help of the proposed experiments we will collect information about neuromodulatory functions and possible regional differences in in vivo like synaptic plasticity in the HIP. With these data we should be able to better understand how different signaling cascades act either independent or in concert to form memory traces. Additionally, our results will provide insights into the multitude of ways for activity-dependent potentiation and depression phenomena contributing to learning and memory processes.