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

内源性多巴胺和 BDNF 对海马尖峰时间依赖性可塑性的调节：协同作用还是不同的机制？

• 批准号: 315008722
• 负责人: Dr. Elke Edelmann
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315008722?language=en
• 关键词: Regulation; hippocampal; spike; timing; dependent

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.

未损坏的学习和记忆过程对于个人的正常行为很重要。因此，神经科学家对了解与记忆相关的大脑功能感兴趣。为了了解大脑的工作原理，科学家专注于学习和记忆所涉及的细胞过程。人们认为，在神经元突触功效的长期变化中，人们认为记忆的细胞包膜被认为是形成的，如果神经元之间的突触传播或长期抑郁症（LTD）长期增加，这被称为长期增强（LTP）。为了防止大脑的普遍过度兴奋或过度抑郁，可以使用其他补偿性稳态可塑性机制，以使大脑保持有益的活性模式。海马（髋关节），尤其是CA1区域是中央大脑区域或与学习和记忆过程有关的区域。在我们的赠款应用中，我们将研究髋关节可塑性中生理上高度相关的尖峰时序依赖性可塑性（STDP）方案的作用。我们专注于已显示在体​​内情况下发生的STDP范式，并将指出诸如脑衍生的神经营养因子（BDNF）或多巴胺（DA）之类的神经调节剂如何影响这种类型的海马突触形态。我们的实验将确定不同的刺激模式是否参与不同的信号级联和随后的表达机制。为此，我们将采用药理学和光遗传学方法，并通过电生理记录对突触可塑性产生影响。此外，我们的项目集中在神经调节作用的时间约束上，我们询问神经调节剂是否在LTP或LTD期间某些特定的时间点起作用。平行实验将解决补偿性稳态可塑性机制的作用。由于众所周知，髋关节的不同子区域参与了不同的记忆函数，因此我们将研究STDP和神经调节功效的区域差异。实验将通过解决仍然开放的问题来解决DA如何将DA输送到髋关节，以及腹侧段区域是否是海马DA的实际来源。在实验的最后一部分中，我们将在与单位连接的CA3-CA1金字塔神经元的配对记录中确认对STDP的DA和BDNF依赖性调节的关键发现。在拟议的实验的帮助下，我们将收集有关神经调节功能的信息，以及有关神经调节功能和可能的区域差异。有了这些数据，我们应该能够更好地理解不同的信号级联如何独立或共同行动以形成内存轨迹。此外，我们的结果将提供有关活动依赖性增强和抑郁现象的多种方式的见解，这有助于学习和记忆过程。